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Sample records for glp-1 physiological effects

  1. Pancreatic effects of GLP-1

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2014-01-01

    -dependent manner. But perhaps equally importantly, GLP-1’s glucose lowering effects are attributable to a strong inhibition of glucagon secretion, and, thereby, a reduction of hepatic glucose output. The effects of GLP-1 on insulin secretion are mediated by binding of the hormone to the receptor (GLP-1r......) on the pancreatic β-cell, which increases intracellular cAMP levels and sets in motion a plethora of events that lead to secretion. In contrast, the inhibitory effect of GLP-1 on the α-cell may be indirect, involving paracrine intra-islet regulation by somatostatin and possibly also insulin, although GLP-1 also...... inhibits glucagon secretion in patients with type 1 diabetes mellitus. Besides these acute effects on the endocrine pancreas, GLP-1 also appears to have a positive effect on β-cell mass. In the following we will review GLP-1’s pancreatic effects with particular focus on its effects on pancreatic islets...

  2. On the physiology of GIP and GLP-1

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2005-01-01

    circulation. Apparently, before it is degraded, GLP-1 activates sensory afferents in the gastrointestinal mucosa with cell bodies in the nodose ganglion, signaling onwards to the brain stem and the hypothalamus. A similar mechanism seems to be involved in GLP-1's effect on gastrointestinal motility...... and secretion, and perhaps its actions on appetite and food intake, all of which may be even more physiologically important than its effects on the beta cells. Cardiovascular and neuroprotective actions of GLP-1 have also recently been reported. Regarding GIP, several lines of evidence suggest that GIP......Recent studies have indicated that GIP and GLP-1 are about as important as each other in the incretin effect, being released rapidly after meals and being active already at fasting glucose levels. Although the density of GLP-1 producing cells is higher distally, GlP-1 is normally secreted...

  3. Effect of Oxyntomodulin, Glucagon, GLP-1 and Combined Glucagon +GLP-1 Infusion on Food Intake, Appetite and Resting Energy Expenditure

    DEFF Research Database (Denmark)

    Bagger, Jonatan I; Holst, Jens J; Hartmann, Bolette

    2015-01-01

    Context: The gut hormone, oxyntomodulin, is a proglucagon product with body weight-lowering potential. It binds to both the glucagon-like peptide-1 (GLP-1) receptor and the glucagon receptor; however, the mechanism behind the body weight-lowering effect remains elusive. Objective: We wanted.......86 pmol × kg−1 × min−1), oxyntomodulin (3 pmol × kg−1 × min−1), or glucagon+GLP-1 (same doses). Main Outcome Measures: We evaluated resting energy expenditure (measured as oxygen uptake, gastric emptying (GE), composite appetite scores (CAS), and food intake. Results: Oxyntomodulin, GLP-1, and GLP-1...

  4. Effects of glucagon-like peptide-1 (GLP-1) receptor agonists on cardiovascular risk factors

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Vilsbøll, Tina; Knop, Filip K

    2018-01-01

    with continuous-acting treatments, while large GLP-1RAs had a reduced effect on body weight compared with small GLP-1RAs. For glycaemic control, short-acting GLP-1RAs had a greater impact on post-prandial glucose levels versus continuous-acting GLP-1RAs, but for fasting plasma glucose levels and HbA1c, continuous...

  5. Inhibitory effect of GLP-1 on gastric motility persists after vagal deafferentation in pigs

    DEFF Research Database (Denmark)

    Nagell, Carl Frederik; Wettergren, André; Ørskov, Cathrine

    2006-01-01

    BACKGROUND: Glucagon-like peptide 1 (GLP-1) is an intestinal hormone that is secreted in response to meal ingestion. GLP-1 inhibits gastric emptying and reduces postprandial gastric secretion and may play a physiological regulatory role in controlling appetite and energy intake in humans. The GLP-1...

  6. The physiological role of the brain GLP-1 system in stress

    OpenAIRE

    Holt, M. K.; Trapp, S.

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) within the brain is a potent regulator of food intake and most studies have investigated the anorexic effects of central GLP-1. A range of brain regions have now been found to be involved in GLP-1 mediated anorexia, including some which are not traditionally associated with appetite regulation. However, a change in food intake can be indicative of not only reduced energy demand, but also changes in the organism's motivation to eat following stressful stimuli. I...

  7. The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics

    DEFF Research Database (Denmark)

    Lehrskov-Schmidt, Louise; Lehrskov-Schmidt, Lars; Nielsen, Signe T

    2015-01-01

    levels impairs GLP-1's effects on glucose metabolism. Design: Randomized, controlled, cross-over trial. Setting: Hospital clinical research laboratory. Participants: Twelve healthy males (age 24±3 y; BMI 22.9±1.3 kg/m(2)). Interventions: Following an overnight fast, either saline (0.9%) or recombinant......Context: GLP-1 analogues have recently been promoted as anti-hyperglycemic agents in critically ill patients with systemic inflammation, but the effects of TNF-α on glucose metabolism during GLP-1 administration are unknown. Objective: To determine whether infusion of TNF-α at high physiological...... human TNF-α (1000 ng/m(2)/h) was infused from t = 0-6 hours. At t = 2 hours, GLP-1 infusion (0.5 pmol/kg/min) began. From t = 4-6 hours, the GLP-1 infusion rate was increased to 1.2 pmol/kg/min. Plasma glucose was clamped at 5 mmol/L throughout via a variable-rate 20% dextrose infusion. Trials were 7...

  8. Brain GLP-1 and insulin sensitivity.

    Science.gov (United States)

    Sandoval, Darleen; Sisley, Stephanie R

    2015-12-15

    Type 2 diabetes is often treated with a class of drugs referred to as glucagon-like peptide-1 (GLP-1) analogs. GLP-1 is a peptide secreted by the gut that acts through only one known receptor, the GLP-1 receptor. The primary function of GLP-1 is thought to be lowering of postprandial glucose levels. Indeed, medications utilizing this system, including the long-acting GLP-1 analogs liraglutide and exenatide, are beneficial in reducing both blood sugars and body weight. GLP-1 analogs were long presumed to affect glucose control through their ability to increase insulin levels through peripheral action on beta cells. However, multiple lines of data point to the ability of GLP-1 to act within the brain to alter glucose regulation. In this review we will discuss the evidence for a central GLP-1 system and the effects of GLP-1 in the brain on regulating multiple facets of glucose homeostasis including glucose tolerance, insulin production, insulin sensitivity, hepatic glucose production, muscle glucose uptake, and connections of the central GLP-1 system to the gut. Although the evidence indicates that GLP-1 receptors in the brain are not necessary for physiologic control of glucose regulation, we discuss the research showing a strong effect of acute manipulation of the central GLP-1 system on glucose control and how it is relevant to type 2 diabetic patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. The cardioprotective and inotropic components of the postconditioning effects of GLP-1 and GLP-1(9-36)a in an isolated rat heart

    DEFF Research Database (Denmark)

    Ossum, Alvilde; van Deurs, Ulla; Engstrøm, Thomas

    2009-01-01

    GLP-1 and its metabolite GLP-1(9-36)a have been shown to exert cardiotropic effects, and were demonstrated to be cardioprotective agents in isolated, postischemic rat or mouse hearts. An agent's total effect on myocardial performance in a postconditioning paradigm is a sum of its myocyte-preservi......GLP-1 and its metabolite GLP-1(9-36)a have been shown to exert cardiotropic effects, and were demonstrated to be cardioprotective agents in isolated, postischemic rat or mouse hearts. An agent's total effect on myocardial performance in a postconditioning paradigm is a sum of its myocyte...... protocol, as exemplified by use of GLP-1 and GLP-1(9-36)a following a global ischemia in isolated rat hearts. Peptides were administered during the first 15min of 120min reperfusion. GLP-1 0.3nM reduced infarct size from 23.2+/-2.4% to 14.1+/-2.3% of area-at-risk (n=15, P=0.0223), an effect abolished......, rather than any true inotropic effect. In contrast, GLP-1(9-36)a did not reduce infarct size significantly, but acted as a strong negative inotrope in postischemic hearts, causing a contractility deficit (LVDP 58.8%, P=0.0004; RPP 58.2%, P=0.0007; dP/dt(max)=58.2%, P=0.0012), quantifiable by an analysis...

  10. The anorectic effect of GLP-1 in rats is nutrient dependent.

    Directory of Open Access Journals (Sweden)

    Darleen Sandoval

    Full Text Available GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3(rd cerebroventricularly (i3vt-administered GLP-1 to reduce food intake. However, fasted animals maintained the anorexic response to melanotan II, a melanocortin receptor agonist, indicating a specific effect of fasting on GLP-1 action. We also found that i3vt administration of leptin, which is also decreased with fasting, was not able to potentiate GLP-1 action in fasted animals. However, we did find that CNS glucose sensing is important in GLP-1 action. Specifically, we found that i3vt injection of 2DG, a drug that blocks cellular glucose utilization, and AICAR which activates AMPK, both blocked GLP-1-induced reductions in food intake. To examine the role of glucokinase, an important CNS glucose sensor, we studied glucokinase-heterozygous knockout mice, but found that they responded normally to peripherally administered GLP-1 and exendin-4. Interestingly, oral, but not i3vt or IP glucose potentiated GLP-1's anorectic action. Thus, CNS and peripheral fuel sensing are both important in GLP-1-induced reductions in food intake.

  11. Characterization of GLP-1 effects on beta-cell function after meal ingestion in humans

    DEFF Research Database (Denmark)

    Ahrén, Bo; Holst, Jens Juul; Mari, Andrea

    2003-01-01

    OBJECTIVE: Glucagon-like peptide 1 (GLP-1) is an incretin that augments insulin secretion after meal intake and is developed for treatment of type 2 diabetes. As a novel therapeutic agent, characteristics of its beta-cell effects are important to establish. Previously, beta-cell effects of GLP-1...... have been characterized in humans during graded intravenous infusions of glucose, whereas its effects after more physiological stimuli, like meal intake, are not known. RESEARCH DESIGN AND METHODS: Eight women (aged 69 years, fasting glucose 3.7-10.3 mmol/l, BMI 22.4-43.9 kg/m(2)) who had fasted...... meal augments insulin secretion in humans by a dose...

  12. The insulinotropic effect of exogenous GLP-1 is not affected by acute vagotomy in anaesthetized pigs

    DEFF Research Database (Denmark)

    Veedfald, Simon; Hansen, Marie; Christensen, Louise Wulff

    2016-01-01

    importance? We found no effect of truncal vagotomy on the insulinotropic effect of exogenous GLP-1 and speculate that high circulating levels of GLP-1 after intravenous infusion may have overshadowed any neural signalling component. We propose that further investigations in to the possible vagal afferent...... the vagal trunks were severed in 4/6 groups (vagal trunks were left intact in 2/6 groups), whereupon all infusions were repeated. We found no effect of vagotomy on insulin or glucagon secretion during administration of exogenous GLP-1 in any experiment. We speculate that the effect of exogenous GLP-1...

  13. Purslane Effect on GLP-1 and GLP-1 receptor in type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Roja Daliri

    2013-01-01

    Full Text Available Abstract:Background: The aim of this study was to examine the effect of purslane seeds in glucagon-like peptide-1 concentration and glucagon-like peptide-1 receptor in women with diabetes.Methods: This was a quasi-experimental study. The population was consisted of the city of Sari where diabetic women with diabetes II who had no history of using purslane seeds. All individuals used the same dose of metformin under the specialist supervision. Among these individuals, 16 were assigned at random to Purslane group and control group. The purslane group consumed 2.5 grams Purslane with lunch and along with 5 grams of purslane (Portulaca oleracea seeds 7.5 g daily with dinner meals twice daily for 8 weeks. Blood sample was taken before and after 8 weeks, after 12 hours of fasting to 5 ml of the left brachial vein.Results: After 8 weeks using purslane seeds in the experimental group, a significant increase was seen in glucagon-like peptide-1 concentrations (p<0.007, but there was no significant difference in the concentration of glucagon-like peptide-1 receptor (p <0.455. No significant relationship was found between changes in glucagon-like peptide-1 and its receptor.Conclusion: The use of purslane seeds improved Type II diabetes; therefore it can be effective in improving the health of women with diabetes.

  14. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    Science.gov (United States)

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  15. GLP-1-based therapies have no microvascular effects in type 2 diabetes mellitus

    NARCIS (Netherlands)

    Smits, Mark M.; Tonneijck, Lennart; Muskiet, Marcel H.A.; Hoekstra, Trynke; Kramer, Mark H.H.; Diamant, Michaela; Serné, Erik H.; Van Raalte, Daniël H.

    2016-01-01

    Objective - To assess the effects of glucagon-like peptide (GLP)-1-based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. Approach and Results - We studied 57 patients with type 2 diabetes mellitus

  16. Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia-reperfusion injury in rat heart

    DEFF Research Database (Denmark)

    Sonne, David P; Engstrøm, Thomas; Treiman, Marek

    2007-01-01

    to exert cardiovascular effects in a number of experimental models. Here we tested exendin-4 (Exe-4), a peptide agonist at GLP-1 receptors, and GLP-1(9-36) amide, the primary endogenous metabolite of GLP-1 (both in the concentration range 0.03-3.0 nM), for their protective effects against ischemia......-reperfusion injury (IRI) in an isolated rat heart preparation. When administered, the agents were only present for the first 15 min of a 120 min reperfusion period (postconditioning protocol). Exe-4, but not GLP-1(9-36) amide, showed a strong infarct-limiting action (from 33.2% +/-2.7% to 14.5% +/-2.......2% of the ischemic area, pamide were able to augment left ventricular performance (left ventricular developed pressure and rate-pressure product) during...

  17. Bariatric surgery may reduce the risk of Alzheimer's diseases through GLP-1 mediated neuroprotective effects.

    Science.gov (United States)

    Keshava, Hari B; Mowla, Ashkan; Heinberg, Leslie J; Schauer, Philip R; Brethauer, Stacy A; Aminian, Ali

    2017-07-01

    Obesity and diabetes are associated with deficits in multiple neurocognitive domains and increased risk for dementia. Over the last two decades, there has been a significant increase in bariatric and metabolic surgery worldwide, driven by rising intertwined pandemics of obesity and diabetes, along with improvement in surgical techniques. Patients undergoing bariatric surgery achieve a significant decrease in their excess weight and a multitude of sequela associated with obesity, diabetes, and metabolic syndrome. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide that has been implicated as one of the weight loss-independent mechanisms in how bariatric surgery affects type 2 diabetes. GLP-1 improves insulin secretion, inhibits apoptosis and induce pancreatic islet neogenesis, promotes satiety, and can regulate heart rate and blood pressure. Moreover, numerous studies have demonstrated potential neuroprotective and neurotrophic effects of GLP-1. Increased GLP-1 activity has been shown to increase cortical activity, promote neuronal growth, and inhibit neuronal degeneration. Specifically, in experimental studies on Alzheimer's disease, GLP-1 decreases amyloid deposition and neurofibrillary tangles. Furthermore, recent studies have also suggested that GLP-1 based therapies, new class of antidiabetic drugs, have favorable effects on neurodegenerative disorders such as Alzheimer's disease. We present a hypothesis that bariatric surgery can help delay or even prevent the onset of Alzheimer's disease in long-term by increasing the levels of GLP-1. This hypothesis has a potential for many studies from basic science projects to large population studies to fully understand the neurological and cognitive consequences of bariatric surgery and associated rise in GLP-1. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Neuroprotective effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson's disease mouse model

    OpenAIRE

    Zhang, YanFang; Chen, YiMei; Li, Lin; Holscher, Christian

    2015-01-01

    Glucagon-like peptide 1 (GLP-1) is a hormone and a growth factor. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. They also have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a first clinical trial in PD patients showed promising results. (Val8)GLP-1-glu-PAL is a new GLP-1 analogue which has a longer biologica...

  19. The Effect of Exogenous GLP-1 on Food Intake is Lost in Male Truncally Vagotomized Subjects with Pyloroplasty

    DEFF Research Database (Denmark)

    Plamboeck, Astrid; Veedfald, Simon; Deacon, Carolyn F

    2013-01-01

    . Subjects received GLP-1 (7-36 amide) or saline infusions during and after a standardized liquid mixed meal and a subsequent ad libitum meal. Despite no effect on appetite sensations, GLP-1 significantly reduced ad libitum food intake in the control group, but had no effect in the vagotomized group. Gastric...... with pyloroplasty impairs the effects of exogenous GLP-1 on food intake, gastric emptying, insulin and glucagon secretion, suggesting that intact vagal innervation may be important for GLP-1's actions....... emptying was accelerated in vagotomized subjects and was decreased by GLP-1 in controls but not in vagotomized subjects. Postprandial glucose levels were reduced by the same percentage by GLP-1 in both groups. Peak postprandial GLP-1 levels were ~5-fold higher in the vagotomized subjects. Insulin secretion...

  20. Obesity - an indication for GLP-1 treatment?

    DEFF Research Database (Denmark)

    Torekov, S S; Madsbad, S; Holst, Jens Juul

    2011-01-01

    Obesity is common and associated with a high rate of morbidity and mortality; therefore, treatment is of great interest. At present, bariatric surgery is the only truly successful treatment of severe obesity. Mimicking one of the effects of bariatric surgery, namely the increased secretion...... of glucagon-like peptide (GLP)-1, by artificially increasing the levels of GLP-1 might prove successful as obesity treatment. Recent studies have shown that GLP-1 is a physiological regulator of appetite and food intake. The effect on food intake and satiety is preserved in obese subjects and GLP-1 may...... therefore have a therapeutic potential. The GLP-1 analogues result in a moderate average weight loss, which is clinically relevant in relation to reducing the risk of type 2 diabetes and cardiovascular disease. Inspired by the hormone profile after gastric bypass, a future strategy in obesity drug...

  1. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Mentis, Nikolaos; Vardarli, Irfan; Köthe, Lars D

    2011-01-01

    OBJECTIVE The incretin glucagon-like peptide 1 (GLP-1) exerts insulinotropic activity in type 2 diabetic patients, whereas glucose-dependent insulinotropic polypeptide (GIP) no longer does. We studied whether GIP can alter the insulinotropic or glucagonostatic activity of GLP-1 in type 2 diabetic...... patients. RESEARCH DESIGN AND METHODS Twelve patients with type 2 diabetes (nine men and three women; 61 ± 10 years; BMI 30.0 ± 3.7 kg/m2; HbA1c 7.3 ± 1.5%) were studied. In randomized order, intravenous infusions of GLP-1(7-36)-amide (1.2 pmol · kg-1 · min-1), GIP (4 pmol · kg-1 · min-1), GLP-1 plus GIP...... the insulinotropic and glucose-lowering effects of GLP-1 in type 2 diabetes. Rather, the suppression of glucagon by GLP-1 is antagonized by GIP....

  2. Neuroprotective effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson's disease mouse model.

    Science.gov (United States)

    Zhang, YanFang; Chen, YiMei; Li, Lin; Hölscher, Christian

    2015-10-15

    Glucagon-like peptide 1 (GLP-1) is a hormone and a growth factor. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. They also have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a first clinical trial in PD patients showed promising results. (Val8)GLP-1-glu-PAL is a new GLP-1 analogue which has a longer biological half-life than exendin-4. We previously showed that (Val8)GLP-1-glu-PAL has neuroprotective properties. Here we tested the drug in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected (30mg/kg i.p.) along with (Val8)GLP-1-glu-PAL (25nmol/kg i.p.) once-daily for 8 days. (Val8)GLP-1-glu-PAL showed good effects in preventing the MPTP-induced motor impairment (Rotarod, open field locomotion, swim test), reduction in tyrosine hydroxylase levels (dopamine synthesis) in the substantia nigra, a reduction of activated caspase 3 levels, of TUNEL positive cell numbers, of the pro-apoptotic signaling molecule BAX and an increase in the growth signaling molecule Bcl-2. The results demonstrate that (Val8)GLP-1-glu-PAL shows promise as a novel treatment of PD. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis

    DEFF Research Database (Denmark)

    Edholm, T; Degerblad, M; Grybäck, P

    2010-01-01

    Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on glucoregulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emptying and appetite after a mixed meal, and effects...

  4. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome

    DEFF Research Database (Denmark)

    Glintborg, Dorte; Mumm, Hanne; Holst, Jens Juul

    2017-01-01

    CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS...

  5. GLP-1 and Amylin in the Treatment of Obesity

    DEFF Research Database (Denmark)

    Jorsal, T; Rungby, J; Knop, F K

    2016-01-01

    for treatment of diabetes and obesity. This review will outline the physiology and pharmacological potential of amylin and GLP-1, respectively, and focus on innovative peptide drug development leading to drugs acting on two or more distinct receptors, such as an amylin and GLP-1 peptide hybrid, potentially...... producing a more effective treatment strategy to combat the rapidly increasing global obesity....

  6. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Dorte Glintborg

    2017-06-01

    Full Text Available Context: Insulin resistance in polycystic ovary syndrome (PCOS may increase the risk of reactive hypoglycaemia (RH and decrease glucagon-like peptide-1 (GLP-1 secretion. The possible effects of treatment with oral contraceptives (OCP and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined. Setting: Outpatient clinic. Patients and interventions: Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol, metformin (2 g/day or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT measuring fasting and area under the curve (AUC for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls. Main outcome measures: Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT. Results: Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01 and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01. Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI. Conclusions: AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion.

  7. Selective beneficial cardiometabolic effects of vertical sleeve gastrectomy are predominantly mediated through glucagon-like peptide (GLP-1 in Zucker diabetic fatty rats

    Directory of Open Access Journals (Sweden)

    Sunil Kumar

    2016-12-01

    Conclusion: Enhanced GLP-1 secretion post VSG imparted beneficial cardiometabolic effects on blood glucose, insulin, total cholesterol, triglyceride, bile acids and L-PGDS levels which were abated in the presence of GLP-1 antagonist.

  8. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycemia in PCOS

    DEFF Research Database (Denmark)

    Glintborg, Dorte; Mumm, Hanne; Holst, Jens Juul

    2017-01-01

    CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS ...... significantly lower in obese vs. lean patients and were inversely associated with BMI. CONCLUSIONS: AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin +OCP could be associated with increased insulin secretion.......CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS......, glucose, insulin, and C-peptide during 5 h OGTT. RESULTS: Fasting GLP-1 levels increased during metformin+OCP vs. OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P

  9. No effect of beta-adrenergic blockade on hypoglycaemic effect of glucagon-like peptide-1 (GLP-1) in normal subjects

    DEFF Research Database (Denmark)

    Toft-Nielsen, M; Hvidberg, A; Hilsted, Jannik

    1996-01-01

    GLP-1 administration decreases blood glucose levels in normal subjects and non-insulin-dependent diabetes mellitus patients and is therefore proposed as a treatment for diabetic hyperglycaemia. The glucose lowering effect of GLP-1 is glucose dependent and therefore self-limiting, but it is not kn...... on the two GLP-1 infusion days; and (5) an increase in catecholamine levels in the GLP-1/saline experiment and also in the beta-blockade experiments. We conclude that adrenergic counterregulation plays an insignificant role in curtailing GLP-1's glucose lowering effect....

  10. Metabolic effects of short-term GLP-1 treatment in insulin resistant heart failure patients

    DEFF Research Database (Denmark)

    Nielsen, Bent Roni Ranghøj; Wiggers, H; Halbirk, M

    2012-01-01

    calorimetry, forearm, and tracer methods.7 insulin resistant HF (EF 28%±2) patients completed the protocol. GLP-1 decreased plasma glucose levels (p=0.048) and improved glucose tolerance. 4 patients had hypoglycemic events during GLP-1 vs. none during placebo. GLP-1 treatment tended to increase whole body...

  11. Absence of a memory effect for the insulinotropic action of glucagon-like peptide 1 (GLP-1) in healthy volunteers

    DEFF Research Database (Denmark)

    Meier, S; Hücking, K; Ritzel, R

    2003-01-01

    of glucose was injected intravenously (0.33 g/kg body weight). GLP-1 was infused from (b). - 60 to 120 min, (c). - 210 to - 30 min, or (d). - 300 to - 120 min. Glucose (glucose oxidase), insulin, C-peptide, GLP-1, and glucagon (immunoassays) were determined. Statistical analysis was carried out by ANOVA......BACKGROUND/AIMS: The term memory effect refers to the phenomenon that B cell stimuli retain some of their insulinotropic effects after they have been removed. Memory effects exist for glucose and sulfonylureas. It is not known whether there is a B-cell memory for incretin hormones such as GLP-1...... and appropriate post hoc tests. RESULTS: GLP-1 plasma levels during the infusion periods were elevated to 89 +/- 9, 85 +/- 13, and 89 +/- 6 pmol/l (p Glucose was eliminated faster (p

  12. Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM

    DEFF Research Database (Denmark)

    Nauck, M A; Wollschläger, D; Werner, J

    1996-01-01

    with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p ....0001, respectively) and inhibited glucagon secretion (p ... emptying for 30-45 min (p statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous...

  13. The Effect of Pumpkin on GLP-1 and HOMA-β in Hypercholesterolemic Rats

    Directory of Open Access Journals (Sweden)

    Sunarti

    2016-03-01

    Full Text Available Background and aim: High fat and fructose diet may impair β cell function through oxidative stress that is induced by subsequent hypercholesterolemia. The β cell function is usually quantified by homeostatic model assessment beta-cell function (HOMA-β. Oxidative stress may be decreased by β-carotene from pumpkin (Cucurbita maxima. This study aimed to evaluate the effects of pumpkin powder on glucagon-like peptide-1 (GLP-1 level and HOMA-β in rats with high fat and fructose diet.

  14. The central GLP-1: implications for food and drug reward

    Directory of Open Access Journals (Sweden)

    Karolina Patrycja Skibicka

    2013-10-01

    Full Text Available Glucagon-like-peptide-1 (GLP-1 and its long acting analogues comprise a novel class of type 2 diabetes (T2D treatment. What makes them unique among other T2D drugs is their concurrent ability to reduce food intake, a great benefit considering the frequent comorbidity of T2D and obesity. The precise neural site of action underlying this beneficial effect is vigorously researched. In accordance with the classical model of food intake control GLP-1 action on feeding has been primarily ascribed to receptor populations in the hypothalamus and the hindbrain. In contrast to this common view, relevant GLP-1 receptor populations are distributed more widely, with a prominent mesolimbic complement emerging. The physiological relevance of the mesolimbic GLP-1 is suggested by the demonstration that similar anorexic effects can be obtained by independent stimulation of the mesolimbic and hypothalamic GLP-1 receptors. Results reviewed here support the idea that mesolimbic GLP-1 receptors are sufficient to reduce hunger-driven feeding, the hedonic value of food and food-motivation. In parallel, emerging evidence suggests that the range of action of GLP-1 on reward behavior is not limited to food-derived reward but extends to cocaine, amphetamine and alcohol reward. The new discoveries concerning GLP-1 action on the mesolimbic reward system significantly extend the potential therapeutic range of this drug target.

  15. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    and liraglutide, as well as the emerging GLP-1R agonists including the long-acting compounds. Expert opinion: An emerging therapeutic trend toward initial or early combination therapy with metformin- and incretin-based therapy is anticipated for patients with type 2 diabetes. GLP-1-based therapy has so far proven...... development may improve the effects of GLP-1 even further with optimized pharmacokinetic profiles resulting in fewer side effects. Meta-analyses have shown promising effects on cardiovascular disease and data from ongoing multicenter trials with cardiovascular endpoints are expected in 2015....

  16. Anti-inflammatory role of GLP-1 and the effect of gastric bypass on diabetes- and obesity-associated inflammation

    DEFF Research Database (Denmark)

    Bovbjerg, Kirsten Katrine Lindegaard

    with a set of metabolic abnormalities comprising the metabolic syndrome, such as hypertension, dyslipidemia, and insulin resistance. Although the exact causes for the onset of clinical disease remain largely unknown, emerging evidence seems to suggest that obesity-induced inflammation, especially...... in the adipose tissue, is involved in the metabolic dysregulation and therefore plays an important role in the pathogenesis of this deteriorating disease.Bariatric surgery, including the Roux-en Y gastric bypass (RYGB), is one of the most effective treatments for severe obesity. In addition to weight loss...... body of literature reports antiinflammatory and other immunological effects of GLP-1 in animals and in humans suggesting that GLP-1 acts beyond purely glucoregulatory mechanisms. The exaggerated postprandial GLP-1 secretion following RYGB may thus be involved in the beneficial metabolic effects both...

  17. Effects of PYY3-36 and GLP-1 on energy intake, energy expenditure and appetite in overweight men

    DEFF Research Database (Denmark)

    Schmidt, Julie Berg; Gregersen, Nikolaj Ture; Pedersen, Sue D

    2014-01-01

    Aim: To examine the effects of GLP-1 and PYY3-36, separately and in combination, on energy intake, energy expenditure, appetite sensations, glucose and fat metabolism, ghrelin and vital signs in healthy overweight men. Methods: 25 healthy, male subjects participated in this randomized, double...... of appetite sensations, energy expenditure and fat oxidation, vital signs and blood variables were collected throughout the infusion period. Results: No effect on energy intake was found after monoinfusions of PYY3-36 (-4.2±4.8%, P=0.8) or GLP-1 (-3.0±4.5%, P=0.9). However, the co-infusion reduced energy...

  18. Preserved GLP-1 effects in a diabetic patient with Cushing's disease

    DEFF Research Database (Denmark)

    Ritzel, R A; Kleine, N; Holst, Jens Juul

    2007-01-01

    CONTEXT: A patient with diabetes mellitus, who participated in a study with intravenous administration of GLP-1, was later found to have Cushing's disease (markedly elevated 24 h urinary cortisol excretion and inadequate suppression of fasting cortisol with 2 mg dexamethasone). His diabetic state...... mellitus due to Cushing's disease with GLP-1 actions in typical type 2 diabetes. DESIGN AND METHODS: GLP-1 (1.2 pmol/kg/min) and placebo had been infused into ten patients with diabetes mellitus over 4 h in the fasting state. The results from the patient with Cushing's disease (C) were compared to the data...... with Cushing's disease compared to those with type 2 diabetes. CONCLUSIONS: The insulinotropic, glucagonostatic and glucose-lowering actions of GLP-1 in a patient with diabetes mellitus due to cortisol excess were similar to actions in typical type 2 diabetes. Therefore incretin mimetics might be a novel...

  19. GLP-1 defects in diabetes

    DEFF Research Database (Denmark)

    Janus, Charlotte; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2015-01-01

    with type 2 diabetes (T2D) but the underlying mechanisms are still incompletely understood. In subjects with impaired glucose tolerance (IGT) and T2D, reduced levels of circulating GLP-1 have been observed in cross-sectional studies. Regardless of other changes, a reduced GLP-1 secretion must result...... glucose disturbances to frank diabetes. Therefore, further studies are required. Ideally, longitudinal studies of predisposed subjects (i.e. obesity, first-degree relatives, post gestational diabetes) followed until diagnosis of T2D would be necessary for elucidating if, indeed, impaired GLP-1 secretion......Glucagon-like peptide-1 (GLP-1) is secreted from the intestinal L-cells upon nutrient stimulation and regulates glucose levels by stimulating secretion of insulin (insulinotropic effects) in a glucose-dependent manner (the incretin effect). The incretin effect is severely impaired in subjects...

  20. Quantification of the contribution of GLP-1 to mediating insulinotropic effects of DPP-4 inhibition with vildagliptin in healthy subjects and type 2-diabetic patients using exendin [9-39] as a GLP-1 receptor antagonist

    DEFF Research Database (Denmark)

    Nauck, Michael A; Kind, J; Köthe, Lars D

    2016-01-01

    We quantified the contribution of GLP-1 as a mediator of the therapeutic effects of dipeptidyl peptidase 4 (DPP-4) inhibition (vildagliptin) by using the GLP-1 receptor antagonist exendin [9-39] in patients with type 2 diabetes and in healthy subjects. Thirty-two patients with type 2 diabetes...... and 29 age-and weight-matched healthy control subjects were treated in randomized order with 100 mg once daily vildagliptin or placebo for 10 days. Meal tests were performed (days 9 and 10) without and with a high-dose intravenous infusion of exendin [9-39]. The main end point was the ratio of the areas...... under the curve (AUCs) of integrated insulin secretion rates (total AUC(ISR)) and glucose (total AUC(glucose)) over 4 h after the meal. Vildagliptin treatment more than doubled responses of intact GLP-1 and glucose-dependent insulinotropic polypeptide and lowered glucose responses without changing AUC...

  1. Ghrelin suppresses cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) in the intestine, and attenuates the anorectic effects of CCK, PYY and GLP-1 in goldfish (Carassius auratus).

    Science.gov (United States)

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Valenciano, Ana Isabel; Delgado, María Jesús; Unniappan, Suraj

    2017-07-01

    Ghrelin is an important gut-derived hormone with an appetite stimulatory role, while most of the intestinal hormones, including cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), are appetite-inhibitors. Whether these important peptides with opposing roles on food intake interact to regulate energy balance in fish is currently unknown. The aim of this study was to characterize the putative crosstalk between ghrelin and CCK, PYY and GLP-1 in goldfish (Carassius auratus). We first determined the localization of CCK, PYY and GLP-1 in relation to ghrelin and its main receptor GHS-R1a (growth hormone secretagogue 1a) in the goldfish intestine by immunohistochemistry. Colocalization of ghrelin/GHS-R1a and CCK/PYY/GLP-1 was found primarily in the luminal border of the intestinal mucosa. In an intestinal explant culture, a significant decrease in prepro-cck, prepro-pyy and proglucagon transcript levels was observed after 60min of incubation with ghrelin, which was abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6 (except for proglucagon). The protein expression of PYY and GLP-1 was also downregulated by ghrelin. Finally, intraperitoneal co-administration of CCK, PYY or GLP-1 with ghrelin results in no modification of food intake in goldfish. Overall, results of the present study show for the first time in fish that ghrelin exerts repressive effects on enteric anorexigens. It is likely that these interactions mediate the stimulatory effects of ghrelin on feeding and metabolism in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Effects of microwave exposure on glucagon-like peptide-1 (GLP-1) and its receptor and the relationship with learning and memory injury

    International Nuclear Information System (INIS)

    Zhang Lei; Zhou Zhou; Zhang Guangbin; Yu Zhengping

    2007-01-01

    In order to explore the effects of microwave exposure on GLP-1 and its receptor, the relationship between the changes of GLP-1 and its receptor and learning and memory injury induced by microwave exposure has been studied in this paper. Morris water maze was used to evaluate learning and memory ability of rats. The changes of the plasma GLP-1 level were measured by ELISA assay. Alteration of the GLP-1R mRNA expression in rat hippocampus was determined by RT-PCR and Apoptosis was detected by TUNEL. Our study showed that microwave exposure injured the learning and memory abilities of rats meanwhile plasma GLP-1 level was decreased and GLP-1R expression in hippocampus was down-regulated, which can be protected by pretreatment with GLP-1. Alterations in GLP-1 and GLP-1R are, at least partially, responsible for the microwave exposure induced learning and memory dysfunction and neuronal injury. These data provide some new clues to investigate the mechanisms of microwave exposure induced neuronal injury and develop clinical approaches for treatment of microwave exposure induced injury. It can provide some new ideals for investigation of related mechanism and development of clinical treatment under exposed microwave irradiation. (authors)

  3. GLP-1 and GIP Levels in Patients With Hyperthyroidism: The Effect of Antithyroid Treatment.

    Science.gov (United States)

    Cira, Duygu Kalkan; Sari, Ramazan; Ozdem, Sebahat; Yilmaz, Nusret; Bozkurt, Selen

    2017-08-01

    Incretin hormones (glucagon-like peptide-1 [GLP-1] and gastric inhibitory polypeptide [GIP]) may play a role in the development of glucose intolerance and hyperglycemia in patients with hyperthyroidism. We aimed to assess both incretin levels and treatment-induced changes in incretin levels in those with hyperthyroidism. A total of 24 subjects (12 with hyperthyroidism and 12 healthy) were enrolled in the study. Oral glucose tolerance test was performed and serum glucose, insulin GLP1, and GIP levels were evaluated at 0 (baseline), 30, 60, 90, and 120 minutes using ELISA. Measurements were repeated after euthyroidism was reached in subjects with hyperthyroidism. The baseline glucose level was higher in those with hyperthyroidism compared with controls ( P = 0.03). GLP-1 and GIP responses to oral glucose load did not differ significantly between those with hyperthyroidism and controls. Peak GLP-1 and GIP levels were reached in both groups at 60 and 90 minutes, respectively. Areas under the curve (AUCs) for GLP1 and GIP were similar in those with hyperthyroidism and controls. Although GLP-1 and GIP levels did not change before and after antithyroid treatment in subjects with hyperthyroidism, time to peak GLP-1 and GIP levels were reached at 30 minutes after euthyroid state was achieved. Reversal of hyperthyroid to euthyroid status did not induce significant changes in AUCs for incretins. The findings of the present study suggest that the total incretin response to oral glucose load is preserved in patients with hypertyhroidism, but peak incretin responses may change after achieving euthyroid state.

  4. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors.

    Science.gov (United States)

    Ronn, Jonas; Jensen, Elisa P; Wewer Albrechtsen, Nicolai J; Holst, Jens Juul; Sorensen, Charlotte M

    2017-12-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP-1. We hypothesized that GLP-1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP-1 receptor were used to localize GLP-1 receptors in the kidney. Sevoflurane-anesthetized normotensive Sprague-Dawley rats and SHR received a 20 min intrarenal infusion of GLP-1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP-1 was assessed in isolated interlobar arteries from normo- and hypertensive rats. We found no expression of GLP-1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP-1 receptor. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  5. At the centennial of Michaelis and Menten, competing Michaelis-Menten steps explain effect of GLP-1 on blood-brain transfer and metabolism of glucose

    DEFF Research Database (Denmark)

    Jensen, Michael Gejl; Rungby, Jørgen; Brock, Birgitte

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic incretin hormone with pancreatic and extrapancreatic effects. Studies reveal significant effects in regions of brain tissue that regulate appetite and satiety. The effects cause that mimetics of GLP-1 serves as treatment of type 2 diabete...

  6. Supplementation with a fish protein hydrolysate (Micromesistius poutassou: effects on body weight, body composition, and CCK/GLP-1 secretion

    Directory of Open Access Journals (Sweden)

    Vincenzo Nobile

    2016-01-01

    Full Text Available Background: Fish protein hydrolysates (FPHs have been reported as a suitable source of proteins for human nutrition because of their balanced amino acid composition and positive effect on gastrointestinal absorption. Objective: Here, we investigated the effect of a FPH, Slimpro®, obtained from blue whiting (Micromesistius poutassou muscle by enzymatic hydrolysis, on body composition and on stimulating cholecystokinin (CCK and glucagon-like peptide-1 (GLP-1 secretion. Design: A randomized clinical study was carried out on 120, slightly overweight (25 kg/m2 ≤ BMI<30 kg/m2, male (25% and female (75% subjects. FPH was tested in a food supplement at two doses (1.4 and 2.8 g to establish if a dose–effect relationship exists. Product use was associated with a mild hypocaloric diet (−300 kcal/day. Body composition (body weight; fat mass; extracellular water; and circumference of waist, thighs, and hips and CCK/GLP-1 blood levels were measured at the beginning of the study and after 45 and 90 days of product use. CCK/GLP-1 levels were measured since they are involved in controlling food intake. Results: Treated subjects reported an improvement of body weight composition and an increased blood concentration of both CCK and GLP-1. No differences were found between the 1.4 and 2.8 g FPH doses, indicating a plateau effect starting from 1.4 g FPH. Conclusions: Both 1.4 and 2.8 g of FPH were effective in improving body composition and in increasing CCK and GLP-1 blood levels.

  7. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Krarup, Thure; Madsbad, Sten

    2003-01-01

    was to evaluate this. Eight healthy male volunteers (mean age: 23 (range 20-25) years; mean body mass index: 22.2 (range 19.3-25.4) kg/m2) participated in studies involving stepwise glucose clamping at fasting plasma glucose levels and at 6 and 7 mmol/l. Physiological amounts of either GIP (1.5 pmol/kg/min), GLP......-1(7-36)amide (0.33 pmol/kg/min) or saline were infused for three periods of 30 min at each glucose level, with 1 h "washout" between the infusions. On a separate day, a standard meal test (566 kcal) was performed. During the meal test, peak insulin concentrations were observed after 30 min...... and amounted to 223+/-27 pmol/l. Glucose+saline infusions induced only minor increases in insulin concentrations. GLP-1 and GIP infusions induced significant and similar increases at fasting glucose levels and at 6 mmol/l. At 7 mmol/l, further increases were seen, with GLP-1 effects exceeding those of GIP...

  8. Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist.

    Directory of Open Access Journals (Sweden)

    Qinghua Wang

    2010-09-01

    Full Text Available GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2168 h. Intraperitoneal glucose tolerance test (IPGTT in mice showed that GLP-1/hIgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hIgG2 fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1/hIgG2 was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Together, the long-lasting bioactive GLP-1/hIgG2 retains native GLP-1 activities and thus may serve as a potent GLP-1 receptor agonist.

  9. Liraglutide Modulates Appetite and Body Weight Via GLP-1R-Expressing Glutamatergic Neurons.

    Science.gov (United States)

    Adams, Jessica M; Pei, Hongjuan; Sandoval, Darleen A; Seeley, Randy J; Chang, Rui B; Liberles, Stephen D; Olson, David P

    2018-05-18

    Glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) impact appetite and body weight are still not fully understood. Here, we determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the acute and chronic effects of the GLP1RA liraglutide on food intake, visceral illness, body weight and neural network activation. We found that mice lacking GLP-1Rs in vGAT -expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2 -expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects, and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons. © 2018 by the American Diabetes Association.

  10. The effect of a subcutaneous infusion of GLP-1, OXM and PYY on Energy intake and Expenditure in Obese volunteers

    DEFF Research Database (Denmark)

    Tan, Tricia; Behary, Preeshila; Tharakan, George

    2017-01-01

    has been postulated to contribute to its metabolic benefits. Objective: We hypothesised that infusion of the three gut hormones to achieve levels similar to those encountered post-prandially in RYGB patients might be effective in suppressing appetite. The aim of this study was to investigate...... the effect of a continuous infusion of GLP-1, OXM and PYY (GOP) on energy intake and expenditure in obese volunteers. Methods: Obese volunteers were randomised to receive an infusion of GOP or placebo in a single-blinded randomised placebo-controlled cross-over study for 10.5 hours a day. This was delivered......Background: Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for obesity, although limited by availability and operative risk. The gut hormones Glucagon-like peptide-1 (GLP-1), Peptide YY (PYY) and Oxyntomodulin (OXM) are elevated post-prandially after RYGB, which...

  11. Effect of GLP-1 Receptor Agonist Treatment on Body weight in Obese Antipsychotic-treated Patients with Schizophrenia

    DEFF Research Database (Denmark)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V

    2017-01-01

    AIMS: Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D2 receptor antagonists and the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects like obesity...... and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. MATERIAL AND METHODS......: Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for three months. The primary outcome was body weight loss after treatment and repeated measures...

  12. Emerging GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2011-01-01

    development may improve the effects of GLP-1 even further with optimized pharmacokinetic profiles resulting in fewer side effects. Meta-analyses have shown promising effects on cardiovascular disease and data from ongoing multicenter trials with cardiovascular endpoints are expected in 2015....

  13. Liraglutide Versus Lixisenatide: Long-Term Cost-Effectiveness of GLP-1 Receptor Agonist Therapy for the Treatment of Type 2 Diabetes in Spain

    OpenAIRE

    Mezquita-Raya, Pedro; Ram?rez de Arellano, Antonio; Kragh, Nana; Vega-Hernandez, Gabriela; P?hlmann, Johannes; Valentine, William J.; Hunt, Barnaby

    2017-01-01

    Introduction Glucagon-like peptide-1 (GLP-1) receptor agonists are used successfully in the treatment of patients with type 2 diabetes as they are associated with low hypoglycemia rates, weight loss and improved glycemic control. This study compared, in the Spanish setting, the cost-effectiveness of liraglutide 1.8?mg versus lixisenatide 20??g, both GLP-1 receptor agonists, for patients with type 2 diabetes who had not achieved glycemic control targets on metformin monotherapy. Methods The IM...

  14. Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain.

    Science.gov (United States)

    McGovern, Stephen F J; Hunter, Kerry; Hölscher, Christian

    2012-09-14

    Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Effects of exendin-4 and selenium on the expression of GLP-1R, IRS-1, and preproinsulin in the pancreas of diabetic rats.

    Science.gov (United States)

    Barakat, Ghinwa; Moustafa, Mohamed E; Khalifeh, Ibrahim; Hodroj, Mohammad H; Bikhazi, Anwar; Rizk, Sandra

    2016-08-01

    The mechanisms by which exendin-4 and selenium exert their antidiabetic actions are still unclear. Here, we investigated the effects of exendin-4 or selenium administration on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and preproinsulin in the pancreas of diabetic rats. Diabetes was induced by streptozotocin administration. Diabetic rats were injected intraperitoneally with 0.03 μg exendin-4/kg body weight/daily or treated with 5 ppm selenium in drinking water for a period of 4 weeks. GLP-1R and IRS-1 levels were decreased while the level of preproinsulin messenger RNA (mRNA) was increased in the pancreas of diabetic untreated rats, as compared to that in control rats. Treatment of diabetic rats with exendin-4 increased protein and mRNA levels of GLP-1R, and IRS-1, and the mRNA level of preproinsulin in the pancreas, as compared to their levels in diabetic untreated rats. Selenium treatment of diabetic rats increased the pancreatic mRNA levels of GLP-1R, IRS-1, and preproinsulin. Exendin-4 or selenium treatment of diabetic rats also increased the numbers of pancreatic islets and GLP-1R molecules in the pancreas. Therefore, exendin-4 and selenium may exert their antidiabetic effects by increasing GLP-1R, IRS-1, and preproinsulin expression in the pancreas and by increasing the number of pancreatic islets.

  16. GLP-1 nanomedicine alleviates gut inflammation.

    Science.gov (United States)

    Anbazhagan, Arivarasu N; Thaqi, Mentor; Priyamvada, Shubha; Jayawardena, Dulari; Kumar, Anoop; Gujral, Tarunmeet; Chatterjee, Ishita; Mugarza, Edurne; Saksena, Seema; Onyuksel, Hayat; Dudeja, Pradeep K

    2017-02-01

    The gut hormone, glucagon like peptide-1 (GLP-1) exerts anti-inflammatory effects. However, its clinical use is limited by its short half-life. Previously, we have shown that GLP-1 as a nanomedicine (GLP-1 in sterically stabilized phospholipid micelles, GLP-1-SSM) has increased in vivo stability. The current study was aimed at testing the efficacy of this GLP-1 nanomedicine in alleviating colonic inflammation and associated diarrhea in dextran sodium sulfate (DSS) induced mouse colitis model. Our results show that GLP-1-SSM treatment markedly alleviated the colitis phenotype by reducing the expression of pro-inflammatory cytokine IL-1β, increasing goblet cells and preserving intestinal epithelial architecture in colitis model. Further, GLP-1-SSM alleviated diarrhea (as assessed by luminal fluid) by increasing protein expression of intestinal chloride transporter DRA (down regulated in adenoma). Our results indicate that GLP-1 nanomedicine may act as a novel therapeutic tool in alleviating gut inflammation and associated diarrhea in inflammatory bowel disease (IBD). Published by Elsevier Inc.

  17. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow.

    Science.gov (United States)

    Jensen, Elisa P; Poulsen, Steen S; Kissow, Hannelouise; Holstein-Rathlou, Niels-Henrik; Deacon, Carolyn F; Jensen, Boye L; Holst, Jens J; Sorensen, Charlotte M

    2015-04-15

    Glucagon-like peptide (GLP)-1 has a range of extrapancreatic effects, including renal effects. The mechanisms are poorly understood, but GLP-1 receptors have been identified in the kidney. However, the exact cellular localization of the renal receptors is poorly described. The aim of the present study was to localize renal GLP-1 receptors and describe GLP-1-mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and that activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using (125)I-labeled GLP-1, (125)I-labeled exendin-4 (GLP-1 analog), and (125)I-labeled exendin 9-39 (GLP-1 receptor antagonist) was performed in rodents to localize specific GLP-1 receptor binding. GLP-1-mediated effects on blood pressure, renal blood flow (RBF), heart rate, renin secretion, urinary flow rate, and Na(+) and K(+) excretion were investigated in anesthetized rats. Effects of GLP-1 on afferent arterioles were investigated in isolated mouse kidneys. Specific binding of (125)I-labeled GLP-1, (125)I-labeled exendin-4, and (125)I-labeled exendin 9-39 was observed in the renal vasculature, including afferent arterioles. Infusion of GLP-1 increased blood pressure, RBF, and urinary flow rate significantly in rats. Heart rate and plasma renin concentrations were unchanged. Exendin 9-39 inhibited the increase in RBF. In isolated murine kidneys, GLP-1 and exendin-4 significantly reduced the autoregulatory response of afferent arterioles in response to stepwise increases in pressure. We conclude that GLP-1 receptors are located in the renal vasculature, including afferent arterioles. Activation of these receptors reduces the autoregulatory response of afferent arterioles to acute pressure increases and increases RBF in normotensive rats. Copyright © 2015 the American Physiological Society.

  18. No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia.

    Science.gov (United States)

    Ishøy, P L; Fagerlund, B; Broberg, B V; Bak, N; Knop, F K; Glenthøj, B Y; Ebdrup, B H

    2017-07-01

    Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive-enhancing effects. In this investigator-initiated, double-blind, randomized, placebo-controlled trial, we tested non-metabolic effects of exenatide once-weekly (Bydureon™) in obese, antipsychotic-treated patients with schizohrenia spectrum disorder. Before and after 3 months of exenatide (N = 20) or placebo (N = 20) treatment, patients were assessed with the following: Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterreith complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP) and the Positive and Negative Syndrome Scale (PANSS). We used BACS composite score as the main outcome measure. Repeated measures analysis of variance on BACS composite score showed significant effect of 'Time' (P schizophrenia could reflect a general problem of translating cognitive-enhancing effects of GLP-1RAs from animals to humans or be explained by factors specifically related to schizophrenia spectrum patients with obesity such as antipsychotic treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia

    DEFF Research Database (Denmark)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V

    2017-01-01

    and placebo groups experienced significant ( P  = .004), however similar ( P  = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment. CONCLUSIONS: Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients......AIMS: Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D2 receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects...... such as obesity and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. MATERIAL...

  20. At the centennial of Michaelis and Menten, competing Michaelis-Menten steps explain effect of GLP-1 on blood-brain transfer and metabolism of glucose.

    Science.gov (United States)

    Gejl, Michael; Rungby, Jørgen; Brock, Birgitte; Gjedde, Albert

    2014-08-01

    Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic incretin hormone with both pancreatic and extrapancreatic effects. Studies of GLP-1 reveal significant effects in regions of brain tissue that regulate appetite and satiety. GLP-1 mimetics are used for the treatment of type 2 diabetes mellitus. GLP-1 interacts with peripheral functions in which the autonomic nervous system plays an important role, and emerging pre-clinical findings indicate a potential neuroprotective role of the peptide, for example in models of stroke and in neurodegenerative disorders. A century ago, Leonor Michaelis and Maud Menten described the steady-state enzyme kinetics that still apply to the multiple receptors, transporters and enzymes that define the biochemical reactions of the brain, including the glucose-dependent impact of GLP-1 on blood-brain glucose transfer and metabolism. This MiniReview examines the potential of GLP-1 as a molecule of interest for the understanding of brain energy metabolism and with reference to the impact on brain metabolism related to appetite and satiety regulation, stroke and neurodegenerative disorders. These effects can be understood only by reference to the original formulation of the Michaelis-Menten equation as applied to a chain of kinetically controlled steps. Indeed, the effects of GLP-1 receptor activation on blood-brain glucose transfer and brain metabolism of glucose depend on the glucose concentration and relative affinities of the steps both in vitro and in vivo, as in the pancreas. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  1. Endogenous GLP-1 in lateral septum contributes to stress-induced hypophagia.

    Science.gov (United States)

    Terrill, Sarah J; Maske, Calyn B; Williams, Diana L

    2018-03-03

    Glucagon-like peptide 1 (GLP-1) neurons of the caudal brainstem project to many brain areas, including the lateral septum (LS), which has a known role in stress responses. Previously, we showed that endogenous GLP-1 in the LS plays a physiologic role in the control of feeding under non-stressed conditions, however, central GLP-1 is also involved in behavioral and endocrine responses to stress. Here, we asked whether LS GLP-1 receptors (GLP-1R) contribute to stress-induced hypophagia. Male rats were implanted with bilateral cannulas targeting the dorsal subregion of the LS (dLS). In a within-subjects design, shortly before the onset of the dark phase, rats received dLS injections of saline or the GLP-1R antagonist Exendin (9-39) (Ex9) prior to 30 min restraint stress. Food intake was measured continuously for the next 20 h. The stress-induced hypophagia observed within the first 30 min of dark was not influenced by Ex9 pretreatment, but Ex9 tended to blunt the effect of stress as early as 1 and 2 h into the dark phase. By 4-6 h, there were significant stress X drug interactions, and Ex9 pretreatment blocked the stress-induced suppression of feeding. These effects were mediated entirely through changes in average meal size; stress suppressed meal size while dLS Ex9 attenuated this effect. Using a similar design, we examined the role of dLS GLP-1R in the neuroendocrine response to acute restraint stress. As expected, stress potently increased serum corticosterone, but blockade of dLS GLP-1Rs did not affect this response. Together, these data show that endogenous GLP-1 action in the dLS plays a role in some but not all of the physiologic responses to acute stress. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Elevated Postoperative Endogenous GLP-1 Levels Mediate Effects of Roux-en-Y Gastric Bypass on Neural Responsivity to Food Cues

    DEFF Research Database (Denmark)

    Ten Kulve, Jennifer S; Veltman, Dick J; Gerdes, Victor E A

    2017-01-01

    of the GLP-1 receptor antagonist exendin 9-39 (Ex9-39) and placebo were assessed in 10 women before and after RYGB. We used functional MRI to investigate CNS activation in response to visual food cues (pictures) and gustatory food cues (consumption of chocolate milk), comparing results with Ex9-39 versus...... in response to visual and gustatory food cues may be mediated by central effects of GLP-1. Our findings provide further insights into the mechanisms underlying the weight-lowering effects of RYGB.......OBJECTIVE: It has been suggested that weight reduction and improvements in satiety after Roux-en-Y gastric bypass (RYGB) are partly mediated via postoperative neuroendocrine changes. Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted after food ingestion and is associated with appetite...

  3. A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease.

    Science.gov (United States)

    Yuan, Ziyue; Li, Dongfang; Feng, Peng; Xue, Guofang; Ji, Chenhui; Li, Guanglai; Hölscher, Christian

    2017-10-05

    Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Cardiovascular safety and benefits of GLP-1 receptor agonists

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Brønden, Andreas; Lauritsen, Tina Vilsbøll

    2017-01-01

    INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss...... and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients...

  5. Recombinant human GLP-1(rhGLP-1) alleviating renal tubulointestitial injury in diabetic STZ-induced rats.

    Science.gov (United States)

    Yin, Weiqin; Xu, Shiqing; Wang, Zai; Liu, Honglin; Peng, Liang; Fang, Qing; Deng, Tingting; Zhang, Wenjian; Lou, Jinning

    2018-01-01

    GLP-1-based treatment improves glycemia through stimulation of insulin secretion and inhibition of glucagon secretion. Recently, more and more findings showed that GLP-1 could also protect kidney from diabetic nephropathy. Most of these studies focused on glomeruli, but the effect of GLP-1 on tubulointerstitial and tubule is not clear yet. In this study, we examined the renoprotective effect of recombinant human GLP-1 (rhGLP-1), and investigated the influence of GLP-1 on inflammation and tubulointerstitial injury using diabetic nephropathy rats model of STZ-induced. The results showed that rhGLP-1 reduced urinary albumin without influencing the body weight and food intake. rhGLP-1 could increased the serum C-peptide slightly but not lower fasting blood glucose significantly. In diabetic nephropathy rats, beside glomerular sclerosis, tubulointerstitial fibrosis was very serious. These lesions could be alleviated by rhGLP-1. rhGLP-1 decreased the expression of profibrotic factors collagen I, α-SMA, fibronectin, and inflammation factors MCP-1 and TNFα in tubular tissue and human proximal tubular cells (HK-2 cells). Furthermore, rhGLP-1 significantly inhibited the phosphorylation of NF-κB, MAPK in both diabetic tubular tissue and HK-2 cells. The inhibition of the expression of TNFα, MCP-1, collagen I and α-SMA in HK-2 cells by GLP-1 could be mimicked by blocking NF-κB or MAPK. These results indicate that rhGLP-1 exhibit renoprotective effect by alleviation of tubulointerstitial injury via inhibiting phosphorylation of MAPK and NF-κB. Therefore, rhGLP-1 may be a potential drug for treatment of diabetic nephropathy. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. GLP-1-Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus: An Acute and 12-Week Randomized, Double-Blind, Placebo-Controlled Trial.

    Science.gov (United States)

    Smits, Mark M; Tonneijck, Lennart; Muskiet, Marcel H A; Hoekstra, Trynke; Kramer, Mark H H; Diamant, Michaela; Serné, Erik H; van Raalte, Daniël H

    2016-10-01

    To assess the effects of glucagon-like peptide (GLP)-1-based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m(2); HbA1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo (P>0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P12-week study, no effects on vasomotion were observed. Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1-based therapies on glucose are not mediated through microvascular responses. © 2016 American Heart Association, Inc.

  7. Direct effects of exendin-(9,39) and GLP-1-(9,36)amide on insulin action, β-cell function, and glucose metabolism in nondiabetic subjects.

    Science.gov (United States)

    Sathananthan, Matheni; Farrugia, Luca P; Miles, John M; Piccinini, Francesca; Dalla Man, Chiara; Zinsmeister, Alan R; Cobelli, Claudio; Rizza, Robert A; Vella, Adrian

    2013-08-01

    Exendin-(9,39) is a competitive antagonist of glucagon-like peptide-1 (GLP-1) at its receptor. However, it is unclear if it has direct and unique effects of its own. We tested the hypothesis that exendin-(9,39) and GLP-1-(9,36)amide have direct effects on hormone secretion and β-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-(3)H]glucose was infused to mimic the systemic appearance of glucose after a meal. Saline, GLP-1-(9,36)amide, or exendin-(9,39) at 30 pmol/kg/min (Ex 30) or 300 pmol/kg/min (Ex 300) were infused in random order on separate days. Integrated glucose concentrations were slightly but significantly increased by exendin-(9,39) (365 ± 43 vs. 383 ± 35 vs. 492 ± 49 vs. 337 ± 50 mmol per 6 h, saline, Ex 30, Ex 300, and GLP-1-[9,36]amide, respectively; P = 0.05). Insulin secretion did not differ among groups. However, insulin action was lowered by exendin-(9,39) (25 ± 4 vs. 20 ± 4 vs. 18 ± 3 vs. 21 ± 4 10(-4) dL/kg[min per μU/mL]; P = 0.02), resulting in a lower disposition index (DI) during exendin-(9,39) infusion (1,118 ± 118 vs. 816 ± 83 vs. 725 ± 127 vs. 955 ± 166 10(-14) dL/kg/min(2) per pmol/L; P = 0.003). Endogenous glucose production and glucose disappearance did not differ significantly among groups. We conclude that exendin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans.

  8. The effects of aerobic exercises and 25(OH D supplementation on GLP1 and DPP4 level in Type II diabetic patients

    Directory of Open Access Journals (Sweden)

    Naser Rahimi

    2017-01-01

    Full Text Available Background: The purpose of this study was to investigate the effects of an 8-week aerobic exercise and supplementation of 25(OHD3 on GLP1 and DDP4 levels in men with type II diabetes. Methods: In this semiexperimental research, among 40–60-year-old men with type II diabetes who were referred to the diabetic center of Isabn-E Maryam hospital in Isfahan; of whom, 48 patients were voluntarily accepted and then were randomly divided into 4 groups: aerobic exercise group, aerobic exercise with 25(OH D supplement group, 25(OH D supplement group, and the control group. An aerobic exercise program was conducted for 8 weeks (3 sessions/week, each session 60 to75 min with 60–80% HRmax. The supplement user group received 50,000 units of oral Vitamin D once weekly for 8 weeks. The GLP1, DPP4, and 25(OH D levels were measured before and after the intervention. At last, the data were statistically analyzed using the ANCOVA and post hoc test of least significant difference. Results: The results of ANCOVA showed a significant difference between the GLP1 and DPP4 levels in aerobic exercise with control group while these changes were not statistically significant between the 25(OH D supplement group with control group (P < 0.05. Conclusions: Aerobic exercises have resulted an increase in GLP1 level and a decrease in DPP4 level. However, consumption of Vitamin D supplement alone did not cause any changes in GLP1and DPP4 levels but led to an increase in 25-hydroxy Vitamin D level.

  9. CREB mediates the insulinotropic and anti-apoptotic effects of GLP-1 signaling in adult mouse β-cells

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    Soona Shin

    2014-11-01

    Conclusions: In sum, our studies using conditional gene deletion put into question current notions about the importance of CREB in regulating β-cell function and mass. However, we reveal an important role for CREB in the β-cell response to GLP-1 receptor signaling, further validating CREB as a therapeutic target for diabetes.

  10. Combining GLP-1 receptor agonists with insulin

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Vilsbøll, T

    2013-01-01

    Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among...... physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose......, compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic...

  11. Effect of GLP-1 on the expression of NADPH oxidase subunits in the kidney of type 1 diabetic rats

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    Jin-jin LIU

    2013-09-01

    Full Text Available Objective To observe the effect of exenatide, a glucagon-like peptide-1 (GLP-1 receptor agonist, on the expression of NADPH oxidase subunits NOX4 and p22phox and connective tissue growth factor (CTGF in the kidney of streptozotocin (STZ-induced type 1 diabetic rats, and explore the protective effects and mechanisms of exenatide on the kidney of diabetic rats. Methods Thirty male Sprague-Dawley (SD rats were divided into control group (group A, n=7 and diabetic model group (n=23. Type 1 diabetic model was reproduced by intraperitoneal injection of streptozotocin. It was successful in 19 rats. Diabetic rats were randomly divided into diabetic control group (group B, n=10 and diabetic with treatment of exenatide group (group C, n=9. Rats in group C were injected subcutaneously with exenatide in dose of 5μg/kg twice daily. Rats in group A and B were given equivalent volume of normal saline by subcutaneous injection. All rats were sacrificed after eight weeks. The mRNA expression of renal p22phox and NOX4 were detected by real-time fluorescence quantitative PCR. The protein expression of CTGF was detected by immunohistochemical staining. Results The levels of blood glucose, lipids, creatinine, and urea nitrogen, the albumin excretion rate, kidney index, the mRNA expressions of renal NOX4 and p22phox, and the protein expression of renal CTGF were significantly increased in group B compared with that in group A (P0.05. Conclusion Exenatide can decrease the expressions of renal NOX4, p22phox and CTGF, decline the index of urinary protein, and alleviate the kidney hypertrophy in type 1 diabetic rats, implying that exenatide exerted a protective effect on the kidney.

  12. The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice

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    Laurie L. Baggio

    2017-11-01

    Conclusions: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.

  13. A tripeptide Diapin effectively lowers blood glucose levels in male type 2 diabetes mice by increasing blood levels of insulin and GLP-1.

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    Jifeng Zhang

    Full Text Available The prevalence of type 2 diabetes (T2D is rapidly increasing worldwide. Effective therapies, such as insulin and Glucagon-like peptide-1 (GLP-1, require injections, which are costly and result in less patient compliance. Here, we report the identification of a tripeptide with significant potential to treat T2D. The peptide, referred to as Diapin, is comprised of three natural L-amino acids, GlyGlyLeu. Glucose tolerance tests showed that oral administration of Diapin effectively lowered blood glucose after oral glucose loading in both normal C57BL/6J mice and T2D mouse models, including KKay, db/db, ob/ob mice, and high fat diet-induced obesity/T2D mice. In addition, Diapin treatment significantly reduced casual blood glucose in KKay diabetic mice in a time-dependent manner without causing hypoglycemia. Furthermore, we found that plasma GLP-1 and insulin levels in diabetic models were significantly increased with Diapin treatment compared to that in the controls. In summary, our findings establish that a peptide with minimum of three amino acids can improve glucose homeostasis and Diapin shows promise as a novel pharmaceutical agent to treat patients with T2D through its dual effects on GLP-1 and insulin secretion.

  14. Neuroprotective properties of GLP-1

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Burcelin, Remy; Nathanson, Esther

    2011-01-01

    emptying. Furthermore, data are beginning to emerge that indicate a potential role for GLP-1 in neuroprotection. The increased risk of Alzheimer's disease, Parkinson's disease and stroke in people with type 2 diabetes suggests that shared mechanisms/pathways of cell death, possibly related to insulin...... path towards cellular dysfunction and death. This article summarizes the evidence for neuronal activity of GLP-1 and examines the limited data that currently exist on the therapeutic potential of GLP-1 in specific neurological and neurodegenerative conditions, namely Alzheimer's disease, Parkinson...

  15. Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial.

    Science.gov (United States)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V; Bak, Nikolaj; Andersen, Ulrik B; Jørgensen, Niklas R; Holst, Jens J; Glenthøj, Birte Y; Ebdrup, Bjørn H

    2017-02-01

    Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D 2 receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis. Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment. Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  16. Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity.

    Science.gov (United States)

    Lee, Shin J; Sanchez-Watts, Graciela; Krieger, Jean-Philippe; Pignalosa, Angelica; Norell, Puck N; Cortella, Alyssa; Pettersen, Klaus G; Vrdoljak, Dubravka; Hayes, Matthew R; Kanoski, Scott; Langhans, Wolfgang; Watts, Alan G

    2018-05-01

    Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization. GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies. Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

  17. Gut peptide GLP-1 and its analogue, Exendin-4, decrease alcohol intake and reward.

    Directory of Open Access Journals (Sweden)

    Rozita H Shirazi

    Full Text Available Glucagon-like-peptide-1 (GLP-1 is a gut- and neuro-peptide with an important role in the regulation of food intake and glucose metabolism. Interestingly, GLP-1 receptors (GLP-1R are expressed in key mesolimbic reward areas (including the ventral tegmental area, VTA, innervated by hindbrain GLP-1 neurons. Recently GLP-1 has emerged as a potential regulator of food reward behavior, an effect driven by the mesolimbic GLP-1Rs. Its role in other reward behaviors remains largely unexplored. Since a considerable overlap has been suggested for circuitry controlling reward behavior derived from food and alcohol we hypothesized that GLP-1 and GLP-1Rs could regulate alcohol intake and alcohol reward. We sought to determine whether GLP-1 or its clinically safe stable analogue, Exendin-4, reduce alcohol intake and reward. To determine the potential role of the endogenous GLP-1 in alcohol intake we evaluated whether GLP-1R antagonist, Exendin 9-39, can increase alcohol intake. Furthermore, we set out to evaluate whether VTA GLP-1R activation is sufficient to reduce alcohol intake. Male Wistar rats injected peripherally with GLP-1 or Exendin-4 reduced their alcohol intake in an intermittent access two bottle free choice drinking model. Importantly, a contribution of endogenously released GLP-1 is highlighted by our observation that blockade of GLP-1 receptors alone resulted in an increased alcohol intake. Furthermore, GLP-1 injection reduced alcohol reward in the alcohol conditioned place preference test in mice. To evaluate the neuroanatomical substrate linking GLP-1 with alcohol intake/reward, we selectively microinjected GLP-1 or Exendin 4 into the VTA. This direct stimulation of the VTA GLP-1 receptors potently reduced alcohol intake. Our findings implicate GLP-1R signaling as a novel modulator of alcohol intake and reward. We show for the first time that VTA GLP-1R stimulation leads to reduced alcohol intake. Considering that GLP-1 analogues are already

  18. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    DEFF Research Database (Denmark)

    Kielgast, Urd; Holst, Jens Juul; Madsbad, Sten

    2009-01-01

    for a beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes......, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential...... appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence...

  19. [Safety and tolerability of GLP-1 receptor agonists].

    Science.gov (United States)

    Soldevila, Berta; Puig-Domingo, Manel

    2014-09-01

    Glucagon-like peptide-1 receptor agonists (GLP-1ra) are a new group of drugs with a glucose-lowering action due to their incretin effect. The GLP-1 receptor is expressed in various human tissues, which could be related to the pleiotropic effects of human GLP-1, as well as to the adverse effects described in patients treated with GLP-1ra. The risk of hypoglycaemia is low, which is one of the main considerations in the safety of this family of compounds and is also important to patients with diabetes. The most frequent adverse effect is nausea, which usually occurs at the start of treatment and is transient in 20-60% of affected patients. This article also reviews the information available on antibody formation, the potential effect on the thyroid gland, and the controversial association between this group of drugs with pancreatitis and cancer. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  20. Ability of GLP-1 to decrease food intake is dependent on nutritional status.

    Science.gov (United States)

    Ronveaux, Charlotte C; de Lartigue, Guillaume; Raybould, Helen E

    2014-08-01

    Gut-derived glucagon like peptide-1 (GLP-1) acts in the postprandial period to stimulate insulin secretion and inhibit gastrointestinal motor and secretory function; whether endogenous peripheral GLP-1 inhibits food intake is less clear. We hypothesized that GLP-1 inhibits food intake in the fed, but not fasted, state. There is evidence that GLP-1 acts via stimulation of vagal afferent neurons (VAN); we further hypothesized that the satiating effects of endogenous GLP-1 in the postprandial period is determined either by a change in GLP-1 receptor (GLP-1R) expression or localization to different cellular compartments in VAN. Food intake was recorded following administration of GLP-1 (50μg/kg or 100μg/kg) or saline (IP) in Wistar rats fasted for 18h or fasted then re-fed with 3g chow. GLP-1R protein expression and localization on VAN were determined by immunocytochemistry and immunoblots in animals fasted for 18h or fasted then re-fed for 40min. GLP-1R mRNA level was detected in animals fasted for 18h or fasted and re-fed ad libitum for 2h. GLP-1 (100μg/kg) significantly reduced 40min food intake by 38% in re-fed but not fasted rats (pfasted rats. However, GLP-1R localization to the plasma membrane was significantly increased in VAN by feeding. Feeding changes the ability of peripheral GLP-1 to inhibit food intake. GLP-1Rs are trafficked to the plasma membrane in response to a meal. GLP-1 may play a role in regulating food intake in the postprandial period. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Evidence for paracrine/autocrine regulation of GLP-1-producing cells

    DEFF Research Database (Denmark)

    Kappe, Camilla; Zhang, Qimin; Holst, Jens Juul

    2013-01-01

    Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent...... studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin...... as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our...

  2. Effect of Age on Blood Glucose and Plasma Insulin, Glucagon, Ghrelin, CCK, GIP, and GLP-1 Responses to Whey Protein Ingestion

    Directory of Open Access Journals (Sweden)

    Caroline Giezenaar

    2017-12-01

    Full Text Available Protein-rich supplements are used widely to prevent and manage undernutrition in older people. We have previously shown that healthy older, compared to younger, adults have less suppression of energy intake by whey protein—although the effects of age on appetite-related gut hormones are largely unknown. The aim of this study was to determine and compare the acute effects of whey protein loads on blood glucose and plasma gut hormone concentrations in older and younger adults. Sixteen healthy older (eight men, eight women; mean ± SEM: age: 72 ± 1 years; body mass index: 25 ± 1 kg/m2 and 16 younger (eight men, eight women; 24 ± 1 years; 23 ± 0.4 kg/m2 adults were studied on three occasions in which they ingested 30 g (120 kcal or 70 g (280 kcal whey protein, or a flavored-water control drink (~2 kcal. At regular intervals over 180 min, blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK, gastric inhibitory peptide (GIP, and glucagon-like peptide-1 (GLP-1 concentrations were measured. Plasma ghrelin was dose-dependently suppressed and insulin, glucagon, CCK, GIP, and GLP-1 concentrations were dose-dependently increased by the whey protein ingestion, while blood glucose concentrations were comparable during all study days. The stimulation of plasma CCK and GIP concentrations was greater in older than younger adults. In conclusion, orally ingested whey protein resulted in load-dependent gut hormone responses, which were greater for plasma CCK and GIP in older compared to younger adults.

  3. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine

    DEFF Research Database (Denmark)

    Christensen, Louise Wulff; Kuhre, Rune Ehrenreich; Janus, Charlotte

    2015-01-01

    -protein-cou- pled receptor, FFAR1 (previously GPR40), expressed on L cells and activated by long-chain fatty acids (LCFAs) is a potential target. A link between FFAR1 activation and GLP-1 secretion has been demonstrated in cellular models and small-molecule FFAR1 agonists have been developed. In this study, we exam......- ined the effect of FFAR1 activation on GLP-1 secretion using isolated, per- fused small intestines from rats, a physiologically relevant model allowing distinction between direct and indirect effects of FFAR1 activation. The endogenous FFAR1 ligand, linoleic acid (LA), and four synthetic FFAR1 ago...

  4. Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Østergaard, L; Frandsen, Christian S.; Madsbad, S

    2016-01-01

    Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases...... satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other...... gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA....

  5. GLP-1 regulation of glucagon, somatostatin and insulin in naidm patients: evidence of direct inhibition of A - cells by GLP - 1

    International Nuclear Information System (INIS)

    Naveed, A.K.; Khan, F.A.

    2006-01-01

    Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut into the circulation after meals and is the most potent physiological insulinotropic hormone in man. In contrast to presently available therapeutic agents for non-insulin dependent diabetes mellitus (NIDDM), GLP-1 has the advantages of both suppressing glucagon secretion and delaying gastric emptying. We report first study of subcutaneous GLP-1 treatment to determine the optimum dose required to control the NIDDM. Seven patients, with poorly controlled NIDDM were entered in the study who visited at four visits with intervals of 2-4 days and received saline, 40, 100 and 200 nmol subcutaneous GLP-1, immediately after meals. A standerdized test meal was given. A significant hypoglycaemic response (p<0.05) was achieved in patients given 40, 100 and 200 nmol GLP-1. An increase in insulin levels (p<0.05) was observed as compared to control, when 100 and 200 nmol GLP-1 was given. There was no significant difference between insulin and glucose responses when 100 and 200 nmol of GLP-1 were compared with each. The glucagon levels were significant less (p< 0.05) in patients, given 100 and 200 nmol doses as compared to control. Glucagon inhibitory response to GLP-1, when given in doses of 200 nmol was more (p< 0.05) than 100 nmol GLP-1. Somatostatin levels decreased dose dependently by GLP-1 infusions. It is concluded that suppression of glucagon secretion and inhibition of somatostatin corresponded to dose of GLP-1 used. There was no significant difference in glucose and insulin levels between 100 and 200 nmol GLP-1 doses. Therefore, present study has helped in ascertaining the optimum dose for GLP-1 i.e. 100 nmol. Down regulation of GLP-1 receptors on cells occurred at higher dose while, A and D cells inhibition occurred dose dependently. These results revealed that GLP-1 affects A and D cells directly and also through stimulation of cells. These findings will significantly contribute in the possible role

  6. Functional importance of GLP-1 receptor species and expression levels in cell lines.

    Science.gov (United States)

    Knudsen, Lotte Bjerre; Hastrup, Sven; Underwood, Christina Rye; Wulff, Birgitte Schjellerup; Fleckner, Jan

    2012-04-10

    Of the mammalian species, only the GLP-1 receptors of rat and human origin have been described and characterized. Here, we report the cloning of the homologous GLP-1 receptors from mouse, rabbit, pig, cynomolgus monkey and chimp. The GLP-1 receptor is highly conserved across species, thus underlining the physiological importance of the peptide hormone and its receptor across a wide range of mammals. We expressed the receptors by stable transfection of BHK cells, both in cell lines with high expression levels of the cloned receptors, as well as in cell lines with lower expression levels, more comparable to endogenous expression of these receptors. High expression levels of cloned GLP-1 receptors markedly increased the potency of GLP-1 and other high affinity ligands, whereas the K(d) values were not affected. For a low affinity ligand like the ago-allosteric modulator Compound 2, expression levels of the human GLP-1 receptor were important for maximal efficacy as well as potency. The two natural metabolites of GLP-1, GLP-1(9-37) and GLP-1(9-36)amide were agonists when tested on a cell line with high expression of the recombinant human GLP-1 receptor, whereas they behaved as (low potent) antagonists on a cell line that expressed the receptor endogenously, as well as cells expressing a moderate level of the recombinant human GLP-1 receptor. The amide form was a more potent agonist than the free acid from. In conclusion, receptor expression level is an important parametre for selecting cell lines with cloned GLP-1 receptors for functional characterization of physiological and pharmaceutical ligands. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. GLP-1 Treatment Improves Diabetic Retinopathy by Alleviating Autophagy through GLP-1R-ERK1/2-HDAC6 Signaling Pathway.

    Science.gov (United States)

    Cai, Xiangsheng; Li, Jingjing; Wang, Mingzhu; She, Miaoqin; Tang, Yongming; Li, Jinlong; Li, Hongwei; Hui, Hongxiang

    2017-01-01

    Objective: Apoptosis and autophagy of retinal cells, which may be induced by oxidative stress, are tightly associated with the pathogenesis of diabetic retinopathy (DR). The autophagy induced by oxidative stress is considered as excessively stimulated autophagy, which accelerates the progression of DR. This study aims to investigate the protective effect of GLP-1 treatment on alleviating apoptosis and autophagy of retinal cells in type 2 diabetic rats and reveals its possible mechanism. Methods: Type 2 diabetic rats were induced by fed with high sugar, high fat diet and followed with streptozotocin injection. GLP-1 was applied to treat the diabetic rats for one week after the onset of diabetes. The expressions of oxidative stress-related enzymes, retinal GLP-1R, mitochondria-dependent apoptosis- related genes, autophagy markers, and autophagy-associated pathway genes were studied by Western blotting or immunohistochemistry analysis. Results: GLP-1treatment reduced the levels of NOX3 and SOD2 in DR. The expression of BCL2 was increased, while the levels of caspase3 and LC3B were reduced through GLP-1 treatment in DR . GLP-1 treatment restored the GLP-1R expression and decreased the levels of phosphorylated AKT and phosphorylated ERK1/2, which was accompanied with the reduction of the HDAC6 levels in DR. Conclusions: GLP-1 treatment can alleviate autophagy which may be induced by oxidative stress; this protective effect is likely through GLP-1R-ERK1/2-HDAC6 signaling pathway.

  8. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes : A 12-week, randomized, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Tonneijck, Lennart; Smits, Mark M.; Muskiet, Marcel H A; Hoekstra, Trynke; Kramer, Mark H H; Danser, A. H Jan; Ter Wee, Piet M.; Diamant, Michaela; Joles, Jaap A.; Van Raalte, Daniël H.

    2016-01-01

    OBJECTIVE To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal hemodynamics, tubular functions, and markers of renal damage in overweight patients with type 2 diabetes without chronic kidney

  9. Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report.

    Science.gov (United States)

    Horikawa, Yukio; Enya, Mayumi; Komagata, Makie; Hashimoto, Ken-Ichi; Kagami, Masayo; Fukami, Maki; Takeda, Jun

    2018-02-01

    Diabetes patients with Prader-Willi syndrome (PWS) are obese because of hyperphagia; weight control by dietary modification and medicine is required for glycemic control. There are several recent reports showing the effectiveness of GLP-1 receptor agonists (GLP-1RAs) for diabetes treatment in PWS. A 36-year-old Japanese male patient was diagnosed with PWS at 10 years of age. At age 16 years, he was diagnosed with diabetes and began to take several kinds of oral hypoglycemic agents. At age 29 years, his BMI was 39.1 kg/m 2 and he was referred to our department for diabetes and obesity treatment. In the present case, the HbA1c was not improved by GLP-1RAs despite a 28-kg BW reduction, which included a 9-kg loss of muscle. Apprehensive of further loss of muscle mass, basal insulin of insulin glargine was administered in addition to GLP-1RAs. Immediately after the addition of tofogliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, the patient's HbA1c decreased dramatically with only about an additional 3% BW reduction. We note an improvement in our case of lipid deposition in the pancreas confirmed by abdominal CT after the improvement of HbA1c. It is unknown whether this improvement of fatty pancreas was a cause or an effect of the improved glycemic control in the present case. This finding clearly supports the effectiveness of combining SGLT2 inhibitors with GLP-1RAs for treatment of patients with PWS and non-alcoholic fatty pancreas disease.

  10. Glucose-Lowering Effects and Low Risk of Hypoglycemia in Patients With Maturity-Onset Diabetes of the Young When Treated With a GLP-1 Receptor Agonist

    DEFF Research Database (Denmark)

    Ostoft, S. H.; Bagger, J. I.; Hansen, Torben

    2014-01-01

    OBJECTIVE The most common form of maturity-onset diabetes of the young (MODY), hepatocyte nuclear factor 1 alpha (HNF1A diabetes: MODY3) is often treated with sulfonylureas that confer a high risk of hypoglycemia. We evaluated treatment with GLP-1 receptor agonists (GLP-1RAs) in patients with HNF1A...... diabetes. RESEARCH DESIGN AND METHODS Sixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23-67 years]; BMI 24.9 +/- 0.5 kg/m(2) [mean +/- SEM]; fasting plasma glucose [FPG] 9.9 +/- 0.9 mmol/L; HbA(1c) 6.4 +/- 0.2% [47 +/- 3 mmol/mol]) received 6 weeks of treatment with a GLP-1RA...

  11. Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist.

    Directory of Open Access Journals (Sweden)

    Mi-Kyung Kim

    Full Text Available Beta cell death caused by endoplasmic reticulum (ER stress is a key factor aggravating type 2 diabetes. Exenatide, a glucagon-like peptide (GLP-1 receptor agonist, prevents beta cell death induced by thapsigargin, a selective inhibitor of ER calcium storage. Here, we report on our proteomic studies designed to elucidate the underlying mechanisms. We conducted comparative proteomic analyses of cellular protein profiles during thapsigargin-induced cell death in the absence and presence of exenatide in INS-1 rat insulinoma cells. Thapsigargin altered cellular proteins involved in metabolic processes and protein folding, whose alterations were variably modified by exenatide treatment. We categorized the proteins with thapsigargin initiated alterations into three groups: those whose alterations were 1 reversed by exenatide, 2 exaggerated by exenatide, and 3 unchanged by exenatide. The most significant effect of thapsigargin on INS-1 cells relevant to their apoptosis was the appearance of newly modified spots of heat shock proteins, thimet oligopeptidase and 14-3-3β, ε, and θ, and the prevention of their appearance by exenatide, suggesting that these proteins play major roles. We also found that various modifications in 14-3-3 isoforms, which precede their appearance and promote INS-1 cell death. This study provides insights into the mechanisms in ER stress-caused INS-1 cell death and its prevention by exenatide.

  12. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice

    DEFF Research Database (Denmark)

    Sorensen, Gunnar; Reddy, India A.; Weikop, Pia

    2015-01-01

    implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction....

  13. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects

    DEFF Research Database (Denmark)

    Kjems, Lise L; Holst, Jens J; Vølund, Aage

    2003-01-01

    . However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2...

  14. Effects of fat supplementation on postprandial GIP, GLP-1, ghrelin and IGFBP-1 levels: a pilot study on adolescents with type 1 diabetes

    DEFF Research Database (Denmark)

    Lodefalk, M; Carlsson-Skwirut, C; Holst, Jens Juul

    2010-01-01

    Aims: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia. Methods: On different days and in a random order, 7 adolescents with T1DM ingested...... by the paracetamol absorption method. Results: The area under the curve (AUC) for GIP(0-240 min) and for GLP-1(0-120 min) was larger, but smaller for relative ghrelin(0-240 min), after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals....... Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007). Conclusion: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal...

  15. The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich

    2018-01-01

    AIMS: The discovery of the specific bile acid receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in enteroendocrine L cells has prompted research focusing on the impact of bile acids on glucagon-like peptide-1 (GLP-1) secretion and glucose metabolism. The aim of t...

  16. GLP-1 improves neuropathology after murine cold lesion brain trauma

    DEFF Research Database (Denmark)

    DellaValle, Brian; Hempel, Casper; Johansen, Flemming Fryd

    2014-01-01

    brain trauma. METHODS: Severe trauma was induced with a stereotactic cryo-lesion in mice and thereafter treated with vehicle, liraglutide, or liraglutide + GLP-1 receptor antagonist. A therapeutic window was established and lesion size post-trauma was determined. Reactive oxygen species were visualized......-neurodegenerative proteins increased with Lira-driven CREB activation. INTERPRETATION: These results show that Lira has potent effects after experimental trauma in mice and thus should be considered a candidate for critical care intervention post-injury. Moreover, activation of CREB in the brain by Lira - described......OBJECTIVES: In this study, we address a gap in knowledge regarding the therapeutic potential of acute treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist after severe brain trauma. Moreover, it remains still unknown whether GLP-1 treatment activates the protective, anti...

  17. Direct effects of glucose, insulin, GLP-1, and GIP on bulbospinal neurons in the rostral ventrolateral medulla in neonatal wistar rats.

    Science.gov (United States)

    Oshima, Naoki; Onimaru, Hiroshi; Matsubara, Hidehito; Uchida, Takahiro; Watanabe, Atsushi; Imakiire, Toshihiko; Nishida, Yasuhiro; Kumagai, Hiroo

    2017-03-06

    Although patients with diabetes mellitus (DM) often exhibit hypertension, the mechanisms responsible for this correlation are not well known. We hypothesized that the bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are affected by the levels of glucose, insulin, or incretins (glucagon like peptide-1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) in patients with DM. To investigate whether RVLM neurons are activated by glucose, insulin, GLP-1, or GIP, we examined changes in the membrane potentials of bulbospinal RVLM neurons using whole-cell patch-clamp technique during superfusion with various levels of glucose or these hormones in neonatal Wistar rats. A brainstem-spinal cord preparation was used for the experiments. A low level of glucose stimulated bulbospinal RVLM neurons. During insulin superfusion, almost all the RVLM neurons were depolarized, while during GLP-1 or GIP superfusion, almost all the RVLM neurons were hyperpolarized. Next, histological examinations were performed to examine transporters for glucose and receptors for insulin, GLP-1, and GIP on RVLM neurons. Low-level glucose-depolarized RVLM neurons exhibited the presence of glucose transporter 3 (GLUT3). Meanwhile, insulin-depolarized, GLP-1-hyperpolarized, and GIP-hyperpolarized RVLM neurons showed each of the respective specific receptor. These results indicate that a low level of glucose stimulates bulbospinal RVLM neurons via specific transporters on these neurons, inducing hypertension. Furthermore, an increase in insulin or a reduction in incretins may also activate the sympathetic nervous system and induce hypertension by activating RVLM neurons via their own receptors. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  18. GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker; Holst, Jens Juul; Rattigan, Stephen

    2014-01-01

    The insulinotropic gut hormone, glucagon-like-peptide-1 (GLP-1) has been proposed to have effects on vascular function and glucose disposal. However, whether GLP-1 is able to increase microvascular recruitment (MVR) in humans has not been investigated. GLP-1 was infused in the femoral artery...... in overnight fasted healthy young men. Microvascular recruitment was measured with real time contrast-enhanced ultrasound and leg glucose uptake by the leg balance technique with and without inhibition of the insulinotropic response of GLP-1 by co-infusion of octreotide. As a positive control, MVR and leg...

  19. Role and development of GLP-1 receptor agonists in the management of diabetes

    Directory of Open Access Journals (Sweden)

    Chee W Chia

    2009-05-01

    Full Text Available Chee W Chia, Josephine M EganNational Institutes of Health, National Institute on Aging, Intramural Research Program, Baltimore, Maryland, USAAbstract: Glucagon-like peptide-1 (GLP-1 is a hormone secreted from enteroendocrine L cells of the intestine in response to food. Exogenous GLP-1 administration at pharmacological doses results in many effects that are beneficial for treating type 2 diabetes, these include: (1 an increase in insulin secretion from β cells; (2 a suppression of glucagon secretion from α cells in the presence of hyperglycemia but not hypoglycemia; (3 a delay in gastric emptying and gut motility which in turns delays absorption of ingested nutrients and dampens post-prandial glucose excursion; and (4 an increase in the duration of postprandial satiety therefore suppressing appetite and decreasing food intake which eventually leads to weight loss. However, GLP-1 is subject to rapid enzymatic degradation, and therefore, not suitable for long-term treatment. A synthetic enzyme-resistant GLP-1 receptor agonist that reproduces the biological effects of GLP-1 is in use and more are under development. This review aims at providing a summary of the properties of GLP-1 and the development of GLP-1-based therapies for treatment of diabetes.Keywords: incretin, GLP-1, GLP-1R agonist, diabetes

  20. Long-term Cost-effectiveness of Two GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus in the Italian Setting: Liraglutide Versus Lixisenatide.

    Science.gov (United States)

    Hunt, Barnaby; Kragh, Nana; McConnachie, Ceilidh C; Valentine, William J; Rossi, Maria C; Montagnoli, Roberta

    2017-07-01

    Maintaining glycemic control is the key treatment target for patients with type 2 diabetes mellitus. In addition, the glucagon-like peptide-1 (GLP-1) receptor agonists may be associated with other favorable treatment characteristics, such as reduction in body weight and reduced risk of hypoglycemia compared with traditional diabetes interventions. The aim of the present analysis was to compare the long-term cost-effectiveness of 2 GLP-1 receptor agonists, liraglutide 1.8 mg and lixisenatide 20 μg (both administered once daily), in the treatment of patients with type 2 diabetes failing to achieve glycemic control with metformin monotherapy in the Italian setting. The IMS CORE Diabetes Model was used to project long-term clinical outcomes and subsequent costs (in 2015 Euros [€]) associated with liraglutide 1.8 mg versus lixisenatide 20 μg treatment in a cohort with baseline characteristics derived from the open-label LIRA-LIXI trial (Efficacy and Safety of Liraglutide Versus Lixisenatide as Add-on to Metformin in Subjects With Type 2 Diabetes; NCT01973231) over patient lifetimes from the perspective of a health care payer. Efficacy data were taken from the 26-week end points of the same trial, including changes in glycated hemoglobin, body mass index, serum lipid levels, and hypoglycemic event rates. Outcomes projected included life expectancy, quality-adjusted life expectancy, cumulative incidence and time to onset of diabetes-related complications, and direct medical costs. Outcomes were discounted at 3% annually, and sensitivity analyses were performed. Liraglutide 1.8 mg was associated with improved discounted life expectancy (14.07 vs 13.96 years) and quality-adjusted life expectancy (9.18 vs 9.06 quality-adjusted life years [QALYs]) compared with lixisenatide 20 μg. These improvements were mostly attributable to a greater reduction in glycated hemoglobin level with liraglutide 1.8 mg versus lixisenatide 20 μg, leading to reduced incidence and

  1. GLP-1 agonists for type 2 diabetes

    DEFF Research Database (Denmark)

    Jespersen, Maria J; Knop, Filip K; Christensen, Mikkel

    2013-01-01

    and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration. EXPERT OPINION: GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes......Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles. AREAS COVERED: This review describes the pharmacokinetics...

  2. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  3. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    International Nuclear Information System (INIS)

    Waser, Beatrice; Reubi, Jean Claude

    2014-01-01

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the 125 iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer 125 I-GLP-1(7-36)amide. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist 125 I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer 125 I-GLP-1(7-36)amide. For comparison, 125 I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with 125 I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  4. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow

    DEFF Research Database (Denmark)

    Jensen, Elisa Pouline; Poulsen, Steen Seier; Kissow, Hannelouise

    2015-01-01

    was to localize renal GLP-1 receptors and describe GLP-1 mediated effects on the renal vasculature. We hypothesized that renal GLP-1 receptors are located in the renal microcirculation and activation of these affects renal autoregulation and increases renal blood flow. In vivo autoradiography using 125I-GLP-1......, 125I-exendin-4 (GLP-1 analog) and 125I-exendin 9-39 (GLP-1 receptor antagonist) was performed in rodents to localize specific GLP-1 receptor binding. GLP-1 mediated effects on blood pressure (BP), renal blood flow (RBF), heart rate (HR), renin secretion, urinary flow rate and Na+ and K+ excretion were...... conclude that GLP-1 receptors are located in the renal vasculature including afferent arterioles. Activation of these receptors reduces the autoregulatory response of afferent arterioles to acute pressure increases and increases renal blood flow in normotensive rats....

  5. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors

    DEFF Research Database (Denmark)

    Ronn, Jonas; Jensen, Elisa P; Wewer Albrechtsen, Nicolai J

    2017-01-01

    to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect......Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads...... in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e...

  6. GLP-1 does not not acutely affect insulin sensitivity in healthy man

    DEFF Research Database (Denmark)

    Orskov, L; Holst, J J; Møller, J

    1996-01-01

    Previous studies have suggested that glucagon-like peptide-1 (GLP-1) (7-36 amide) may have the direct effect of increasing insulin sensitivity in healthy man. To evaluate this hypothesis we infused GLP-1 in seven lean healthy men during a hyper insulinaemic (0.8 mU.kg-1.min-1), euglycaemic (5 mmo...

  7. Does a GLP-1 receptor agonist change glucose tolerance in patients treated with antipsychotic medications?

    DEFF Research Database (Denmark)

    Larsen, Julie Rask; Vedtofte, Louise; Holst, Jens Juul

    2014-01-01

    . Additionally, patients with schizophrenia-spectrum disorders not infrequently consume alcohol. Glucagon-like peptide-1 (GLP-1) has shown to improve glycaemic control and reduce alcohol intake among patients with type 2 diabetes. OBJECTIVES: To investigate whether the beneficial effects of GLP-1 analogues...

  8. Combined MSC and GLP-1 Therapy Modulates Collagen Remodeling and Apoptosis following Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Elizabeth J. Wright

    2016-01-01

    Full Text Available Background. Mesenchymal stem cells (MSCs and glucagon-like peptide-1 (GLP-1 are being tested as treatment strategies for myocardial infarction (MI; however, their mechanisms in the heart are not fully understood. Methods. We examined the effects of MSCs, either native, or engineered to secrete a GLP-1 fusion protein (MSCs ± GLP-1, on human cardiomyocyte apoptosis in vitro. The effect on cardiac remodeling when encapsulated in alginate beads (CellBeads-MSC and CellBeads-MSC + GLP-1 was also evaluated in a pig MI model, whereby pigs were treated with Empty Beads, CellBeads-MSC, or CellBeads-MSC + GLP-1 and sacrificed at one or four weeks following MI. Results. MSC + GLP-1 conditioned media demonstrated antiapoptotic effects on ischaemic human cardiomyocytes in vitro. In vivo, qRT-PCR revealed large changes in the expression of several genes involved in extracellular matrix remodeling, which were altered following MSC ± GLP treatment. After four weeks, infarcted areas were imaged using atomic force microscopy, demonstrating significant alterations between groups in the structure of collagen fibrils and resulting scar. Conclusions. These data demonstrate that MSCs ± GLP-1 exhibit modulatory effects on healing post-MI, affecting both apoptosis and collagen scar formation. These data support the premise that both MSCs and GLP-1 could be beneficial in MI treatment.

  9. GLP-1 acts on habenular avoidance circuits to control nicotine intake.

    Science.gov (United States)

    Tuesta, Luis M; Chen, Zuxin; Duncan, Alexander; Fowler, Christie D; Ishikawa, Masago; Lee, Brian R; Liu, Xin-An; Lu, Qun; Cameron, Michael; Hayes, Matthew R; Kamenecka, Theodore M; Pletcher, Matthew; Kenny, Paul J

    2017-05-01

    Tobacco smokers titrate their nicotine intake to avoid its noxious effects, sensitivity to which may influence vulnerability to tobacco dependence, yet mechanisms of nicotine avoidance are poorly understood. Here we show that nicotine activates glucagon-like peptide-1 (GLP-1) neurons in the nucleus tractus solitarius (NTS). The antidiabetic drugs sitagliptin and exenatide, which inhibit GLP-1 breakdown and stimulate GLP-1 receptors, respectively, decreased nicotine intake in mice. Chemogenetic activation of GLP-1 neurons in NTS similarly decreased nicotine intake. Conversely, Glp1r knockout mice consumed greater quantities of nicotine than wild-type mice. Using optogenetic stimulation, we show that GLP-1 excites medial habenular (MHb) projections to the interpeduncular nucleus (IPN). Activation of GLP-1 receptors in the MHb-IPN circuit abolished nicotine reward and decreased nicotine intake, whereas their knockdown or pharmacological blockade increased intake. GLP-1 neurons may therefore serve as 'satiety sensors' for nicotine that stimulate habenular systems to promote nicotine avoidance before its aversive effects are encountered.

  10. Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice

    International Nuclear Information System (INIS)

    Kubo, Fumiyo; Miyatsuka, Takeshi; Sasaki, Shugo; Takahara, Mitsuyoshi; Yamamoto, Yuichi; Shimo, Naoki; Watada, Hirotaka; Kaneto, Hideaki; Gannon, Maureen; Matsuoka, Taka-aki; Shimomura, Iichiro

    2016-01-01

    Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1"P"B-CreER"T"M; CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions. - Highlights: • Expression levels of incretin receptors were significantly decreased in diabetic db/db islets after the age of eight weeks. • A transgenic mouse model expressing Glp1r specifically in β cells was generated. • Exogenous expression of Glp1r in β cells did not affect metabolic profiles in nondiabetic mice. • Sustained expression of Glp1r in diabetic db/db β cells deteriorated glucose

  11. Sustained expression of GLP-1 receptor differentially modulates β-cell functions in diabetic and nondiabetic mice

    Energy Technology Data Exchange (ETDEWEB)

    Kubo, Fumiyo [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Miyatsuka, Takeshi, E-mail: miyatsuka-takeshi@umin.net [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Sasaki, Shugo; Takahara, Mitsuyoshi; Yamamoto, Yuichi; Shimo, Naoki [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Watada, Hirotaka [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Kaneto, Hideaki [Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Japan Okayama 701-0192 (Japan); Gannon, Maureen [Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, 2220 Pierce Ave. 746 PRB, Nashville, TN 37232-6303 (United States); Matsuoka, Taka-aki; Shimomura, Iichiro [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

    2016-02-26

    Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks. To investigate whether restored expression of Glp1r affects the diabetic phenotypes, we generated the transgenic mouse model Pdx1{sup PB}-CreER{sup TM}; CAG-CAT-Glp1r (βGlp1r) that allows for induction of Glp1r expression specifically in β cells. Whereas the expression of exogenous Glp1r had no measurable effect on glucose tolerance in nondiabetic βGlp1r;db/misty mice, βGlp1r;db/db mice exhibited higher glucose and lower insulin levels in blood on glucose challenge test than control db/db littermates. In contrast, four weeks of treatment with exendin-4 improved the glucose profiles and increased serum insulin levels in βGlp1r;db/db mice, to significantly higher levels than those in control db/db mice. These differential effects of exogenous Glp1r in nondiabetic and diabetic mice suggest that downregulation of Glp1r might be required to slow the progression of β-cell failure under diabetic conditions. - Highlights: • Expression levels of incretin receptors were significantly decreased in diabetic db/db islets after the age of eight weeks. • A transgenic mouse model expressing Glp1r specifically in β cells was generated. • Exogenous expression of Glp1r in β cells did not affect metabolic profiles in nondiabetic mice. • Sustained expression of Glp1r in diabetic db/db β cells deteriorated

  12. Potential new approaches to modifying intestinal GLP-1 secretion in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Holst, Jens Juul; McGill, Maria A

    2012-01-01

    Type 2 diabetes mellitus is associated with a progressive decline in insulin-producing pancreatic ß-cells, an increase in hepatic glucose production, and a decrease in insulin sensitivity. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1....... The currently available incretin-based therapies, GLP-1 receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 (DPP-4) inhibitors (CD26 antigen inhibitors) [incretin enhancers], are safe and effective in the treatment of type 2 diabetes. However, they may be unable to halt the progression of type 2...... diabetes, perhaps because they do not increase secretion of endogenous GLP-1. Therapies that directly target intestinal L cells to stimulate secretion of endogenous GLP-1 could possibly prove more effective than treatment with GLP-1 receptor agonists and DPP-4 inhibitors. Potential new approaches...

  13. Carboxy-terminal truncation activates glp-1 protein to specify vulval fates in Caenorhabditis elegans.

    Science.gov (United States)

    Mango, S E; Maine, E M; Kimble, J

    1991-08-29

    The glp-1 and lin-12 genes encode homologous transmembrane proteins that may act as receptors for cell interactions during development. The glp-1 product is required for induction of germ-line proliferation and for embryogenesis. By contrast, lin-12 mediates somatic cell interactions, including those between the precursor cells that form the vulval hypodermis (VPCs). Here we analyse an unusual allele of glp-1, glp-1(q35), which displays a semidominant multivulva phenotype (Muv), as well as the typical recessive, loss-of-function Glp phenotypes (sterility and embryonic lethality). We find that the effects of glp-1(q35) on VPC development mimic those of dominant lin-12 mutations, even in the absence of lin-12 activity. The glp-1(q35) gene bears a nonsense mutation predicted to eliminate the 122 C-terminal amino acids, including a ProGluSerThr (PEST) sequence thought to destabilize proteins. We suggest that the carboxy terminus bears a negative regulatory domain which normally inactivates glp-1 in the VPCs. We propose that inappropriate glp-1(q35) activity can substitute for lin-12 to determine vulval fate, perhaps by driving the VPCs to proliferate.

  14. Oral L-Arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Smajilovic, Sanela; Smith, Eric P

    2013-01-01

    Pharmacological and surgical interventions that increase glucagon-like peptide 1 (GLP-1) action are effective to improve glucose homeostasis in type 2 diabetes mellitus. In light of this, nutritional strategies to enhance postprandial GLP-1 secretion, particularly in the context of diet......-induced obesity, may provide an alternative therapeutic approach. Importantly, recent evidence suggests the amino acid l-arginine, a well-known insulin secretagogue, can also stimulate release of GLP-1 from isolated rat intestine. Here we tested the hypothesis that oral l-arginine acts as a GLP-1 secretagogue...... in vivo, to augment postprandial insulin secretion and improve glucose tolerance. To test this, we administered l-arginine or vehicle by oral gavage, immediately prior to an oral glucose tolerance test in lean and diet-induced obese mice. In both lean and obese mice oral l-arginine increased plasma GLP-1...

  15. Molecular mechanisms of lipoapoptosis and metformin protection in GLP-1 secreting cells

    DEFF Research Database (Denmark)

    Kappe, Camilla; Holst, Jens Juul; Zhang, Qimin

    2012-01-01

    Evidence is emerging that elevated serum free fatty acids (hyperlipidemia) contribute to the pathogenesis of type-2-diabetes, and lipotoxicity is observed in many cell types. We recently published data indicating lipotoxic effects of simulated hyperlipidemia also in GLP-1-secreting cells, where...... the antidiabetic drug metformin conferred protection from lipoapoptosis. The aim of the present study was to identify mechanisms involved in mediating lipotoxicity and metformin lipoprotection in GLP-1 secreting cells. These signaling events triggered by simulated hyperlipidemia may underlie reduced GLP-1...... secretion in diabetic subjects, and metformin lipoprotection by metformin could explain elevated plasma GLP-1 levels in diabetic patients on chronic metformin therapy. The present study may thus identify potential molecular targets for increasing endogenous GLP-1 secretion through enhanced viability of GLP...

  16. The regulation of function, growth and survival of GLP-1-producing L-cells

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Holst, Jens Juul; Kappe, Camilla

    2016-01-01

    that regulate the growth, survival and function of these cells are largely unknown. We recently showed that prolonged exposure to high concentrations of the fatty acid palmitate induced lipotoxic effects, similar to those operative in insulin-producing cells, in an in vitro model of GLP-1-producing cells...... absorption and disposal, as well as cell proliferation and survival. In Type 2 Diabetes (T2D) reduced plasma levels of GLP-1 have been observed, and plasma levels of GLP-1, as well as reduced numbers of GLP-1 producing cells, have been correlated to obesity and insulin resistance. Increasing endogenous...... secretion of GLP-1 by selective targeting of the molecular mechanisms regulating secretion from the L-cell has been the focus of much recent research. An additional and promising strategy for enhancing endogenous secretion may be to increase the L-cell mass in the intestinal epithelium, but the mechanisms...

  17. The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans

    DEFF Research Database (Denmark)

    Meier, Juris J; Gethmann, Arnica; Nauck, Michael A

    2006-01-01

    Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP-1-(7-36) amide is degraded to the metabolite GLP-1-(9-36) amide. The effects of GLP-1-(9-36) amide in humans are less well characterized. Fourteen...... healthy volunteers were studied with intravenous infusion of GLP-1-(7-36) amide, GLP-1-(9-36) amide, or placebo over 390 min. After 30 min, a solid test meal was served, and gastric emptying was assessed. Blood was drawn for GLP-1 (total and intact), glucose, insulin, C-peptide, and glucagon measurements....... Administration of GLP-1-(7-36) amide and GLP-1-(9-36) amide significantly raised total GLP-1 plasma levels. Plasma concentrations of intact GLP-1 increased to 21 +/- 5 pmol/l during the infusion of GLP-1-(7-36) amide but remained unchanged during GLP-1-(9-36) amide infusion [5 +/- 3 pmol/l; P

  18. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes

    DEFF Research Database (Denmark)

    Nauck, M A; Vardarli, I; Deacon, C F

    2011-01-01

    The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP......-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency...... with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual incretin secretory responses and explain some...

  19. New screening strategy and analysis for identification of allosteric modulators for glucagon-like peptide-1 receptor using GLP-1 (9-36) amide.

    Science.gov (United States)

    Nakane, Atsushi; Gotoh, Yusuke; Ichihara, Junji; Nagata, Hidetaka

    2015-12-15

    The glucagon-like peptide-1 receptor (GLP-1R) is an important physiologic regulator of insulin secretion and a major therapeutic target for diabetes mellitus. GLP-1 (7-36) amide (active form of GLP-1) is truncated to GLP-1 (9-36) amide, which has been described as a weak agonist of GLP-1R and the major form of GLP-1 in the circulation. New classes of positive allosteric modulators (PAMs) for GLP-1R may offer improved therapeutic profiles. To identify these new classes, we developed novel and robust primary and secondary high-throughput screening (HTS) systems in which PAMs were identified to enhance the GLP-1R signaling induced by GLP-1 (9-36) amide. Screening enabled identification of two compounds, HIT-465 and HIT-736, which possessed new patterns of modulation of GLP-1R. We investigated the ability of these compounds to modify GLP-1R signaling enhanced GLP-1 (9-36) amide- and/or GLP-1 (7-36) amide-mediated cyclic adenosine monophosphate (cAMP) accumulation. These compounds also had unique profiles with regard to allosteric modulation of multiple downstream signaling (PathHunter β-arrestin signaling, PathHunter internalization signaling, microscopy-based internalization assay). We found allosteric modulation patterns to be obviously different among HIT-465, HIT-736, and Novo Nordisk compound 2. This work may enable the design of new classes of drug candidates by targeting modulation of GLP-1 (7-36) amide and GLP-1 (9-36) amide. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers

    DEFF Research Database (Denmark)

    Hansen, Lasse Bremholm; Andersen, Ulrik B; Hornum, Mads

    2017-01-01

    arteries. GLP-1 significantly increased heart rate (two-way ANOVA, injection [P = 0.0162], time [P = 0.0038], and injection × time [P = 0.082]; Tukey post hoc GLP-1 vs. saline and GLP-19-36amide [P stroke volume compared to GLP-19-36 amide...... subcutaneous injections of GLP-1, GLP-19-36 amide (bioactive metabolite), exenatide (stable GLP-1 agonist), or saline on four separate days. Blood flow in mesenteric, celiac, and renal arteries was measured by Doppler ultrasound. Blood pressure, heart rate, cardiac output, and stroke volume were measured...

  1. Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Nauck, Michael A; El-Ouaghlidi, Andrea; Gabrys, Bartholomäus

    2004-01-01

    ) and an "isoglycaemic" intravenous glucose infusion. Blood was drawn over 240 min for plasma glucose (glucose oxidase), insulin, C-peptide, GIP and glucagon-like peptide 1 (GLP-1; specific immunoassays). RESULTS: The pattern of glucose concentrations could precisely be copied by the intravenous glucose infusion (p=0......AIMS/HYPOTHESIS: Since insulin secretion in response to exogenous gastric inhibitory polypeptide (GIP) is diminished not only in patients with type 2 diabetes, but also in their normal glucose-tolerant first-degree relatives, it was the aim to investigate the integrity of the entero-insular axis...... in such subjects. METHODS: Sixteen first-degree relatives of patients with type 2 diabetes (4 male, 12 female, age 50+/-12 years, BMI 26.1+/-3.8 kg/m(2)) and 10 matched healthy controls (negative family history, 6 male, 4 female, 45+/-13 years, 26.1+/-4.2 kg/m(2)) were examined with an oral glucose load (75 g...

  2. GLP-1 receptor localization in monkey and human tissue

    DEFF Research Database (Denmark)

    Pyke, Charles; Heller, R Scott; Kirk, Rikke K

    2014-01-01

    and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial...

  3. Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter

    DEFF Research Database (Denmark)

    Larsen, Philip J; Holst, Jens Juul

    2005-01-01

    normal and pathophysiological role of GLP-1 have been published over the last two decades and our understanding of GLP-1 action has widened considerably. In the present review, we have tried to cover our current understanding of GLP-1 actions both as a peripheral hormone and as a central neurotransmitter...

  4. A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson’s disease by reducing chronic inflammation in the brain

    OpenAIRE

    Lijun, Cao; Li, Dongfang; Feng, Peng; Li, Lin; Xue, Guofang; Li, Guanglai; Holscher, Christian

    2016-01-01

    The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson’s disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report ...

  5. Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it?

    Science.gov (United States)

    Smith, Eric P; Polanco, Georgina; Yaqub, Abid; Salehi, Marzieh

    2018-06-01

    Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1). Meal-induced GLP-1 secretion is as much as tenfold higher in patients after GB compared to non-surgical individuals and inhibition of GLP-1 action during meals reduces postprandial hyperinsulinemia after GB two to three times more than that in persons without surgery. Moreover, in a subgroup of patients with the late complication of postprandial hyperinsulinemic hypoglycemia after GB, GLP1R blockade reverses hypoglycemia by reducing meal stimulated insulin secretion. The role of enteroinsular axis activity after SG, an increasingly popular alternative to GB, is less understood but, similar to GB, SG accelerates nutrient delivery to the intestine, improves glucose tolerance, and increases postprandial GLP-1 secretion. This review will focus on the current evidence for and against the role of GLP-1 on glycemic effects of GB and will also highlight differences between GB and SG. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shuyuan [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Chen, Jiaxi [The University of Texas Southwestern Medical Center at Dallas, Medical School, 5235 Harry Hine Blvd., Dallas, TX (United States); Huang, Pintong [Department of Ultrasonography, The 2nd Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, Zhejiang Province (China); Meng, Xing-Li; Clayton, Sandra; Shen, Jin-Song [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Grayburn, Paul A., E-mail: paulgr@baylorhealth.edu [Baylor Research Institute, Baylor University Medical Center, 3812 Elm Street, Dallas, TX (United States); Department of Internal Medicine, Division of Cardiology, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall St, Suite H030, Dallas, TX (United States)

    2015-03-20

    Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation.

  7. Myocardial regeneration in adriamycin cardiomyopathy by nuclear expression of GLP1 using ultrasound targeted microbubble destruction

    International Nuclear Information System (INIS)

    Chen, Shuyuan; Chen, Jiaxi; Huang, Pintong; Meng, Xing-Li; Clayton, Sandra; Shen, Jin-Song; Grayburn, Paul A.

    2015-01-01

    Recently GLP-1 was found to have cardioprotective effects independent of those attributable to tight glycemic control. Methods and results: We employed ultrasound targeted microbubble destruction (UTMD) to deliver piggybac transposon plasmids encoding the GLP-1 gene with a nuclear localizing signal to rat hearts with adriamycin cardiomyopathy. After a single UTMD treatment, overexpression of transgenic GLP-1 was found in nuclei of rat heart cells with evidence that transfected cardiac cells had undergone proliferation. UTMD-GLP-1 gene therapy restored LV mass, fractional shortening index, and LV posterior wall diameter to nearly normal. Nuclear overexpression of GLP-1 by inducing phosphorylation of FoxO1-S256 and translocation of FoxO1 from the nucleus to the cytoplasm significantly inactivated FoxO1 and activated the expression of cyclin D1 in nuclei of cardiac muscle cells. Reversal of adriamycin cardiomyopathy appeared to be mediated by dedifferentiation and proliferation of nuclear FoxO1-positive cardiac muscle cells with evidence of embryonic stem cell markers (OCT4, Nanog, SOX2 and c-kit), cardiac early differentiation markers (NKX2.5 and ISL-1) and cellular proliferation markers (BrdU and PHH3) after UTMD with GLP-1 gene therapy. Conclusions: Intranuclear myocardial delivery of the GLP-1gene can reverse established adriamycin cardiomyopathy by stimulating myocardial regeneration. - Highlights: • The activation of nuclear FoxO1 in cardiac muscle cells associated with adriamycin cardiomyopathy. • Myocardial nuclear GLP-1 stimulates myocardial regeneration and reverses adriamycin cardiomyopathy. • The process of myocardial regeneration associated with dedifferentiation and proliferation

  8. GLP-1 and GLP-2 act in concert to inhibit fasted, but not fed, small bowel motility in the rat

    DEFF Research Database (Denmark)

    Bozkurt, Ayhan; Näslund, Erik; Holst, Jens Juul

    2002-01-01

    Small bowel motility was studied in rats at increasing (1-20 pmol/kg/min) intravenous doses of either glucagon-like peptide-1 (GLP-1) or glucagon-like peptide-2 (GLP-2) alone, or in combination in the fasted and fed state. There was a dose-dependent inhibitory action of GLP-1 on the migrating myo...... demonstrates an additive effect of peripheral administration of GLP-1 and GLP-2 on fasted small bowel motility. In the fed state, GLP-1 and GLP-2 seem to display counter-balancing effects on motility of the small intestine....... myoelectric complex (MMC), where the dose of 5 pmol/kg/min induced an increased MMC cycle length. No effect was seen with GLP-2 alone, but the combination of GLP-1 and GLP-2 induced a more pronounced inhibitory effect, with significant increase of the MMC cycle length from a dose of 2 pmol/kg/min. During fed...

  9. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist--protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study

    DEFF Research Database (Denmark)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V

    2014-01-01

    -associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non-diabetes. The primary endpoint of this trial is weight loss after 3 months...... of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI....

  10. Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system.

    Directory of Open Access Journals (Sweden)

    Jennifer E Richard

    Full Text Available The gut/brain peptide, glucagon like peptide 1 (GLP-1, suppresses food intake by acting on receptors located in key energy balance regulating CNS areas, the hypothalamus or the hindbrain. Moreover, GLP-1 can reduce reward derived from food and motivation to obtain food by acting on its mesolimbic receptors. Together these data suggest a neuroanatomical segregation between homeostatic and reward effects of GLP-1. Here we aim to challenge this view and hypothesize that GLP-1 can regulate food reward behavior by acting directly on the hindbrain, the nucleus of the solitary tract (NTS, GLP-1 receptors (GLP-1R. Using two models of food reward, sucrose progressive ratio operant conditioning and conditioned place preference for food in rats, we show that intra-NTS microinjections of GLP-1 or Exendin-4, a stable analogue of GLP-1, inhibit food reward behavior. When the rats were given a choice between palatable food and chow, intra-NTS Exendin-4 treatment preferentially reduced intake of palatable food but not chow. However, chow intake and body weight were reduced by the NTS GLP-1R activation if chow was offered alone. The NTS GLP-1 activation did not alter general locomotor activity and did not induce nausea, measured by PICA. We further show that GLP-1 fibers are in close apposition to the NTS noradrenergic neurons, which were previously shown to provide a monosynaptic connection between the NTS and the mesolimbic system. Central GLP-1R activation also increased NTS expression of dopamine-β-hydroxylase, a key enzyme in noradrenaline synthesis, indicating a biological link between these two systems. Moreover, NTS GLP-1R activation altered the expression of dopamine-related genes in the ventral tegmental area. These data reveal a food reward-suppressing role of the NTS GLP-1R and indicate that the neurobiological targets underlying food reward control are not limited to the mesolimbic system, instead they are distributed throughout the CNS.

  11. Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system.

    Science.gov (United States)

    Richard, Jennifer E; Anderberg, Rozita H; Göteson, Andreas; Gribble, Fiona M; Reimann, Frank; Skibicka, Karolina P

    2015-01-01

    The gut/brain peptide, glucagon like peptide 1 (GLP-1), suppresses food intake by acting on receptors located in key energy balance regulating CNS areas, the hypothalamus or the hindbrain. Moreover, GLP-1 can reduce reward derived from food and motivation to obtain food by acting on its mesolimbic receptors. Together these data suggest a neuroanatomical segregation between homeostatic and reward effects of GLP-1. Here we aim to challenge this view and hypothesize that GLP-1 can regulate food reward behavior by acting directly on the hindbrain, the nucleus of the solitary tract (NTS), GLP-1 receptors (GLP-1R). Using two models of food reward, sucrose progressive ratio operant conditioning and conditioned place preference for food in rats, we show that intra-NTS microinjections of GLP-1 or Exendin-4, a stable analogue of GLP-1, inhibit food reward behavior. When the rats were given a choice between palatable food and chow, intra-NTS Exendin-4 treatment preferentially reduced intake of palatable food but not chow. However, chow intake and body weight were reduced by the NTS GLP-1R activation if chow was offered alone. The NTS GLP-1 activation did not alter general locomotor activity and did not induce nausea, measured by PICA. We further show that GLP-1 fibers are in close apposition to the NTS noradrenergic neurons, which were previously shown to provide a monosynaptic connection between the NTS and the mesolimbic system. Central GLP-1R activation also increased NTS expression of dopamine-β-hydroxylase, a key enzyme in noradrenaline synthesis, indicating a biological link between these two systems. Moreover, NTS GLP-1R activation altered the expression of dopamine-related genes in the ventral tegmental area. These data reveal a food reward-suppressing role of the NTS GLP-1R and indicate that the neurobiological targets underlying food reward control are not limited to the mesolimbic system, instead they are distributed throughout the CNS.

  12. Inflammation meets metabolic disease: Gut feeling mediated by GLP-1

    Directory of Open Access Journals (Sweden)

    Tamara eZietek

    2016-04-01

    Full Text Available Chronic diseases such as obesity and diabetes, cardiovascular and inflammatory bowel diseases (IBD share common features in their pathology. Metabolic disorders exhibit strong inflammatory underpinnings and vice versa, inflammation is associated with metabolic alterations. Next to cytokines and cellular stress pathways like the unfolded protein response (UPR, alterations in the enteroendocrine system are intersections of various pathologies. Enteroendocrine cells (EEC have been studied extensively for their ability to regulate gastrointestinal motility, secretion, and insulin release by release of peptide hormones. In particular the L cell-derived incretin hormone glucagon-like peptide 1 (GLP-1 has gained enormous attention due to its insulinotropic action and relevance in the treatment of type 2 diabetes (T2D. Yet, accumulating data indicates a critical role for EEC and in particular for GLP-1 in metabolic adaptation and in orchestrating immune responses beyond blood glucose control. EEC sense the lamina propria and luminal environment including the microbiota via receptors and transporters. Subsequently mediating signals by secreting hormones and cytokines, EEC can be considered as integrators of metabolic and inflammatory signaling.This review focuses on L cell and GLP-1 functions in the context of metabolic and inflammatory diseases. The effects of incretin-based therapies on metabolism and immune system are discussed and the interrelation and common features of metabolic and immune-mediated disorders are highlighted. Moreover, it presents data on the impact of inflammation, in particular of IBD on EEC and discusses the potential role of the microbiota as link between nutrients, metabolism, immunity and disease.

  13. The Dietary Furocoumarin Imperatorin Increases Plasma GLP-1 Levels in Type 1-Like Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Lin-Yu Wang

    2017-10-01

    Full Text Available Imperatorin, a dietary furocoumarin, is found not only in medicinal plants, but also in popular culinary herbs, such as parsley and fennel. Recently, imperatorin has been shown to activate GPR119 in cells. Another GPR, GPR131, also called TGR5 or G-protein-coupled bile acid receptor 1 (GPBAR1, is known to regulate glucose metabolism. Additionally, TGR5 activation increases glucagon-like peptide (GLP-1 secretion to lower blood sugar levels in animals. Therefore, the present study aims to determine whether the effects of imperatorin on GLP-1 secretion are mediated by TGR5. First, we transfected cultured Chinese hamster ovary cells (CHO-K1 cells with the TGR5 gene. Glucose uptake was confirmed in the transfected cells using a fluorescent indicator. Moreover, NCI-H716 cells, which secrete GLP-1, were used to investigate the changes in calcium concentrations and GLP-1 levels. In addition, streptozotocin (STZ-induced type 1-like diabetic rats were used to identify the effects of imperatorin in vivo. Imperatorin dose-dependently increased glucose uptake in CHO-K1 cells expressing TGR5. In STZ diabetic rats, similar to the results in NCI-H716 cells, imperatorin induced a marked increase of GLP-1 secretion that was reduced, but not totally abolished, by a dose of triamterene that inhibited TGR5. Moreover, increases in GLP-1 secretion induced by imperatorin and GPR119 activation were shown in NCI-H716 cells. We demonstrated that imperatorin induced GLP-1 secretion via activating TGR5 and GPR119. Therefore, imperatorin shall be considered as a TGR5 and GPR119 agonist.

  14. The Aversive Agent Lithium Chloride Suppresses Phasic Dopamine Release Through Central GLP-1 Receptors.

    Science.gov (United States)

    Fortin, Samantha M; Chartoff, Elena H; Roitman, Mitchell F

    2016-02-01

    Unconditioned rewarding stimuli evoke phasic increases in dopamine concentration in the nucleus accumbens (NAc) while discrete aversive stimuli elicit pauses in dopamine neuron firing and reductions in NAc dopamine concentration. The unconditioned effects of more prolonged aversive states on dopamine release dynamics are not well understood and are investigated here using the malaise-inducing agent lithium chloride (LiCl). We used fast-scan cyclic voltammetry to measure phasic increases in NAc dopamine resulting from electrical stimulation of dopamine cell bodies in the ventral tegmental area (VTA). Systemic LiCl injection reduced electrically evoked dopamine release in the NAc of both anesthetized and awake rats. As some behavioral effects of LiCl appear to be mediated through glucagon-like peptide-1 receptor (GLP-1R) activation, we hypothesized that the suppression of phasic dopamine by LiCl is GLP-1R dependent. Indeed, peripheral pretreatment with the GLP-1R antagonist exendin-9 (Ex-9) potently attenuated the LiCl-induced suppression of dopamine. Pretreatment with Ex-9 did not, however, affect the suppression of phasic dopamine release by the kappa-opioid receptor agonist, salvinorin A, supporting a selective effect of GLP-1R stimulation in LiCl-induced dopamine suppression. By delivering Ex-9 to either the lateral or fourth ventricle, we highlight a population of central GLP-1 receptors rostral to the hindbrain that are involved in the LiCl-mediated suppression of NAc dopamine release.

  15. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1 Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Henrik H Hansen

    Full Text Available One of the major histopathological hallmarks of Alzheimer's disease (AD is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1 receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP and presenilin-1 (PS1 are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9 of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c., or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.. In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  16. Recent Advances in GLP-1 Receptor Agonists for Use in Diabetes Mellitus.

    Science.gov (United States)

    McBrayer, Dominic N; Tal-Gan, Yftah

    2017-09-01

    Preclinical Research Mimetics of Glucagon-like peptide 1 (GLP-1) represent a useful alternative or complementary treatment choice to insulin in the treatment of diabetes mellitus. The lack of hypoglycemia as a side effect when GLP-1 receptor agonists are used along with the tendency of these therapeutic agents to prevent or even reduce weight gain makes them valuable targets in therapy development. However, native GLP-1 and many of its early analogues have very short half-lives, requiring repeated treatment to maintain therapeutic levels. As all current treatments are injected subcutaneously, a large focus has been made on trying to extend the half-lives of GLP-1 analogues while retaining bioactivity. Most success in this regard has been achieved with the use of peptide-protein fusions, which are not as well suited for oral administration. However, recent work focused on the development of non-fusion peptides with increased half-lives that may be more appropriate for oral administration. This minireview discusses the structural characteristics of past and present analogues as well as the recent work conducted toward developing novel GLP-1 receptor agonists. Drug Dev Res 78 : 292-299, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  17. GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion

    DEFF Research Database (Denmark)

    Deacon, Carolyn F; Plamboeck, Astrid; Møller, Søren

    2002-01-01

    impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7-36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1......-(9-36) amide, was investigated for any ability to influence these responses. GLP-1-(7-36) amide enhanced insulin secretion (P amide was without effect, either alone or when coinfused with GLP-1-(7-36) amide. In contrast, GLP-1-(9-36) amide did affect glucose responses (P...... amide (73 +/- 19 mmol x l(-1) x min; P amide (62 +/- 13 mmol x l(-1) x min; P amide + GLP-1-(9-36) amide (50 +/-13 mmol x l(-1) x min; P

  18. Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Gribble, Fiona M; Hartmann, Bolette

    2014-01-01

    Nutrients often stimulate gut hormone secretion, but the effects of fructose are incompletely understood. We studied the effects of fructose on a number of gut hormones with particular focus on glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In healthy humans......, fructose intake caused a rise in blood glucose and plasma insulin and GLP-1, albeit to a lower degree than isocaloric glucose. Cholecystokinin secretion was stimulated similarly by both carbohydrates, but neither peptide YY3-36 nor glucagon secretion was affected by either treatment. Remarkably, while...... glucose potently stimulated GIP release, fructose was without effect. Similar patterns were found in the mouse and rat, with both fructose and glucose stimulating GLP-1 secretion, whereas only glucose caused GIP secretion. In GLUTag cells, a murine cell line used as model for L cells, fructose...

  19. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome.

    Science.gov (United States)

    Tzotzas, Themistoklis; Karras, Spyridon N; Katsiki, Niki

    2017-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females and is often associated with a number of cardiometabolic disorders such as central obesity, dyslipidaemia, hypertension, insulin resistance, hyperinsulinaemia, glucose intolerance and type 2 diabetes mellitus (T2DM). Glucagon-like peptide-1 (GLP-1), a gut hormone secreted after a meal, enhances glucosestimulated insulin secretion and additionally suppresses appetite and gastric motility. Most studies found impaired GLP-1 kinetics in obese individuals, whereas small studies in PCOS reported reduced, normal or even elevated GLP-1 levels. Apart from their efficacy in patients with T2DM, some GLP-1 receptor agonists (GLP-1 RAs) have been successfully tested in terms of both efficiency and safety in obese individuals without diabetes and liraglutide 3 mg once daily has been approved as an antiobesity drug in the USA and the European Union. Recently, some small trials of short duration using GLP-1 RAs as monotherapy or combined with metformin in obese PCOS women showed positive results regarding weight reduction and a decrease in testosterone levels but without significant effects on insulin levels, insulin sensitivity and menstrual patterns. Longer term studies with more patients and higher doses of liraglutide (as this drug is already approved for obese individuals) are required to determine the precise indications of GLP-1 RAs in PCOS and to evaluate safety issues. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Gastric myoelectric activity during cisplatin-induced acute and delayed emesis reveals a temporal impairment of slow waves in ferrets: effects not reversed by the GLP-1 receptor antagonist, exendin (9-39).

    Science.gov (United States)

    Lu, Zengbing; Ngan, Man P; Lin, Ge; Yew, David T W; Fan, Xiaodan; Andrews, Paul L R; Rudd, John A

    2017-11-17

    Preclinical studies show that the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin (9-39), can reduce acute emesis induced by cisplatin. In the present study, we investigate the effect of exendin (9-39) (100 nmol/24 h, i.c.v), on cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis and changes indicative of 'nausea' in ferrets. Cisplatin induced 37.2 ± 2.3 and 59.0 ± 7.7 retches + vomits during the 0-24 (acute) and 24-72 h (delayed) periods, respectively. Cisplatin also increased ( P Advanced multifractal detrended fluctuation analysis revealed that the slow wave signal shape became more simplistic during delayed emesis. Cisplatin did not affect blood pressure (BP), but transiently increased heart rate, and decreased heart rate variability (HRV) during acute emesis; HRV spectral analysis indicated a shift to 'sympathetic dominance'. A hyperthermic response was seen during acute emesis, but hypothermia occurred during delayed emesis and there was also a decrease in HR. Exendin (9-39) did not improve feeding and drinking but reduced cisplatin-induced acute emesis by ~59 % ( P waves may represent a novel approach to treat the side effects of chemotherapy.

  1. Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1)

    DEFF Research Database (Denmark)

    Bak, Monika Judyta; Albrechtsen, Nicolai Jacob Wewer; Pedersen, Jens

    2014-01-01

    assessed with 3 commercial kits. RESULTS: The USCN LIFE assay detected none of the GLP-1 isoforms. The active GLP-1 ELISAs from Millipore and DRG seemed identical and were specific for intact GLP-1 in buffer and plasma. The Meso Scale Discovery Total GLP-1 kit detected all six GLP-1 isoforms, although...

  2. Gastric bypass surgery: Improving psoriasis through a GLP-1-dependent mechanism?

    DEFF Research Database (Denmark)

    Faurschou, Annesofie; Zachariae, Claus; Skov, Lone

    2011-01-01

    surgery. This most likely contributes importantly to the acute remission of type 2 diabetes, which is often induced by gastric bypass operations. The hormone is not hypersecreted after the purely restrictive bariatric procedure gastric banding and no case reports exist on improvement in psoriasis...... following gastric banding. Intriguingly, recent studies describe that GLP-1 may convey anti-inflammatory effects in addition to its effects on glucose homeostasis. Also, GLP-1 reduces appetite and gastrointestinal motility including gastric emptying, which reduces food intake and leads to weight loss. Thus...

  3. Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia

    DEFF Research Database (Denmark)

    Toft-Nielsen, M; Madsbad, Sten; Holst, Jens Juul

    1998-01-01

    The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is impo......The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects...

  4. Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents

    Energy Technology Data Exchange (ETDEWEB)

    Brink, Willem van den; Emerenciana, Annette [Systems Pharmacology, Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden (Netherlands); Medicines Evaluation Board, Utrecht (Netherlands); Bellanti, Francesco [Systems Pharmacology, Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden (Netherlands); Della Pasqua, Oscar [Systems Pharmacology, Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden (Netherlands); Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge (United Kingdom); Clinical Pharmacology & Therapeutics, UCL, School of Life and Medical Sciences, London (United Kingdom); Laan, Jan Willem van der, E-mail: jw.vd.laan@cbg-meb.nl [Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden (Netherlands); Medicines Evaluation Board, Utrecht (Netherlands)

    2017-04-01

    Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2 years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. - Highlights: • An integrative PKPD model is applied to

  5. Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents

    International Nuclear Information System (INIS)

    Brink, Willem van den; Emerenciana, Annette; Bellanti, Francesco; Della Pasqua, Oscar; Laan, Jan Willem van der

    2017-01-01

    Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2 years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. - Highlights: • An integrative PKPD model is applied to

  6. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Knop, Filip K; Holst, Jens J

    2009-01-01

    Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys...... of the anticipated effects of lixisenatide on glycemic measures and weight; favorable results would place lixisenatide for consideration among other GLP-1R agonists in the treatment armamentarium for T2DM....

  7. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Rouse, Rodney, E-mail: rodney.rouse@fda.hhs.gov; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-04-15

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.

  8. High fat diet and GLP-1 drugs induce pancreatic injury in mice

    International Nuclear Information System (INIS)

    Rouse, Rodney; Xu, Lin; Stewart, Sharron; Zhang, Jun

    2014-01-01

    Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6 weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6 weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment

  9. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

    Directory of Open Access Journals (Sweden)

    Valborg Gudmundsdottir

    Full Text Available Glucagon-like peptide 1 (GLP-1 stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126. This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100. Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05 with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated

  10. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

    OpenAIRE

    Gejl, Michael; Lerche, Susanne; Egefjord, L?rke; Brock, Birgitte; M?ller, Niels; Vang, Kim; Rodell, Anders B.; Bibby, Bo M.; Holst, Jens J.; Rungby, J?rgen; Gjedde, Albert

    2013-01-01

    In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven h...

  11. Effect of the low- versus high-intensity exercise training on endoplasmic reticulum stress and GLP-1 in adolescents with type 2 diabetes mellitus.

    Science.gov (United States)

    Lee, Sung Soo; Yoo, Jae Ho; So, Yong Seok

    2015-10-01

    [Purpose] The primary objective of this study was to investigate the effect of low-intensity exercise training compare with high-intensity exercise training on endoplasmic reticulum stress and glucagon-like peptide-1 in adolescents with type 2 diabetes mellitus. [Subjects and Methods] The low-intensity exercise training group performed aerobic exercise training at an intensity of ≤ 45% of the heart rate reserve. The high-intensity interval exercise training group performed interval exercise training at an intensity of ≥ 80% of the heart rate reserve. The exercise-related energy consumption was determined for both groups on a per-week basis (1,200 kcal/week). [Results] Both groups showed improvement in the glucose-regulated protein 78 and dipeptidyl peptidase-4, but the size of the between-group effect was not statistically significant. The high-intensity interval exercise training group showed a significant reduction in percentage body fat. The C-peptide level increased after the 12-weeks programs and was significantly different, between the groups. Fasting glucose, insulin resistance in the fasting state according to homeostasis model assessment, and leptin decreased after the 12-weeks exercise program and were significantly different between the groups, and glucagon-like peptide-1 increased after the 12-week exercise programs and was significantly different between the groups. [Conclusion] In conclusion high-intensity interval exercise training, as defined in this study, may lead to improvements in body composition, glycemic control, endoplasmic reticulum stress, and the glucagon-like peptide-1 in adolescents with type 2 diabetes mellitus.

  12. A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment.

    Science.gov (United States)

    Consoli, Agostino; Formoso, Gloria; Baldassarre, Maria Pompea Antonia; Febo, Fabrizio

    2018-03-01

    Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials. Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile. Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes. Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a 'similar' safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.

  13. Effects of Substitution, and Adding of Carbohydrate and Fat to Whey-Protein on Energy Intake, Appetite, Gastric Emptying, Glucose, Insulin, Ghrelin, CCK and GLP-1 in Healthy Older Men—A Randomized Controlled Trial

    Directory of Open Access Journals (Sweden)

    Caroline Giezenaar

    2018-01-01

    Full Text Available Protein-rich supplements are used widely for the management of malnutrition in the elderly. We reported previously that the suppression of energy intake by whey protein is less in older than younger adults. The aim was to determine the effects of substitution, and adding of carbohydrate and fat to whey protein, on ad libitum energy intake from a buffet meal (180–210 min, gastric emptying (3D-ultrasonography, plasma gut hormone concentrations (0–180 min and appetite (visual analogue scales, in healthy older men. In a randomized, double-blind order, 13 older men (75 ± 2 years ingested drinks (~450 mL containing: (i 70 g whey protein (280 kcal; ‘P280’; (ii 14 g protein, 28 g carbohydrate, 12.4 g fat (280 kcal; ‘M280’; (iii 70 g protein, 28 g carbohydrate, 12.4 g fat (504 kcal; ‘M504’; or (iv control (~2 kcal. The caloric drinks, compared to a control, did not suppress appetite or energy intake; there was an increase in total energy intake (drink + meal, p < 0.05, which was increased most by the M504-drink. P280- and M504-drink ingestion were associated with slower a gastric-emptying time (n = 9, lower ghrelin, and higher cholecystokinin (CCK and glucagon-like peptide-1 (GLP-1 than M280 (p < 0.05. Glucose and insulin were increased most by the mixed-macronutrient drinks (p < 0.05. In conclusion, energy intake was not suppressed, compared to a control, and particularly whey protein, affected gastric emptying and gut hormone responses.

  14. Robust GLP-1 secretion by basic L-amino acids does not require the GPRC6A receptor

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Jørgensen, Christinna V; Smajilovic, Sanela

    2017-01-01

    (GLP-1) secretion is unclear. Therefore, to probe if the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands: L-arginine and L-ornithine, and assessed GLP-1 levels...... in circulation. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion...... at the 30 and 60 minute time points in the KO mice were attenuated and did not reach statistical significance. In summary, these data confirm that L-arginine is a potent GLP-1 secretagogue and show that the main effect occurs independently of GPRC6A. In addition, this is the first study to show that also L...

  15. Minor Contribution of Endogenous GLP-1 and GLP-2 to Postprandial Lipemia in Obese Men

    DEFF Research Database (Denmark)

    Matikainen, Niina; Björnson, Elias; Söderlund, Sanni

    2016-01-01

    CONTEXT: Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified. OBJECTIVE: To explore the responses of GLP-1, GLP-2 and GIP after...... and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m2) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal. MAIN OUTCOME MEASURES: Postprandial responses (area under the curve, AUC) for glucose...... AUCs were lower, but the AUCs for GLP-1, GLP-2 and GIP were significantly higher after the fat-rich meal than after the OGTT. The peak value for all hormones appeared at 120 minutes after the fat-rich meal, compared to 30 minutes after the OGTT. After the fat-rich meal, the AUCs for GLP-1, GLP-2...

  16. Emerging technologies to achieve oral delivery of GLP-1 and GLP-1 analogs for treatment of type 2 diabetes mellitus (T2DM

    Directory of Open Access Journals (Sweden)

    Shengwu Ma

    2017-04-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a gastrointestinal (GI peptide hormone that stimulates insulin secretion, gene expression and β-cell proliferation, representing a potentially novel and promising therapeutic agent for the treatment of T2DM. DPP-IV-resistant, long-acting GLP-1 analogs have already been approved by FDA as injectable drugs for treating patients with T2DM. Oral delivery of therapeutic peptides and proteins would be preferred owing to advantages of lower cost, ease of administration and greater patient adherence. However, oral delivery of proteins can be affected by rapid enzymatic degradation in the GI tract and poor penetration across the intestinal membrane, which may require amounts that exceed practical consideration. Various production strategies have been explored to overcome challenges associated with the oral delivery of therapeutic peptides and proteins. The goal of this review is to provide an overview of the current state of progress made towards the oral delivery of GLP-1 and its analogs in the treatment of T2DM, with special emphasis on the development of plant and food-grade bacterial delivery systems. Recently, genetically engineered plants and food-grade bacteria have been increasingly explored as novel carrier systems for the oral delivery of peptide and protein drugs. These have a largely unexplored potential to serve both as an expression system and as a delivery vehicle for clinically relevant, cost effective therapeutics. As such, they hold great promise for human biopharmaceuticals and novel therapies against various diseases.

  17. Mechanism-based population modelling for assessment of L-cell function based on total GLP-1 response following an oral glucose tolerance test

    DEFF Research Database (Denmark)

    Møller, Jonas B.; Jusko, William J.; Gao, Wei

    2011-01-01

    was to build a mechanism-based population model that describes the time course of total GLP-1 and provides indices for capability of secretion in each subject. The goal was thus to model the secretion of GLP-1, and not its effect on insulin production. Single 75 g doses of glucose were administered orally......GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study....... The individual estimates of absorption rate constants were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI. The final transit/indirect-response model obtained for GLP-1 production following an OGTT included two...

  18. Sitagliptin reduces cardiac apoptosis, hypertrophy and fibrosis primarily by insulin-dependent mechanisms in experimental type-II diabetes. Potential roles of GLP-1 isoforms.

    Directory of Open Access Journals (Sweden)

    Belén Picatoste

    Full Text Available BACKGROUND: Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1 enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart. METHODS: Goto-Kakizaki (GK rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin or vehicle (n=10, each. After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays. RESULTS: Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36, alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells. CONCLUSIONS: Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36 promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

  19. GLP-1-RA Corrects Mitochondrial Labile Iron Accumulation and Improves β-Cell Function in Type 2 Wolfram Syndrome.

    Science.gov (United States)

    Danielpur, Liron; Sohn, Yang-Sung; Karmi, Ola; Fogel, Chen; Zinger, Adar; Abu-Libdeh, Abdulsalam; Israeli, Tal; Riahi, Yael; Pappo, Orit; Birk, Ruth; Zangen, David H; Mittler, Ron; Cabantchik, Zvi-Ioav; Cerasi, Erol; Nechushtai, Rachel; Leibowitz, Gil

    2016-10-01

    Type 2 Wolfram syndrome (T2-WFS) is a neuronal and β-cell degenerative disorder caused by mutations in the CISD2 gene. The mechanisms underlying β-cell dysfunction in T2-WFS are not known, and treatments that effectively improve diabetes in this context are lacking. Unraveling the mechanisms of β-cell dysfunction in T2-WFS and the effects of treatment with GLP-1 receptor agonist (GLP-1-RA). A case report and in vitro mechanistic studies. We treated an insulin-dependent T2-WFS patient with the GLP-1-RA exenatide for 9 weeks. An iv glucose/glucagon/arginine stimulation test was performed off-drug before and after intervention. We generated a cellular model of T2-WFS by shRNA knockdown of CISD2 (nutrient-deprivation autophagy factor-1 [NAF-1]) in rat insulinoma cells and studied the mechanisms of β-cell dysfunction and the effects of GLP-1-RA. Treatment with exenatide resulted in a 70% reduction in daily insulin dose with improved glycemic control, as well as an off-drug 7-fold increase in maximal insulin secretion. NAF-1 repression in INS-1 cells decreased insulin content and glucose-stimulated insulin secretion, while maintaining the response to cAMP, and enhanced the accumulation of labile iron and reactive oxygen species in mitochondria. Remarkably, treatment with GLP-1-RA and/or the iron chelator deferiprone reversed these defects. NAF-1 deficiency leads to mitochondrial labile iron accumulation and oxidative stress, which may contribute to β-cell dysfunction in T2-WFS. Treatment with GLP-1-RA and/or iron chelation improves mitochondrial function and restores β-cell function. Treatment with GLP-1-RA, probably aided by iron chelation, should be considered in WFS and other forms of diabetes associated with iron dysregulation.

  20. Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core.

    Science.gov (United States)

    Fortin, Samantha M; Roitman, Mitchell F

    2017-07-01

    Drugs of abuse increase the frequency and magnitude of brief (1-3s), high concentration (phasic) dopamine release events in terminal regions. These are thought to be a critical part of drug reinforcement and ultimately the development of addiction. Recently, metabolic regulatory peptides, including the satiety signal glucagon-like peptide-1 (GLP-1), have been shown to modulate cocaine reward-driven behavior and sustained dopamine levels after cocaine administration. Here, we use fast-scan cyclic voltammetry (FSCV) to explore GLP-1 receptor (GLP-1R) modulation of dynamic dopamine release in the nucleus accumbens (NAc) during cocaine administration. We analyzed dopamine release events in both the NAc shell and core, as these two subregions are differentially affected by cocaine and uniquely contribute to motivated behavior. We found that central delivery of the GLP-1R agonist Exendin-4 suppressed the induction of phasic dopamine release events by intravenous cocaine. This effect was selective for dopamine signaling in the NAc core. Suppression of phasic signaling in the core by Exendin-4 could not be attributed to interference with cocaine binding to one of its major substrates, the dopamine transporter, as cocaine-induced increases in reuptake were unaffected. The results suggest that GLP-1R activation, instead, exerts its suppressive effects by altering dopamine release - possibly by suppressing the excitability of dopamine neurons. Given the role of NAc core dopamine in the generation of conditioned responses based on associative learning, suppression of cocaine-induced dopamine signaling in this subregion by GLP-1R agonism may decrease the reinforcing properties of cocaine. Thus, GLP-1Rs remain viable targets for the treatment and prevention of cocaine seeking, taking and relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering.

    Science.gov (United States)

    Kahles, Florian; Meyer, Christina; Möllmann, Julia; Diebold, Sebastian; Findeisen, Hannes M; Lebherz, Corinna; Trautwein, Christian; Koch, Alexander; Tacke, Frank; Marx, Nikolaus; Lehrke, Michael

    2014-10-01

    Hypoglycemia and hyperglycemia are both predictors for adverse outcome in critically ill patients. Hyperinsulinemia is induced by inflammatory stimuli as a relevant mechanism for glucose lowering in the critically ill. The incretine hormone GLP-1 was currently found to be induced by endotoxin, leading to insulin secretion and glucose lowering under inflammatory conditions in mice. Here, we describe GLP-1 secretion to be increased by a variety of inflammatory stimuli, including endotoxin, interleukin-1β (IL-1β), and IL-6. Although abrogation of IL-1 signaling proved insufficient to prevent endotoxin-dependent GLP-1 induction, this was abolished in the absence of IL-6 in respective knockout animals. Hence, we found endotoxin-dependent GLP-1 secretion to be mediated by an inflammatory cascade, with IL-6 being necessary and sufficient for GLP-1 induction. Functionally, augmentation of the GLP-1 system by pharmacological inhibition of DPP-4 caused hyperinsulinemia, suppression of glucagon release, and glucose lowering under endotoxic conditions, whereas inhibition of the GLP-1 receptor led to the opposite effect. Furthermore, total GLP-1 plasma levels were profoundly increased in 155 critically ill patients presenting to the intensive care unit (ICU) in comparison with 134 healthy control subjects. In the ICU cohort, GLP-1 plasma levels correlated with markers of inflammation and disease severity. Consequently, GLP-1 provides a novel link between the immune system and the gut with strong relevance for metabolic regulation in context of inflammation. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  2. Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extracellular domain.

    Science.gov (United States)

    Runge, Steffen; Schimmer, Susann; Oschmann, Jan; Schiødt, Christine Bruun; Knudsen, Sanne Möller; Jeppesen, Claus Bekker; Madsen, Kjeld; Lau, Jesper; Thøgersen, Henning; Rudolph, Rainer

    2007-05-15

    Glucagon-like peptide-1 (GLP-1) and exendin-4 (Ex4) are homologous peptides with established potential for treatment of type 2 diabetes. They bind and activate the pancreatic GLP-1 receptor (GLP-1R) with similar affinity and potency and thereby promote insulin secretion in a glucose-dependent manner. GLP-1R belongs to family B of the seven transmembrane G-protein coupled receptors. The N-terminal extracellular domain (nGLP-1R) is a ligand binding domain with differential affinity for Ex4 and GLP-1: low affinity for GLP-1 and high affinity for exendin-4. The superior affinity of nGLP-1R for Ex4 was previously explained by an additional interaction between nGLP-1R and the C-terminal Trp-cage of Ex4. In this study we have combined biophysical and pharmacological approaches thus relating structural properties of the ligands in solution to their relative binding affinity for nGLP-1R. We used both a tracer competition assay and ligand-induced thermal stabilization of nGLP-1R to measure the relative affinity of full length, truncated, and chimeric ligands for soluble refolded nGLP-1R. The ligands in solution and the conformational consequences of ligand binding to nGLP-1R were characterized by circular dichroism and fluorescence spectroscopy. We found a correlation between the helical content of the free ligands and their relative binding affinity for nGLP-1R, supporting the hypothesis that the ligands are helical at least in the segment that binds to nGLP-1R. The Trp-cage of Ex4 was not necessary to maintain a superior helicity of Ex4 compared to GLP-1. The results suggest that the differential affinity of nGLP-1R is explained almost entirely by divergent residues in the central part of the ligands: Leu10-Gly30 of Ex4 and Val16-Arg36 of GLP-1. In view of our results it appears that the Trp-cage plays only a minor role for the interaction between Ex4 and nGLP-1R and for the differential affinity of nGLP-1R for GLP-1 and Ex4.

  3. Gastric bypass surgery: Improving psoriasis through a GLP-1-dependent mechanism?

    DEFF Research Database (Denmark)

    Faurschou, Annesofie; Zachariae, Claus; Skov, Lone

    2011-01-01

    surgery. This most likely contributes importantly to the acute remission of type 2 diabetes, which is often induced by gastric bypass operations. The hormone is not hypersecreted after the purely restrictive bariatric procedure gastric banding and no case reports exist on improvement in psoriasis......, both a direct anti-inflammatory effect of GLP-1 as well as an indirect effect through weight loss could contribute to improvement in psoriasis. A potential involvement of GLP-1 in the remission of psoriasis observed after bariatric surgery offers exciting possibilities for research and eventually...... bypass surgery in patients with psoriasis may result in complete remission of the disease. A substantial weight loss is achieved in the months following surgery, which is likely to reduce psoriasis symptoms and risk of comorbidities. Interestingly, however, it has been described that improvement...

  4. South Asian Consensus Guideline: Use of GLP-1 analogue therapy in diabetes during Ramadan

    Directory of Open Access Journals (Sweden)

    Md Faruque Pathan

    2012-01-01

    Full Text Available Ramadan is a lunar based month, during which Muslims across the world observe the ritual fast. This provides a challenge not only to the diabetic patient who wishes to observe the fast but also to the health care professional managing his diabetes. The challenge is to use therapies which are effective in maintaining good glycemic control and at the same time have a low propensity to cause hypoglycemia during the several hours of no calorie intake. The GLP-1 analogues are unique agents which are effective in providing glycemic reduction with a very low risk of hypoglycemia and hence find an important place in the management of diabetes during Ramadan. This Consensus Statement describes the pre-Ramadan assessment, planning, prescription and management and monitoring of patients who are on GLP-1 analogues, with or without other antidiabetic therapies.

  5. Specific inhibition of bile acid transport alters plasma lipids and GLP-1

    DEFF Research Database (Denmark)

    Rudling, Mats; Camilleri, Michael; Graffner, Hans

    2015-01-01

    mellitus. The objectives of this study were to evaluate metabolic effects of elobixibat. Effects on plasma lipids and BA synthesis were evaluated utilizing a 4-week, placebo-controlled study in patients with dyslipidemia while changes of glucagon-like peptide-1 (GLP-1) by elobixibat was assayed in samples......: In the dyslipidemia study LDL cholesterol was reduced by 7.4 % (p = 0.044), and the LDL/HDL ratio was decreased by 18 % (p = 0.004). Serum C4 increased, indicating that BA synthesis was induced. No serious adverse events were recorded. In the CC study, GLP-1 increased significantly in both the 15 mg (20.7 ± 2.4 pmol...

  6. Implementation of GLP-1 based therapy of type 2 diabetes mellitus using DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2003-01-01

    GLP-1 is a peptide hormone from the intestinal mucosa. It is secreted in response to meal ingestion and normally functions in the so-called ileal brake i. e. inhibition of upper gastrointestinal motility and secretion when nutrients are present in the distal small intestine. It also induces satiety...... of the peptide is necessary because of an exceptionally rapid rate of degradation catalyzed the enzyme dipeptidyl peptidase IV. With inhibitors of this enzyme, it is possible to protect the endogenous hormone and thereby elevate both fasting and postprandial levels of the active hormone. This leads to enhanced...... insulin secretion and glucose turnover. But will DPP-IV inhibition enhance all effects of the endogenous peptide? The mode of action of GLP-1 is complex involving also interactions with sensory neurons and the central nervous system, where a DPP-IV mediated degradation does not seem to occur. Therefore...

  7. GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes

    DEFF Research Database (Denmark)

    Halden, Thea A S; Egeland, Erlend J; Åsberg, Anders

    2016-01-01

    OBJECTIVE: Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon...... h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS: Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups...... to arginine (P = 0.01) but similar glucagon and proinsulin responses compared with control subjects. In the preclamp phase, GLP-1 lowered fasting plasma glucose to the same extent in both groups but reduced glucagon only in PTDM patients. During hyperglycemic clamp, GLP-1 reduced glucagon concentrations...

  8. Therapies for inter-relating diabetes and obesity - GLP-1 and obesity

    DEFF Research Database (Denmark)

    Iepsen, Eva Pers Winning; Torekov, Signe S; Holst, Jens Juul

    2014-01-01

    INTRODUCTION: The dramatic rise in the prevalence of obesity and type 2 diabetes mellitus (T2DM) is associated with increased mortality, morbidity as well as public health care expenses worldwide. The need for effective and long-lasting pharmaceutical treatment is obvious. The record of anti-obesity...... drugs has been poor so far and the only efficient treatment today is bariatric surgery. Research has indicated that appetite inhibiting hormones from the gut may have a therapeutic potential in obesity. The gut incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral...... and central pathways mediating satiety. Clinical trials have shown that two GLP-1 receptor agonists exenatide and liraglutide have a weight-lowering potential in non-diabetic obese individuals. Furthermore, they may also hold a potential in preventing diabetes as compared to other weight loss agents. AREAS...

  9. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.

    Science.gov (United States)

    Nogueiras, Ruben; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Morgan, Donald A; Varela, Luis; Haynes, William G; Patterson, James T; Disse, Emmanuel; Pfluger, Paul T; López, Miguel; Woods, Stephen C; DiMarchi, Richard; Diéguez, Carlos; Rahmouni, Kamal; Rohner-Jeanrenaud, Françoise; Tschöp, Matthias H

    2009-05-06

    We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

  10. GLP-1 receptor agonists in the treatment of polycystic ovary syndrome.

    Science.gov (United States)

    Lamos, Elizabeth Mary; Malek, Rana; Davis, Stephen N

    2017-04-01

    Polycystic ovarian syndrome (PCOS) affects many women of child-bearing age and is characterized by hyperandrogenism, ovulatory and metabolic dysfunction. A primary treatment goal is weight reduction. The weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RA), previously demonstrated in diabetic and obese non-diabetic patients, offer a unique opportunity to expand the medical options available to PCOS patients. Areas covered: Available clinical trials of glucagon-like peptide-1 receptor agonist therapy in PCOS were reviewed. Literature was searched from PubMed using appropriate search terms up to November 2016. Expert commentary: The available studies of GLP-1 RA therapy in the treatment of excess body weight in women with PCOS demonstrate that exenatide and liraglutide are effective in weight reduction either as monotherapy or in combination with metformin. A few studies showed that androgens may be modestly decreased and menstrual frequency may be increased. Eating behavior may be improved with liraglutide therapy. Glucose parameters are generally improved. GLP-1RAs were well-tolerated, with nausea being the most significant adverse side effect. Barriers to utilization may be the short duration studies, lack of familiarity of the medication, the route of administration (injection) and the variable outcomes on ovulation and hyperandrogenism.

  11. Appetite-related peptides in childhood and adolescence: role of ghrelin, PYY, and GLP-1.

    Science.gov (United States)

    Horner, Katy; Lee, SoJung

    2015-11-01

    During childhood and adolescence, a number of factors, including age, puberty, sex, race, and body composition, may contribute to differences in satiety, food intake, and appetite-related peptides. These peptides include the orexigenic peptide ghrelin and anorexigenic gut peptides peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). For example, lower fasting ghrelin levels, lower postprandial ghrelin suppression, and blunted PYY and GLP-1 responses to food intake could contribute to a dysregulation of appetite in already obese children and adolescents. Whereas, changes in these peptides observed during puberty could facilitate growth. A greater understanding of the major moderating factors of appetite-related peptides in the pediatric population is essential to improve interpretation of study findings and for effective tailoring of strategies targeting appetite control to individuals. While more studies are needed, there is some evidence to suggest that exercise-based lifestyle interventions could be a potential therapeutic strategy to improve appetite-peptide profiles in overweight and obese children and adolescents. The aim of this review is (i) to discuss the potential moderating factors of ghrelin, PYY, and GLP-1, including age and puberty, sex, race and body composition; and (ii) to examine the effects of exercise interventions on these appetite-related gut peptides in children and adolescents.

  12. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Ten Kulve, Jennifer S; Veltman, Dick J; van Bloemendaal, Liselotte

    2015-01-01

    Aims/hypothesis The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised that end......Aims/hypothesis The central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised...... that endogenous GLP-1 has effects on CNS reward and satiety circuits. Methods This was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible...

  13. Preserved inhibitory potency of GLP-1 on glucagon secretion in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Hare, Kristine J; Knop, Filip K; Asmar, Meena

    2009-01-01

    OBJECTIVE: Glucagon-like peptide-1 (GLP-1) is insulinotropic, but its effect on the alpha-cell is less clear. We investigated the dose-response relationship for GLP-1-induced glucagon suppression in patients with type 2 diabetes (T2DM) and healthy controls. DESIGN: Ten patients with T2DM (duration...... to d 2 (1733 +/- 193 3h x pmol/liter; P 2DM. A similar reduction in AUC for glucagon was observed in healthy controls [1122 +/- 186 (d 1) vs. 1733 +/- 312 3h x pmol/liter (d 2); P diabetic alpha-cell appears to be highly sensitive to the inhibitory...... of DM, 4 +/- 1 yr; glycosylated hemoglobin, 7.1 +/- 0.3%) were studied on 2 d, with stepwise increasing GLP-1 infusions (0.25, 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1)) (d 1) or saline (d 2) with plasma glucose (PG) clamped at fasting level. On d 3, patient PG was normalized overnight using a variable...

  14. Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture

    Directory of Open Access Journals (Sweden)

    Andrea V. Rozo

    2017-07-01

    Conclusion: These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.

  15. Immunoassays for the incretin hormones GIP and GLP-1

    DEFF Research Database (Denmark)

    Deacon, Carolyn F; Holst, Jens J

    2009-01-01

    The measurement of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), using immunologically based assays is made difficult by the fact that the processing of the precursor molecules gives rise to a number of different peptides which cross......-react with antisera raised against the two hormones. For GLP-1, the picture is further complicated because of the necessity to differentiate between the intestinal and pancreatic proglucagon products. Finally, once secreted, both incretins are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4) to generate....... The use of highly specific assays using well-characterised antisera and careful sample handling is therefore required for a reliable determination of incretin hormone concentrations....

  16. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion

    DEFF Research Database (Denmark)

    Kårhus, Martin L; Brønden, Andreas; Sonne, David P

    2017-01-01

    Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have...... current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid...... sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism....

  17. Qing-Hua Granule induces GLP-1 secretion via bitter taste receptor in db/db mice.

    Science.gov (United States)

    Li, Junyan; Xu, Jie; Hou, Ruifang; Jin, Xin; Wang, Jingyi; Yang, Na; Yang, Li; Liu, Li; Tao, Feng; Lu, Hao

    2017-05-01

    Qing-Hua Granule (QHG), the modified formulation of a classical Chinese prescription named Gegen Qinlian Decoction, was clinically employed to treat type 2 diabetes mellitus (T2DM) through regulation of glucagon-like peptide-1 (GLP-1). However, the potential mechanism is unknown. We investigate whether QHG induces GLP-1 secretion via activation of bitter taste receptor (TAS2R) pathway in the gastrointestinal tract of db/db mice. The db/db mice were intragastrically (i.g.) administered QHG (low/medium/high dose) once daily for 8 weeks. GLP-1 secretion was evaluated. The bitter receptor signaling pathway, which regulates GLP-1 secretion, including TAS2R5 (a subtype of TAS2R), α-gustducin (Gαgust), 1-phosphatidylinositol-4, 5-bisphosphate phosphodiesterase beta-2 (PLCβ2), transient receptor potential cation channel subfamily M member 5 (TRPM5), was assessed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry (IHC). The biochemical observations of ileum and pancreas tissue were detected histopathologically. Acquity Ultra Performance LCTM - Micromass ZQ 2000 (UPLC-MS) was used for the phytochemical analysis. QHG exhibited significant and dose-dependent effect on GLP-1 secretion in db/db mice, along with significant up-regulation of TAS2R5 mRNA level and activation of TAS2R pathway (p<0.05). In addition, QHG improved the histopathological structure of ileum and pancreatic tissue. Seventeen compounds were identified in QHG. In conclusion, QHG induces GLP-1 secretion in db/db mice, most likely through the bitter taste receptor pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Anorexigenic postprandial responses of PYY and GLP1 to slow ice cream consumption: preservation in obese adolescents, but not in obese adults.

    Science.gov (United States)

    Rigamonti, A E; Agosti, F; Compri, E; Giunta, M; Marazzi, N; Muller, E E; Cella, S G; Sartorio, A

    2013-03-01

    Eating slowly increases the postprandial responses of some anorexigenic gut hormones in healthy lean subjects. As the rate of food intake is positively associated with obesity, the aim of the study was to determine whether eating the same meal at different rates evokes different postprandial anorexigenic responses in obese adolescent and adult subjects. Eighteen obese adolescents and adults were enrolled. A test meal was consumed on two different sessions by each subject, meal duration taking either 5  min (fast feeding) or 30  min (slow feeding). Circulating levels of glucagon-like peptide 1 (GLP1), peptide YY (PYY), glucose, insulin, and triglycerides were measured over 210  min. Visual analog scales were used to evaluate the subjective feelings of hunger and satiety. fast feeding did not stimulate GLP1 release in obese adolescent and adults, whereas slow feeding increased circulating levels of GLP1 only in obese adolescents. Plasma PYY concentrations increased both in obese adolescents and in adults, irrespective of the eating rate, but slow feeding was more effective in stimulating PYY release in obese adolescents than in adults. simultaneously, slow feeding evoked a higher satiety only in obese adolescents compared with fast feeding but not in obese adults. in obese adolescents, slow feeding decreased hunger (only at 210 min). irrespective of the eating rate, postprandial responses of insulin and triglycerides were higher in obese adults than in obese adolescents. Slow feeding leads to higher concentrations of anorexigenic gut peptides and favors satiety in obese adolescents, but this physiological control of food intake is lost in obese adults.

  19. Amylin and GLP-1 target different populations of area postrema neurons that are both modulated by nutrient stimuli.

    Science.gov (United States)

    Züger, Daniela; Forster, Karoline; Lutz, Thomas A; Riediger, Thomas

    2013-03-15

    The area postrema mediates the hypophagic effect of the pancreatic hormone amylin and is also sensitive to glucagon-like peptide 1 (GLP-1). Protein seems to modulate amylin responsiveness because amylin seems to produce a stronger hypophagic effect and a stronger c-Fos expression when protein is absent from the diet. Accordingly, amylin induces a stronger c-Fos expression in the AP when injected in fasted compared to ad libitum fed rats. Here we tested the hypothesis that diet-derived protein attenuates the amylin dependent suppression of feeding and AP activation using isocaloric diets that differed in their protein content. Moreover, we investigated whether peripheral amino acid injection attenuates amylin-induced c-Fos expression in fasted rats. Since recent evidence suggests that GLP-1 may also reduce eating via the AP we tested whether 24 h fasting also increases neuronal AP responsiveness to GLP-1 similar to the fasting-induced increase in amylin responsiveness. Finally, we used the calcitonin receptor (CTR) as an immunohistochemical marker for amylin-receptive AP neurons to investigate whether amylin's target neurons differ from GLP-1 responsive AP neurons. We also dissociated amylin responsive cells from neurons implicated in other AP-mediated functions such as aversion or blood pressure regulation. For this purpose, we conducted c-Fos/CTR double staining after LiCl or angiotensin II treatment, respectively. Amylin (5 μg/kg s.c.) was more effective to reduce the intake of a 1% vs. an 8% or 18% protein diet and to induce c-Fos expression in the AP in rats receiving 1% vs. 18% protein diet. Increased protein intake was associated with increased blood amino acid levels. Peripheral injection of amino acids (1 g/kg i.p.) attenuated the amylin-induced AP activation in 24 h fasted rats. Similar to amylin, GLP-1 (100 μg/kg i.p.) elicited a significant c-Fos response only in fasted but not in ad libitum fed rats. However, in contrast to a high co-localization of

  20. Feedback suppression of meal-induced glucagon-like peptide-1 (GLP-1) secretion mediated through elevations in intact GLP-1 caused by dipeptidyl peptidase-4 inhibition

    DEFF Research Database (Denmark)

    Baranov, Oleg; Kahle, Melanie; Deacon, Carolyn F

    2016-01-01

    AIM: To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. METHODS: A total of 24 patients (12 on a diet/exercise re......AIM: To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. METHODS: A total of 24 patients (12 on a diet....../exercise regimen, 12 on metformin) were treated, in randomized order, for 7-9 days, with either vildagliptin (50 mg twice daily = 100 mg/d), sitagliptin (100 mg once daily in those on diet, 50 mg twice daily in those on metformin treatment = 100 mg/d) or placebo (twice daily). A mixed-meal test was performed....... RESULTS: Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide concentrations were doubled by both DPP-4 inhibitors. Meal-related total GLP-1 responses were reduced by vildagliptin and sitagliptin treatment alike in the majority of patients (vildagliptin: p = 0...

  1. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

    DEFF Research Database (Denmark)

    Gejl, Michael; Lerche, Susanne; Egefjord, Lærke

    2013-01-01

    phosphorylation velocity (V max) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (T max) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain...

  2. GLP-1 secretion is stimulated by 1,10-phenanthroline via colocalized T2R5 signal transduction in human enteroendocrine L cell

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jiyoung; Kim, Ki-Suk; Kim, Kang-Hoon; Lee, In-Seung; Jeong, Hyeon-soo; Kim, Yumi; Jang, Hyeung-Jin, E-mail: hjjang@khu.ac.kr

    2015-12-04

    Glucagon-like peptide-1 (GLP-1) hormone is known to regulate blood glucose by an insulinotropic effect and increases proliferation as and also prevents apoptosis of pancreatic β cells. We know that GLP-1 is secreted by nutrients such as fatty acids and sweet compounds but also bitter compounds via stimulation of G-protein coupled receptors (GPCRs) in the gut. Among these, bitter compounds are multiply-contained in phytochemicals or artificial materials and perceived as ligands of various bitter taste receptors. We hypothesized that GLP-1 hormone is secreted through stimulation of a single bitter taste receptor by 1,10-phenanthroline which is known agonist of taste receptor type 2 member 5 (T2R5). To prove this hypothesis, we used the representatively well-known 1,10-phenanthroline as ligand of single receptor and evaluated the existence of T2R5 by double-labeling immunofluorescence and then 1,10-phenanthroline is able to secrete GLP-1 hormone through stimulation of T2R5 in human enteroendocrine cells. Consequently, we verify that GLP-1 hormone is colocalized with T2R5 in the human duodenum and ileum tissue and is secreted by 1,10-phenanthroline via T2R5 signal transduction in differentiated human enteroendocrine L cells. - Highlights: • Taste receptor type 2 member 5 (T2R5) is colocalized with GLP-1 hormone in human enteroendocrine cells. • GLP-1 secretion is stimulated by 1,10-phenanthroline via stimulation of T2R5. • Inhibition of the bitter taste pathway reduce GLP-1 secretion.

  3. GLP-1 secretion is stimulated by 1,10-phenanthroline via colocalized T2R5 signal transduction in human enteroendocrine L cell

    International Nuclear Information System (INIS)

    Park, Jiyoung; Kim, Ki-Suk; Kim, Kang-Hoon; Lee, In-Seung; Jeong, Hyeon-soo; Kim, Yumi; Jang, Hyeung-Jin

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) hormone is known to regulate blood glucose by an insulinotropic effect and increases proliferation as and also prevents apoptosis of pancreatic β cells. We know that GLP-1 is secreted by nutrients such as fatty acids and sweet compounds but also bitter compounds via stimulation of G-protein coupled receptors (GPCRs) in the gut. Among these, bitter compounds are multiply-contained in phytochemicals or artificial materials and perceived as ligands of various bitter taste receptors. We hypothesized that GLP-1 hormone is secreted through stimulation of a single bitter taste receptor by 1,10-phenanthroline which is known agonist of taste receptor type 2 member 5 (T2R5). To prove this hypothesis, we used the representatively well-known 1,10-phenanthroline as ligand of single receptor and evaluated the existence of T2R5 by double-labeling immunofluorescence and then 1,10-phenanthroline is able to secrete GLP-1 hormone through stimulation of T2R5 in human enteroendocrine cells. Consequently, we verify that GLP-1 hormone is colocalized with T2R5 in the human duodenum and ileum tissue and is secreted by 1,10-phenanthroline via T2R5 signal transduction in differentiated human enteroendocrine L cells. - Highlights: • Taste receptor type 2 member 5 (T2R5) is colocalized with GLP-1 hormone in human enteroendocrine cells. • GLP-1 secretion is stimulated by 1,10-phenanthroline via stimulation of T2R5. • Inhibition of the bitter taste pathway reduce GLP-1 secretion.

  4. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans

    DEFF Research Database (Denmark)

    Schjoldager, B T; Mortensen, P E; Christiansen, J

    1989-01-01

    Glucagon-like peptide 1 amide (GLP-1 amide), a predicted product of the glucagon gene (proglucagon 72-107-amide), and truncated GLP-1 (proglucagon 78-107-amide), recently isolated from porcine small intestine, were infused in doses of 100 and 400 ng/kg/hr and 12.5 and 50 ng/kg/hr, respectively...

  5. Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide

    Directory of Open Access Journals (Sweden)

    Jonathan Pinkney

    2010-08-01

    Full Text Available Jonathan Pinkney1, Thomas Fox1, Lakshminarayan Ranganath21Department of Diabetes and Endocrinology, Peninsula College of Medicine and Dentistry, Plymouth, United Kingdom; 2Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool University Hospital, Liverpool, United KingdomAbstract: Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1 plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Although the short duration of action of GLP-1 renders it unsuited to therapeutic use, 2 long-acting GLP-1 receptor agonists, exenatide and liraglutide, represent a significant advance in treatment. In controlled trials, both produce short-term glucose-lowering effects, with the reduction in hemoglobin A1c of up to 1.3%. These responses are often superior to those observed with additional oral agents. However, unlike sulfonylureas, thiazolidinediones, or insulin, all of which lead to significant weight gain, GLP-1 receptor agonists uniquely result in long-term weight loss of around 5 kg, and higher doses may enhance this further. Reduction in blood pressure of 2–7 mm Hg also has been observed. Both drugs produce transient mild gastrointestinal side effects; although mild hypoglycemia can occur, this is usually in combination with other hypoglycemic therapies. However, serious hypoglycemia and acute pancreatitis are rare. The once-daily dosage of liraglutide makes it more convenient than twice-daily dosage of prandial exenatide, and a superior glucose-lowering effect was observed in the only head-to-head comparison reported so far. Besides cost, these considerations currently favor liraglutide over exenatide. Further studies are needed to confirm long-term safety, and most importantly, that short-term benefits translate into long-term reductions of diabetes-related cardiovascular events and other complications.Keywords: diabetes, weight loss, glycemic control

  6. Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice.

    Science.gov (United States)

    Ahlkvist, L; Vikman, J; Pacini, G; Ahrén, B

    2012-10-10

    Apart from glucose, proteins and lipids also stimulate incretin and islet hormone secretion. However, the glucoregulatory effect of macronutrients in combination is poorly understood. We therefore developed an oral mixed meal model in mice to 1) explore the glucagon-like peptide-1 (GLP-1) and islet hormone responses to mixed meal versus isocaloric glucose, and 2) characterize the relative contribution of individual macronutrients to these responses. Anesthetized C57BL/6J female mice were orally gavaged with 1) a mixed meal (0.285 kcal; glucose, whey protein and peanut oil; 60/20/20% kcal) versus an isocaloric glucose load (0.285 kcal), and 2) a mixed meal (0.285 kcal) versus glucose, whey protein or peanut oil administered individually in their mixed meal caloric quantity, i.e., 0.171, 0.055 and 0.055 kcal, respectively. Plasma was analyzed for glucose, insulin and intact GLP-1 before and during oral challenges. Plasma glucose was lower after mixed meal versus after isocaloric glucose ingestion. In spite of this, the peak insulin response (P=0.02), the peak intact GLP-1 levels (P=0.006) and the estimated β-cell function (P=0.005) were higher. Furthermore, the peak insulin (P=0.004) and intact GLP-1 (P=0.006) levels were higher after mixed meal ingestion than the sum of responses to individual macronutrients. Compared to glucose alone, we conclude that there is a marked early insulin response to mixed meal ingestion, which emanates from a synergistic, rather than an additive, effect of the individual macronutrients in the mixed meal and is in part likely caused by increased levels of GLP-1. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

    International Nuclear Information System (INIS)

    Waser, Beatrice; Reubi, Jean Claude

    2011-01-01

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-Bolton-Hunter-exendin(9-39) antagonist radioligands were performed in mice pancreas and insulinomas as well as in human insulinomas; competition experiments were performed in the presence of increasing concentration of GLP-1(7-36)amide or exendin(9-39). The antagonist 125 I-Bolton-Hunter-exendin(9-39) labels mouse pancreatic β-cells and mouse insulinomas, but it does not label human pancreatic β-cells and insulinomas. High affinity displacement (IC 50 approximately 2 nM) is observed in mouse β-cells and insulinomas with either the exendin(9-39) antagonist or GLP-1(7-36)amide agonist. For comparison, the agonist 125 I-GLP-1(7-36)amide intensively labels mouse pancreatic β-cells, mouse insulinoma and human insulinomas; high affinity displacement is observed for the GLP-1(7-36)amide in all tissues; however, a 5 and 20 times lower affinity is found for exendin(9-39) in the mouse and human tissues, respectively. This study reports a species-dependent behaviour of the GLP-1 receptor antagonist exendin(9-39) that can optimally target GLP-1 receptors in mice but not in human tissue. Due to its overly low binding affinity, this antagonist is an inadequate targeting agent for human GLP-1 receptor-expressing tissues, as opposed to the GLP-1 receptor agonist, GLP-1(7-36)amide. (orig.)

  8. Value of the radiolabelled GLP-1 receptor antagonist exendin(9-39) for targeting of GLP-1 receptor-expressing pancreatic tissues in mice and humans

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Bern (Switzerland)

    2011-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. Moreover, it was recently reported that antagonist tracers were superior to agonist tracers for somatostatin and gastrin-releasing peptide receptor targeting of tumours. The present preclinical study determines therefore the value of an established GLP-1 receptor antagonist for the in vitro visualization of GLP-1 receptor-expressing tissues in mice and humans. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-Bolton-Hunter-exendin(9-39) antagonist radioligands were performed in mice pancreas and insulinomas as well as in human insulinomas; competition experiments were performed in the presence of increasing concentration of GLP-1(7-36)amide or exendin(9-39). The antagonist {sup 125}I-Bolton-Hunter-exendin(9-39) labels mouse pancreatic {beta}-cells and mouse insulinomas, but it does not label human pancreatic {beta}-cells and insulinomas. High affinity displacement (IC{sub 50} approximately 2 nM) is observed in mouse {beta}-cells and insulinomas with either the exendin(9-39) antagonist or GLP-1(7-36)amide agonist. For comparison, the agonist {sup 125}I-GLP-1(7-36)amide intensively labels mouse pancreatic {beta}-cells, mouse insulinoma and human insulinomas; high affinity displacement is observed for the GLP-1(7-36)amide in all tissues; however, a 5 and 20 times lower affinity is found for exendin(9-39) in the mouse and human tissues, respectively. This study reports a species-dependent behaviour of the GLP-1 receptor antagonist exendin(9-39) that can optimally target GLP-1 receptors in mice but not in human tissue. Due to its overly low binding affinity, this antagonist is an inadequate targeting agent for human GLP-1 receptor-expressing tissues, as opposed to the GLP-1 receptor agonist, GLP-1(7-36)amide. (orig.)

  9. Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells

    DEFF Research Database (Denmark)

    Wu, Bingbing; Wei, Shunhui; Petersen, Natalia

    2015-01-01

    Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca(2+). Ca(2+) then binds to synaptotagmin-7 as a major Ca(2+) sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment...... is ameliorated by glucagon-like peptide-1 (GLP-1) or by GLP-1 receptor agonists, which improve glucose homeostasis. However, the mechanism by which GLP-1 receptor agonists boost insulin secretion remains unclear. Here, we report that GLP-1 stimulates protein kinase A (PKA)-dependent phosphorylation...... of synaptotagmin-7 at serine-103, which enhances glucose- and Ca(2+)-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca(2+)-triggered exocytosis, whereas a phospho-inactive synaptotagmin-7 mutant disrupts GLP-1...

  10. Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion

    DEFF Research Database (Denmark)

    Hagemann, Dirk; Holst, Jens Juul; Gethmann, Arnica

    2007-01-01

    INTRODUCTION: Ghrelin is an orexigenic peptide predominantly secreted by the stomach. Ghrelin plasma levels rise before meal ingestion and sharply decline afterwards, but the mechanisms controlling ghrelin secretion are largely unknown. Since meal ingestion also elicits the secretion...... of the incretin hormone glucagon-like peptide 1 (GLP-1), we examined whether exogenous GLP-1 administration reduces ghrelin secretion in humans. PATIENTS AND METHODS: 14 healthy male volunteers were given intravenous infusions of GLP-1(1.2 pmol x kg(-1) min(-1)) or placebo over 390 min. After 30 min, a solid test...... meal was served. Venous blood was drawn frequently for the determination of glucose, insulin, C-peptide, GLP-1 and ghrelin. RESULTS: During the infusion of exogenous GLP-1 and placebo, GLP-1 plasma concentrations reached steady-state levels of 139+/-15 pmol/l and 12+/-2 pmol/l, respectively (p

  11. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors.

    Science.gov (United States)

    Secrest, Matthew H; Udell, Jacob A; Filion, Kristian B

    2017-04-01

    In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism

    DEFF Research Database (Denmark)

    Gejl, Michael; Gjedde, Albert; Egefjord, Lærke

    2016-01-01

    In animal models, the incretin hormone GLP-1 affects Alzheimer's disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients...... with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe...

  13. Rate of Homologous Desensitization and Internalization of the GLP-1 Receptor.

    Science.gov (United States)

    Shaaban, Ghina; Oriowo, Mabayoje; Al-Sabah, Suleiman

    2016-12-26

    The glucagon-like peptide-1 receptor (GLP-1R) is an important target in the treatment of type 2 diabetes mellitus. The aim of this study was to compare the rate of agonist stimulated desensitization and internalization of GLP-1R. To this end, an N-terminally myc-tagged GLP-1R was stably expressed in HEK-293 cells. Homologous desensitization was assessed by measuring the cAMP response to agonist stimulation following pre-incubation with agonist for up to 120 min. Receptor internalization was monitored using an indirect ELISA-based method and confocal microscopy. Pre-incubation with GLP-1 resulted in a time-dependent loss of response to a second stimulation. Washing cells following pre-incubation failed to bring cAMP levels back to basal. Taking this into account, two desensitization rates were calculated: "apparent" (t 1/2 = 19.27 min) and "net" (t 1/2 = 2.99 min). Incubation of cells with GLP-1 also resulted in a time-dependent loss of receptor cell surface expression (t 1/2 = 2.05 min). Rapid agonist-stimulated internalization of GLP-1R was confirmed using confocal microscopy. Stimulation of GLP-1R with GLP-1 results in rapid desensitization and internalization of the receptor. Interestingly, the rate of "net" desensitization closely matches the rate of internalization. Our results suggest that agonist-bound GLP-1R continues to generate cAMP after it has been internalized.

  14. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

    Directory of Open Access Journals (Sweden)

    Jingru Meng

    2016-04-01

    Full Text Available Glucagon-like peptide 1 (GLP-1 plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4 promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs, but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis.

  15. Nutrient Induced Type 2 and Chemical Induced Type 1 Experimental Diabetes Differently Modulate Gastric GLP-1 Receptor Expression

    Directory of Open Access Journals (Sweden)

    Olga Bloch

    2015-01-01

    Full Text Available T2DM patients demonstrate reduced GLP-1 receptor (GLP-1R expression in their gastric glands. Whether induced T2DM and T1DM differently affect the gastric GLP-1R expression is not known. This study assessed extrapancreatic GLP-1R system in glandular stomach of rodents with different types of experimental diabetes. T2DM and T1DM were induced in Psammomys obesus (PO by high-energy (HE diet and by streptozotocin (STZ in Sprague Dawly (SD rats, respectively. GLP-1R expression was determined in glandular stomach by RT PCR and immunohistomorphological analysis. The mRNA expression and cellular association of the GLP-1R in principal glands were similar in control PO and SD rats. However, nutrient and chemical induced diabetes resulted in opposite alterations of glandular GLP-1R expression. Diabetic PO demonstrated increased GLP-1R mRNA expression, intensity of cellular GLP-1R immunostaining, and frequency of GLP-1R positive cells in the neck area of principal glands compared with controls. In contrast, SD diabetic rats demonstrated decreased GLP-1 mRNA, cellular GLP-1R immunoreactivity, and frequency of GLP-1R immunoreactive cells in the neck area compared with controls. In conclusion, nutrient and chemical induced experimental diabetes result in distinct opposite alterations of GLP-1R expression in glandular stomach. These results suggest that induced T1DM and T2DM may differently modulate GLP-1R system in enteropancreatic axis.

  16. Pancreatic beta-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes.

    Science.gov (United States)

    Asmar, Meena; Højberg, Patricia V; Deacon, Carolyn F; Hare, Kristine; Holst, Jens J; Madsbad, Sten

    2010-02-25

    This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood glucose (BG) using insulin (mean diurnal BG: 6.4+/-0.3 mmol/l; HbA(1)c: 6.6+/-0.3%). Nine matched healthy subjects acted as controls. In controls, area-under-curve (AUC) for amylin, C-peptide and proinsulin were higher with GLP-1 than saline (PAUC amylin/C-peptide ratio was similar on both days, while AUC proinsulin/C-peptide ratio was higher with GLP-1 (P=0.02). In the patients, amylin, C-peptide and proinsulin AUCs were unaltered by near-normoglycaemia per se. Proinsulin responses to GLP-1 were unchanged, but amylin and C-peptide AUCs increased (PAUC amylin/C-peptide ratios rose to control levels. Near-normoglycaemia tended to reduce AUC proinsulin/C-peptide ratio, which was significant (P=0.04) with GLP-1, but still higher than with saline (P=0.004). In conclusion, amylin, C-peptide and proinsulin responses to glucose were unaffected by four weeks of near-normoglycaemia, whereas GLP-1 increased amylin and C-peptide secretion and amylin/C-peptide ratio. Near-normoglycaemia reduced proinsulin/C-peptide ratio during stimulation with GLP-1, suggesting that strict glycaemic control might ameliorate some of the disturbances in beta-cell function characterizing T2DM. Copyright 2010 Elsevier B.V. All rights reserved.

  17. A novel dual GLP-1 and GIP incretin receptor agonist is neuroprotective in a mouse model of Parkinson's disease by reducing chronic inflammation in the brain.

    Science.gov (United States)

    Cao, Lijun; Li, Dongfang; Feng, Peng; Li, Lin; Xue, Guo-Fang; Li, Guanglai; Hölscher, Christian

    2016-04-13

    The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are growth factors. GLP-1 mimetics are on the market as treatments for type 2 diabetes. Both GLP-1 and GIP mimetics have shown neuroprotective properties in previous studies. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed to treat diabetes. Here, we report the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once daily (20 mg/kg intraperitoneally) for 7 days and the dual agonist was coinjected once daily (50 nmol/kg intraperitoneally). We found that the drug reduced most of the MPTP-induced motor impairments in the rotarod, open-field locomotion, and muscle strength test. The number of tyrosine hydroxylase-positive neurons in the substantia nigra and striatum was reduced by MPTP and increased by DA-JC1. Synapse numbers (synaptophysin expression) were reduced in the substantia nigra and the striatum by MPTP and DA-JC1 reversed this effect. The activation of a chronic inflammation response by MPTP was considerably reduced by the dual agonist (DA) (astroglia and microglia activation). Therefore, dual agonists show promise as a novel treatment of PD.

  18. GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons.

    Science.gov (United States)

    Griffioen, Kathleen J; Wan, Ruiqian; Okun, Eitan; Wang, Xin; Lovett-Barr, Mary Rachael; Li, Yazhou; Mughal, Mohamed R; Mendelowitz, David; Mattson, Mark P

    2011-01-01

    glucagon-like peptide 1 (GLP-1) is an incretin hormone released from the gut in response to food intake. Whereas GLP-1 acts in the periphery to inhibit glucagon secretion and stimulate insulin release, it also acts in the central nervous system to mediate autonomic control of feeding, body temperature, and cardiovascular function. Because of its role as an incretin hormone, GLP-1 receptor analogs are used as a treatment for type 2 diabetes. Central or peripheral administration of GLP-1 increases blood pressure and heart rate, possibly by activating brainstem autonomic nuclei and increasing vagus nerve activity. However, the mechanism(s) by which GLP-1 receptor stimulation affects cardiovascular function are unknown. We used the long-lasting GLP-1 receptor agonist Exendin-4 (Ex-4) to test the hypothesis that GLP-1 signalling modulates central parasympathetic control of heart rate. using a telemetry system, we assessed heart rate in mice during central Ex-4 administration. Heart rate was increased by both acute and chronic central Ex-4 administration. Spectral analysis indicated that the high frequency and low frequency powers of heart rate variability were diminished by Ex-4 treatment. Finally, Ex-4 decreased both excitatory glutamatergic and inhibitory glycinergic neurotransmission to preganglionic parasympathetic cardiac vagal neurons. these data suggest that central GLP-1 receptor stimulation diminishes parasympathetic modulation of the heart thereby increasing heart rate.

  19. GLP-1 Receptor Activation Modulates Appetite- and Reward-Related Brain Areas in Humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; IJzerman, R.G.; ten Kulve, J.S.; Barkhof, F.; Konrad, R.J.; Drent, M.L.; Veltman, D.J.; Diamant, M.

    2014-01-01

    Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We

  20. Brainstem GLP-1 signalling contributes to cancer anorexia-cachexia syndrome in the rat.

    Science.gov (United States)

    Borner, Tito; Liberini, Claudia G; Lutz, Thomas A; Riediger, Thomas

    2018-03-15

    The cancer anorexia-cachexia syndrome (CACS) is a frequent and severe condition in cancer patients. Currently, no pharmacological treatment is approved for the therapy of CACS. Centrally, glucagon-like peptide-1 (GLP-1) is expressed in the nucleus tractus solitarii (NTS) and is implicated in malaise, nausea and food aversion. The NTS is reciprocally connected to brain sites implicated in the control of energy balance including the area postrema (AP), which mediates CACS in certain tumour models. Given the role of GLP-1 as a mediator of anorexia under acute sickness conditions, we hypothesized that brainstem GLP-1 signalling might play a role in the mediation of CACS. Using hepatoma tumour-bearing (TB) rats, we first tested whether the chronic delivery of the GLP-1R antagonist exendin-9 (Ex-9) into the fourth ventricle attenuates CACS. Second, we investigated whether a genetic knockdown of GLP-1 expression in the NTS ameliorates CACS. Ex-9 attenuated anorexia, body weight loss, muscle and fat depletion compared to TB controls. Similarly, TB animals with a knockdown of GLP-1 expression in the NTS had higher food intake, reduced body weight loss, and higher lean and fat mass compared to TB controls. Our study identifies brainstem GLP-1 as crucial mediator of CACS in hepatoma TB rats. The GLP-1R represents a promising target against CACS and possibly other forms of disease-related anorexia/cachexia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Normalization of fasting glycaemia by intravenous GLP-1 ([7-36 amide] or [7-37]) in type 2 diabetic patients

    DEFF Research Database (Denmark)

    Nauck, M A; Weber, I; Bach, I

    1998-01-01

    (glucose-oxidase), insulin and C-peptide (ELISA) was measured during infusion and for 4 h thereafter. Indirect calorimetry was performed. Fasting hyperglycaemia was 11.7+/-0.9 [7-36 amide] and 11.3+/-0.9 mmol l(-1) [7-37]. GLP-1 infusions stimulated insulin secretion approximately 3-fold (insulin peak 168......Intravenous GLP-1 [7-36 amide] can normalize fasting hyperglycaemia in Type 2 diabetic patients. Whether GLP-1 [7-37] has similar effects and how quickly plasma glucose concentrations revert to hyperglycaemia after stopping GLP-1 is not known. Therefore, 8 patients with Type 2 diabetes (5 female, 3...... male; 65+/-6 years; BMI 34.3+/-7.9 kg m(-2); HbA1c 9.6+/-1.2%; treatment with diet alone (n=2), sulphonylurea (n=5), metformin (n=1)) were examined twice in randomized order. GLP-1 [7-36 amide] or [7-37] (1 pmol kg(-1)min(-1) were infused intravenously over 4 h in fasted subjects. Plasma glucose...

  2. CORRELATION BETWEEN PRE AND POSTOPERATIVE LEVELS OF GLP-1/GLP-2 AND WEIGHT LOSS AFTER ROUX-EN-Y GASTRIC BYPASS: A PROSPECTIVE STUDY

    Science.gov (United States)

    CAZZO, Everton; GESTIC, Martinho Antonio; UTRINI, Murillo Pimentel; PAREJA, José Carlos; CHAIM, Elinton Adami; GELONEZE, Bruno; BARRETO, Maria Rita Lazzarini; MAGRO, Daniéla Oliveira

    2016-01-01

    ABSTRACT Background: The role of gut hormones in glucose homeostasis and weight loss achievement and maintenance after bariatric surgery appears to be a key point in the understanding of the beneficial effects observed following these procedures. Aim: To determine whether there is a correlation between the pre and postoperative levels of both GLP-1 and GLP-2 and the excess weight loss after Roux-en-Y gastric bypass (RYGB). Methods: An exploratory prospective study which enrolled 11 individuals who underwent RYGB and were followed-up for 12 months. GLP-1 and GLP-2 after standard meal tolerance test (MTT) were determined before and after surgery and then correlated with the percentage of excess loss (%EWL). Results: GLP-2 AUC presented a significant postoperative increase (945.3±449.1 vs.1787.9±602.7; p=0.0037); GLP-1 AUC presented a non-significant trend towards increase after RYGB (709.6±320.4 vs. 1026.5±714.3; p=0.3808). Mean %EWL was 66.7±12.2%. There was not any significant correlation between both the pre and postoperative GLP-1 AUCs and GLP-2 AUCs and the %EWL achieved after one year. Conclusion: There was no significant correlation between the pre and postoperative levels of the areas under the GLP-1 and GLP-2 curves with the percentage of weight loss reached after one year. PMID:28076481

  3. Development of a cysteine-deprived and C-terminally truncated GLP-1 receptor

    DEFF Research Database (Denmark)

    Underwood, Christina Rye; Knudsen, Lotte Bjerre; Garibay, Patrick W.

    2013-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) belongs to family B of the G-protein coupled receptors (GPCRs), and has become a promising target for the treatment of type 2 diabetes. Here we describe the development and characterization of a fully functional cysteine-deprived and C......-terminally truncated GLP-1R. Single cysteines were initially substituted with alanine, and functionally redundant cysteines were subsequently changed simultaneously. Our results indicate that Cys174, Cys226, Cys296 and Cys403 are important for the GLP-1-mediated response, whereas Cys236, Cys329, Cys341, Cys347, Cys438...... that the membrane proximal part of the C-terminal is involved in receptor expression at the cell surface. The results show that seven cysteines and more than half of the C-terminal tail can be removed from GLP-1R without compromising GLP-1 binding or function....

  4. The Antidiabetic Mechanisms of Polyphenols Related to Increased Glucagon-Like Peptide-1 (GLP1 and Insulin Signaling

    Directory of Open Access Journals (Sweden)

    J. Abraham Domínguez Avila

    2017-05-01

    Full Text Available Type-2 diabetes mellitus (T2DM is an endocrine disease related to impaired/absent insulin signaling. Dietary habits can either promote or mitigate the onset and severity of T2DM. Diets rich in fruits and vegetables have been correlated with a decreased incidence of T2DM, apparently due to their high polyphenol content. Polyphenols are compounds of plant origin with several documented bioactivities related to health promotion. The present review describes the antidiabetic effects of polyphenols, specifically related to the secretion and effects of insulin and glucagon-like peptide 1 (GLP1, an enteric hormone that stimulates postprandial insulin secretion. The evidence suggests that polyphenols from various sources stimulate L-cells to secrete GLP1, increase its half-life by inhibiting dipeptidyl peptidase-4 (DPP4, stimulate β-cells to secrete insulin and stimulate the peripheral response to insulin, increasing the overall effects of the GLP1-insulin axis. The glucose-lowering potential of polyphenols has been evidenced in various acute and chronic models of healthy and diabetic organisms. Some polyphenols appear to exert their effects similarly to pharmaceutical antidiabetics; thus, rigorous clinical trials are needed to fully validate this claim. The broad diversity of polyphenols has not allowed for entirely describing their mechanisms of action, but the evidence advocates for their regular consumption.

  5. Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on Bone Cell Metabolism.

    Science.gov (United States)

    Hansen, Morten S S; Tencerova, Michaela; Frølich, Jacob; Kassem, Moustapha; Frost, Morten

    2018-01-01

    The relationship between gut and skeleton is increasingly recognized as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibit several physiological functions including regulation of islet hormone secretion and glucose levels. A number of GLP-1 receptor agonists (GLP-1RAs) are currently used in treatment of type 2 diabetes and obesity. However, GIP and GLP-1 cognate receptors are widely expressed suggesting that incretin hormones mediate effects beyond control of glucose homeostasis, and reports on associations between incretin hormones and bone metabolism have emerged. The aim of this MiniReview was to provide an overview of current knowledge regarding the in vivo and in vitro effects of GIP and GLP-1 on bone metabolism. We identified a total of 30 pre-clinical and clinical investigations of the effects of GIP, GLP-1 and GLP-1RAs on bone turnover markers, bone mineral density (BMD), bone microarchitecture and fracture risk. Studies conducted in cell cultures and rodents demonstrated that GIP and GLP-1 play a role in regulating skeletal homeostasis, with pre-clinical data suggesting that GIP inhibits bone resorption whereas GLP-1 may promote bone formation and enhance bone material properties. These effects are not corroborated by clinical studies. While there is evidence of effects of GIP and GLP-1 on bone metabolism in pre-clinical investigations, clinical trials are needed to clarify whether similar effects are present and clinically relevant in humans. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  6. Impact of Diabetes-Specific Nutritional Formulas versus Oatmeal on Postprandial Glucose, Insulin, GLP-1 and Postprandial Lipidemia

    Directory of Open Access Journals (Sweden)

    Adham Mottalib

    2016-07-01

    Full Text Available Diabetes-specific nutritional formulas (DSNFs are frequently used as part of medical nutrition therapy for patients with diabetes. This study aims to evaluate postprandial (PP effects of 2 DSNFs; Glucerna (GL and Ultra Glucose Control (UGC versus oatmeal (OM on glucose, insulin, glucagon-like peptide-1 (GLP-1, free fatty acids (FFA and triglycerides (TG. After an overnight fast, 22 overweight/obese patients with type 2 diabetes were given 200 kcal of each of the three meals on three separate days in random order. Blood samples were collected at baseline and at 30, 60, 90, 120, 180 and 240 min. Glucose area under the curve (AUC0–240 after GL and UGC was lower than OM (p < 0.001 for both. Insulin positive AUC0–120 after UGC was higher than after OM (p = 0.02. GLP-1 AUC0–120 and AUC0–240 after GL and UGC was higher than after OM (p < 0.001 for both. FFA and TG levels were not different between meals. Intake of DSNFs improves PP glucose for 4 h in comparison to oatmeal of similar caloric level. This is achieved by either direct stimulation of insulin secretion or indirectly by stimulating GLP-1 secretion. The difference between their effects is probably related to their unique blends of amino acids, carbohydrates and fat.

  7. Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

    Science.gov (United States)

    Scott, Robert A.; Freitag, Daniel F.; Li, Li; Chu, Audrey Y.; Surendran, Praveen; Young, Robin; Grarup, Niels; Stancáková, Alena; Chen, Yuning; V.Varga, Tibor; Yaghootkar, Hanieh; Luan, Jian'an; Zhao, Jing Hua; Willems, Sara M.; Wessel, Jennifer; Wang, Shuai; Maruthur, Nisa; Michailidou, Kyriaki; Pirie, Ailith; van der Lee, Sven J.; Gillson, Christopher; Olama, Ali Amin Al; Amouyel, Philippe; Arriola, Larraitz; Arveiler, Dominique; Aviles-Olmos, Iciar; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês; Garcia, Sara Benlloch; Bis, Joshua C.; Blankenberg, Stefan; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Borecki, Ingrid B.; Bork-Jensen, Jette; Bowden, Sarah; Caldas, Carlos; Caslake, Muriel; Cupples, L. Adrienne; Cruchaga, Carlos; Czajkowski, Jacek; den Hoed, Marcel; Dunn, Janet A.; Earl, Helena M.; Ehret, Georg B.; Ferrannini, Ele; Ferrieres, Jean; Foltynie, Thomas; Ford, Ian; Forouhi, Nita G.; Gianfagna, Francesco; Gonzalez, Carlos; Grioni, Sara; Hiller, Louise; Jansson, Jan-Håkan; Jørgensen, Marit E.; Jukema, J. Wouter; Kaaks, Rudolf; Kee, Frank; Kerrison, Nicola D.; Key, Timothy J.; Kontto, Jukka; Kote-Jarai, Zsofia; Kraja, Aldi T.; Kuulasmaa, Kari; Kuusisto, Johanna; Linneberg, Allan; Liu, Chunyu; Marenne, Gaëlle; Mohlke, Karen L.; Morris, Andrew P.; Muir, Kenneth; Müller-Nurasyid, Martina; Munroe, Patricia B.; Navarro, Carmen; Nielsen, Sune F.; Nilsson, Peter M.; Nordestgaard, Børge G.; Packard, Chris J.; Palli, Domenico; Panico, Salvatore; Peloso, Gina M.; Perola, Markus; Peters, Annette; Poole, Christopher J.; Quirós, J. Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Salomaa, Veikko; Sánchez, María-José; Sattar, Naveed; Sharp, Stephen J.; Sims, Rebecca; Slimani, Nadia; Smith, Jennifer A.; Thompson, Deborah J.; Trompet, Stella; Tumino, Rosario; van der A, Daphne L.; van der Schouw, Yvonne T.; Virtamo, Jarmo; Walker, Mark; Walter, Klaudia; Abraham, Jean E.; Amundadottir, Laufey T.; Aponte, Jennifer L.; Butterworth, Adam S.; Dupuis, Josée; Easton, Douglas F.; Eeles, Rosalind A.; Erdmann, Jeanette; Franks, Paul W.; Frayling, Timothy M.; Hansen, Torben; Howson, Joanna M. M.; Jørgensen, Torben; Kooner, Jaspal; Laakso, Markku; Langenberg, Claudia; McCarthy, Mark I.; Pankow, James S.; Pedersen, Oluf; Riboli, Elio; Rotter, Jerome I.; Saleheen, Danish; Samani, Nilesh J.; Schunkert, Heribert; Vollenweider, Peter; O'Rahilly, Stephen; Deloukas, Panos; Danesh, John; Goodarzi, Mark O.; Kathiresan, Sekar; Meigs, James B.; Ehm, Margaret G.; Wareham, Nicholas J.; Waterworth, Dawn M.

    2016-01-01

    Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process. PMID:27252175

  8. Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual ß-cell function

    DEFF Research Database (Denmark)

    Kielgast, Urd; Holst, Jens Juul; Madsbad, Sten

    2011-01-01

    To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual ß-cell function.......To investigate the effect of exogenous as well as endogenous glucagon-like peptide 1 (GLP-1) on postprandial glucose excursions and to characterize the secretion of incretin hormones in type 1 diabetic patients with and without residual ß-cell function....

  9. Major adverse cardiovascular event reduction with GLP-1 and SGLT2 agents: evidence and clinical potential

    Science.gov (United States)

    Røder, Michael E.

    2017-01-01

    Treatment of patients with type 2 diabetes is directed against treating symptoms of hyperglycemia, minimizing the risk of hypoglycemia, and the risk of microvascular and macrovascular complications. The majority of patients with type 2 diabetes die from cardiovascular or cerebrovascular disease. Future therapies should therefore focus on reducing cardiovascular morbidity in this high-risk population. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are two drug classes with proven antihyperglycemic effect in type 2 diabetes. However, these drugs seem to have other effects such as weight reduction, low risk of hypoglycemia, and blood pressure reduction. Emerging evidence suggests pleiotropic effects, which potentially could be important in reducing cardiovascular risk. Prompted by regulatory authorities demanding cardiovascular outcome trials (CVOTs) assessing the cardiovascular safety of new antihyperglycemic drug candidates, many CVOTs are ongoing and a few of these are finalized. Somewhat surprising recent CVOTs in both drug classes have shown promising data on cardiovascular morbidity and mortality in patients with a very high risk of cardiovascular events. It is uncertain whether this is a class effect of the two drug classes, and it is yet unproven whether long-term cardiovascular benefits of these drugs can be extrapolated to populations at lower risk of cardiovascular disease. The aim of the present review is to give an overview of our current knowledge of the GLP-1RA and SGLT2-i classes, with specific focus on mechanisms of action, effects on cardiovascular risk factors and cardiovascular morbidity and mortality from the CVOTs presently available. The clinical potential of these data is discussed. PMID:29344329

  10. Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea.

    Science.gov (United States)

    De Jonghe, Bart C; Holland, Ruby A; Olivos, Diana R; Rupprecht, Laura E; Kanoski, Scott E; Hayes, Matthew R

    2016-01-01

    While chemotherapy-induced nausea and vomiting are clinically controlled in the acute (anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24 h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48 h) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis.

    LENUS (Irish Health Repository)

    Hogan, A E

    2011-11-01

    The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells.

  12. A surface plasmon resonance assay for characterisation and epitope mapping of anti-GLP-1 antibodies.

    Science.gov (United States)

    Thomsen, Lasse; Gurevich, Leonid

    2018-04-19

    The incretin hormone glucagon-like peptide-1 (GLP-1) has been subject to substantial pharmaceutical research regarding the treatment of type 2 diabetes mellitus. However, quantification of GLP-1 levels remains complicated due to the low circulation concentration and concurrent existence of numerous metabolites, homologous peptides, and potentially introduced GLP-1 receptor agonists. Surface plasmon resonance (SPR) facilitates real-time monitoring allowing a more detailed characterisation of the interaction compared with conventional enzyme-linked immunosorbent assays (ELISA). In this paper, we describe the development of the first SPR assays for characterisation of anti-GLP-1 antibodies for ELISA purposes. Binding responses were obtained on covalently immobilised anti-GLP-1 antibodies at 12°C, 25°C, and 40°C and fitted to a biomolecular (1:1) interaction model showing association rates of 1.01 × 10 3 to 4.54 × 10 3  M -1  s -1 and dissociation rates of 3.56 × 10 -5 to 1.56 × 10 -3  s -1 leading to affinities of 35.2 to 344 nM, depending on the temperature. Determination of thermodynamic properties revealed an enthalpy driven interaction (ΔH polar amino acids (ΔC p  < 0). Pair-wise epitope mapping was performed on captured anti-GLP-1 antibodies followed by subsequent interaction with GLP-1 (7-36) and other anti-GLP-1 antibodies. A global evaluation of every binding response led to an epitope map elucidating the potential of various anti-GLP-1 antibody pairs for sandwich ELISA and hence pinpointing the optimal antibody combinations. The SPR assays proved capable of providing vital information for ELISA development endorsing it as a useful optimisation tool. Copyright © 2018 John Wiley & Sons, Ltd.

  13. GLP-1 analog raises glucose transport capacity of blood-brain barrier in Alzheimer's disease

    DEFF Research Database (Denmark)

    Gejl, M.; Brock, B.; Egefjord, L.

    2017-01-01

    transport capacity (Tmax) with [18F]FDG (FDG) (ClinicalTrials.gov NCT01469351). Results: In both groups, the Tmax estimates declined in proportion to the duration of AD. The GLP-1 analog treatment very significantly (P cerebral cortex as a whole compared...... and degeneration. Hypothesis: The incretin hormone GLP-1 prevents the decline of the cerebral metabolic rate of glucose that signifies cognitive impairment, synaptic dysfunction, and disease evolution in AD, and GLP-1 may directly activate GLUT1 transport in brain capillary endothelium. For this reason, we here...

  14. GLP-1 Amidation Efficiency Along the Length of the Intestine in Mice, Rats and Pigs and in GLP-1 Secreting Cell Lines

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Albrechtsen, Nicolai Jacob Wewer; Windeløv, Johanne Agerlin

    2014-01-01

    and whether this varied with the six different locations. We also analyzed the amidation in 3 GLP-1 secreting cell lines (GLUTag, NCI-H716 and STC-1). To our surprise there were marked differences between the 3 species with respect to the concentration of GLP-1 in gut. In the mouse, concentrations increased...... sites, whereas rats and pigs on average had around 2.5 and 4 times higher levels of amidated compared to non-amidated GLP-1, although the ratio varied depending upon the location. GLUTag, NCI-H716 and STC-1 cells all exhibited partial amidation with 2-4 times higher levels of amidated compared to non...

  15. Transmembrane α-Helix 2 and 7 Are Important for Small Molecule-Mediated Activation of the GLP-1 Receptor

    DEFF Research Database (Denmark)

    Underwood, Christina Rye; Møller Knudsen, Sanne; Schjellerup Wulff, Birgitte

    2011-01-01

    Glucagon-like peptide-1 (GLP-1) activates the GLP-1 receptor (GLP-1R), which belongs to family B of the G-protein-coupled receptors. We previously identified a selective small molecule ligand, compound 2, that acted as a full agonist and allosteric modulator of GLP-1R. In this study, the structur......Glucagon-like peptide-1 (GLP-1) activates the GLP-1 receptor (GLP-1R), which belongs to family B of the G-protein-coupled receptors. We previously identified a selective small molecule ligand, compound 2, that acted as a full agonist and allosteric modulator of GLP-1R. In this study......, the structurally related small molecule, compound 3, stimulated cAMP production from GLP-1R, but not from the homologous glucagon receptor (GluR). The receptor selectivity encouraged a chimeric receptor approach to identify domains important for compound 3-mediated activation of GLP-1R. A subsegment of the GLP-1R...... transmembrane domain containing TM2 to TM5 was sufficient to transfer compound 3 responsiveness to GluR. Therefore, divergent residues in this subsegment of GLP-1R and GluR are responsible for the receptor selectivity of compound 3. Functional analyses of other chimeric receptors suggested that the existence...

  16. 99mTc Labeled Glucagon-Like Peptide-1-Analogue (99mTc-GLP1) Scintigraphy in the Management of Patients with Occult Insulinoma

    Science.gov (United States)

    Sowa-Staszczak, Anna; Trofimiuk-Müldner, Małgorzata; Stefańska, Agnieszka; Tomaszuk, Monika; Buziak-Bereza, Monika; Gilis-Januszewska, Aleksandra; Jabrocka-Hybel, Agata; Głowa, Bogusław; Małecki, Maciej; Bednarczuk, Tomasz; Kamiński, Grzegorz; Kowalska, Aldona; Mikołajczak, Renata; Janota, Barbara; Hubalewska-Dydejczyk, Alicja

    2016-01-01

    Introduction The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma. Materials and Methods Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions. Results Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of 99mTcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that 99mTc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient). Conclusions 99mTc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective

  17. Modulation of taste sensitivity by GLP-1 signaling in taste buds.

    Science.gov (United States)

    Martin, Bronwen; Dotson, Cedrick D; Shin, Yu-Kyong; Ji, Sunggoan; Drucker, Daniel J; Maudsley, Stuart; Munger, Steven D

    2009-07-01

    Modulation of sensory function can help animals adjust to a changing external and internal environment. Even so, mechanisms for modulating taste sensitivity are poorly understood. Using immunohistochemical, biochemical, and behavioral approaches, we found that the peptide hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) are expressed in mammalian taste buds. Furthermore, we found that GLP-1 signaling plays an important role in the modulation of taste sensitivity: GLP-1R knockout mice exhibit a dramatic reduction in sweet taste sensitivity as well as an enhanced sensitivity to umami-tasting stimuli. Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of taste function in mammals.

  18. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine

    DEFF Research Database (Denmark)

    Mortensen, Kristine; Christensen, Louise Lundby; Holst, Jens Juul

    2003-01-01

    BACKGROUND: The incretin hormones GIP and GLP-1 are thought to be produced in separate endocrine cells located in the proximal and distal ends of the mammalian small intestine, respectively. METHODS AND RESULTS: Using double immunohistochemistry and in situ hybridization, we found that GLP-1 was ....... CONCLUSIONS: Our results provide a morphological basis to suggest simultaneous, rather than sequential, secretion of these hormones by postprandial luminal stimulation....

  19. Enteroendocrine L Cells Sense LPS after Gut Barrier Injury to Enhance GLP-1 Secretion

    Directory of Open Access Journals (Sweden)

    Lorène J. Lebrun

    2017-10-01

    Full Text Available Summary: Glucagon-like peptide 1 (GLP-1 is a hormone released from enteroendocrine L cells. Although first described as a glucoregulatory incretin hormone, GLP-1 also suppresses inflammation and promotes mucosal integrity. Here, we demonstrate that plasma GLP-1 levels are rapidly increased by lipopolysaccharide (LPS administration in mice via a Toll-like receptor 4 (TLR4-dependent mechanism. Experimental manipulation of gut barrier integrity after dextran sodium sulfate treatment, or via ischemia/reperfusion experiments in mice, triggered a rapid rise in circulating GLP-1. This phenomenon was detected prior to measurable changes in inflammatory status and plasma cytokine and LPS levels. In human subjects, LPS administration also induced GLP-1 secretion. Furthermore, GLP-1 levels were rapidly increased following the induction of ischemia in the human intestine. These findings expand traditional concepts of enteroendocrine L cell biology to encompass the sensing of inflammatory stimuli and compromised mucosal integrity, linking glucagon-like peptide secretion to gut inflammation. : Lebrun et al. demonstrate that enteroendocrine L cells sense lipopolysaccharides (pro-inflammatory bacterial compounds after gut injury and respond by secreting glucagon-like peptide 1. These findings expand concepts of L cell function to include roles as both a nutrient and pathogen sensor, linking glucagon-like peptide secretion to gut inflammation. Keywords: glucagon-like peptide 1, lipopolysaccharides, enteroendocrine cells, TLR4, gut injury, intestinal ischemia, inflammation

  20. The antagonistic metabolite of GLP-1, GLP-1 (9-36)amide, does not influence gastric emptying and hunger sensations in man

    DEFF Research Database (Denmark)

    Nagell, Carl Frederic; Pedersen, Jan F; Holst, Jens Juul

    2007-01-01

    and antral emptying of a meal. MATERIAL AND METHODS: Six healthy volunteers were tested in a double-blind, placebo-controlled fashion. Antral emptying of a liquid meal and hunger ratings were determined using ultrasound technology and visual analogue scale scoring during infusions of saline or GLP-1 (9...

  1. Cost-effectiveness of once daily GLP-1 receptor agonist lixisenatide compared to bolus insulin both in combination with basal insulin for the treatment of patients with type 2 diabetes in Norway.

    Science.gov (United States)

    Huetson, Pernilla; Palmer, James L; Levorsen, Andrée; Fournier, Marie; Germe, Maeva; McLeod, Euan

    2015-01-01

    Lixisenatide is a potent, selective and short-acting once daily prandial glucagon-like peptide-1 receptor agonist which lowers glycohemoglobin and body weight by clinically significant amounts in patients with type 2 diabetes treated with basal insulin, with limited risk of hypoglycemia. To assess the cost-effectiveness of lixisenatide versus bolus insulin, both in combination with basal insulin, in patients with type 2 diabetes in Norway. The IMS CORE Diabetes Model, a non-product-specific and validated simulation model, was used to make clinical and cost projections. Transition probabilities, risk adjustments and the progression of complication risk factors were derived from the UK Prospective Diabetes Study, supplemented with Norwegian data. Patients were assumed to receive combination treatment with basal insulin, lixisenatide or bolus insulin therapy for 3 years, followed by intensification of a basal-bolus insulin regimen for their remaining lifetime. Simulated healthcare costs, taken from the public payer perspective, were derived from microcosting and diagnosis related groups, discounted at 4% per annum and reported in Norwegian krone (NOK). Productivity costs were also captured based on extractions from the Norwegian Labor and Welfare Administration. Health state utilities were derived from a systematic literature review. Sensitivity and scenario analyses were performed. Lixisenatide in combination with basal insulin was associated with increased quality-adjusted life years (QALYs) and reduced lifetime healthcare costs compared to bolus insulin in combination with basal insulin in patients with Type 2 diabetes, and can be considered dominant. The net monetary benefit of lixisenatide versus bolus insulin was NOK 39,369 per patient. Results were sensitive to discounting, the application of excess body weight associated disutility and uncertainty surrounding the changes in HbA1c. Lixisenatide may be considered an economically efficient therapy in combination

  2. Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice

    Directory of Open Access Journals (Sweden)

    Katsunori Nonogaki

    2018-01-01

    Full Text Available A recent report suggested that brain-derived serotonin (5-HT is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1 receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph inhibitor p-chlorophenylalanine (PCPA for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high-affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors.

  3. Serum lipase activity and concentration during intravenous infusions of GLP-1 and PYY3-36 and after ad libitum meal ingestion in overweight men

    DEFF Research Database (Denmark)

    Schmidt, Julie Berg; Sjödin, Anders Mikael; Stevner, Lene Susanne

    2016-01-01

    To examine the effect on serum lipase activity and protein concentration of intravenous infusions of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY3-36) and of an ad libitum meal in healthy overweight men. Twenty-five healthy, male subjects participated in this randomized, double-blinded, pl......To examine the effect on serum lipase activity and protein concentration of intravenous infusions of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY3-36) and of an ad libitum meal in healthy overweight men. Twenty-five healthy, male subjects participated in this randomized, double...... the infusion and after intake of an ad libitum meal for measurement of serum lipase. Serum lipase levels measured by enzyme-linked immunosorbent assay (ELISA) following mono-infusions of GLP-1 and PYY3-36 were comparable to serum lipase levels following placebo (P = 0.054 and P = 0.873, respectively......). Following the co-infusion of GLP-1 and PYY3-36, serum lipase levels measured by ELISA decreased over time compared to placebo (P = 0.012). However, the between-group difference was not consistent when each time point was analyzed separately. On the placebo day, serum lipase levels measured by ELISA after...

  4. Current evidence for a role of GLP-1 in Roux-en-Y gastric bypass-induced remission of type 2 diabetes

    DEFF Research Database (Denmark)

    Rhee, Nicolai Alexander; Vilsbøll, T; Knop, F K

    2012-01-01

    Weight-reducing surgical procedures such as Roux-en-Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM......-induced remission of T2DM are lacking. This article critically evaluates the current evidence for a role of GLP-1 in RYGB-induced remission of T2DM.......Weight-reducing surgical procedures such as Roux-en-Y gastric bypass (RYGB) have proven efficient as means of decreasing excess body weight. Furthermore, some studies report that up to 80% of patients with type 2 diabetes mellitus (T2DM) undergoing RYGB experience complete remission of their T2DM...... antidiabetic effects of GLP-1 are thought to be key mediators in RYGB-induced remission of T2DM. However, the published studies on the impact of RYGB on GLP-1 secretion are few, small and often not controlled properly. Furthermore, mechanistic studies delineating the role of endogenous GLP-1 secretion in RYGB...

  5. A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson's disease by increasing expression of BNDF.

    Science.gov (United States)

    Ji, Chenhui; Xue, Guo-Fang; Lijun, Cao; Feng, Peng; Li, Dongfang; Li, Lin; Li, Guanglai; Hölscher, Christian

    2016-03-01

    The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed and are tested in diabetic patients. Here we demonstrate the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20 mg/kg i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD. Copyright © 2016. Published by Elsevier B.V.

  6. Co-culture of clonal beta cells with GLP-1 and glucagon-secreting cell line impacts on beta cell insulin secretion, proliferation and susceptibility to cytotoxins.

    Science.gov (United States)

    Green, Alastair D; Vasu, Srividya; Moffett, R Charlotte; Flatt, Peter R

    2016-06-01

    We investigated the direct effects on insulin releasing MIN6 cells of chronic exposure to GLP-1, glucagon or a combination of both peptides secreted from GLUTag L-cell and αTC1.9 alpha-cell lines in co-culture. MIN6, GLUTag and αTC1.9 cell lines exhibited high cellular hormone content and release of insulin, GLP-1 and glucagon, respectively. Co-culture of MIN6 cells with GLUTag cells significantly increased cellular insulin content, beta-cell proliferation, insulin secretory responses to a range of established secretogogues and afforded protection against exposure cytotoxic concentrations of glucose, lipid, streptozotocin or cytokines. Benefits of co-culture of MIN6 cells with αTC1.9 alphacells were limited to enhanced beta-cell proliferation with marginal positive actions on both insulin secretion and cellular protection. In contrast, co-culture of MIN6 with GLUTag cells plus αTC1.9 cells, markedly enhanced both insulin secretory responses and protection against beta-cell toxins compared with co-culture with GLUTag cells alone. These data indicate important long-term effects of conjoint GLP-1 and glucagon exposure on beta-cell function. This illustrates the possible functional significance of alpha-cell GLP-1 production as well as direct beneficial effects of dual agonism at beta-cell GLP-1 and glucagon receptors. Copyright © 2016 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

  7. Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Sikirica MV

    2017-09-01

    Full Text Available Mirko V Sikirica,1 Alan A Martin,2 Robert Wood,3 Andrea Leith,3 James Piercy,3 Victoria Higgins3 1Value Evidence and Outcomes, GlaxoSmithKline, Collegeville, PA, USA; 2Value Evidence and Outcomes, GlaxoSmithKline, London, UK; 3Diabetes, Adelphi Real World, Bollington, Cheshire, UK Aim: Nonadherence to glucagon-like peptide-1 receptor agonists (GLP1 RAs is relatively common among patients with type 2 diabetes mellitus (T2DM. This study sought to identify reasons why patients discontinue GLP1 RAs.Materials and methods: Retrospective data from the Adelphi Diabetes Disease Specific Programme were used. Physicians managing patients with T2DM were surveyed via face-to-face interviews, and patients treated for T2DM were surveyed via self-completed questionnaires. Patient data were stratified by current versus prior GLP1 RA use.Results: Physicians (n=443 most frequently reported inadequate blood glucose control (45.6%, nausea/vomiting (43.8%, and gastrointestinal (GI side effects (36.8% as reasons for GLP1 RA discontinuation. Patients (n=194 reported the GI-related issues “Made me feel sick” (64.4% and “Made me throw up” (45.4% as their top reasons for discontinuation. The most common problems reported (excluding cost for those currently using GLP1 RAs were “Prefer oral medication over injections” (patients 56%, physicians 32.6%, “Made me feel sick” (patients 38.1%, physicians 16.3%, and “Did not help lose weight” (patients 25.4%, physicians 18%. The most bothersome problems for patients globally (frequency reporting very/extremely bothersome (excluding cost were “Difficult to plan meals around” (55.6%, “Made me throw up” (51.6%, and “Caused weight gain” (50%.Conclusion: Both patients and physicians reported GI-related issues as a prominent factor, but disparities between patient experiences and physician perceptions were revealed, suggesting gaps in physician–patient communication. Understanding patients

  8. Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in patients with type 2 diabetes.

    Science.gov (United States)

    Temizkan, S; Deyneli, O; Yasar, M; Arpa, M; Gunes, M; Yazici, D; Sirikci, O; Haklar, G; Imeryuz, N; Yavuz, D G

    2015-02-01

    Artificial sweeteners were thought to be metabolically inactive, but after demonstrating that the gustatory mechanism was also localized in the small intestine, suspicions about the metabolic effects of artificial sweeteners have emerged. The objective of this study was to determine the effect of artificial sweeteners (aspartame and sucralose) on blood glucose, insulin, c-peptide and glucagon-like peptide-1 (GLP-1) levels. Eight newly diagnosed drug-naive type 2 diabetic patients (mean age 51.5±9.2 years; F/M: 4/4) and eight healthy subjects (mean age 45.0±4.1 years; F/M: 4/4) underwent 75 g oral glucose tolerance test (OGTT). During OGTT, glucose, insulin, c-peptide and GLP-1 were measured at 15- min intervals for 120 min. The OGTTs were performed at three settings on different days, where subjects were given 72 mg of aspartame and 24 mg of sucralose in 200 ml of water or 200 ml of water alone 15 min before OGTT in a single-blinded randomized order. In healthy subjects, the total area under the curve (AUC) of glucose was statistically significantly lower in the sucralose setting than in the water setting (P=0.002). There was no difference between the aspartame setting and the water setting (P=0.53). Total AUC of insulin and c-peptide was similar in aspartame, sucralose and water settings. Total AUC of GLP-1 was significantly higher in the sucralose setting than in the water setting (P=0.04). Total AUC values of glucose, insulin, c-peptide and GLP-1 were not statistically different in three settings in type 2 diabetic patients. Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in newly diagnosed type 2 diabetic patients.

  9. Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion

    DEFF Research Database (Denmark)

    Mingrone, G; Nolfe, G; Gissey, G Castagneto

    2009-01-01

    AIMS/HYPOTHESIS: We tested the hypothesis that the reversibility of insulin resistance and diabetes observed after biliopancreatic diversion (BPD) is related to changes in circadian rhythms of gastrointestinal hormones. METHODS: Ten morbidly obese participants, five with normal glucose tolerance......(-1)). CONCLUSIONS/INTERPRETATION: An incretin circadian rhythm was shown for the first time in morbid obesity. The effect of BPD on the 24 h pattern of incretin differed between NGT and diabetic patients. GLP1 secretion impairment was reversed in NGT and could not be overcome by surgery in diabetes...

  10. In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

    Science.gov (United States)

    Araújo, F.; Shrestha, N.; Gomes, M. J.; Herranz-Blanco, B.; Liu, D.; Hirvonen, J. J.; Granja, P. L.; Santos, H. A.; Sarmento, B.

    2016-05-01

    Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.

  11. 18F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

    International Nuclear Information System (INIS)

    Kiesewetter, Dale O.; Ma, Ying; Niu, Gang; Quan, Qimeng; Guo, Ning; Chen, Xiaoyuan; Gao, Haokao

    2012-01-01

    Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging. We prepared 18 F radioligands for GLP-1R by the reaction of [ 18 F]FBEM, a maleimide prosthetic group, with [Cys 0 ] and [Cys 40 ] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice. The [ 18 F]FBEM-[Cys x ]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [ 18 F]FBEM, and had a specific activity of 45.51 ± 16.28 GBq/μmol (1.23 ± 0.44 Ci/μmol, n = 7) at the end of synthesis. The C-terminal isomer, [ 18 F]FBEM-[Cys 40 ]-exendin-4, had higher affinity for INS-1 tumor cells (IC 50 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [ 18 F]FBEM-[Cys 0 ]-exendin-4 (IC 50 2.99 ± 0.06 nM, uptake 7.20 ± 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys x ]-exendin-4 (p 18 F]FBEM-[Cys 40 ]-exendin-4 and [ 18 F]FBEM-[Cys 0 ]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [ 18 F]FBEM-[Cys 40 ]-exendin-4 suggests that this compound would be the better tracer for imaging

  12. Physiological and pathophysiological aspects of incretin hormones and glucagon

    DEFF Research Database (Denmark)

    Bagger, Jonatan Ising

    2017-01-01

    Infusion of oxyntomodulin and the separate and combined infusion of GLP-1 and glucagon inhibited food intake similarly in healthy individuals, with no superior effect of combining GLP-1 and glucagon. We confirm the inhibitory effects of oxyntomodulin and GLP-1, respectively, on GE and appetite sc...

  13. Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

    Science.gov (United States)

    Viscarra, Jose A; Rodriguez, Ruben; Vazquez-Medina, Jose Pablo; Lee, Andrew; Tift, Michael S; Tavoni, Stephen K; Crocker, Daniel E; Ortiz, Rudy M

    2013-08-01

    Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation.

  14. GLP-1 suppresses gastrointestinal motility and inhibits the migrating motor complex in healthy subjects and patients with irritable bowel syndrome

    DEFF Research Database (Denmark)

    Hellström, P M; Näslund, E; Edholm, T

    2008-01-01

    hormones, and gut tissue expression of GLP-1 receptor was studied. In healthy subjects, GLP-1 0.7 pmol kg(-1) min(-1) reduced the migrating motor complexes (MMCs) from a median of 2 (range 2-3) to 0.5 (0-2), and motility index from 4.9 +/- 0.1 to 4.3 +/- 0.3 ln Sigma(mmHg*s min(-1)) in jejunum, while GLP-1...

  15. Distinct regions in the C-Terminus required for GLP-1R cell surface expression, activity and internalisation.

    Science.gov (United States)

    Thompson, Aiysha; Kanamarlapudi, Venkateswarlu

    2015-09-15

    The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), an important drug target in the treatment of type 2 diabetes, is a G-protein coupled receptor (GPCR) that mediates insulin secretion by GLP-1. The N-terminus controls GLP-1R biosynthetic trafficking to the cell surface but the C-terminus involvement in that trafficking is unknown. The aim of this study was to identify distinct regions within the C-terminal domain required for human GLP-1R (hGLP-1R) cell surface expression, activity and internalisation using a number of C-terminal deletions and site-directed mutations. The results of this study revealed that the residues 411-418 within the C-terminal domain of the hGLP-1R are critical in targeting the newly synthesised receptor to the plasma membrane. The residues 419-430 are important for cAMP producing activity of the receptor, most likely by coupling to Gαs. However, the residues 431-450 within the C-terminus are essential for agonist-induced hGLP-1R internalisation. In conclusion, these findings demonstrate the hGLP-1R has distinct regions within the C-terminal domain required for its cell surface expression, activity and agonist-induced internalisation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2012-01-01

    Incretin-based therapies, which include the GLP-1 receptor agonists and DPP-4 inhibitors, use the antidiabetic properties of potentiating the GLP-1 receptor signalling via the regulation of insulin and glucagon secretion, inhibition of gastric emptying and suppression of appetite. Most physicians...... will start antidiabetic treatment with metformin, but adding a GLP-1 receptor agonist as the second drug seems to be optimal since more patients will reach an HbA1c below 7% than with a DPP-4 inhibitor or another oral antidiabetic agents and with minimal risk of hypoglycaemia. The GLP-1 receptor agonists...

  17. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice

    DEFF Research Database (Denmark)

    Ørgaard, Anne; Holst, Jens J

    2017-01-01

    AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion...... on glucagon secretion is heavily debated. Glucagon inhibition is also said to be glucose-dependent, although it is unclear what is meant by this. We hypothesise here that GLP-1 does not inhibit glucagon secretion during hypoglycaemia because the inhibition depends on somatostatin secretion, which in turn...

  18. GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice

    DEFF Research Database (Denmark)

    Jolivalt, CG; Fineman, M; Deacon, Carolyn F.

    2011-01-01

    not affect blood sugar, insulin levels or paw thermal response latencies in either control or diabetic mice. However, the reductions of motor nerve conduction velocity and paw intraepidermal fibre density seen in diabetic mice were attenuated by exenatide treatment. Conclusions: These data show...... that the peripheral nerve of diabetic rodents exhibits functional GLP-1R and suggest that GLP-1R-mediated ERK-signalling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control....

  19. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity.

    Science.gov (United States)

    Shi, Xuemei; Chacko, Shaji; Li, Feng; Li, Depei; Burrin, Douglas; Chan, Lawrence; Guan, Xinfu

    2017-11-01

    Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp. We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neurons NTS enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly. We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  20. Microbial regulation of GLP-1 and L-cell biology

    DEFF Research Database (Denmark)

    Greiner, Thomas U; Bäckhed, Gert Fredrik

    2016-01-01

    BACKGROUND: The gut microbiota is associated with several of metabolic diseases, including obesity and type 2 diabetes and affects host physiology through distinct mechanisms. The microbiota produces a vast array of metabolites that signal to host cells in the intestine as well as in more distal...... organs. SCOPE OF REVIEW: Enteroendocrine cells acts as 'chemo sensors' of the intestinal milieu by expressing a large number of receptors, which respond to different metabolites and nutrients, and signal to host by a wide variety of hormones. However, enteroendocrine cells differ along the length...... of the gut in terms of hormones expressed and receptor repertoire. Also, the microbial ecology and dietary substrates differ along the length of the gut, providing further evidence for unique functions of specific subpopulations among enteroendocrine cells. Here we will review how the gut microbiota...

  1. Radio-immunoassays for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2)

    DEFF Research Database (Denmark)

    Orskov, C; Holst, J J

    1987-01-01

    Gene-sequencing studies have shown that the glucagon precursor contains two additional glucagon-like sequences, the so-called glucagon-like peptides 1 and 2 (GLP-1 and GLP-2). We developed radio-immunoassays against synthetic peptides corresponding to these sequences. Antisera were raised in rabb...

  2. Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging.

    Science.gov (United States)

    Zhang, Liang; Thurber, Greg M

    2016-02-01

    Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type 1 diabetes. The glucagon-like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower-clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.

  3. The influence of GLP-1 on glucose-stimulated insulin secretion

    DEFF Research Database (Denmark)

    Kjems, Lise L; Holst, Jens Juul; Vølund, Aage

    2003-01-01

    . However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2...

  4. Gq and Gs signaling acting in synergy to control GLP-1 secretion

    DEFF Research Database (Denmark)

    Pedersen, Maria Hauge; Ekberg, Jeppe Hvidtfeldt; Engelstoft, Maja Storm

    2017-01-01

    GPR40 is generally known to signal through Gq. However, in transfected cells, certain synthetic agonists can make the receptor signal also through Gs and cAMP (Hauge et al., 2015). Here we find that, in colonic crypt cultures, the GLP-1 secretion induced by such Gq + Gs GPR40 agonists is indeed i...

  5. Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Torekov, Signe Sørensen; Kipnes, M S; Harley, R E

    2011-01-01

    To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles....

  6. Presence and dynamics of leptin, GLP-1, and PYY in human breast milk at early postpartum.

    Science.gov (United States)

    Schueler, Jessica; Alexander, Brenda; Hart, Ann Marie; Austin, Kathleen; Larson-Meyer, D Enette

    2013-07-01

    The presence of appetite hormones, namely glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and leptin in breast milk may be important in infant feeding regulation and infant growth. This study evaluated whether concentrations of GLP-1, PYY, and leptin change across a single feeding (from fore- to hindmilk), and are associated with maternal and infant anthropometrics. Thirteen postpartum women (mean ± SD: 25.6 ± 4.5 years, 72.0 ± 11.9 kg) provided fore- and hindmilk samples 4-5 weeks after delivery and underwent measurements of body weight and composition by Dual X-ray Absorptiometry. GLP-1, PYY, and leptin concentrations were measured using radioimmunoassay, and milk fat content was determined by creamatocrit. Concentration of GLP-1 and content of milk fat was higher in hindmilk than foremilk (P ≤ 0.05). PYY and leptin concentrations did not change between fore- and hindmilk. Both leptin concentration and milk fat content were correlated with indices of maternal adiposity, including body mass index (r = 0.65-0.85, P milk may be important in infant appetite and growth regulation. Copyright © 2013 The Obesity Society.

  7. Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus

    DEFF Research Database (Denmark)

    Bonde, L; Vilsbøll, T; Nielsen, T

    2013-01-01

    AIM: We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established. METHODS: Eleven women with GDM [plasma glucose (PG) concentration...

  8. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity

    Science.gov (United States)

    Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the Brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose Homeostasis. The objective of this study was to determine whethe...

  9. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials.

    Science.gov (United States)

    Mazidi, Mohsen; Karimi, Ehsan; Rezaie, Peyman; Ferns, Gordon A

    2017-07-01

    To undertake a systematic review and meta-analysis of randomized controlled trials of the effect of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) therapy on serum C-reactive protein (CRP) concentrations. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched for the period up until March 16, 2016. Prospective studies evaluating the impact of GLP-1 RAs on serum CRP were identified. A random effects model (using the DerSimonian-Laird method) and generic inverse variance methods were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Heterogeneity was quantitatively assessed using the I 2 index. Random effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential moderator. International Prospective Register for Systematic Reviews (PROSPERO) number CRD42016036868. Meta-analysis of the data from 7 treatment arms revealed a significant reduction in serum CRP concentrations following treatment with GLP-1 RAs (WMD -2.14 (mg/dL), 95% CI -3.51, -0.78, P=0.002; I 2 96.1%). Removal of one study in the meta-analysis did not change the result in the sensitivity analysis (WMD -2.14 (mg/dL), 95% CI -3.51, -0.78, P=0.002; I 2 96.1%), indicating that our results could not be solely attributed to the effect of a single study. Random effects meta-regression was performed to evaluate the impact of potential moderator on the estimated effect size. Changes in serum CRP concentration were associated with the duration of treatment (slope -0.097, 95% CI -0.158, -0.042, Pmeta-analysis suggests that GLP-1 RAs therapy causes a significant reduction in CRP. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice

    NARCIS (Netherlands)

    Kooijman, Sander; Wang, Yanan; Parlevliet, Edwin T.; Boon, Mariëtte R.; Edelschaap, David; Snaterse, Gido; Pijl, Hanno; Romijn, Johannes A.; Rensen, Patrick C. N.

    2015-01-01

    Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of

  11. Emotional eating is associated with increased brain responses to food-cues and reduced sensitivity to GLP-1 receptor activation

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D.J.; ten Kulve, J.S.; Drent, M.L.; Barkhof, F.; Diamant, M.; IJzerman, R.G.

    2015-01-01

    Objective The neural correlates and pathophysiology of emotional eating are insufficiently known. Glucagon-like peptide-1 (GLP-1), a postprandial hormone, plays a role in feeding behavior by signaling satiety to the brain. GLP-1 receptor agonists, used for treatment of type 2 diabetes (T2DM),

  12. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Finan, Brian; Fischer, Katrin

    2015-01-01

    We assessed the efficacy of simultaneous agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the melanocortin-4 receptor (MC4R) for the treatment of obesity and diabetes in rodents. Diet-induced obese (DIO) mice were chronically treated with either the long-acting GLP-1R agonist liraglut...

  13. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

    Energy Technology Data Exchange (ETDEWEB)

    He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming, E-mail: dr_dongming@126.com

    2016-08-05

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. -- Highlights: •Liraglutide reduces lipid accumulation in hepatic steatosis both in vivo and in vitro. •Autophagy was involved in relieving effects of liraglutide on hepatic steatosis. •AMPK/mTOR pathway was involved in liraglutide-induced autophagy.

  14. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

    International Nuclear Information System (INIS)

    He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming

    2016-01-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and induced hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. -- Highlights: •Liraglutide reduces lipid accumulation in hepatic steatosis both in vivo and in vitro. •Autophagy was involved in relieving effects of liraglutide on hepatic steatosis. •AMPK/mTOR pathway was involved in liraglutide-induced autophagy.

  15. Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight.

    Science.gov (United States)

    López-Ferreras, L; Richard, J E; Noble, E E; Eerola, K; Anderberg, R H; Olandersson, K; Taing, L; Kanoski, S E; Hayes, M R; Skibicka, K P

    2017-09-12

    Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon-like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH. Ingestive behavior and metabolic parameters, as well as molecular and efferent targets, of the LH GLP-1R activation were also evaluated. Food motivation was reduced by activation of LH GLP-1R. Conversely, acute pharmacological blockade of LH GLP-1R increased food motivation but only in male rats. GLP-1R activation also induced a robust reduction in food intake and body weight. Chronic knockdown of LH GLP-1R induced by intraparenchymal delivery of an adeno-associated virus-short hairpin RNA construct was sufficient to markedly and persistently elevate ingestive behavior and body weight and ultimately resulted in a doubling of fat mass in males and females. Interestingly, increased food reinforcement was again found only in males. Our data identify the LH GLP-1R as an indispensable element of normal food reinforcement, food intake and body weight regulation. These findings also show, for we believe the first time, that brain GLP-1R manipulation can result in a robust and chronic body weight gain. The broader implications of these findings are that the LH differs between females and males in its ability to control motivated and ingestive behaviors.Molecular Psychiatry advance online publication, 12 September 2017; doi:10.1038/mp.2017.187.

  16. Physiologic effects of bowel preparation

    DEFF Research Database (Denmark)

    Holte, Kathrine; Nielsen, Kristine Grubbe; Madsen, Jan Lysgård

    2004-01-01

    PURPOSE: Despite the universal use of bowel preparation before colonoscopy and colorectal surgery, the physiologic effects have not been described in a standardized setting. This study was designed to investigate the physiologic effects of bowel preparation. METHODS: In a prospective study, 12...

  17. GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon-like peptide-1 analogues: past, present and future

    International Nuclear Information System (INIS)

    Hubalewska-Dydejczyk, A.; Sowa-Staszczak, A.; Tomaszuk, M.; Stefańska, A.

    2015-01-01

    Glucagon-like peptide 1 (GLP-1) receptors expression has been found on many types of cancer cells. In case of benign insulinoma the density of those receptors is even higher than the density of somatostatin receptors. This article presents the results of clinical trials proving the utility of GLP-1 receptors imaging. Scintigraphy or positron emission tomography with the use of GLP-1 analogues labelled with appropriate radioisotopes ( 111I n, 99m Tc, 68 Ga, 18 F or 64 Cu) seem to be superior compared with other available techniques in diagnosis of hardly detectable benign insulinoma. While surgery is the only effective therapy for insulinoma patients, therefore proper preoperative localization of the tumor allows sparing operation. Glucagon-like peptide 1 receptors might become also a target for imaging of other tumors such as gastrinoma, pheochromocytoma and medullary thyroid cancer (MTC), which also were shown to over express this type of receptors. However, studies with larger groups of patients are required to prove the clinical usefulness of this indication. Moreover GLP-1 receptor imaging seems to be a potential tool to evaluate pancreatic beta cell mass (BCM). It may be useful in the early diagnosis of beta cell loss in preclinical phases of diabetes. The panceratic beta cells imaging may influence the prophylaxis of diabetes and management of diabetic patients. Presented results of clinical trials prove that glucagon-like peptide 1 receptor imaging might become helpful diagnostic strategy particularly in case of patients with benign insulinoma tumors, but also patients with gastrinoma, pheochromocytoma, medullary thyroid cancer and diabetes.

  18. Glucagon-like peptide 1 receptor agonist (GLP-1 RA)

    DEFF Research Database (Denmark)

    von Scholten, Bernt Johan; Hansen, Tine Willum; Goetze, Jens Peter

    2015-01-01

    was to investigate the long-term effect on kidney function. METHODS: We included 30 patients in a one-year extension study, all initially treated with liraglutide for seven weeks. During follow-up 23 were treated with liraglutide and seven untreated. Primary outcome was change in GFR ((51)Cr-EDTA plasma clearance......). RESULTS: Patients were 61.5 (10.0) years and HbA(1c) 60.1 (13.8) mmol/mol. Baseline GFR was 100.6 (24.9) mL/min/1.73 m(2) and was reduced by 11 (95% CI: 6.6-15.7, p 24-h systolic blood pressure (SBP), weight, UAER or HbA(1c) (p≥0.33). Geometric mean (IQR......) of UAER was 25.5 (9.9-50.9) mg/d and was reduced by 27 (95% CI: 5-44; p = 0.020)%, and 24-h SBP was reduced by 8.2 (p = 0.048) mmHg. No changes occurred in untreated patients. CONCLUSIONS: Long-term treatment with liraglutide was associated with a reduction in measured GFR similar to the effect during...

  19. Pancreatic beta-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Asmar, Meena; Højberg, Patricia V; Deacon, Carolyn F

    2010-01-01

    glucose (BG) using insulin (mean diurnal BG: 6.4+/-0.3 mmol/l; HbA(1)c: 6.6+/-0.3%). Nine matched healthy subjects acted as controls. In controls, area-under-curve (AUC) for amylin, C-peptide and proinsulin were higher with GLP-1 than saline (PAUC amylin/C-peptide ratio was similar on both......This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood...... amylin/C-peptide ratios rose to control levels. Near-normoglycaemia tended to reduce AUC proinsulin/C-peptide ratio, which was significant (P=0.04) with GLP-1, but still higher than with saline (P=0.004). In conclusion, amylin, C-peptide and proinsulin responses to glucose were unaffected by four weeks...

  20. Pancreatic ß-cell responses to GLP-1 after near-normalization of blood glucose in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Asmar, Meena; Højberg, Patricia; Deacon, Carolyn F.

    2010-01-01

    glucose (BG) using insulin (mean diurnal BG: 6.4+/-0.3 mmol/l; HbA(1)c: 6.6+/-0.3%). Nine matched healthy subjects acted as controls. In controls, area-under-curve (AUC) for amylin, C-peptide and proinsulin were higher with GLP-1 than saline (PAUC amylin/C-peptide ratio was similar on both......This study investigated the effects of strict glycaemic control on beta-cell function in nine obese subjects with type 2 diabetes (T2DM), using graded glucose infusions together with infusions of saline or GLP-1 before (HbA(1)c: 8.0+/-0.4%) and after four weeks of near-normalization of blood...... amylin/C-peptide ratios rose to control levels. Near-normoglycaemia tended to reduce AUC proinsulin/C-peptide ratio, which was significant (P=0.04) with GLP-1, but still higher than with saline (P=0.004). In conclusion, amylin, C-peptide and proinsulin responses to glucose were unaffected by four weeks...

  1. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

    DEFF Research Database (Denmark)

    Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Allebrandt, Karla Viviani

    2018-01-01

    Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin...... secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS...... P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P

  2. Estudio del dominio carboxi-terminal del receptor de GLP-1(7-36) amida

    OpenAIRE

    Vázquez Pérez, Patricia

    2002-01-01

    El péptido relacionado con el glucagón de tipo 1 (GLP-1), está implicado en muchas funciones biológicas, como son el aumento de al secreción de insulina dependiente de glucosa, así como la estimación de la presión arterial y producción de surfactante pulmonar. A nivel central el GLP-1(7-36)amida estimula la liberación selectiva de neurotransmisores y participa en la regulación de procesos tales como la ingesta de alimentos y agua, la temperatura corporal y el control de ciertas funciones card...

  3. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist—protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study: the TAO study protocol

    Science.gov (United States)

    Ishøy, Pelle L; Knop, Filip K; Broberg, Brian V; Baandrup, Lone; Fagerlund, Birgitte; Jørgensen, Niklas R; Andersen, Ulrik B; Rostrup, Egill; Glenthøj, Birte Y; Ebdrup, Bjørn H

    2014-01-01

    Introduction Antipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against antipsychotic-associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non-diabetes. The primary endpoint of this trial is weight loss after 3 months of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI. Methods and analysis 40 obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised to subcutaneous injection of exenatide once weekly (2 mg) or placebo for 3 months, adjunctive to their antipsychotic treatment. Ethics and dissemination The trial has been approved by the Danish Health and Medicines Authority, the National Committee on Health Research Ethics and the Danish Data Protection Agency. Trial participation presupposes theoral and written patient informed consent. An external, independent monitoring committee (Good Clinical Practice Unit at Copenhagen University Hospital) will monitor the study according to the GCP Guidelines. Trial data, including positive, negative and inconclusive results, will be presented at national and international scientific meetings and conferences. Papers will be submitted to peer-reviewed journals. Trial registration ClinicalTrials.gov identifier: NCT01794429; National Committee on Health Research Ethics project number: 36378; EudraCT nr: 2012-005404-17; The

  4. GLP-1/glucagon coagonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet

    DEFF Research Database (Denmark)

    Clemmensen, Christoffer; Chabenne, Joseph; Finan, Brian

    2014-01-01

    We recently reported restoration of leptin responsiveness in diet-induced obese (DIO) mice using a pharmacologically optimized, polyethylene-glycolated (PEG)-leptin analog in combination with exendin-4 or FGF21. However, the return of leptin action required discontinuation of high-fat diet (HFD...... cotreatment. In summary, we report that GLP-1/glucagon coagonism restores leptin responsiveness in mice maintained on a HFD, thus emphasizing the translational value of this polypharmacotherapy for the treatment of obesity and diabetes....

  5. Strategies to improve outcome after islet transplantation using the GLP-1 receptor agonist, extendin-4

    OpenAIRE

    Sharma, Amit

    2007-01-01

    Transplantation of pancreatic islets into the liver via the portal vein has emerged as a treatment option for patients with type I diabetes mellitus. However, loss of functional beta cell mass during isolation and following implantation is a major obstacle in obtaining good long-term results. Exendin-4, a glucagonlike peptide-1 (GLP-1) receptor agonist, improves glucose homeostasis in patients with diabetes. It also has anti-apoptotic and beta cell proliferative properties t...

  6. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity

    OpenAIRE

    Xuemei Shi; Shaji Chacko; Feng Li; Depei Li; Douglas Burrin; Lawrence Chan; Xinfu Guan

    2017-01-01

    Objective: Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. Methods: We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected...

  7. GLP-1 receptor antagonist as a potential probe for pancreatic β-cell imaging

    International Nuclear Information System (INIS)

    Mukai, Eri; Toyoda, Kentaro; Kimura, Hiroyuki; Kawashima, Hidekazu; Fujimoto, Hiroyuki; Ueda, Masashi; Temma, Takashi; Hirao, Konomu; Nagakawa, Kenji; Saji, Hideo; Inagaki, Nobuya

    2009-01-01

    We examined exendin(9-39), an antagonist of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), as a potential probe for imaging of pancreatic β-cells. To evaluate in vitro receptor specificity, binding assay was performed using dispersed mouse islet cells. Binding assay showed competitive inhibition of [ 125 I]BH-exendin(9-39) binding by non-radioactive exendin(9-39). To assess in vivo selectivity, the biodistribution was evaluated by intravenous administration of [ 125 I]BH-exendin(9-39) to mice. Radioactivity of harvested pancreas reached highest levels at 60 and 120 min among organs examined except lung. Pre-administration of excess non-radioactive exendin(9-39) remarkably and specifically blocked the radioactivity of pancreas. After [ 125 I]BH-exendin(9-39) injection into transgenic mice with pancreatic β-cells expressing GFP, fluorescent and radioactive signals of sections of pancreas were evaluated with an image analyzer. Imaging analysis showed that the fluorescent GFP signals and the radioactive signals were correspondingly located. Thus, the GLP-1R antagonist exendin(9-39) may serve as a useful probe for pancreatic β-cell imaging.

  8. Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus--an adaptive response to hyperglycaemia?

    DEFF Research Database (Denmark)

    Hansen, A M K; Bödvarsdottir, T B; Nordestgaard, D N E

    2011-01-01

    of the study was to evaluate if, during the development of diabetes, alpha cells produce GLP-1 that, in turn, might trigger beta cell growth. Methods Beta cell mass, GLP-1 and insulin levels were measured in the gerbil Psammomys obesus (P. obesus), a rodent model of nutritionally induced diabetes. Furthermore...... from alpha cells is upregulated in P. obesus during the development of diabetes. A similar response is seen in islets exposed to high glucose, which supports the hypothesis that GLP-1 released from alpha cells promotes an increase in beta cell mass and function during metabolic challenge...

  9. Physiological effects of dietary fructans extracted from Agave tequilana Gto. and Dasylirion spp.

    Science.gov (United States)

    Urías-Silvas, Judith E; Cani, Patrice D; Delmée, Evelyne; Neyrinck, Audrey; López, Mercedes G; Delzenne, Nathalie M

    2008-02-01

    Recent data reported that inulin-type fructans extracted from chicory roots regulate appetite and lipid/glucose metabolism, namely, by promoting glucagon-like peptide-1 (GLP-1) production in the colon. The Agave genus growing in different regions of Mexico also contains important amounts of original fructans, with interesting nutritional and technological properties, but only few data report their physiological effect when added in the diet. Therefore, we decided to evaluate in parallel the effect of supplementation with 10 % agave or chicory fructans on glucose and lipid metabolism in mice. Male C57Bl/6J mice were fed a standard (STD) diet or diet supplemented with Raftilose P95 (RAF), fructans from Agave tequilana Gto. (TEQ) or fructans from Dasylirion spp. (DAS) for 5 weeks. The body weight gain and food intake in mice fed fructans-containing diets were significantly lower than the ones of mice fed the STD diet, TEQ leading to the lowest value. Serum glucose and cholesterol were similarly lower in all fructans-fed groups than in the STD group and correlated to body weight gain. Only RAF led to a significant decrease in serum TAG. As previously shown for RAF, the supplementation with agave fructans (TEQ and DAS) induced a higher concentration of GLP-1 and its precursor, proglucagon mRNA, in the different colonic segments, thus suggesting that fermentable fructans from different botanical origin and chemical structure are able to promote the production of satietogenic/incretin peptides in the lower part of the gut, with promising effects on glucose metabolism, body weight and fat mass development.

  10. Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas

    DEFF Research Database (Denmark)

    Holst, J J; Poulsen, Steen Seier

    1986-01-01

    We developed specific antibodies and RIAs for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), two predicted products of the glucagon gene, and studied the occurrence, nature, and secretion of immunoreactive GLP-1 and GLP-2 in pig pancreas and small intestine. Immunoreactive GLP-1 and GLP-2 were...

  11. Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes

    DEFF Research Database (Denmark)

    Jimenez-Solem, Espen; Rasmussen, Mette H; Christensen, Mikkel

    2010-01-01

    Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog being developed by Eli Lilly for the treatment of type 2 diabetes mellitus (T2DM). Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby protecting the GLP-1 moiety from...

  12. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors

    DEFF Research Database (Denmark)

    Dalsgaard, Niels B; Vilsbøll, Tina; Knop, Filip K

    2018-01-01

    with continuous-acting treatments, while large GLP-1RAs had a reduced effect on body weight compared with small GLP-1RAs. For glycaemic control, short-acting GLP-1RAs had a greater impact on postprandial glucose levels vs continuous-acting GLP-1RAs, but for fasting plasma glucose levels and HbA1c, continuous...

  13. The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans.

    Science.gov (United States)

    Mandøe, Mette J; Hansen, Katrine B; Hartmann, Bolette; Rehfeld, Jens F; Holst, Jens J; Hansen, Harald S

    2015-09-01

    Dietary triglycerides can, after digestion, stimulate the intestinal release of incretin hormones through activation of G protein-coupled receptor (GPR) 119 by 2-monoacylglycerol and by the activation of fatty acid receptors for long- and short-chain fatty acids. Medium-chain fatty acids do not stimulate the release of intestinal hormones. To dissect the mechanism of fat-induced glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) release in humans, we compared the effects of tributyrin (containing short-chain fatty acids; i.e., butyric acid), olive oil [containing long-chain fatty acids; e.g., oleic acid plus 2-oleoyl glycerol (2-OG)], and 1,3-dioctanoyl-2-oleoyl glycerol (C8-dietary oil), which is digested to form medium-chain fatty acids : i.e., octanoic acid : and 2-OG. In a randomized, single-blinded crossover study, 12 healthy white men [mean age: 24 y; BMI (in kg/m(2)): 22] were given the following 4 meals on 4 different days: 200 g carrots + 6.53 g tributyrin, 200 g carrots + 13.15 g C8-dietary oil, 200 g carrots + 19 g olive oil, or 200 g carrots. All of the lipids totaled 0.0216 mol. Main outcome measures were incremental areas under the curve for total GLP-1, GIP, and cholecystokinin (CCK) in plasma. C8-dietary oil and olive oil showed the same GLP-1 response [583 ± 101 and 538 ± 71 (pmol/L) × 120 min; P = 0.733], whereas the GIP response was higher for olive oil than for C8-dietary oil [3293 ± 404 and 1674 ± 270 (pmol/L) × 120 min; P = 0.002]. Tributyrin and carrots alone resulted in no increase in any of the measured hormones. Peptide YY (PYY) and neurotensin responses resembled those of GLP-1. Only olive oil stimulated CCK release. Under our study conditions, 2-OG and GPR119 activation can fully explain the olive oil-induced secretion of GLP-1, PYY, and neurotensin. In contrast, both oleic acid and 2-OG contributed to the GIP response. Dietary butyrate did not stimulate gut hormone secretion. Olive oil

  14. cAMP-secretion coupling is impaired in diabetic GK/Par rat β-cells: a defect counteracted by GLP-1.

    Science.gov (United States)

    Dolz, Manuel; Movassat, Jamileh; Bailbé, Danielle; Le Stunff, Hervé; Giroix, Marie-Hélène; Fradet, Magali; Kergoat, Micheline; Portha, Bernard

    2011-11-01

    cAMP-raising agents with glucagon-like peptide-1 (GLP-1) as the first in class, exhibit multiple actions that are beneficial for the treatment of type 2 diabetic (T2D) patients, including improvement of glucose-induced insulin secretion (GIIS). To gain additional insight into the role of cAMP in the disturbed stimulus-secretion coupling within the diabetic β-cell, we examined more thoroughly the relationship between changes in islet cAMP concentration and insulin release in the GK/Par rat model of T2D. Basal cAMP content in GK/Par islets was significantly higher, whereas their basal insulin release was not significantly different from that of Wistar (W) islets. Even in the presence of IBMX or GLP-1, their insulin release did not significantly change despite further enhanced cAMP accumulation in both cases. The high basal cAMP level most likely reflects an increased cAMP generation in GK/Par compared with W islets since 1) forskolin dose-dependently induced an exaggerated cAMP accumulation; 2) adenylyl cyclase (AC)2, AC3, and G(s)α proteins were overexpressed; 3) IBMX-activated cAMP accumulation was less efficient and PDE-3B and PDE-1C mRNA were decreased. Moreover, the GK/Par insulin release apparatus appears less sensitive to cAMP, since GK/Par islets released less insulin at submaximal cAMP levels and required five times more cAMP to reach a maximal secretion rate no longer different from W. GLP-1 was able to reactivate GK/Par insulin secretion so that GIIS became indistinguishable from that of W. The exaggerated cAMP production is instrumental, since GLP-1-induced GIIS reactivation was lost in the presence the AC blocker 2',5'-dideoxyadenosine. This GLP-1 effect takes place in the absence of any improvement of the [Ca(2+)](i) response and correlates with activation of the cAMP-dependent PKA-dependent pathway.

  15. The physiology of glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2007-01-01

    Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut...... and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before...... postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists...

  16. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors

    DEFF Research Database (Denmark)

    Brighton, Cheryl A.; Rievaj, Juraj; Kuhre, Rune E.

    2015-01-01

    Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium......-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L...... to either TLCA or TDCA. We conclude that the action of bile acids on GLP-1 secretion is predominantly mediated by GPBAR1 located on the basolateral L-cell membrane, suggesting that stimulation of gut hormone secretion may include postabsorptive mechanisms....

  17. Serum levels of glucagon-like peptide (GLP-1 and GLP-2 in patients with Hashimoto′s thyroiditis

    Directory of Open Access Journals (Sweden)

    Yue Jin

    2015-01-01

    Full Text Available Background: The influence of Hashimoto′s thyroiditis (HT with subclinical hypothyroidism or euthyroid status on the alteration of glucagon-like peptide (GLP-1 and GLP-2 levels remains uncertain. Materials and Methods: Twenty-four untreated HT patients with subclinical hypothyroidism, 24 euthyroid HT patients, and 24 age- and gender-matched controls were enrolled in the study. The levels of GLP-1, GLP-2, glucose, glycated albumin, insulin, thyroid hormone, and thyroid autoantibodies were measured and evaluated. Results: The levels of GLP-1, blood glucose, and triglyceride were higher in HT patients with subclinical hypothyroidism than in controls (all P < 0.05, respectively. However, the above variables, including GLP-2, were similar in euthyroid patients and controls. Neither GLP-1 nor GLP-2 was correlated with thyroid hormone, thyroid autoantibodies or metabolic parameters. Conclusion: The serum levels of GLP-1, not GLP-2, were increased in patients with subclinical hypothyroidism. Our data suggest that subclinical hypothyroidism affects circulating GLP-1 levels.

  18. Exercise Effects on Sleep Physiology

    Directory of Open Access Journals (Sweden)

    Sunao eUchida

    2012-04-01

    Full Text Available This mini-review focuses on the effects of exercise on sleep. In its early days, sleep research largely focused on central nervous system (CNS physiology using standardized tabulations of several sleep-specific landmark electroencephalogram (EEG waveforms. Though coarse, this method has enabled the observation and inspection of numerous uninterrupted sleep phenomena. Thus, research on the effects of exercise on sleep began, in the 1960’s, with a focus primarily on sleep EEG (CNS sleep changes. Those early studies found only small effects of exercise on sleep. More recent sleep research has explored not only CNS functioning, but somatic physiology as well. As physical exercise mostly affects somatic functions, endocrine and autonomic nervous system (ANS changes that occur during sleep should be affected by daytime exercise. Since endocrinological, metabolic and autonomic changes can be measured during sleep, it should be possible to assess exercise effects on somatic physiology in addition to CNS sleep quality, building from standard polysomnographic (PSG techniques. Incorporating measures of somatic physiology in the quantitative assessment of sleep could further our understanding of sleep's function as an auto-regulatory, global phenomenon.

  19. Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice

    Directory of Open Access Journals (Sweden)

    Yun Wan

    2017-05-01

    Full Text Available GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD for 6 months to induce obesity and then subjected to supaglutide treatment (300 μg/kg, bi-weekly for 4 weeks, and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS. Cold tolerance test was performed to evaluate brown-adipose tissue (BAT activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1 in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT and aspartic transaminase (AST content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that

  20. {sup 18}F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma

    Energy Technology Data Exchange (ETDEWEB)

    Kiesewetter, Dale O.; Ma, Ying; Niu, Gang; Quan, Qimeng; Guo, Ning; Chen, Xiaoyuan [National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Laboratory of Molecular Imaging and Nanomedicine (LOMIN), Bethesda, MD (United States); Gao, Haokao [National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Laboratory of Molecular Imaging and Nanomedicine (LOMIN), Bethesda, MD (United States); Fourth Military Medical University, Department of Cardiology, Xijing Hospital, Xi' an (China)

    2012-03-15

    Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic {beta}-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic {beta}-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging. We prepared {sup 18}F radioligands for GLP-1R by the reaction of [{sup 18}F]FBEM, a maleimide prosthetic group, with [Cys{sup 0}] and [Cys{sup 40}] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice. The [{sup 18}F]FBEM-[Cys{sup x}]-exendin-4 analogs were obtained in good yield (34.3 {+-} 3.4%, n = 11), based on the starting compound [{sup 18}F]FBEM, and had a specific activity of 45.51 {+-} 16.28 GBq/{mu}mol (1.23 {+-} 0.44 Ci/{mu}mol, n = 7) at the end of synthesis. The C-terminal isomer, [{sup 18}F]FBEM-[Cys{sup 40}]-exendin-4, had higher affinity for INS-1 tumor cells (IC{sub 50} 1.11 {+-} 0.057 nM) and higher tumor uptake (25.25 {+-} 3.39 %ID/g at 1 h) than the N-terminal isomer, [{sup 18}F]FBEM-[Cys{sup 0}]-exendin-4 (IC{sub 50} 2.99 {+-} 0.06 nM, uptake 7.20 {+-} 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys{sup x}]-exendin-4 (p < 0.05). [{sup 18}F]FBEM-[Cys{sup 40}]-exendin-4 and [{sup 18}F]FBEM-[Cys{sup 0}]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors

  1. Flavonoid-rich extract of Chromolaena odorata modulate circulating GLP-1 in Wistar rats: computational evaluation of TGR5 involvement.

    Science.gov (United States)

    Omotuyi, Olaposi Idowu; Nash, Oyekanmi; Inyang, Olumide Kayode; Ogidigo, Joyce; Enejoh, Ojochenemi; Okpalefe, Okiemute; Hamada, Tsuyoshi

    2018-02-01

    Chromolaena odorata is a major bio-resource in folkloric treatment of diabetes. In the present study, its anti-diabetic component and underlying mechanism were investigated. A library containing 140 phytocompounds previously characterized from C. odorata was generated and docked (Autodock Vina) into homology models of dipeptidyl peptidase (DPP)-4, Takeda-G-protein-receptor-5 (TGR5), glucagon-like peptide 1 (GLP1) receptor, renal sodium dependent glucose transporter (SGLUT)-1/2 and nucleotide-binding oligomerization domain (NOD) proteins 1&2. GLP-1 gene (RT-PCR) modulation and its release (EIA) by C. odorata were confirmed in vivo. From the docking result above, TGR5 was identified as a major target for two key C. odorata flavonoids (5,7-dihydroxy-6-4-dimethoxyflavanone and homoesperetin-7-rutinoside); sodium taurocholate and C. odorata powder included into the diet of the animals both raised the intestinal GLP-1 expression versus control ( p  < 0.05); When treated with flavonoid-rich extract of C. odorata (CoF) or malvidin, circulating GLP-1 increased by 130.7% in malvidin-treated subjects (0 vs. 45 min). CoF treatment also resulted in 128.5 and 275% increase for 10 and 30 mg/kg b.w., respectively. The results of this study support that C. odorata flavonoids may modulate the expression of GLP-1 and its release via TGR5. This finding may underscore its anti-diabetic potency.

  2. Glucose Tolerance, Lipids, and GLP-1 Secretion in JCR:LA-cp Rats Fed a High Protein Fiber Diet

    Science.gov (United States)

    Reimer, Raylene A.; Russell, James C.

    2013-01-01

    Background We have shown that individually, dietary fiber and protein increase secretion of the anorexigenic and insulinotropic hormone, glucagon-like peptide-1 (GLP-1). Objective Our objective was to combine, in one diet, high levels of fiber and protein to maximize GLP-1 secretion, improve glucose tolerance, and reduce weight gain. Methods and Procedures Lean (+/?) and obese (cp/cp) male James C Russell corpulent (JCR:LA-cp) rats lacking a functional leptin receptor were fed one of four experimental diets (control, high protein (HP), high fiber (HF, prebiotic fiber inulin), or combination (CB)) for 3 weeks. An oral glucose tolerance test (OGTT) was performed to evaluate plasma GLP-1, insulin and glucose. Plasma lipids and intestinal proglucagon mRNA expression were determined. Results Energy intake was lower with the HF diet in lean and obese rats. Weight gain did not differ between diets. Higher colonic proglucagon mRNA in lean rats fed a CB diet was associated with higher GLP-1 secretion during OGTT. The HP diet significantly reduced plasma glucose area under the curve (AUC) during OGTT in obese rats, which reflected both an increased GLP-1 AUC and higher fasting insulin. Diets containing inulin resulted in the lowest plasma triglyceride and total cholesterol levels. Discussion Overall, combining HP with HF in the diet increased GLP-1 secretion in response to oral glucose, but did not improve glucose tolerance or lipid profiles more than the HF diet alone did. We also suggest that glycemic and insulinemic response to prebiotics differ among rat models and future research work should examine their role in improving glucose tolerance in diet-induced vs. genetic obesity with overt hyperleptinemia. PMID:18223610

  3. The GLP-1 Analogue Exenatide Improves Hepatic and Muscle Insulin Sensitivity in Diabetic Rats: Tracer Studies in the Basal State and during Hyperinsulinemic-Euglycemic Clamp

    Directory of Open Access Journals (Sweden)

    Hui Wu

    2014-01-01

    Full Text Available Objective. Glucagon-like peptide-1 (GLP-1 analogues (e.g., exenatide increase insulin secretion in diabetes but less is known about their effects on glucose production or insulin-stimulated glucose uptake in peripheral tissues. Methods. Four groups of Sprague-Dawley rats were studied: nondiabetic (control, C; nondiabetic + exenatide (C + E; diabetic (D; diabetic + exenatide (D + E with diabetes induced by streptozotocin and high fat diet. Infusion of 3-3H-glucose and U-13C-glycerol was used to measure basal rates of appearance (Ra of glucose and glycerol and gluconeogenesis from glycerol (GNG. During hyperinsulinemic-euglycemic clamp, glucose uptake into gastrocnemius muscles was measured with 2-deoxy-D-14C-glucose. Results. In the diabetic rats, exenatide reduced the basal Ra of glucose (P<0.01 and glycerol (P<0.01 and GNG (P<0.001. During the clamp, Ra of glucose was also reduced, whereas the rate of disappearance of glucose increased and there was increased glucose uptake into muscle (P<0.01 during the clamp. In the nondiabetic rats, exenatide had no effect. Conclusion. In addition to its known effects on insulin secretion, administration of the GLP-1 analogue, exenatide, is associated with increased inhibition of gluconeogenesis and improved glucose uptake into muscle in diabetic rats, implying improved hepatic and peripheral insulin sensitivity.

  4. GLP1 and glucagon co-secreting pancreatic neuroendocrine tumor presenting as hypoglycemia after gastric bypass

    DEFF Research Database (Denmark)

    Guimarães, Marta; Rodrigues, Pedro; Pereira, Sofia S

    2015-01-01

    for the treatment of severe obesity, a 54-year-old female with previous type 2 diabetes, developed post-prandial sweating, fainting and hypoglycemic episodes, which eventually led to the finding by ultrasound of a 1.8-cm solid mass in the pancreatic head. The 72-h fast test and the plasma chromogranin A levels were...... (471 pmol/g), insulin (139 pmol/g) and somatostatin (23 pmol/g). This is the first report of a GLP1 and glucagon co-secreting pNET presenting as hypoglycemia after gastric bypass surgery. Although pNET are rare, they should be considered in the differential diagnosis of the clinical approach...

  5. Proinsulin, GLP-1, and glucagon are associated with partial remission in children and adolescents with newly diagnosed type 1 diabetes

    DEFF Research Database (Denmark)

    Kaas, A.; Andersen, M. L. M.; Fredheim, Siri

    2012-01-01

    .002) were significantly lower in remitters than in non-remitters at 6 and 12 months. Proinsulin associated positively with GLP-1 at 1 month (p = 0.004) and negatively at 6 (p = 0.002) and 12 months (p = 0.0002). Conclusions: In type 1 diabetes, patients in partial remission have higher levels of proinsulin......1C), glucagon-like peptide-1 (GLP-1), glucagon, and remission status the first year after diagnosis of type 1 diabetes. Methods: Juvenile patients (n = 275) were followed 1, 6, and 12 months after diagnosis. At each visit, partial remission was defined as IDAA1C = 9%. The patients had a liquid meal...

  6. Síndrome metabólico. Asociación entre GLP-1 y factores de riesgo cardiovascular

    OpenAIRE

    Pérez-Durillo, Francsco Tomás

    2017-01-01

    [ES] Objetivos: Determinar la variación de niveles plasmáticos de péptido similar al glucagón (GLP-1) y de actividad dipeptidil peptidasa 4 (DPP4) en pacientes con síndrome metabólico (SM). Diseño: Estudio descriptivo transversal. 46 sujetos (entre 50-65 años) distribuidos en grupo SM y grupo sin SM. Resultados: Los niveles postprandiales de GLP-1 fueron superiores en hombres con SM respecto a las mujeres y en mujeres sin SM respecto a los hombres. Los pacientes diagnosticados de SM de ...

  7. Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

    Directory of Open Access Journals (Sweden)

    Francis S. Willard

    2012-01-01

    Full Text Available The glucagon-like peptide-1 (GLP-1 receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM. Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.

  8. Failure of sucrose replacement with the non-nutritive sweetener erythritol to alter GLP-1 or PYY release or test meal size in lean or obese people.

    Science.gov (United States)

    Overduin, Joost; Collet, Tinh-Hai; Medic, Nenad; Henning, Elana; Keogh, Julia M; Forsyth, Faye; Stephenson, Cheryl; Kanning, Marja W; Ruijschop, Rianne M A J; Farooqi, I Sadaf; van der Klaauw, Agatha A

    2016-12-01

    There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Difference in postprandial GLP-1 response despite similar glucose kinetics after consumption of wheat breads with different particle size in healthy men.

    Science.gov (United States)

    Eelderink, Coby; Noort, Martijn W J; Sozer, Nesli; Koehorst, Martijn; Holst, Jens J; Deacon, Carolyn F; Rehfeld, Jens F; Poutanen, Kaisa; Vonk, Roel J; Oudhuis, Lizette; Priebe, Marion G

    2017-04-01

    Underlying mechanisms of the beneficial health effects of low glycemic index starchy foods are not fully elucidated yet. We varied the wheat particle size to obtain fiber-rich breads with a high and low glycemic response and investigated the differences in postprandial glucose kinetics and metabolic response after their consumption. Ten healthy male volunteers participated in a randomized, crossover study, consuming 13 C-enriched breads with different structures; a control bread (CB) made from wheat flour combined with wheat bran, and a kernel bread (KB) where 85 % of flour was substituted with broken wheat kernels. The structure of the breads was characterized extensively. The use of stable isotopes enabled calculation of glucose kinetics: rate of appearance of exogenous glucose, endogenous glucose production, and glucose clearance rate. Additionally, postprandial plasma concentrations of glucose, insulin, glucagon, incretins, cholecystokinin, and bile acids were analyzed. Despite the attempt to obtain a bread with a low glycemic response by replacing flour by broken kernels, the glycemic response and glucose kinetics were quite similar after consumption of CB and KB. Interestingly, the glucagon-like peptide-1 (GLP-1) response was much lower after KB compared to CB (iAUC, P bread did not result in a difference in glucose response and kinetics, but in a pronounced difference in GLP-1 response. Thus, changing the processing conditions of wheat for baking bread can influence the metabolic response beyond glycemia and may therefore influence health.

  10. GLP-1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance

    DEFF Research Database (Denmark)

    Matikainen, Niina; Bogl, Leonie H; Hakkarainen, Antti

    2014-01-01

    OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for o...... Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults....... under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min...... GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS...

  11. Sweet Taste Receptor Activation in the Gut Is of Limited Importance for Glucose-Stimulated GLP-1 and GIP Secretion

    DEFF Research Database (Denmark)

    Saltiel, Monika Yosifova; Kuhre, Rune Ehrenreich; Christiansen, Charlotte Bayer

    2017-01-01

    Glucose stimulates the secretion of the incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). It is debated whether the sweet taste receptor (STR) triggers this secretion. We investigated the role of STR activation for glucose-stimulated incretin...

  12. Weight loss and weight maintenance obtained with or without GLP-1 analogue treatment decrease branched chain amino acid levels

    DEFF Research Database (Denmark)

    Engelbrechtsen, Line; Iepsen, Eva Pers Winning; Galijatovic, Ehm Astrid Andersson

    2016-01-01

    increased during weight loss (p = 5.2 × 10−15) and showed inverse correlation with insulin resistance measured by HOMA–IR levels (r = −0.318, p = 0.025). Valine concentrations were lower in the control group compared to the GLP-1RA group during weight maintenance (p = 0.005). Conclusion Weight loss...

  13. Physiological Effects of Touching Wood

    Directory of Open Access Journals (Sweden)

    Harumi Ikei

    2017-07-01

    Full Text Available This study aimed to clarify the physiological effects of touching wood with the palm, in comparison with touching other materials on brain activity and autonomic nervous activity. Eighteen female university students (mean age, 21.7  ±  1.6 years participated in the study. As an indicator of brain activity, oxyhemoglobin (oxy-Hb concentrations were measured in the left/right prefrontal cortex using near-infrared time-resolved spectroscopy. Heart rate variability (HRV was used as an indicator of autonomic nervous activity. The high-frequency (HF component of HRV, which reflected parasympathetic nervous activity, and the low-frequency (LF/HF ratio, which reflected sympathetic nervous activity, were measured. Plates of uncoated white oak, marble, tile, and stainless steel were used as tactile stimuli. After sitting at rest with their eyes closed, participants touched the materials for 90 s. As a result, tactile stimulation with white oak significantly (1 decreased the oxy-Hb concentration in the left/right prefrontal cortex relative to marble, tile, and stainless steel and (2 increased ln(HF-reflected parasympathetic nervous activity relative to marble and stainless steel. In conclusion, our study revealed that touching wood with the palm calms prefrontal cortex activity and induces parasympathetic nervous activity more than other materials, thereby inducing physiological relaxation.

  14. Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice

    DEFF Research Database (Denmark)

    Kissow, Hannelouise; Hartmann, Bolette; Holst, Jens Juul

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel from the intestinal endocrine cells after nutrient intake. GLP-1 is an incretin hormone and analogues are available for the treatment of type 2 diabetes mellitus (T2DM). GLP-2 is an intestinal growth horm...

  15. Molecular Characterisation of Small Molecule Agonists Effect on the Human Glucagon Like Peptide-1 Receptor Internalisation.

    Science.gov (United States)

    Thompson, Aiysha; Stephens, Jeffrey W; Bain, Stephen C; Kanamarlapudi, Venkateswarlu

    2016-01-01

    The glucagon-like peptide receptor (GLP-1R), which is a G-protein coupled receptor (GPCR), signals through both Gαs and Gαq coupled pathways and ERK phosphorylation to stimulate insulin secretion. The aim of this study was to determine molecular details of the effect of small molecule agonists, compounds 2 and B, on GLP-1R mediated cAMP production, intracellular Ca2+ accumulation, ERK phosphorylation and its internalisation. In human GLP-1R (hGLP-1R) expressing cells, compounds 2 and B induced cAMP production but caused no intracellular Ca2+ accumulation, ERK phosphorylation or hGLP-1R internalisation. GLP-1 antagonists Ex(9-39) and JANT-4 and the orthosteric binding site mutation (V36A) in hGLP-1R failed to inhibit compounds 2 and B induced cAMP production, confirming that their binding site distinct from the GLP-1 binding site on GLP-1R. However, K334A mutation of hGLP-1R, which affects Gαs coupling, inhibited GLP-1 as well as compounds 2 and B induced cAMP production, indicating that GLP-1, compounds 2 and B binding induce similar conformational changes in the GLP-1R for Gαs coupling. Additionally, compound 2 or B binding to the hGLP-1R had significantly reduced GLP-1 induced intracellular Ca2+ accumulation, ERK phosphorylation and hGLP-1R internalisation. This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B.

  16. Molecular Characterisation of Small Molecule Agonists Effect on the Human Glucagon Like Peptide-1 Receptor Internalisation.

    Directory of Open Access Journals (Sweden)

    Aiysha Thompson

    Full Text Available The glucagon-like peptide receptor (GLP-1R, which is a G-protein coupled receptor (GPCR, signals through both Gαs and Gαq coupled pathways and ERK phosphorylation to stimulate insulin secretion. The aim of this study was to determine molecular details of the effect of small molecule agonists, compounds 2 and B, on GLP-1R mediated cAMP production, intracellular Ca2+ accumulation, ERK phosphorylation and its internalisation. In human GLP-1R (hGLP-1R expressing cells, compounds 2 and B induced cAMP production but caused no intracellular Ca2+ accumulation, ERK phosphorylation or hGLP-1R internalisation. GLP-1 antagonists Ex(9-39 and JANT-4 and the orthosteric binding site mutation (V36A in hGLP-1R failed to inhibit compounds 2 and B induced cAMP production, confirming that their binding site distinct from the GLP-1 binding site on GLP-1R. However, K334A mutation of hGLP-1R, which affects Gαs coupling, inhibited GLP-1 as well as compounds 2 and B induced cAMP production, indicating that GLP-1, compounds 2 and B binding induce similar conformational changes in the GLP-1R for Gαs coupling. Additionally, compound 2 or B binding to the hGLP-1R had significantly reduced GLP-1 induced intracellular Ca2+ accumulation, ERK phosphorylation and hGLP-1R internalisation. This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B.

  17. Physiology of the hormetic effect

    International Nuclear Information System (INIS)

    Totter, J.R.

    1987-01-01

    Beneficial (hormetic) effects of ionizing radiation have been largely ignored in developing radiobiological theory, chiefly because a suitable explanatory hypothesis is lacking. Examination of the relevant literature has revealed that food restriction effects in animals resemble those of low-level, low-LET, whole-body ionizing radiation exposure (without food restriction) in two major respects: increased longevity and change in the variance of longevity. These physiological changes can be interpreted as resulting from alteration of the steady-state flux of oxygen radicals which affect the endocrine balance. Oxy-radical-producing, low-level ionizing radiation exposure (whole body) is interpreted by the body as excess food intake, thus lowering the appetite and reducing caloric intake which, in turn, increases longevity. The greater variance in longevity accompanying increases in the median age at death with food restriction alters the ratio of long-lived to short-lived descendants and hastens the population's adaptation to semi-permanently diminished rates of food supply. Less variance and earlier mean ages at death result from an increased rate of food supply. Whole-body ionizing radiation exposure results in a mixed response, because it reduces caloric intake while signaling that an increase has occurred

  18. GLP-1 analogues for neuroprotection after out-of-hospital cardiac arrest: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Wiberg, Sebastian; Hassager, Christian; Thomsen, Jakob Hartvig; Frydland, Martin; Høfsten, Dan Eik; Engstrøm, Thomas; Køber, Lars; Schmidt, Henrik; Møller, Jacob Eifer; Kjaergaard, Jesper

    2016-06-30

    Attenuating the neurological damage occurring after out-of-hospital cardiac arrest is an ongoing research effort. This dual-centre study investigates the neuroprotective effects of the glucagon-like-peptide-1 analogue Exenatide administered within 4 hours from the return of spontaneous circulation to comatose patients resuscitated from out-of-hospital cardiac arrest. This pilot study will randomize a total of 120 unconscious patients with sustained return of spontaneous circulation after out-of-hospital cardiac arrest undergoing targeted temperature management in a blinded one-to-one fashion to a 6-hour and 15-minute infusion of either Exenatide or placebo. Patients are eligible for inclusion if resuscitated from cardiac arrest with randomization from 20 minutes to 240 minutes after return of spontaneous circulation. The co-primary endpoint is feasibility, defined as the initiation of treatment within the inclusion window in more than 90 % of participants, and efficacy, defined as the area under the neuron-specific enolase curve from 0 to 72 hours after admission. Secondary endpoints include all-cause mortality at 30 days and Cerebral Performance Category as well as a modified Rankin Score at 180 days. The study has been approved by the Danish National Board of Health and the local Ethics Committee and is monitored by Good Clinical Practice units. The study is currently enrolling. This paper presents the methods and planned statistical analyses used in the GLP-1 trial and aims to minimize bias and data-driven reporting of results. 1) Danish National Board of Health, EudraCT 2013-004311-45. Registered on 25 March 2014. 2) Videnskabsetisk komité C, Region Hovedstaden, No. 45728. Registered on 29 January 2014. 3) Clinicaltrial.gov, NCT02442791 . Registered on 25 of January 2015.

  19. Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response

    Directory of Open Access Journals (Sweden)

    Hilary M. Dorton

    2018-01-01

    Full Text Available Sugar consumption in the United States exceeds recommendations from the American Heart Association. Overconsumption of sugar is linked to risk for obesity and metabolic disease. Animal studies suggest that high-sugar diets alter functions in brain regions associated with reward processing, including the dorsal and ventral striatum. Human neuroimaging studies have shown that these regions are responsive to food cues, and that the gut-derived satiety hormones, glucagon-like peptide-1 (GLP-1, and peptide YY (PYY, suppress striatal food-cue responsivity. We aimed to determine the associations between dietary added sugar intake, striatal responsivity to food cues, and postprandial GLP-1 and PYY levels. Twenty-two lean volunteers underwent a functional magnetic resonance imaging (fMRI scan during which they viewed pictures of food and non-food items after a 12-h fast. Before scanning, participants consumed a glucose drink. A subset of 19 participants underwent an additional fMRI session in which they consumed water as a control condition. Blood was sampled for GLP-1, and PYY levels and hunger ratings were assessed before and ~75 min after drink consumption. In-person 24-h dietary recalls were collected from each participant on three to six separate occasions over a 2-month period. Average percent calories from added sugar were calculated using information from 24-h dietary recalls. A region-of-interest analysis was performed to compare the blood oxygen level-dependent (BOLD response to food vs. non-food cues in the bilateral dorsal striatum (caudate/putamen and ventral striatum (nucleus accumbens. The relationships between added sugar, striatal responses, and hormone changes after drink consumption were assessed using Spearman’s correlations. We observed a positive correlation between added sugar intake and BOLD response to food cues in the dorsal striatum and a similar trend in the nucleus accumbens after glucose, but not water, consumption

  20. Body weight loss, reduced urge for palatable food and increased release of GLP-1 through daily supplementation with green-plant membranes for three months in overweight women.

    Science.gov (United States)

    Montelius, Caroline; Erlandsson, Daniel; Vitija, Egzona; Stenblom, Eva-Lena; Egecioglu, Emil; Erlanson-Albertsson, Charlotte

    2014-10-01

    The frequency of obesity has risen dramatically in recent years but only few effective and safe drugs are available. We investigated if green-plant membranes, previously shown to reduce subjective hunger and promote satiety signals, could affect body weight when given long-term. 38 women (40-65 years of age, body mass index 25-33 kg/m(2)) were randomized to dietary supplementation with either green-plant membranes (5 g) or placebo, consumed once daily before breakfast for 12 weeks. All individuals were instructed to follow a three-meal paradigm without any snacking between the meals and to increase their physical activity. Body weight change was analysed every third week as was blood glucose and various lipid parameters. On days 1 and 90, following intake of a standardized breakfast, glucose, insulin and glucagon-like peptide 1 (GLP-1) in plasma were measured, as well as subjective ratings of hunger, satiety and urge for different palatable foods, using visual analogue scales. Subjects receiving green-plant membranes lost significantly more body weight than did those on placebo (p weight loss with green-plant extract was 5.0 ± 2.3 kg compared to 3.5 ± 2.3 kg in the control group. Consumption of green-plant membranes also reduced total and LDL-cholesterol (p meal tests performed on day 1 and day 90 demonstrated an increased postprandial release of GLP-1 and decreased urge for sweet and chocolate on both occasions in individuals supplemented with green-plant membranes compared to control. Waist circumference, body fat and leptin decreased in both groups over the course of the study, however there were no differences between the groups. In conclusion, addition of green-plant membranes as a dietary supplement once daily induces weight loss, improves obesity-related risk-factors, and reduces the urge for palatable food. The mechanism may reside in the observed increased release of GLP-1. Copyright © 2014 The Authors. Published by Elsevier Ltd

  1. Pleiotropic effects of incretins

    Directory of Open Access Journals (Sweden)

    Vishal Gupta

    2012-01-01

    Full Text Available Drugs that augment the incretin system [glucagon like peptide (GLP agonists and dipeptidyl peptidase-4 (DPP-4 inhibitors] represent a novel class of anti-hyperglycemic agents that have shown to improve the health and survival of beta-cells (improvement in postprandial hyperglycemia and suppress glucagon (improvement in fasting hyperglycemia. The incretins represent a large family of molecules referred to as the "glucagon superfamily of peptide hormones" of which more than 90% of the physiological effects of incretins are accomplished by GLP-1 7-37 and GLP1 7-36 amide and gastric insulinotropic peptide (GIP. GLP-1 mediates its effects via the GLP-1 receptor, which has a wide tissue distribution [pancreas, lung, heart, vascular smooth muscle cells, endothelial cells, macrophages and monocytes, kidney, gastrointestinal tract (stomach and intestine, central nervous system (neoortex, cerebellum, hypothalamus, hippocampus, brainstem nucleus tractus solitarius and peripheral nervous system]. This would imply that the incretin system has effects outside the pancreas. Over time data has accumulated to suggest that therapies that augment the incretin system has beneficial pleiotrophic effects. The incretins have shown to possess a cardiac-friendly profile, preserve neuronal cells and safeguard from neuronal degeneration, improve hepatic inflammation and hepatosteatosis, improve insulin resistance, promote weight loss and induce satiety. There is growing evidence that they may also be renoprotective promoting wound healing and bone health.

  2. Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

    DEFF Research Database (Denmark)

    Alssema, Marjan; Rijkelijkhuizen, Josina M; Holst, Jens Juul

    2013-01-01

    OBJECTIVE: To i) compare incretin responses to oral glucose and mixed meal of diabetic patients with the normoglycaemic population and ii) to investigate whether incretin responses are associated with hypertriglyceridaemia and alanine aminotransferase (ALT) as liver fat marker. DESIGN: A population......-based study. METHODS: A total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40-65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucose......-dependent insulinotropic polypeptide (GIP) and glucagon profiles were analysed as total area under the curve (tAUC) and incremental area under the curve. RESULTS: In diabetic patients compared with persons with NGM, we found increased GLP-1 secretion (tAUC per hour) following oral glucose (23.2 pmol/l (95% CI 17...

  3. GLP-1 receptor agonist treatment increases bone formation and prevents bone loss in weight-reduced obese women

    DEFF Research Database (Denmark)

    Iepsen, Eva Pers Winning; Lundgren, Julie Rehné; Hartmann, Bolette

    2015-01-01

    with or without administration of the GLP-1 RA liraglutide (1.2mg/day) for 52 weeks. In case of weight gain, up to two meals per day could be substituted with a low-calorie diet product in order to maintain the weight loss. MAIN OUTCOME MEASURES: Total, pelvic and arm-leg bone mineral content (BMC) and bone...... markers (CTX-1 and P1NP) were investigated before, after weight loss and after 52 weeks weight maintenance. Primary end points: Change in BMC and bone markers after 52 weeks weight maintenance with or without GLP-1 RA treatment. RESULTS: Total, pelvic and arm-leg BMC decreased during weight maintenance...... in the control group (ptotal and arm-leg BMC loss was 4 times greater in the control group compared to the liraglutide group (estimated difference 27g (95% CI 5-48), p=0.01), although the 12% weight loss was maintained in both groups...

  4. Difference in postprandial GLP-1 response despite similar glucose kinetics after consumption of wheat breads with different particle size in healthy men

    DEFF Research Database (Denmark)

    Eelderink, Coby; Noort, Martijn W J; Sozer, Nesli

    2017-01-01

    PURPOSE: Underlying mechanisms of the beneficial health effects of low glycemic index starchy foods are not fully elucidated yet. We varied the wheat particle size to obtain fiber-rich breads with a high and low glycemic response and investigated the differences in postprandial glucose kinetics...... and metabolic response after their consumption. METHODS: Ten healthy male volunteers participated in a randomized, crossover study, consuming (13)C-enriched breads with different structures; a control bread (CB) made from wheat flour combined with wheat bran, and a kernel bread (KB) where 85 % of flour...... in a difference in glucose response and kinetics, but in a pronounced difference in GLP-1 response. Thus, changing the processing conditions of wheat for baking bread can influence the metabolic response beyond glycemia and may therefore influence health....

  5. Treatment with a GLP-1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders

    DEFF Research Database (Denmark)

    Mansur, Rodrigo B; Zugman, Andre; Ahmed, Juhie

    2017-01-01

    regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss......, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function.......Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural...

  6. Postprandial diabetic glucose tolerance is normalized by gastric bypass feeding as opposed to gastric feeding and is associated with exaggerated GLP-1 secretion: a case report

    DEFF Research Database (Denmark)

    Dirksen, Carsten; Hansen, Dorte L; Madsbad, Sten

    2010-01-01

    into the bypassed gastric remnant and on the second day perorally. Plasma glucose, insulin, C-peptide, glucagon, incretin hormones, peptide YY, and free fatty acids were measured. RESULTS: Peroral feeding reduced 2-h postprandial plasma glucose (7.8 vs. 11.1 mmol/l) and incremental area under the glucose curve (iAUC......) (0.33 vs. 0.49 mmol . l(-1) . min(-1)) compared with gastroduodenal feeding. beta-Cell function (iAUC(Cpeptide/Glu)) was more than twofold improved during peroral feeding, and the glucagon-like peptide (GLP)-1 response increased nearly fivefold. CONCLUSIONS: Improvement in postprandial glucose......OBJECTIVE: To examine after gastric bypass the effect of peroral versus gastroduodenal feeding on glucose metabolism. RESEARCH DESIGN AND METHODS: A type 2 diabetic patient was examined on 2 consecutive days 5 weeks after gastric bypass. A standard liquid meal was given on the first day...

  7. Pancreatic Polypeptide Cell Proliferation in the Pancreas and Duodenum Coexisting in a Patient With Pancreatic Adenocarcinoma Treated With a GLP-1 Analog.

    Science.gov (United States)

    Talmon, Geoffrey A; Wren, J David; Nguyen, Christophe L; Pour, Parviz M

    2017-07-01

    A partial pancreaticogastrodudenectomy was performed on a 66-year old man with type 2 diabetes mellitus because of an invasive, moderately differentiated adenocarcinoma in the head of the pancreas. In the adjacent grossly normal tissue of the uncinate process, there was a massive proliferation of pancreatic polypeptide (PP) cells confined to this region and showed invasive pattern. Strikingly, in the heaped area of his duodenum, there was a strikingly large number of PP, glucagon, a few insulin cells in a mini-islet-like patterns composed of glucagon and insulin cells. Among the etiological factors, the possible long-lasting effects of the GLP-1 analog, with which the patient was treated, are discussed. This is the first report in the literature of both the coexistence of a pancreatic adenocarcinoma and invasive PPoma and the occurrence of PP and insulin cells in human duodenal mucosa.

  8. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy.

    Directory of Open Access Journals (Sweden)

    Shvetank Sharma

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is a known outcome of hepatosteatosis. Free fatty acids (FFA induce the unfolded protein response (UPR or endoplasmic reticulum (ER stress that may induce apoptosis. Recent data indicate ER stress to be a major player in the progression of fatty liver to more aggressive lesions. Autophagy on the other hand has been demonstrated to be protective against ER stress-induced cell death. We hypothesized that exendin-4 (GLP-1 analog treatment of fat loaded hepatocytes can reduce steatosis by autophagy which leads to reduced ER stress-related hepatocyte apoptosis.Primary human hepatocytes were loaded with saturated, cis- and trans-unsaturated fatty acids (palmitic, oleic and elaidic acid respectively. Steatosis, induced with all three fatty acids, was significantly resolved after exendin-4 treatment. Exendin-4 sustained levels of GRP78 expression in fat-loaded cells when compared to untreated fat-loaded cells alone. In contrast, CHOP (C/EBP homologous protein; the penultimate protein that leads to ER stress-related cell death was significantly decreased by exendin-4 in hepatocytes loaded with fatty acids. Finally, exendin-4 in fat loaded hepatocytes clearly promoted gene products associated with macroautophagy as measured by enhanced production of both Beclin-1 and LC3B-II, markers for autophagy; and visualized by transmission electron microscopy (TEM. Similar observations were made in mouse liver lysates after mice were fed with high fat high fructose diet and treated with a long acting GLP-1 receptor agonist, liraglutide.GLP-1 proteins appear to protect hepatocytes from fatty acid-related death by prohibition of a dysfunctional ER stress response; and reduce fatty acid accumulation, by activation of both macro-and chaperone-mediated autophagy. These findings provide a novel role for GLP-1 proteins in halting the progression of more aggressive lesions from underlying steatosis in humans afflicted with NAFLD.

  9. Centrally located GLP-1 receptors modulate gastric slow waves and cardiovascular function in ferrets consistent with the induction of nausea.

    Science.gov (United States)

    Lu, Zengbing; Yeung, Chi-Kong; Lin, Ge; Yew, David T W; Andrews, P L R; Rudd, John A

    2017-10-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are indicated for the treatment of Type 2 diabetes and obesity, but can cause nausea and emesis in some patients. GLP-1 receptors are distributed widely in the brain, where they contribute to mechanisms of emesis, reduced appetite and aversion, but it is not known if these centrally located receptors also contribute to a modulation of gastric slow wave activity, which is linked causally to nausea. Our aim was to investigate the potential of the GLP-1 receptor agonist, exendin-4, administered into the 3rd ventricle to modulate emesis, feeding and gastric slow wave activity. Thermoregulation and cardiovascular parameters were also monitored, as they are disturbed during nausea. Ferrets were used as common laboratory rodents do not have an emetic reflex. A guide cannula was implanted into the 3rd ventricle for delivering a previously established dose of exendin-4 (10nmol), which had been shown to induce emesis and behaviours indicative of 'nausea'. Radiotelemetry recorded gastric myoelectric activity (GMA; slow waves), blood pressure and heart rate variability (HRV), and core temperature; food intake and behaviour were also assessed. Exendin-4 (10nmol, i.c.v.) decreased the dominant frequency of GMA, with an associated increase in the percentage of bradygastric power (lasting ~4h). Food intake was inhibited in all animals, with 63% exhibiting emesis. Exendin-4 also increased blood pressure (lasting ~24h) and heart rate (lasting ~7h), decreased HRV (lasting ~24h), and caused transient hyperthermia. None of the above parameters were emesis-dependent. The present study shows for the first time that gastric slow waves may be modulated by GLP-1 receptors in the brain through mechanisms that appear independent from emesis. Taken together with a reduction in HRV, the findings are consistent with changes associated with the occurrence of nausea in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. HOMA-S is associated with greater HbA1c reduction with a GLP-1 analogue in patients with type 2 diabetes.

    Science.gov (United States)

    Heald, A H; Narayanan, R P; Lowes, D; Jarman, E; Onyekwelu, E; Qureshi, Z; Laing, I; Anderson, S G

    2012-07-01

    Exenatide, a glucagon-like peptide-1 (GLP-1) analogue, is an effective glucoregulator for treating overweight individuals, not at target HbA1 c. This prospective study aimed to determine whether estimates of beta cell function (HOMA-B) and insulin sensitivity (HOMA-S) predict response to Exenatide treatment.Prospective data on 43 type 2 diabetes patients were collected for up to 2.8 years in UK primary care. HOMA-B and HOMA-S were estimated prior to initiating Exenatide, with monitoring of cardio-metabolic risk factors.Mean (SD) age and BMI pre-treatment were 54.1±10.5 years and 35.7±7.5 kg/m2 respectively. HbA1c decreased (mean reduction 0.9%, p=0.04; p for trend=0.01) in 61% of patients. In univariate analyses, HOMA-S as a measure of insulin sensitivity was inversely (β=- 0.41, p 0.009) related to change in HbA1c, with no relation for HOMA-B.In a random effects regression model that included age at baseline, weight, LDL-C, HDL-C and triglycerides, change in HbA1c (β= - 0.14, pHOMA-S were 45% more likely to have a fall in HbA1c with an odds ratio (OR) of 0.55 (95% CI 0.47-0.66) p<0.0001 (log likelihood ratio for the model χ2=71.6, p<0.0001).Patients with greater measured insulin sensitivity achieve greater reduction in HbA1c with Exenatide. Determination of insulin sensitivity may assist in guiding outcome expectation in overweight patients treated with GLP-1 analogues. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  11. Increased Postprandial GIP and Glucagon Responses, But Unaltered GLP-1 Response after Intervention with Steroid Hormone, Relative Physical Inactivity, And High-Calorie Diet in Healthy Subjects

    DEFF Research Database (Denmark)

    Hansen, Katrine B; Vilsbøll, Tina; Bagger, Jonatan I

    2011-01-01

    Objective:Increased postprandial glucose-dependent insulinotropic polypeptide (GIP) and glucagon responses and reduced postprandial glucagon-like peptide-1 (GLP-1) responses have been observed in some patients with type 2 diabetes mellitus. The causality of these pathophysiological traits...... postprandial GLP-1 responses as observed in some individuals with type 2 diabetes mellitus....... is unknown. We aimed to determine the impact of insulin resistance and reduced glucose tolerance on postprandial GIP, GLP-1, and glucagon responses in healthy subjects. Research Design and Methods:A 4-h 2200 KJ-liquid meal test was performed in 10 healthy Caucasian males without family history of diabetes...

  12. COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways.

    Directory of Open Access Journals (Sweden)

    Marie Boutant

    Full Text Available The control of the functional pancreatic β-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how β-cell mass is determined.Conditional chicken ovalbumin upstream promoter transcription factor II (COUP-TFII-deficient mice were generated and crossed with mice expressing Cre under the control of pancreatic duodenal homeobox 1 (pdx1 gene promoter. Ablation of COUP-TFII in pancreas resulted in glucose intolerance. Beta-cell number was reduced at 1 day and 3 weeks postnatal. Together with a reduced number of insulin-containing cells in the ductal epithelium and normal β-cell proliferation and apoptosis, this suggests decreased β-cell differentiation in the neonatal period. By testing islets isolated from these mice and cultured β-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces the expression of the β-catenin gene and its target genes such as cyclin D1 and axin 2. Moreover, induction of these genes by glucagon-like peptide 1 (GLP-1 via β-catenin was impaired in absence of COUP-TFII. The expression of two other target genes of GLP-1 signaling, GLP-1R and PDX-1 was significantly lower in mutant islets compared to control islets, possibly contributing to reduced β-cell mass. Finally, we demonstrated that COUP-TFII expression was activated by the Wnt signaling-associated transcription factor TCF7L2 (T-cell factor 7-like 2 in human islets and rat β-cells providing a feedback loop.Our findings show that COUP-TFII is a novel component of the GLP-1 signaling cascade that increases β-cell number during the neonatal period. COUP-TFII is required for GLP-1 activation of the β-catenin-dependent pathway and its expression is under the control of TCF7L2.

  13. Lack of effect of synthetic human gastric inhibitory polypeptide and glucagon-like peptide 1 [7-36 amide] infused at near-physiological concentrations on pentagastrin-stimulated gastric acid secretion in normal human subjects

    DEFF Research Database (Denmark)

    Nauck, M A; Bartels, E; Orskov, C

    1992-01-01

    -stimulated (0.1 micrograms/kg/h from -90 to 120 min) gastric volume, acid and chloride output, on separate occasions, synthetic human GIP (1 pmol/kg/min) and/or GLP-1 [7-36 amide] (0.3 pmol/kg/min) or placebo (0.9% NaCl with 1% albumin) were infused intravenously (from -30 to 120 min) in 9 healthy volunteers...... secretion). In conclusion, (penta)gastrin-stimulated gastric acid secretion is not inhibited by physiological circulating concentrations of GIP or GLP-1 [7-36 amide]. Therefore, the insulinotropic action of these intestinal hormones is physiologically more important than their possible role...

  14. GLP-1 Response to Oral Glucose is Reduced in Pre-diabetes, Screen-detected Type 2 Diabetes, and Obesity and Influenced by Sex

    DEFF Research Database (Denmark)

    Færch, Kristine; Torekov, Signe S; Vistisen, Dorte

    2015-01-01

    concentrations of glucose, insulin and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT, n=774), pre-diabetes (n=523) or screen-detected type 2 diabetes (n=163) who attended the Danish ADDITION-PRO study (n=1,462). Compared with individuals...... with NGT, women with pre-diabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with pre-diabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had 20% reduced GLP-1 response to oral...

  15. Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy

    DEFF Research Database (Denmark)

    Andersen, O; Haugaard, S B; Holst, Jens Juul

    2005-01-01

    concentrations of GLP-1 and GIP were determined frequently during a 3-h, 75-g glucose tolerance test. Insulin secretion rates (ISRs) were calculated by deconvolution of C-peptide concentrations. RESULTS: The incremental area under the curve (incrAUC) for GLP-1 was increased by 250% in IGT patients compared...... without adjustment (r=0.38, Pglucose incrAUC (r=0.49, Pglucose-intolerant, HIV-infected male patients may display enhanced GLP-1 responses to oral glucose compared with normal glucose-tolerant HIV-infected male patients......OBJECTIVES: We investigated whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are major regulators of glucose tolerance through the stimulation of insulin secretion, contribute to impaired glucose tolerance (IGT) among HIV...

  16. GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide

    DEFF Research Database (Denmark)

    Hegedüs, Laszlo; Moses, Alan C; Zdravkovic, Milan

    2011-01-01

    to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects. Methods: Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy....... Results: Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT...

  17. Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2004-01-01

    in the treatment of Type 2 diabetes, causing marked improvements in glycaemic profile, insulin sensitivity and beta-cell performance, as well as weight reduction. The hormone is metabolised rapidly by the enzyme dipeptidyl peptidase IV (DPP-IV) and, therefore, cannot be easily used clinically. Instead, resistant...... with exendin have been carried out for > 6 months and have indicated efficacy in patients inadequately treated with oral antidiabetic agents. Orally active DPP-IV inhibitors, suitable for once-daily administration, have demonstrated similar efficacy. Diabetes therapy, based on GLP-1 receptor activation...

  18. Niveles de GLP-1 tras el test de sobrecarga oral de glucosa en mujeres con antecedentes de diabetes mellitus gestacional

    OpenAIRE

    Maraver Selfa, Silvia María

    2017-01-01

    Se ha descrito una reducción significativa del efecto incretina en pacientes con DM2 que puede deberse a la secreción alterada de las hormonas incretinas y/o a una acción insulinotrópica defectuosa de las mismas. Podría plantearse que este efecto incretina deteriorado en pacientes con trastornos del metabolismo hidrocarbonado, fuese un defecto primario precoz que preceda al desarrollo de la DM2, o secundario a la propia hiperglucemia. Objetivos. Estudiar el patrón de secreción de GLP-1 ...

  19. Benefits and challenges of a QSP approach through case study: Evaluation of a hypothetical GLP-1/GIP dual agonist therapy.

    Science.gov (United States)

    Rieger, Theodore R; Musante, Cynthia J

    2016-10-30

    Quantitative Systems Pharmacology (QSP) is an emerging science with increasing application to pharmaceutical research and development paradigms. Through case study we provide an overview of the benefits and challenges of applying QSP approaches to inform program decisions in the early stages of drug discovery and development. Specifically, we describe the use of a type 2 diabetes systems model to inform a No-Go decision prior to lead development for a potential GLP-1/GIP dual agonist program, enabling prioritization of exploratory programs with higher probability of clinical success. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  20. Proglucagon Promoter Cre-Mediated AMPK Deletion in Mice Increases Circulating GLP-1 Levels and Oral Glucose Tolerance.

    Directory of Open Access Journals (Sweden)

    Sophie R Sayers

    Full Text Available Enteroendocrine L-cells synthesise and release the gut hormone glucagon-like peptide-1 (GLP-1 in response to food transit. Deletion of the tumour suppressor kinase LKB1 from proglucagon-expressing cells leads to the generation of intestinal polyps but no change in circulating GLP-1 levels. Here, we explore the role of the downstream kinase AMP-activated protein kinase (AMPK in these cells.Loss of AMPK from proglucagon-expressing cells was achieved using a preproglucagon promoter-driven Cre (iGluCre to catalyse recombination of floxed alleles of AMPKα1 and α2. Oral and intraperitoneal glucose tolerance were measured using standard protocols. L-cell mass was measured by immunocytochemistry. Hormone and peptide levels were measured by electrochemical-based luminescence detection or radioimmunoassay.Recombination with iGluCre led to efficient deletion of AMPK from intestinal L- and pancreatic alpha-cells. In contrast to mice rendered null for LKB1 using the same strategy, mice deleted for AMPK displayed an increase (WT: 0.05 ± 0.01, KO: 0.09±0.02%, p<0.01 in L-cell mass and elevated plasma fasting (WT: 5.62 ± 0.800 pg/ml, KO: 14.5 ± 1.870, p<0.01 and fed (WT: 15.7 ± 1.48pg/ml, KO: 22.0 ± 6.62, p<0.01 GLP-1 levels. Oral, but not intraperitoneal, glucose tolerance was significantly improved by AMPK deletion, whilst insulin and glucagon levels were unchanged despite an increase in alpha to beta cell ratio (WT: 0.23 ± 0.02, KO: 0.33 ± 0.03, p<0.01.AMPK restricts L-cell growth and GLP-1 secretion to suppress glucose tolerance. Targeted inhibition of AMPK in L-cells may thus provide a new therapeutic strategy in some forms of type 2 diabetes.

  1. Neuroprotective effects of lixisenatide and liraglutide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

    OpenAIRE

    Liu, W.; Jalewa, Jaishree; Sharma, Mohit; Li, G.; Li, L.; Holscher, Christian

    2015-01-01

    Glucagon-like peptide 1 (GLP-1) is a growth factor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first results. Liraglutide and lixisenatide are two newer GLP-1 mimetics which have a ...

  2. A high carbohydrate, but not fat or protein meal attenuates postprandial ghrelin, PYY and GLP-1 responses in Chinese men.

    Directory of Open Access Journals (Sweden)

    Ehsan Parvaresh Rizi

    Full Text Available It is known that the macronutrient content of a meal has different impacts on the postprandial satiety and appetite hormonal responses. Whether obesity interacts with such nutrient-dependent responses is not well characterized. We examined the postprandial appetite and satiety hormonal responses after a high-protein (HP, high-carbohydrate (HC, or high-fat (HF mixed meal. This was a randomized cross-over study of 9 lean insulin-sensitive (mean±SEM HOMA-IR 0.83±0.10 and 9 obese insulin-resistant (HOMA-IR 4.34±0.41 young (age 21-40 years, normoglycaemic Chinese men. We measured fasting and postprandial plasma concentration of glucose, insulin, active glucagon-like peptide-1 (GLP-1, total peptide-YY (PYY, and acyl-ghrelin in response to HP, HF, or HC meals. Overall postprandial plasma insulin response was more robust in the lean compared to obese subjects. The postprandial GLP-1 response after HF or HP meal was higher than HC meal in both lean and obese subjects. In obese subjects, HF meal induced higher response in postprandial PYY compared to HC meal. HP and HF meals also suppressed ghrelin greater compared to HC meal in the obese than lean subjects. In conclusion, a high-protein or high-fat meal induces a more favorable postprandial satiety and appetite hormonal response than a high-carbohydrate meal in obese insulin-resistant subjects.

  3. A high carbohydrate, but not fat or protein meal attenuates postprandial ghrelin, PYY and GLP-1 responses in Chinese men

    Science.gov (United States)

    Parvaresh Rizi, Ehsan; Loh, Tze Ping; Baig, Sonia; Chhay, Vanna; Huang, Shiqi; Caleb Quek, Jonathan; Tai, E. Shyong; Toh, Sue-Anne

    2018-01-01

    It is known that the macronutrient content of a meal has different impacts on the postprandial satiety and appetite hormonal responses. Whether obesity interacts with such nutrient-dependent responses is not well characterized. We examined the postprandial appetite and satiety hormonal responses after a high-protein (HP), high-carbohydrate (HC), or high-fat (HF) mixed meal. This was a randomized cross-over study of 9 lean insulin-sensitive (mean±SEM HOMA-IR 0.83±0.10) and 9 obese insulin-resistant (HOMA-IR 4.34±0.41) young (age 21–40 years), normoglycaemic Chinese men. We measured fasting and postprandial plasma concentration of glucose, insulin, active glucagon-like peptide-1 (GLP-1), total peptide-YY (PYY), and acyl-ghrelin in response to HP, HF, or HC meals. Overall postprandial plasma insulin response was more robust in the lean compared to obese subjects. The postprandial GLP-1 response after HF or HP meal was higher than HC meal in both lean and obese subjects. In obese subjects, HF meal induced higher response in postprandial PYY compared to HC meal. HP and HF meals also suppressed ghrelin greater compared to HC meal in the obese than lean subjects. In conclusion, a high-protein or high-fat meal induces a more favorable postprandial satiety and appetite hormonal response than a high-carbohydrate meal in obese insulin-resistant subjects. PMID:29385178

  4. The GLP-1 analogue liraglutide improves first-phase insulin secretion and maximal beta-cell secretory capacity over 14 weeks of therapy in subjects with Type 2 diabetes

    DEFF Research Database (Denmark)

    Madsbad, Sten; Vilsbøll, Tina; Brock, Birgitte

    Aims: We investigated the clinical effect of liraglutide, a long- acting GLP-1 analogue, on insulin secretion in Type 2 diabetes. Methods: Thirty-nine subjects (28 completed) from a randomised trial received a hyperglycaemic clamp (20 mM) with intravenous arginine stimulation, and an insulin...... group. Conclusion: In subjects with Type 2 diabetes, 14 weeks’ once-daily liraglutide (1.25 and 1.9 mg/day) markedly improves beta-cell function, significantly increases first-phase insulin secretion and maximal beta-cell secretory capacity....

  5. SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives

    Directory of Open Access Journals (Sweden)

    Gurgle HE

    2016-06-01

    Full Text Available Holly E Gurgle, Karen White, Carrie McAdam-Marx Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, UT, USA Abstract: Controversy exists regarding the selection of second-line therapy for patients with type 2 diabetes mellitus (T2DM who are unable to achieve glycemic control with metformin therapy alone. Newer pharmacologic treatments for T2DM include glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter 2 inhibitors. Both the classes of medication are efficacious, exhibit positive effects on weight, and are associated with minimal risk of hypoglycemia. The purpose of this review is to compare the clinical trial and real-world effectiveness data of glucagon-like peptide-1 receptor agonists versus sodium–glucose cotransporter 2 inhibitors related to A1c reduction, weight loss, cost-effectiveness, cardiovascular outcomes, and safety in patients with T2DM. This review summarizes comparative evidence for providers who are determining which of the two classes may be the most appropriate for a specific patient. Keywords: type 2 diabetes mellitus, GLP-1 receptor agonist, SGLT2 inhibitor, A1c, weight loss, adverse effect

  6. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Xuemei Shi

    2017-11-01

    Conclusions: We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity.

  7. physiological effects of the amphetamines during exercise

    African Journals Online (AJOL)

    PHYSIOLOGICAL EFFECTS OF THE AMPHETAMINES DURING EXERCISE* c. H. WYNDHAM, G. G. ROGERS, A. J. S. BENADE AND N. B. STRYDOM, Human Sciences Laboratory, Chamber of. Mines of SOUTh Africa, Johannesburg. SUMMARY. Oxygen consumption, heart rate, minute ventilation and blood lactate were ...

  8. Dehydration: physiology, assessment, and performance effects.

    Science.gov (United States)

    Cheuvront, Samuel N; Kenefick, Robert W

    2014-01-01

    This article provides a comprehensive review of dehydration assessment and presents a unique evaluation of the dehydration and performance literature. The importance of osmolality and volume are emphasized when discussing the physiology, assessment, and performance effects of dehydration. The underappreciated physiologic distinction between a loss of hypo-osmotic body water (intracellular dehydration) and an iso-osmotic loss of body water (extracellular dehydration) is presented and argued as the single most essential aspect of dehydration assessment. The importance of diagnostic and biological variation analyses to dehydration assessment methods is reviewed and their use in gauging the true potential of any dehydration assessment method highlighted. The necessity for establishing proper baselines is discussed, as is the magnitude of dehydration required to elicit reliable and detectable osmotic or volume-mediated compensatory physiologic responses. The discussion of physiologic responses further helps inform and explain our analysis of the literature suggesting a ≥ 2% dehydration threshold for impaired endurance exercise performance mediated by volume loss. In contrast, no clear threshold or plausible mechanism(s) support the marginal, but potentially important, impairment in strength, and power observed with dehydration. Similarly, the potential for dehydration to impair cognition appears small and related primarily to distraction or discomfort. The impact of dehydration on any particular sport skill or task is therefore likely dependent upon the makeup of the task itself (e.g., endurance, strength, cognitive, and motor skill). © 2014 American Physiological Society.

  9. A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin

    DEFF Research Database (Denmark)

    Egerod, Kristoffer Lihme; Engelstoft, Maja Storm; Grunddal, Kaare Villum

    2012-01-01

    Enteroendocrine cells such as duodenal cholecystokinin (CCK cells) are generally thought to be confined to certain segments of the gastrointestinal (GI) tract and to store and release peptides derived from only a single peptide precursor. In the current study, however, transgenic mice expressing...... enhanced green fluorescent protein (eGFP) under the control of the CCK promoter demonstrated a distribution pattern of CCK-eGFP positive cells that extended throughout the intestine. Quantitative PCR and liquid chromatography-mass spectrometry proteomic analyses of isolated, FACS-purified CCK-eGFP-positive...... to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin, suggesting a potential therapeutic target for the treatment and prevention of diabetes and obesity....

  10. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss

    DEFF Research Database (Denmark)

    Iepsen, E W; Lundgren, J; Dirksen, C

    2015-01-01

    of weight gain, low-calorie diet products were allowed to replace up to two meals per day to achieve equal weight maintenance. Glucose tolerance and hormone responses were investigated before and after weight loss and after 52 weeks weight maintenance. Primary end points: increase in soluble leptin receptor.......3 kg (95% CI=-0.6 to -4.0)), and had fewer meal replacements per day compared with the control group (minus one meal per day (95% CI=-0.6 to -1)), P....3±0.1 mmol l(-1) to the level before weight loss (-0.5mmol l(-1) (95% CI=-0.1 to -0.9)), PMeal response of peptide PYY3-36 was higher at week 52 in the GLP-1RA group compared with the control group, P

  11. Distal gastrectomy in pancreaticoduodenectomy is associated with accelerated gastric emptying, enhanced postprandial release of GLP-1, and improved insulin sensitivity

    DEFF Research Database (Denmark)

    Harmuth, Stefan; Wewalka, Marlene; Holst, Jens Juul

    2014-01-01

    resistance (HOMA-IR) and oral glucose insulin sensitivity were calculated from glucose and insulin concentrations. RESULTS: Patients with Whipple procedure as compared to PPPD had accelerated gastric emptying (p = 0.01) which correlated with early (0-30 min) integrated GLP-1 (AUC30; r (2) = 0.61; p = 0.......02) and insulin sensitivity (r (2) = 0.41; p = 0.026) and inversely with HOMA-IR (r (2) = 0.17; p = 0.033). Two of 13 Whipple patients (15 %) as compared to seven of 13 after PPPD (54 %) had postload glucose concentrations (i.e. 120 min postmeal) ≥200 mg/dl (p 

  12. The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons.

    Directory of Open Access Journals (Sweden)

    Sergiy V Korol

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM, an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM plus diazepam (1 μM, only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.

  13. Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients : an acute and 12-week randomised, double-blind, placebo-controlled trial

    NARCIS (Netherlands)

    Smits, Mark M; Tonneijck, Lennart; Muskiet, Marcel H A; Hoekstra, T.; Kramer, Mark H H; Diamant, Michaela; van Raalte, Daniël H

    OBJECTIVE: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients. DESIGN: Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial. METHODS: In total, 57 type 2 diabetes patients

  14. Neurotensin Is Co-Expressed, Co-Released And Acts Together With Glp-1 And Pyy In Enteroendocrine Control Of Metabolism

    DEFF Research Database (Denmark)

    Grunddal, Kaare Villum; Ratner, Cecilia F; Svendsen, Berit

    2016-01-01

    increasingly multi-hormonal, i.e. co-expressing PYY and neurotensin as they move up the villus. Pro-glucagon promoter and pertussis toxin receptor driven cell ablation and reappearance studies indicated that although all the cells die, the GLP-1 cells reappear more quickly than PYY and neurotensin positive...

  15. The Effects Of An Exercise Physiology Program on Physical Fitness Variables, Body Satisfaction, and Physiology Knowledge.

    Science.gov (United States)

    Perry, Arlette C.; Rosenblatt, Evelyn S.; Kempner, Lani; Feldman, Brandon B.; Paolercio, Maria A.; Van Bemden, Angie L.

    2002-01-01

    Examined the effects of an exercise physiology program on high school students' physical fitness, body satisfaction, and physiology knowledge. Intervention students received exercise physiology theory and active aerobic and resistance exercise within their biology course. Data from student surveys and measurements indicated that the integrated…

  16. Excessive islet NO generation in type 2 diabetic GK rats coincides with abnormal hormone secretion and is counteracted by GLP-1.

    Directory of Open Access Journals (Sweden)

    Albert Salehi

    Full Text Available BACKGROUND: A distinctive feature of type 2 diabetes is inability of insulin-secreting beta-cells to properly respond to elevated glucose eventually leading to beta-cell failure. We have hypothesized that an abnormally increased NO production in the pancreatic islets might be an important factor in the pathogenesis of beta-cell dysfunction. PRINCIPAL FINDINGS: We show now that islets of type 2 spontaneous diabetes in GK rats display excessive NO generation associated with abnormal iNOS expression in insulin and glucagon cells, increased ncNOS activity, impaired glucose-stimulated insulin release, glucagon hypersecretion, and impaired glucose-induced glucagon suppression. Pharmacological blockade of islet NO production by the NOS inhibitor N(G-nitro-L-arginine methyl ester (L-NAME greatly improved hormone secretion from GK islets suggesting islet NOS activity being an important target to inactivate for amelioration of islet cell function. The incretin hormone GLP-1, which is used in clinical practice suppressed iNOS and ncNOS expression and activity with almost full restoration of insulin release and partial restoration of glucagon release. GLP-1 suppression of iNOS expression was reversed by PKA inhibition but unaffected by the proteasome inhibitor MG132. Injection of glucose plus GLP-1 in the diabetic rats showed that GLP-1 amplified the insulin response but induced a transient increase and then a poor depression of glucagon. CONCLUSION: The results suggest that abnormally increased NO production within islet cells is a significant player in the pathogenesis of type 2 diabetes being counteracted by GLP-1 through PKA-dependent, nonproteasomal mechanisms.

  17. Physiological Basis for Prompt Health Effects

    International Nuclear Information System (INIS)

    VINCENT, Andrew

    2006-01-01

    As input to design considerations precluding worker radiological exposure that could lead to an acute health effect from a postulated accident condition, an assessment of the short term health effects was performed. To assure that the impact of the accident scenario on the individual is appropriately considered, both external and internal exposures are included in the evaluation. The focus of this evaluation was to develop a quantitative basis from which to consider the level of exposure postulated in an accident that could lead to a defined physiological impact for short term health effects. This paper does not assess latent health effects of radiological exposure associated with normal operations or emergency response guidelines as these are clearly articulated in existing regulations and ICRP documents. The intent of this paper is to facilitate a dialogue on the appropriate meaning of currently undefined terms such as ''significant'' exposure and ''high-hazard material'' in DSA development

  18. Physiological Effects of Touching Coated Wood

    Directory of Open Access Journals (Sweden)

    Harumi Ikei

    2017-07-01

    Full Text Available This study examined the physiological effects of touching wood with various coating with the palm of the hand on brain activity and autonomic nervous activity. Participants were 18 female university students (mean age, 21.7 ± 1.6 years. As an indicator of brain activity, oxyhemoglobin concentrations were measured in the left and right prefrontal cortices using near-infrared time-resolved spectroscopy. Heart rate variability (HRV and heart rate were used as indicators of autonomic nervous activity. The high-frequency (HF component of HRV, which reflects parasympathetic nervous activity, and the low-frequency (LF/HF ratio, which reflects sympathetic nervous activity, were measured. Plates of uncoated, oil-finished, vitreous-finished, urethane-finished, and mirror-finished white oak wood were used as tactile stimuli. After sitting at rest with their eyes closed for 60 s, participants touched the stimuli with their palm for 90 s each. The results indicated that tactile stimulation with uncoated wood calmed prefrontal cortex activity (vs. urethane finish and mirror finish, increased parasympathetic nervous activity (vs. vitreous finish, urethane finish, and mirror finish, and decreased heart rate (vs. mirror finish, demonstrating a physiological relaxation effect. Further, tactile stimulation with oil- and vitreous-finished wood calmed left prefrontal cortex activity and decreased heart rate relative to mirror-finished wood.

  19. Physiological Effects of Touching Coated Wood.

    Science.gov (United States)

    Ikei, Harumi; Song, Chorong; Miyazaki, Yoshifumi

    2017-07-13

    This study examined the physiological effects of touching wood with various coating with the palm of the hand on brain activity and autonomic nervous activity. Participants were 18 female university students (mean age, 21.7 ± 1.6 years). As an indicator of brain activity, oxyhemoglobin concentrations were measured in the left and right prefrontal cortices using near-infrared time-resolved spectroscopy. Heart rate variability (HRV) and heart rate were used as indicators of autonomic nervous activity. The high-frequency (HF) component of HRV, which reflects parasympathetic nervous activity, and the low-frequency (LF)/HF ratio, which reflects sympathetic nervous activity, were measured. Plates of uncoated, oil-finished, vitreous-finished, urethane-finished, and mirror-finished white oak wood were used as tactile stimuli. After sitting at rest with their eyes closed for 60 s, participants touched the stimuli with their palm for 90 s each. The results indicated that tactile stimulation with uncoated wood calmed prefrontal cortex activity (vs. urethane finish and mirror finish), increased parasympathetic nervous activity (vs. vitreous finish, urethane finish, and mirror finish), and decreased heart rate (vs. mirror finish), demonstrating a physiological relaxation effect. Further, tactile stimulation with oil- and vitreous-finished wood calmed left prefrontal cortex activity and decreased heart rate relative to mirror-finished wood.

  20. GLP-1/glucagon receptor co-agonism for treatment of obesity

    DEFF Research Database (Denmark)

    Sánchez-Garrido, Miguel A.; Brandt, Sara J; Clemmensen, Christoffer

    2017-01-01

    Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes......, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited...

  1. GLP-1/glucagon receptor co-agonism for treatment of obesity.

    Science.gov (United States)

    Sánchez-Garrido, Miguel A; Brandt, Sara J; Clemmensen, Christoffer; Müller, Timo D; DiMarchi, Richard D; Tschöp, Matthias H

    2017-10-01

    Over a relatively short period, obesity and type 2 diabetes have come to represent a large medical and economic burden to global societies. The epidemic rise in the prevalence of obesity has metabolic consequences and is paralleled by an increased occurrence of other diseases, such as diabetes, cancer and cardiovascular complications. Together, obesity and type 2 diabetes constitute one of the more preventable causes of premature death and the identification of novel, safe and effective anti-obesity drugs is of utmost importance. Pharmacological attempts to treat obesity have had limited success, with notable adverse effects, rendering bariatric surgery as the only current therapy for substantially improving body weight. Novel unimolecular, multifunctional peptides have emerged as one of the most promising medicinal approaches to enhance metabolic efficacy and restore normal body weight. In this review, we will mainly focus on the discovery and translational relevance of dual agonists that pharmacologically function at the receptors for glucagon and glucagon-like peptide-1. Such peptides have advanced to clinical evaluation and inspired the pursuit of multiple related approaches to achieving polypharmacy within single molecules.

  2. EFFECTS OF PHYTOESTROGENS ON MAMMALIAN REPRODUCTIVE PHYSIOLOGY

    Directory of Open Access Journals (Sweden)

    Socorro Retana-Márquez

    2011-11-01

    Full Text Available Global consumption of phytoestrogens and their effects have increased both in animals and humans due to the augmented use of legumes in animal diets as well as the increase in vegetarian diets in some human populations. Even though the general opinion and that of clinicians toward phytoestrogens is generally positive, many phytoestrogens are now recognized as endocrine disruptor compounds, capable of interfering with the synthesis, secretion, transport, binding, action or elimination of natural hormones in the body that are responsible for reproduction. The effects of phytoestrogens mainly depend on the type, amount and plant species ingested. These compounds are found widely in a variety of plants and fodder, and can have adverse effects mainly on the reproductive tract in most animal species. Many phytoestrogens can act as estrogenic agonists or antagonists, and their effects can vary from infertility to an estrogenic over-response, thus increasing secretions in the reproductive tract and disrupting animal behavior. Presently, there is still a lack of knowledge on this subject, and the effects on reproductive parameters of estrogenic forage in animal production systems are unknown. Therefore, it is necessary to continue research in order to elucidate the effects of phytoestrogens, the doses at which effects are seen, the species, the disruptive or beneficial effects, as well as the mechanisms of action involved. This review focuses on the effects of phytoestrogens in the reproductive physiology of livestock and human, as well as the knowledge obtained from research in animal models.

  3. GLP-1 analogues for neuroprotection after out-of-hospital cardiac arrest

    DEFF Research Database (Denmark)

    Wiberg, Sebastian; Hassager, Christian; Thomsen, Jakob Hartvig

    2016-01-01

    one-to-one fashion to a 6-hour and 15-minute infusion of either Exenatide or placebo. Patients are eligible for inclusion if resuscitated from cardiac arrest with randomization from 20 minutes to 240 minutes after return of spontaneous circulation. The co-primary endpoint is feasibility, defined......Background: Attenuating the neurological damage occurring after out-of-hospital cardiac arrest is an ongoing research effort. This dual-centre study investigates the neuroprotective effects of the glucagon-like-peptide-1 analogue Exenatide administered within 4 hours from the return of spontaneous...... circulation to comatose patients resuscitated from out-of-hospital cardiac arrest. Methods/design: This pilot study will randomize a total of 120 unconscious patients with sustained return of spontaneous circulation after out-of-hospital cardiac arrest undergoing targeted temperature management in a blinded...

  4. Efficacy and Safety of GLP-1 Receptor Agonists for Type 2 Diabetes Mellitus Treatment: Systematic Review

    Directory of Open Access Journals (Sweden)

    Ana Paula Martins

    2016-04-01

    Full Text Available Introduction: Glucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes mellitus that mimic the endogenous hormone glucagon-like peptide 1. Glucagon-like peptide 1 regulates glucose levels by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delayed gastric emptying and promoting satiety. The individualized treatment of type 2 diabetes mellitus, using various glucagon--like peptide receptor agonists, has recently been described and the interest related to these drugs continues to grow. Objectives: To review the efficacy and safety of glucagon-like peptide 1 agonists in patients with inadequately controlled type 2 diabetes mellitus on metformin alone, highlighting their added value in therapeutic use comparatively to second line oral therapies used in type 2 diabetes mellitus. Methods: Studies were obtained from electronic searches of The Cochrane Library and PubMed. Randomized controlled trials were selected if they were at least 8 weeks in duration; compared a glucagon-like peptide 1 analogue with an oral anti-diabetic agent in patients experiencing inadequate glycemic control with metformin monotherapy; and reported hemoglobin A1c data in non-pregnant adults with type 2 diabetes mellitus. Results: Of 72 potentially relevant articles identified, 23 were retrieved for detailed evaluation and 10 met the inclusion criteria. The majority of glucagon-like peptide 1 agonists showed equivalent or superior efficacy than most active comparators for reducing hemoglobin A1c, with a greater proportion of patients achieving hemoglobin A1c <7%. Glucagon-like peptide 1 agonists also showed extra-glycemic effects such as weight loss and the reduction of important cardiovascular parameters. Side effects included gastrointestinal complications, mainly nausea, vomiting and diarrhea. The incidence of hypoglycemia was less common for this class of agents. Conclusion: Glucagon-like peptide 1

  5. The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.

    Science.gov (United States)

    Wootten, Denise; Reynolds, Christopher A; Smith, Kevin J; Mobarec, Juan C; Koole, Cassandra; Savage, Emilia E; Pabreja, Kavita; Simms, John; Sridhar, Rohan; Furness, Sebastian G B; Liu, Mengjie; Thompson, Philip E; Miller, Laurence J; Christopoulos, Arthur; Sexton, Patrick M

    2016-06-16

    Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  6. GLP-1 Receptor Agonists

    Science.gov (United States)

    ... Peer Support Resources Diseases and Conditions Adrenal Disorders Osteoporosis and Bone Health Children and Teen Health Diabetes Heart Health Men's Health Rare Diseases Pituitary Disorders Thyroid Disorders Transgender Health Obesity and Weight Management Women's Health You and Your ...

  7. Mody-3: novel HNF1A mutation and the utility of glucagon-like peptide (GLP)-1 receptor agonist therapy.

    Science.gov (United States)

    Docena, Maricor K; Faiman, Charles; Stanley, Christine M; Pantalone, Kevin M

    2014-02-01

    An estimated 1 to 2% of cases of diabetes mellitus have a monogenic basis; however, delayed diagnosis and misdiagnosis as type 1 and 2 diabetes are common. Correctly identifying the molecular basis of an individual's diabetes may significantly alter the management approach to both the patient and his or her relatives. We describe a case of mature onset diabetes of the young (MODY) with sufficient evidence to support the classification of a novel HNF1A (hepatocyte nuclear factor-1-α) mutation as a cause of MODY-3. A 21-year-old Caucasian female presented to our office with a diagnosis of noninsulin-dependent diabetes mellitus (NIDDM) at age 10; glycemia was initially managed with oral antidiabetic (OAD) agents and insulin detemir. The patient reported a strong family history of early-onset NIDDM in both her mother and maternal grandmother, both of whom eventually required insulin therapy to control glycemia. The patient's medical and family history were highly suggestive of maturity-onset diabetes of the young (MODY), and genetic testing was performed. Genetic screening detected a mutation p. Arg200Trp in the HNF1A gene in the patient, her mother, and maternal grandmother, suggesting a diagnosis of MODY-3. This finding resulted in a change of antidiabetic therapy in all 3 patients, including the addition of once-daily liraglutide therapy, which helped improve their glycemic control. Our case report supports the classification of the p. Arg200Trp mutation as a cause of MODY-3. The findings also suggest that glucagon-like peptide-1 (GLP-1) receptor agonist therapy may be of value in managing glycemia in patients with MODY-3.

  8. β cell membrane remodelling and procoagulant events occur in inflammation-driven insulin impairment: a GLP-1 receptor dependent and independent control.

    Science.gov (United States)

    Gleizes, Céline; Kreutter, Guillaume; Abbas, Malak; Kassem, Mohamad; Constantinescu, Andrei Alexandru; Boisramé-Helms, Julie; Yver, Blandine; Toti, Florence; Kessler, Laurence

    2016-02-01

    Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell-derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon-like peptide (GLP)-1 analogue, is known to promote insulin secretion and β-cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin-m5f β-cell function, TF activity mediated by MPs and their modulation by 1 μM liraglutide were examined in a cell cross-talk model. Methyl-β-cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N-éthylmaleimide-sensitive-factor Attachment protein Receptor (SNARE)-dependent exocytosis. Cytokines induced a two-fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two-fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD-treated cells showed similar patterns. Cells pre-treated by saturating concentration of the GLP-1r antagonist exendin (9-39), showed a partial abolishment of the liraglutide-driven insulin secretion and liraglutide-decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP-1r-dependent and -independent pathways. Our results confirm an integrative β-cell response to GLP-1 that targets receptor-mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation-driven procoagulant events. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and

  9. Effects of gastric inhibitory polypeptide, glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists on Bone Cell Metabolism

    DEFF Research Database (Denmark)

    Hansen, Morten S S; Tencerova, Michaela; Frølich, Jacob

    2018-01-01

    The relationship between gut and skeleton is increasingly recognised as part of the integrated physiology of the whole organism. The incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestine in response to nutrient intake and exhibi......-clinical investigations, clinical trials are needed to clarify if similar effects are present and clinically relevant in humans. This article is protected by copyright. All rights reserved....

  10. [6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pancreatic β-cells and increases RAB8/RAB10-regulated membrane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Leprdb/db type 2 diabetic mice.

    Science.gov (United States)

    Samad, Mehdi Bin; Mohsin, Md Nurul Absar Bin; Razu, Bodiul Alam; Hossain, Mohammad Tashnim; Mahzabeen, Sinayat; Unnoor, Naziat; Muna, Ishrat Aklima; Akhter, Farjana; Kabir, Ashraf Ul; Hannan, J M A

    2017-08-09

    [6]-Gingerol, a major component of Zingiber officinale, was previously reported to ameliorate hyperglycemia in type 2 diabetic mice. Endocrine signaling is involved in insulin secretion and is perturbed in db/db Type-2 diabetic mice. [6]-Gingerol was reported to restore the disrupted endocrine signaling in rodents. In this current study on Lepr db/db diabetic mice, we investigated the involvement of endocrine pathway in the insulin secretagogue activity of [6]-Gingerol and the mechanism(s) through which [6]-Gingerol ameliorates hyperglycemia. Lepr db/db type 2 diabetic mice were orally administered a daily dose of [6]-Gingerol (200 mg/kg) for 28 days. We measured the plasma levels of different endocrine hormones in fasting and fed conditions. GLP-1 levels were modulated using pharmacological approaches, and cAMP/PKA pathway for insulin secretion was assessed by qRT-PCR and ELISA in isolated pancreatic islets. Total skeletal muscle and its membrane fractions were used to measure glycogen synthase 1 level and Glut4 expression and protein levels. 4-weeks treatment of [6]-Gingerol dramatically increased glucose-stimulated insulin secretion and improved glucose tolerance. Plasma GLP-1 was found to be significantly elevated in the treated mice. Pharmacological intervention of GLP-1 levels regulated the effect of [6]-Gingerol on insulin secretion. Mechanistically, [6]-Gingerol treatment upregulated and activated cAMP, PKA, and CREB in the pancreatic islets, which are critical components of GLP-1-mediated insulin secretion pathway. [6]-Gingerol upregulated both Rab27a GTPase and its effector protein Slp4-a expression in isolated islets, which regulates the exocytosis of insulin-containing dense-core granules. [6]-Gingerol treatment improved skeletal glycogen storage by increased glycogen synthase 1 activity. Additionally, GLUT4 transporters were highly abundant in the membrane of the skeletal myocytes, which could be explained by the increased expression of Rab8 and Rab

  11. Effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1

    International Nuclear Information System (INIS)

    Watanabe, Ayahisa; Nishijima, Ken-ichi; Zhao, Songji; Tamaki, Nagara; Kuge, Yuji; Tanaka, Yoshikazu; Itoh, Takeshi; Takemoto, Hiroshi

    2012-01-01

    Glycosylation is generally applicable as a strategy for increasing the activity of bioactive proteins. In this study, we examined the effect of glycosylation on biodistribution of radiolabeled glucagon-like peptide 1 (GLP-1) as a bioactive peptide for type 2 diabetes. Noninvasive imaging studies were performed using a gamma camera after the intravenous administration of 123 I-GLP-1 or 123 I-α2, 6-sialyl N-acetyllactosamine (glycosylated) GLP-1 in rats. In ex vivo biodistribution studies using 125 I-GLP-1 or 125 I-glycosylated GLP-1, organ samples were measured for radioactivity. Plasma samples were added to 15% trichloroacetic acid (TCA) to obtain TCA-insoluble and TCA-soluble fractions. The radioactivity in the TCA-insoluble and TCA-soluble fractions was measured. In the noninvasive imaging studies, a relatively high accumulation level of 123 I-GLP-1 was found in the liver, which is the major organ to eliminate exogenous GLP-1. The area under the time-activity curve (AUC) of 123 I-glycosylated GLP-1 in the liver was significantly lower (89%) than that of 123 I-GLP-1. These results were consistent with those of ex vivo biodistribution studies using 125 I-labeled peptides. The AUC of 125 I-glycosylated GLP-1 in the TCA-insoluble fraction was significantly higher (1.7-fold) than that of GLP-1. This study demonstrated that glycosylation significantly decreased the distribution of radiolabeled GLP-1 into the liver and increased the concentration of radiolabeled GLP-1 in plasma. These results suggested that glycosylation is a useful strategy for decreasing the distribution into the liver of bioactive peptides as desirable pharmaceuticals. (author)

  12. Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

    DEFF Research Database (Denmark)

    Torekov, S S; Ma, L; Grarup, N

    2011-01-01

    The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.......The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits....

  13. Evaluating preferences for profiles of GLP-1 receptor agonists among injection-naïve type 2 diabetes patients in the UK

    Directory of Open Access Journals (Sweden)

    Gelhorn HL

    2015-11-01

    . In this context, dosing frequency and type of delivery system were most important, accounting for over 75% of the RI. While previous studies have identified efficacy as highly important in T2DM medication decisions, this study suggests that when differences in efficacy between medications are small, other treatment features (eg, dosing frequency and delivery system are of much greater importance to patients. Keywords: discrete choice experiment, patient preference, type 2 diabetes, GLP-1 receptor agonist 

  14. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes

    DEFF Research Database (Denmark)

    Zander, M; Taskiran, M; Toft-Nielsen, M B

    2001-01-01

    ) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite. RESULTS: Fasting plasma glucose (day 2...... this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally......) and 11.7 +/- 0.8 (GLP-1) to 9.8 +/- 0.5 (combination) (P = 0.02, no difference between GLP-1 and metformin). Insulin levels were similar between the three regimens, but glucagon levels were significantly reduced with GLP-1 compared with metformin (P = 0.0003). Combination therapy had no additional effect...

  15. Pancreas and liver uptake of new radiolabeled incretins (GLP-1 and Exendin-4) in models of diet-induced and diet-restricted obesity

    International Nuclear Information System (INIS)

    Seo, Daniele; Faintuch, Bluma Linkowski; Aparecida de Oliveira, Erica; Faintuch, Joel

    2017-01-01

    Introduction: Radiolabeled GLP-1 and its analog Exendin-4, have been employed in diabetes and insulinoma. No protocol in conventional Diet-Induced Obesity (DIO), and Diet-Restricted Obesity (DRO), has been identified. Aiming to assess pancreatic beta cell uptake in DIO and DRO, a protocol was designed. Methods: GLP-1-βAla-HYNIC and HYNIC-βAla-Exendin-4 were labeled with technetium-99m. Four Swiss mouse models were adopted: Controls (C), Alloxan Diabetes Controls (ADC), DIO and DRO. Biodistribution and ex-vivo planar imaging were documented. Results: Radiolabeling yield was in the range of 97% and both agents were hydrophilic. Fasting Blood Glucose (FBG) was 79.2 ± 8.2 mg/dl in C, 590.4 ± 23.3 mg/dl in ADC, 234.3 ± 66.7 mg/dl in DIO, and 96.6 ± 9.3 in DRO (p = 0.010). Biodistribution confirmed predominantly urinary excretion. DIO mice exhibited depressed uptake in liver and pancreas, for both radiomarkers, in the range of ADC. DRO only partially restored such values. 99m Tc-HYNIC-βAla-Exendin-4 demonstrated better results than GLP-1-βAla-HYNIC- 99m Tc. Conclusions: 1) Diet-induced obesity remarkably depressed beta cell uptake; 2) Restriction of obesity failed to normalize uptake, despite robust improvement of FBG; 3) HYNIC-βAla-Exendin-4 was the most useful marker; 4) Further studies are recommended in obesity and dieting, including bariatric surgery.

  16. A Systematic Literature Review and Network Meta-Analysis Comparing Once-Weekly Semaglutide with Other GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Previously Receiving 1-2 Oral Anti-Diabetic Drugs.

    Science.gov (United States)

    Witkowski, Michal; Wilkinson, Lars; Webb, Neil; Weids, Alan; Glah, Divina; Vrazic, Hrvoje

    2018-04-19

    Once-weekly semaglutide is a new glucagon-like peptide-1 (GLP-1) analogue administered at a 1.0 or 0.5 mg dose. As head-to-head trials assessing once-weekly semaglutide as an add-on to 1-2 oral anti-diabetic drugs (OADs) vs other GLP-1 receptor agonists (GLP-1 RAs) are limited, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of once-weekly semaglutide vs GLP-1 RAs in patients with type 2 diabetes (T2D) inadequately controlled on 1-2 OADs. A systematic literature review (SLR) was conducted in order to identify trials of GLP-1 RAs in patients inadequately controlled on 1-2 OADs. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in a NMA), which included the key outcomes of change from baseline in glycated hemoglobin (HbA 1c ), systolic blood pressure (SBP), and weight, as well as discontinuation due to adverse events (AEs). Data were synthesized using a NMA and a Bayesian framework. In total, 26 studies were included across the base case analyses. Once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA 1c and weight vs all GLP-1 RA comparators. Once-weekly semaglutide 0.5 mg also achieved significantly greater reductions in HbA 1c and weight compared with the majority of other GLP-1 RAs. Both doses of once-weekly semaglutide were associated with similar odds of discontinuation due to AEs compared with other GLP-1 RAs. Overall, once-weekly semaglutide 1.0 mg as an add-on to 1-2 OADs is the most efficacious GLP-1 RA in terms of the reduction of HbA 1c and weight from baseline after 6 months of treatment. In addition, the analysis suggests that once-weekly semaglutide is well tolerated and not associated with an increase in discontinuations due to AEs compared with other GLP-1 RAs. Novo Nordisk.

  17. The analgesic, haematological and some physiological effects of ...

    African Journals Online (AJOL)

    The aim of this research is to investigate the analgesic, haematologic and some physiological effects of extradural bupivacaine on dogs using six clinically healthy adult male dogs. The method used is by obtaining baseline data for physiological variables from each dogs using the multiparameter patient monitors (GD3, ...

  18. Physiological effect of the toxin from Xanthomonas retroflexus on ...

    African Journals Online (AJOL)

    Physiological effect of the toxin from Xanthomonas retroflexus on redroot pigweed (Amaranthus retroflexus). Z Sun, M Li, J Chen, Y Li. Abstract. A new toxin from Xanthomonas retroflexus could cause a series of physiological responses on seedlings of redroot pigweed. The experimental results revealed that respiratory ratio ...

  19. Effect of nitrogen on Safflower physiology and productivity ...

    African Journals Online (AJOL)

    , but its physiological response to agronomic inputs has yet to be fully evaluated. The effect of fertiliser on the physiology and production of Safflower grown in pots filled with standard grade perlite inside a semi-controlled glass house was ...

  20. The 2-monoacylglycerol moiety of dietary fat appears to be responsible for the fat-induced release of GLP-1 in humans

    DEFF Research Database (Denmark)

    Mandøe, Mette J.; Hansen, Katrine B.; Hartmann, Bolette

    2015-01-01

    acid), olive oil [contg. long-chain fatty acids; e.g., oleic acid plus 2-oleoyl glycerol (2-OG)], and 1,3-dioctanoyl-2-oleoyl glycerol (C8-dietary oil), which is digested to form medium-chain fatty acids (i.e., octanoic acid) and 2-OG. Design: In a randomized, single-blinded crossover study, 12 healthy...... white men [mean age: 24 y; BMI (in kg/m2): 22] were given the following 4 meals on 4 different days: 200 g carrots + 6.53 g tributyrin, 200 g carrots + 13.15 g C8-dietary oil, 200 g carrots + 19 g olive oil, or 200 g carrots. All of the lipids totaled 0.0216 mol. Main outcome measures were incremental...... areas under the curve for total GLP-1, GIP, and cholecystokinin (CCK) in plasma. Results: C8-dietary oil and olive oil showed the same GLP-1 response [583 ± 101 and 538 ± 71 (pmol/L) × 120 min; P = 0.733], whereas the GIP response was higher for olive oil than for C8-dietary oil [3293 ± 404 and 1674...

  1. Sex differences in the physiology of eating

    Science.gov (United States)

    Asarian, Lori

    2013-01-01

    Hypothalamic-pituitary-gonadal (HPG) axis function fundamentally affects the physiology of eating. We review sex differences in the physiological and pathophysiological controls of amounts eaten in rats, mice, monkeys, and humans. These controls result from interactions among genetic effects, organizational effects of reproductive hormones (i.e., permanent early developmental effects), and activational effects of these hormones (i.e., effects dependent on hormone levels). Male-female sex differences in the physiology of eating involve both organizational and activational effects of androgens and estrogens. An activational effect of estrogens decreases eating 1) during the periovulatory period of the ovarian cycle in rats, mice, monkeys, and women and 2) tonically between puberty and reproductive senescence or ovariectomy in rats and monkeys, sometimes in mice, and possibly in women. Estrogens acting on estrogen receptor-α (ERα) in the caudal medial nucleus of the solitary tract appear to mediate these effects in rats. Androgens, prolactin, and other reproductive hormones also affect eating in rats. Sex differences in eating are mediated by alterations in orosensory capacity and hedonics, gastric mechanoreception, ghrelin, CCK, glucagon-like peptide-1 (GLP-1), glucagon, insulin, amylin, apolipoprotein A-IV, fatty-acid oxidation, and leptin. The control of eating by central neurochemical signaling via serotonin, MSH, neuropeptide Y, Agouti-related peptide (AgRP), melanin-concentrating hormone, and dopamine is modulated by HPG function. Finally, sex differences in the physiology of eating may contribute to human obesity, anorexia nervosa, and binge eating. The variety and physiological importance of what has been learned so far warrant intensifying basic, translational, and clinical research on sex differences in eating. PMID:23904103

  2. Physiology of incretins in health and disease

    DEFF Research Database (Denmark)

    Deacon, Carolyn F.; Ahren, Bo

    2011-01-01

    factor in humans. The actions of the incretin hormones are crucial for maintaining normal islet function and glucose homeostasis. Furthermore, it is also now being recognized that incretin hormones may have other actions in addition to their glucoregulatory effects. Studies have shown that GLP-1 and GIP...

  3. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans

    DEFF Research Database (Denmark)

    Nauck, M A; Niedereichholz, U; Ettler, R

    1997-01-01

    Glucagon-like peptide 1 (GLP-1) has been shown to inhibit gastric emptying of liquid meals in type 2 diabetic patients. It was the aim of the present study to compare the action of physiological and pharmacological doses of intravenous GLP-1-(7-36) amide and GLP-1-(7-37) on gastric emptying...... (0-240 min), integrated incremental glucose (P inhibits gastric emptying also in normal subjects, 2) physiological doses (0.4 pmol.kg-1.min-1) still have...

  4. The effects of GLP-1 analogues, DPP-4 inhibitors and SGLT2 inhibitors on the renal system.

    Science.gov (United States)

    Schernthaner, Guntram; Mogensen, Carl Erik; Schernthaner, Gerit-Holger

    2014-09-01

    Diabetic nephropathy (DN) affects an estimated 20%-40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway. © The Author(s) 2014.

  5. Acute effects of continuous infusions of glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal absorption in short bowel syndrome (SBS) patients. A placebo-controlled study

    DEFF Research Database (Denmark)

    Madsen, K B; Askov-Hansen, C; Naimi, R M

    2013-01-01

    The ileocolonic brake is impaired in short bowel syndrome (SBS) patients with distal bowel resections. An attenuated meal-stimulated hormone secretion may cause gastric hypersecretion, rapid gastric and intestinal transit and a poor adaptation. Attempting to restore this ileocolonic brake...

  6. Biscuits with No Added Sugar Containing Stevia, Coffee Fibre and Fructooligosaccharides Modifies α-Glucosidase Activity and the Release of GLP-1 from HuTu-80 Cells and Serotonin from Caco-2 Cells after In Vitro Digestion.

    Science.gov (United States)

    Martinez-Saez, Nuria; Hochkogler, Christina Maria; Somoza, Veronika; Del Castillo, Maria Dolores

    2017-07-04

    This study assessed the in vitro effects of the bioaccessible food components released during the simulated human digestion of a coffee fibre-containing biscuit (CFB) on α-glucosidase activity, antioxidant capacity and satiety hormones. Digest of CFB presented a significantly ( p < 0.05) lower amount of sugar (68.6 mg/g) and a higher antioxidant capacity (15.1 mg chlorogenic acid eq./g) than that of a sucrose-containing biscuit (SCB). The CFB significantly reduced ( p < 0.05) α-glucosidase activity (IC50 = 3.3 mg/mL) compared to the SCB (IC50 = 6.2 mg/mL). Serotonin and glucagon-like peptide-1 (GLP-1) release by differentiated Caco-2 and HuTu-80 cells, respectively, was stimulated by the CFB (355% at a concentration of 0.5 mg/mL and 278% at a concentration of 0.05 mg/mL) to the same order of magnitude as those of the SCB. To summarize, the CFB was demonstrated to reduce monosaccharide bioaccessibility, to inhibit a diabetes-related digestive enzyme, and to improve the release of satiety hormones.

  7. Effects of Liraglutide on Heart Rate and Heart Rate Variability

    DEFF Research Database (Denmark)

    Kumarathurai, Preman; Anholm, Christian; Larsen, Bjørn Strøier

    2017-01-01

    OBJECTIVE: Reduced heart rate variability (HRV) and increased heart rate (HR) have been associated with cardiovascular mortality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) increase HR, and studies have suggested that they may reduce HRV. We examined the effect of the GLP-1 RA...

  8. Physiological effects after exposure to heat : A brief literature review

    NARCIS (Netherlands)

    Bogerd, C.P.; Daanen, H.A.M.

    2011-01-01

    Many employees are exposed to heat stress during their work. Although the direct effects of heat are well reported, the long term physiological effects occurring after heat exposure are hardly described. The present manuscript addresses these issues in the form of a brief literature review. Repeated

  9. Physiological and pathological effects of thermal radiation

    Energy Technology Data Exchange (ETDEWEB)

    Hymes, I.

    1983-09-15

    This report deals with man's response to abnormally high levels of thermal radiation. The early sections deal with the properties and biological roles of the skin in some detail as a basis for the definitions and descriptions of pathological damage. The estimation of hazard ranges in thermal radiation exposures requires a moderately accurate knowledge of the intensity and duration of the emitted flux. The (BLEVE) Boiling Liquid Expanding Vapor Explosion fireball conveniently meets this requirement as well as having the capability to inflict severe burn injuries over considerable distances. Liquid Petroleum Gas fireballs have been used as the source term for the thermal radiation calculations which predict threshold lethality and various categories of burn injury. Inevitably there are areas of uncertainty in such calculations, some contributory factors being atmospheric conditions, fuel container rupture pattern, type of clothing worn etc. The sensitivity of the predicted hazard ranges to these influential parameters is exemplified in several of the graphs presented. The susceptibility of everyday clothing to ignite or melt in thermal fluxes greater than about 70 kW/m/sup 2/ is shown to be a matter of some gravity since burning clothing can thwart escape and inflict serious, if not fatal, burns quite apart from injuries directly received from the incident radiation. The various means by which incident heat fluxes can be reduced or their effects mitigated are reviewed. Two major BLEVE case histories are discussed in some detail and the circumstances compared with those predicted by the theoretical calculations. 38 refs., 36 figs.

  10. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agnoist: Protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study - the TAO study

    DEFF Research Database (Denmark)

    Ishøy, Pelle Lau; Knop, Filip Krag; Broberg, Brian Villumsen

    with a GLP-1 receptor agonist (exenatide once-weekly) is safe and facilitates weight loss in non-diabetic schizophrenia patients with antipsychotic-associated obesity. Materials and methods: Forty obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs...

  11. Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist: Protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study – the TAO study

    DEFF Research Database (Denmark)

    Ishøy, Pelle Lau; Knop, Filip Krag; Broberg, Brian Villumsen

    with a GLP-1 receptor agonist (exenatide once-weekly) is safe and facilitates weight loss in non-diabetic schizophrenia patients with antipsychotic-associated obesity. Methods and analysis: Forty obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised...

  12. Effects of exercise on tumor physiology and metabolism.

    Science.gov (United States)

    Pedersen, Line; Christensen, Jesper Frank; Hojman, Pernille

    2015-01-01

    Exercise is a potent regulator of a range of physiological processes in most tissues. Solid epidemiological data show that exercise training can reduce disease risk and mortality for several cancer diagnoses, suggesting that exercise training may directly regulate tumor physiology and metabolism. Here, we review the body of literature describing exercise intervention studies performed in rodent tumor models and elaborate on potential mechanistic effects of exercise on tumor physiology. Exercise has been shown to reduce tumor incidence, tumor multiplicity, and tumor growth across numerous different transplantable, chemically induced or genetic tumor models. We propose 4 emerging mechanistic effects of exercise, including (1) vascularization and blood perfusion, (2) immune function, (3) tumor metabolism, and (4) muscle-to-cancer cross-talk, and discuss these in details. In conclusion, exercise training has the potential to be a beneficial and integrated component of cancer management, but has yet to fully elucidate its potential. Understanding the mechanistic effects of exercise on tumor physiology is warranted. Insight into these mechanistic effects is emerging, but experimental intervention studies are still needed to verify the cause-effect relationship between these mechanisms and the control of tumor growth.

  13. The biomechanical and physiological effect of two dynamic workstations

    NARCIS (Netherlands)

    Botter, J.; Burford, E.M.; Commissaris, D.; Könemann, R.; Mastrigt, S.H.V.; Ellegast, R.P.

    2013-01-01

    The aim of this research paper was to investigate the effect, both biomechanically and physiologically, of two dynamic workstations currently available on the commercial market. The dynamic workstations tested, namely the Treadmill Desk by LifeSpan and the LifeBalance Station by RightAngle, were

  14. Effects of Cadmium on the Growth and Physiological Characteristics ...

    African Journals Online (AJOL)

    Administrator

    2011-11-09

    Nov 9, 2011 ... The effects of cadmium (Cd) stress on the growth and physiological characteristics were studied in 3 sorghum species viz., sweet sorghum [Sorghum bicolor (L.) Moench. cv. Hunnigreen], sorghum hybrid sudangrass (Sorghum bicolor × Sorghum sudanense, cv. Everlush) and sudangrass [Sorghum.

  15. Effects of high concentration of chromium stress on physiological ...

    African Journals Online (AJOL)

    We studied the effects of high concentration of chromium (Cr) stress on physiological and biochemical characters and accumulation of Cr in Pingyang Tezao tea [Camellia sinensis (L) O. Kutze 'Pingyangtezao'] through a pot experiment. The results show that the indicators of photosynthesis were all suppressed with ...

  16. Effects of salicylic acid on morphological and physiological ...

    African Journals Online (AJOL)

    To evaluate the effect of different levels of salicylic acid (SA) on yield and some morphological and physiological characteristics of sweet corn hybrids under water stress, this study was conducted in 2015 using split plots in the base of randomized complete block design with three replications. Treatments were included ...

  17. Physiological Effects of Trace Elements and Chemicals in Water

    Science.gov (United States)

    Varma, M. M.; And Others

    1976-01-01

    The physiological effects on humans and animals of trace amounts of organic and unorganic pollutants in natural and waste waters are examined. The sensitivity of particular organs and species is emphasized. Substances reviewed include mercury, arsenic, cadmium, lead, chromium, fluorides, nitrates and organics, including polychlounated biphenyls.…

  18. Inclusion rate and physiological effects of prolonged feeding of ...

    African Journals Online (AJOL)

    The effect of incluusion of cocoa bean cake (CBC) on productive performance and physiological response of Isa Brown pullets to prolonged feeding of CBC were investigated. Dietary Inclusions or CBC (0, 50, 100 and 200g/ kg-1 diet) were monitored in typical poultry diets from day old to 51 weeks of age. Sexual maturity ...

  19. Effects of cadmium on the growth and physiological characteristics ...

    African Journals Online (AJOL)

    The effects of cadmium (Cd) stress on the growth and physiological characteristics were studied in 3 sorghum species viz., sweet sorghum [Sorghum bicolor (L.) Moench. cv. Hunnigreen], sorghum hybrid sudangrass (Sorghum bicolor × Sorghum sudanense, cv. Everlush) and sudangrass [Sorghum sudanense (Piper) Stapf ...

  20. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    Science.gov (United States)

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  1. Evaluation of an [18F]AlF-NOTA Analog of Exendin-4 for Imaging of GLP-1 Receptor in Insulinoma

    Directory of Open Access Journals (Sweden)

    Dale O. Kiesewetter, Ning Guo, Jinxia Guo, Haokao Gao, Lei Zhu, Ying Ma, Gang Niu, Xiaoyuan Chen

    2012-01-01

    Full Text Available Introduction: The GLP-1 receptor plays an important role in glucose homeostasis and thus is a very important target for diabetes therapy. The receptor is also overexpressed in insulinoma, a tumor of pancreatic beta-cells. We previously evaluated two fluorine-18-labeled analogs of exendin-4 prepared by conjugation with [18F]FBEM (N-[2-(4-[18F]fluorobenzamideethyl]maleimide. Both compounds demonstrated good tumor uptake, but the synthesis of the radiotracers was time consuming. To overcome this challenge, we developed a NOTA analog and performed radiolabeling using aluminum [18F]fluoride complexation.Methods: Cys40-exendin-4 was conjugated with NOTA mono N-ethylmaleimide. [18F]AlF conjugation was conducted and the radiolabeled product purified by preparative HPLC. Dynamic and static PET imaging scans were conducted on nude mice with established INS-1 xenografts. Uptake of tumor and other major organs in static images was quantitated (%ID/g and comparison with blocking studies was made. PET quantification was also compared with ex vivo biodistribution results.Results: The radiosynthesis provided [18F]AlF-NOTA-MAL-cys40-exendin-4 in 23.6 ± 2.4 % radiochemical yield (uncorrected, n = 3 after HPLC; the process required about 55 min. The specific activity at time of injection ranged from 19.6 to 31.4 GBq (0.53-0.85 Ci/µmol. Tumor uptake had reached its maximum (16.09 ± 1.18% ID/g, n = 4 by 5 min and remained nearly constant for the duration of the study. Kidney uptake continued to increase throughout the entire one hour time course. Pre-injection of exendin-4 caused a marked reduction in tissue uptake with the major exception of liver and kidneys, in which uptake was not affected. HPLC analysis of the radioactive components in extracts of the tumor and plasma showed primarily parent compound at 60 min post-injection, whereas extracts of kidney and urine contained exclusively one polar radioactive component.Conclusion: The radiotracer is prepared in

  2. Effect of glucagon-like peptide-1 on alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients

    DEFF Research Database (Denmark)

    Kielgast, Urd; Asmar, Meena; Madsbad, Sten

    2010-01-01

    The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect.......The mechanism by which glucagon-like peptide-1 (GLP-1) suppresses glucagon secretion is uncertain, and it is not determined whether endogenous insulin is a necessary factor for this effect....

  3. Alleviation of insulin resistance and liver damage by oral administration of Imm124-E is mediated by increased Tregs and associated with increased serum GLP-1 and adiponectin: results of a phase I/II clinical trial in NASH

    Directory of Open Access Journals (Sweden)

    Mizrahi M

    2012-12-01

    Full Text Available Meir Mizrahi,1 Yehudit Shabat,1 Ami Ben Ya'acov,1 Gadi Lalazar,1 Tomer Adar,1 Victor Wong,2 Brian Muller,2 Grant Rawlin,2 Yaron Ilan11Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel; 2Immuron Limited, North Melbourne, AustraliaBackground: Nonalcoholic steatohepatitis (NASH is considered to be part of the nonalcoholic fatty liver disorders and its incidence is increasing. Imm124-E (Immuron Ltd, Melbourne, Australia, containing hyperimmune bovine colostrum, has been shown to exert an immunomodulatory effect and to alleviate target organ damage in animal models of NASH. The aim of our study was to determine the safety and efficacy of oral administration of Imm124-E to patients with insulin resistance and NASH.Methods: In an open-label trial, ten patients with biopsy-proven NASH and insulin resistance were orally treated with Imm124-E for 30 days.Results: Oral administration of Imm124-E was safe, and no side effects were noted. Alleviation of insulin resistance was reflected by significantly improved hemoglobin A1c (HbA1c values in all ten treated patients. For between five and eight responders, the following effects were noted: a decrease in fasting glucose levels; improved oral glucose tolerance test (OGGT and homeostatic model assessment insulin resistance (HOMA scores; and alleviation in lipid profile. These effects were accompanied by increased serum levels of glucagon-like peptide 1 (GLP-1, adiponectin and T regulatory cells.Conclusion: Hyperimmune colostrum alleviates NASH.Keywords: NASH, anti-LPS, diabetes, adipokines, regulatory T cells

  4. Effect of fertilization on the physiological maturation of sesame seeds

    Directory of Open Access Journals (Sweden)

    Erivan Isídio Ferreira

    2017-06-01

    Full Text Available Fertilization and harvest time may influence the formation and maturation processes, as well as the physiological quality of seeds. This study aimed at evaluating the effect of fertilization on the physiological maturation of sesame seeds. The following variables were evaluated: fruit color, dry mass and water content of fruits and seeds, germination, first germination count, germination speed, emergence and emergence speed. No significant fertilization effect was observed on fruit maturation for water content or dry mass. However, there was significance for these variables in the seeds. The harvest time had a significant effect on water content and dry mass of fruits and seeds. For the variables that evaluated the seed viability and vigor, both the fertilization and harvest time influenced the physiological maturation. The physiological maturity of the sesame seeds, whose plants were grown with and without fertilization, was reached between 52 and 54 days after anthesis, when the fruits were classified as yellow-greenish 7.5 Y 8/6 and yellow to yellow-red 10.R 4/6.

  5. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    International Nuclear Information System (INIS)

    Puddu, A.; Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L.

    2010-01-01

    Research highlights: → GLP-1 prevents AGEs-induced cell death. → GLP-1 prevents AGEs-induced oxidative stress. → GLP-1 ameliorated AGEs-induced cell dysfunction. → GLP-1 attenuates AGEs-induced RAGE increment. → GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  6. Effects of exercise on tumor physiology and metabolism

    DEFF Research Database (Denmark)

    Pedersen, Line; Christensen, Jesper Frank; Hojman, Pernille

    2015-01-01

    . Here, we review the body of literature describing exercise intervention studies performed in rodent tumor models and elaborate on potential mechanistic effects of exercise on tumor physiology. Exercise has been shown to reduce tumor incidence, tumor multiplicity, and tumor growth across numerous...... different transplantable, chemically induced or genetic tumor models. We propose 4 emerging mechanistic effects of exercise, including (1) vascularization and blood perfusion, (2) immune function, (3) tumor metabolism, and (4) muscle-to-cancer cross-talk, and discuss these in details. In conclusion......, exercise training has the potential to be a beneficial and integrated component of cancer management, but has yet to fully elucidate its potential. Understanding the mechanistic effects of exercise on tumor physiology is warranted. Insight into these mechanistic effects is emerging, but experimental...

  7. Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin

    DEFF Research Database (Denmark)

    Bahne, Emilie; Hansen, Morten; Brønden, Andreas

    2016-01-01

    Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously...... administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin......-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target...

  8. Positive expiratory pressure - Common clinical applications and physiological effects.

    Science.gov (United States)

    Fagevik Olsén, Monika; Lannefors, Louise; Westerdahl, Elisabeth

    2015-03-01

    Breathing out against resistance, in order to achieve positive expiratory pressure (PEP), is applied by many patient groups. Pursed lips breathing and a variety of devices can be used to create the resistance giving the increased expiratory pressure. Effects on pulmonary outcomes have been discussed in several publications, but the expected underlying physiology of the effect is seldom discussed. The aim of this article is to describe the purpose, performance, clinical application and underlying physiology of PEP when it is used to increase lung volumes, decrease hyperinflation or improve airway clearance. In clinical practice, the instruction how to use an expiratory resistance is of major importance since it varies. Different breathing patterns during PEP increase or reduce expiratory flow, result in movement of EPP centrally or peripherally and can increase or decrease lung volume. It is therefore necessary to give the right instructions to obtain the desired effects. As the different PEP techniques are being used by diverse patient groups it is not possible to give standard instructions. Based on the information given in this article the instructions have to be adjusted to give the optimal effect. There is no consensus regarding optimal treatment frequency and number of cycles included in each treatment session and must also be individualized. In future research, more precise descriptions are needed about physiological aims and specific instructions of how the treatments have been performed to assure as good treatment quality as possible and to be able to evaluate and compare treatment effects. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. The impact of short chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon

    DEFF Research Database (Denmark)

    Christiansen, Charlotte Bayer; Gabe, Maria Buur Nordskov; Svendsen, Berit

    2018-01-01

    chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L-cells. We used the isolated perfused rat colon as a model of colonic endocrine secretion and studied the effects...

  10. Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

    NARCIS (Netherlands)

    Yin, Meimei; Sillje, Herman H. W.; Meissner, Maxi; van Gilst, Wiek H.; de Boer, Rudolf A.

    2011-01-01

    Background: Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme

  11. Effects of insemination quantity on honey bee queen physiology.

    Directory of Open Access Journals (Sweden)

    Freddie-Jeanne Richard

    2007-10-01

    Full Text Available Mating has profound effects on the physiology and behavior of female insects, and in honey bee (Apis mellifera queens, these changes are permanent. Queens mate with multiple males during a brief period in their early adult lives, and shortly thereafter they initiate egg-laying. Furthermore, the pheromone profiles of mated queens differ from those of virgins, and these pheromones regulate many different aspects of worker behavior and colony organization. While it is clear that mating causes dramatic changes in queens, it is unclear if mating number has more subtle effects on queen physiology or queen-worker interactions; indeed, the effect of multiple matings on female insect physiology has not been broadly addressed. Because it is not possible to control the natural mating behavior of queens, we used instrumental insemination and compared queens inseminated with semen from either a single drone (single-drone inseminated, or SDI or 10 drones (multi-drone inseminated, or MDI. We used observation hives to monitor attraction of workers to SDI or MDI queens in colonies, and cage studies to monitor the attraction of workers to virgin, SDI, and MDI queen mandibular gland extracts (the main source of queen pheromone. The chemical profiles of the mandibular glands of virgin, SDI, and MDI queens were characterized using GC-MS. Finally, we measured brain expression levels in SDI and MDI queens of a gene associated with phototaxis in worker honey bees (Amfor. Here, we demonstrate for the first time that insemination quantity significantly affects mandibular gland chemical profiles, queen-worker interactions, and brain gene expression. Further research will be necessary to elucidate the mechanistic bases for these effects: insemination volume, sperm and seminal protein quantity, and genetic diversity of the sperm may all be important factors contributing to this profound change in honey bee queen physiology, queen behavior, and social interactions in the

  12. Effect of curd suppression in a milk replacer on physiological ...

    African Journals Online (AJOL)

    Effect of curd suppression in a milk replacer on physiological parameters in calves. I. Digestibility of ... Body mass-gain (kg) and efficiency of feed conversion (kg dry matter intake/kg gain) over the 28-day experimental period were respectively 7,3 and 1,8 (WM); 7,3 and 1,8 (NWM); 4,3 and 3,9 (CM) and 4,9 and 2,9 (NCM).

  13. Effects of gamma irradiation on physiological effectiveness of Korean medicinal herbs

    International Nuclear Information System (INIS)

    Byun, Myung-Woo; Yook, Hong-Sun; Kim, Kyong-Su; Chung, Cha-Kwon

    1999-01-01

    Effects of gamma irradiation on the physiological effectiveness of Korean medicinal herbs were investigated. The physiological effectiveness including antioxidant and anticomplement function, nitrite scavenging and electron donating ability of Korean medicinal herbs by gamma irradiation at 10 kGy did not differ from that of the nonirradiated control

  14. Reflexology: its effects on physiological anxiety signs and sedation needs.

    Science.gov (United States)

    Akin Korhan, Esra; Khorshid, Leyla; Uyar, Mehmet

    2014-01-01

    To investigate whether reflexology has an effect on the physiological signs of anxiety and level of sedation in patients receiving mechanically ventilated support, a single blinded, randomized controlled design with repeated measures was used in the intensive care unit of a university hospital in Turkey. Patients (n = 60) aged between 18 and 70 years and were hospitalized in the intensive care unit and receiving mechanically ventilated support. Participants were randomized to a control group or an intervention group. The latter received 30 minutes of reflexology therapy on their feet, hands, and ears for 5 days. Subjects had vital signs taken immediately before the intervention and at the 10th, 20th, and 30th minutes of the intervention. In the collection of the data, "American Association of Critical-Care Nurses Sedation Assessment Scale" was used. The reflexology therapy group had a significantly lower heart rate, systolic blood pressure, diastolic blood pressure, and respiratory rate than the control group. A statistically significant difference was found between the averages of the scores that the patients included in the experimental and control groups received from the agitation, anxiety, sleep, and patient-ventilator synchrony subscales of the American Association of Critical-Care Nurses Sedation Assessment Scale. Reflexology can serve as an effective method of decreasing the physiological signs of anxiety and the required level of sedation in patients receiving mechanically ventilated support. Nurses who have appropriate training and certification may include reflexology in routine care to reduce the physiological signs of anxiety of patients receiving mechanical ventilation.

  15. Lower glucose-dependent insulinotropic polypeptide (GIP) response but similar glucagon-like peptide 1 (GLP-1), glycaemic, and insulinaemic response to ancient wheat compared to modern wheat depends on processing

    DEFF Research Database (Denmark)

    Bakhøj, S; Flint, A.; Holst, Jens Juul

    2003-01-01

    with honey-salt added, leavening crushed whole grain, and conventional leavening with yeast added. Bread made from modern wheat was prepared by conventional leavening with yeast added. SUBJECTS: A total of 11 healthy young men. RESULTS: The postprandial GIP response was significantly (P... by the Einkorn breads processed with honey-salt leavening and by using crushed whole grain bread compared to the yeast leavened bread made from modern wheat or from Einkorn. No significant differences were found in the responses of GLP-1, insulin or glucose. CONCLUSION: Einkorn honey-salt leavened and Einkorn...... whole grain bread elicit a reduced gastrointestinal response of GIP compared to conventional yeast bread. No differences were found in the glycaemic, insulinaemic and GLP-1 responses. Processing of starchy foods such as wheat may be a powerful tool to modify the postprandial GIP response....

  16. Encapsulated glucagon-like peptide-1-producing mesenchymal stem cells have a beneficial effect on failing pig hearts

    DEFF Research Database (Denmark)

    Wright, Elizabeth J; Farrell, Kelly A; Malik, Nadim

    2012-01-01

    -life in vivo. The effects of prolonged GLP-1 delivery from stromal cells post-MI were evaluated in a porcine model. Human mesenchymal stem cells immortalized and engineered to produce a GLP-1 fusion protein were encapsulated in alginate (bead-GLP-1 MSC) and delivered to coronary artery branches. Control groups...... were cell-free beads and beads containing unmodified MSCs (bead-MSC), n = 4-5 per group. Echocardiography confirmed left ventricular (LV) dysfunction at time of delivery in all groups. Four weeks after intervention, only the bead-GLP-1 MSC group demonstrated LV function improvement toward baseline...... and showed decreased infarction area compared with controls. Histological analysis showed reduced inflammation and a trend toward reduced apoptosis in the infarct zone. Increased collagen but fewer myofibroblasts were observed in infarcts of the bead-GLP-1 MSC and bead-MSC groups, and significantly more...

  17. Exercise and Training at Altitudes: Physiological Effects and Protocols

    Directory of Open Access Journals (Sweden)

    Olga Cecilia Vargas Pinilla

    2014-01-01

    Full Text Available An increase in altitude leads to a proportional fall in the barometric pressure, and a decrease in atmospheric oxygen pressure, producing hypobaric hypoxia that affects, in different degrees, all body organs, systems and functions. The chronically reduced partial pressure of oxygen causes that individuals adapt and adjust to physiological stress. These adaptations are modulated by many factors, including the degree of hypoxia related to altitude, time of exposure, exercise intensity and individual conditions. It has been established that exposure to high altitude is an environmental stressor that elicits a response that contributes to many adjustments and adaptations that influence exercise capacity and endurance performance. These adaptations include in crease in hemoglobin concentration, ventilation, capillary density and tissue myoglobin concentration. However, a negative effect in strength and power is related to a decrease in muscle fiber size and body mass due to the decrease in the training intensity. Many researches aim at establishing how training or living at high altitudes affects performance in athletes. Training methods, such as living in high altitudes training low, and training high-living in low altitudes have been used to research the changes in the physical condition in athletes and how the physiological adaptations to hypoxia can enhanceperformance at sea level. This review analyzes the literature related to altitude training focused on how physiological adaptations to hypoxic environments influence performance, and which protocols are most frequently used to train in high altitudes.

  18. The effect of foot reflexology on physiological parameters

    Directory of Open Access Journals (Sweden)

    Arash Khalili

    2016-09-01

    Full Text Available Reflexology have a positive impact on stabilize the physiological parameters such as blood pressure and heart rate. This study aims to investigate the effects of foot reflexology on physiological parameters of patients before coronary angiography. This study is an interventional study performed in Kashan hospitals and 100 male patients undergoing angioplasty were randomly divided into two groups. In the intervention group for 30 minutes of foot reflexology massage and stimulate the soles of the feet in three points the solar plexus, the pituitary gland and the heart was performed, but in the control group was only Masazhmvmy feet. The vital signs 30 minutes before and after the intervention in both groups were measured. To analyze the data, t-test and ANOVA with repeated observations was used. The mean systolic blood pressure in both groups had significant difference compared to before [0010. = p]. Diastolic blood pressure in both groups had significant difference compared to before [420. = p]. Changes in heart rate before and after the intervention had no significant difference [090. = p]. The average number of breathing in both groups had significant difference compared to before [0010. = p and 0010.> P]. Foot reflexology can sustain physiological parameters such as systolic and diastolic pressure.

  19. Physiological and psychological effects of gardening activity in older adults.

    Science.gov (United States)

    Hassan, Ahmad; Qibing, Chen; Tao, Jiang

    2018-04-06

    Gardening has long been one of most enjoyable pastimes among older adults. Whether gardening activities contribute to the well-being of older adults is a major question. Therefore, the aim of the present study was to clarify the psychophysiological relaxing effects of gardening activities on older adults living in modern institutional care. The study participants were 40 older women aged 79.5 ± 8.09 years (mean ± SD). A cross-over study design was used to investigate the physiological and psychological responses to environments with and without plants. Physiological evaluation was carried out using blood pressure and electroencephalography, and psychological evaluation was carried out using the State-Trait Anxiety Inventory and Semantic Differential method. Blood pressure was significantly lower, and changes in brainwaves were observed. Psychological responses showed that participants were more "comfortable and relaxed" after the plant task than after the control task. In addition, total anxiety levels were significantly lower after carrying out the plant task than after the control task. Our research suggests that gardening activities might enhance physiological and psychological relaxation in older adults. Geriatr Gerontol Int 2018; ••: ••-••. © 2018 Japan Geriatrics Society.

  20. Physiological effects of magnetic iron oxide nanoparticles towards watermelon.

    Science.gov (United States)

    Li, Junli; Chang, Peter R; Huang, Jin; Wang, Yunqiang; Yuan, Hong; Ren, Hongxuan

    2013-08-01

    Nanoparticles (NPs) have been exploited in a diverse range of products in the past decade or so. However, the biosafety/environmental impact or legislation pertaining to this newly created, highly functional composites containing NPs (otherwise called nanomaterials) is generally lagging behind their technological innovation. To advance the agenda in this area, our current primary interest is focused on using crops as model systems as they have very close relationship with us. Thus, the objective of the present study was to evaluate the biological effects of magnetic iron oxide nanoparticles towards watermelon seedlings. We have systematically studied the physiological effects of Fe2O3 nanoparticles (nano-Fe2O3) on watermelon, and present the first evidence that a significant amount of Fe2O3 nanoparticles suspended in a liquid medium can be taken up by watermelon plants and translocated throughout the plant tissues. Changes in important physiological indicators, such as root activity, activity of catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD), chlorophyll and malondialdehyde (MDA) contents, ferric reductase activity, root apoplastic iron content were clearly presented. Different concentrations of nano-Fe2O3 all increased seed germination, seedling growth, and enhanced physiological function to some degree; and the positive effects increased quickly and then slowed with an increase in the treatment concentrations. Changes in CAT, SOD and POD activities due to nano-Fe2O3 were significantly larger than that of the control. The 20 mg/L treatment had the most obvious effect on the increase of root activity. Ferric reductase activity, root apoplastic iron content, and watermelon biomass were significantly affected by exposure to nano-Fe2O3. Results of statistical analysis showed that there were significant differences in all the above indexes between the treatment at optimal concentration and the control. This proved that the proper concentration of nano

  1. Physiological mechanisms of the effect of weightlessness on the body

    Science.gov (United States)

    Kasyan, I. I.; Kopanev, V. I.

    1975-01-01

    Experimental data show that physiological reactions observed under weightlessness conditions are caused by: (1) The direct effect of weightlessness, as a consequence of decrease (""disappearance'') of the weight of body tissues and organs; and (2) the mediated effect of weightlessness, as a result of changes in the functional state of the central nervous system and the cooperative work of the analyzers. The human body adopts to weightless conditions under the prolonged effects of it. In this case, four periods can be distinguished: The first period, a transitional process lasting from 1 to 24 hours; second period, initial adaptation to conditions of weightlessness and readjustment of all functional systems of the body; the third period, adaptation to the unusual mechanical conditions of the external environment, lasting from 3 to 8 days and more; and the fourth period, the stage of possible imbalance of the functions and the systems of some astronauts, as a result of the prolonged effect of weightlessness.

  2. Encapsulated Glucagon-Like Peptide-1-Producing Mesenchymal Stem Cells Have a Beneficial Effect on Failing Pig Hearts

    Science.gov (United States)

    Wright, Elizabeth J.; Farrell, Kelly A.; Malik, Nadim; Kassem, Moustapha; Lewis, Andrew L.; Wallrapp, Christine

    2012-01-01

    Stem cell therapy is an exciting and emerging treatment option to promote post-myocardial infarction (post-MI) healing; however, cell retention and efficacy in the heart remain problematic. Glucagon-like peptide-1 (GLP-1) is an incretin hormone with cardioprotective properties but a short half-life in vivo. The effects of prolonged GLP-1 delivery from stromal cells post-MI were evaluated in a porcine model. Human mesenchymal stem cells immortalized and engineered to produce a GLP-1 fusion protein were encapsulated in alginate (bead-GLP-1 MSC) and delivered to coronary artery branches. Control groups were cell-free beads and beads containing unmodified MSCs (bead-MSC), n = 4–5 per group. Echocardiography confirmed left ventricular (LV) dysfunction at time of delivery in all groups. Four weeks after intervention, only the bead-GLP-1 MSC group demonstrated LV function improvement toward baseline and showed decreased infarction area compared with controls. Histological analysis showed reduced inflammation and a trend toward reduced apoptosis in the infarct zone. Increased collagen but fewer myofibroblasts were observed in infarcts of the bead-GLP-1 MSC and bead-MSC groups, and significantly more vessels per mm2 were noted in the infarct of the bead-GLP-1 MSC group. No differences were observed in myocyte cross-sectional area between groups. Post-MI delivery of GLP-1 encapsulated genetically modified MSCs provided a prolonged supply of GLP-1 and paracrine stem cell factors, which improved LV function and reduced epicardial infarct size. This was associated with increased angiogenesis and an altered remodeling response. Combined benefits of paracrine stem cell factors and GLP-1 were superior to those of stem cells alone. These results suggest that encapsulated genetically modified MSCs would be beneficial for recovery following MI. PMID:23197668

  3. Visual versus auditory Simon effect: A behavioural and physiological investigation.

    Science.gov (United States)

    D'Ascenzo, Stefania; Lugli, Luisa; Baroni, Giulia; Guidotti, Roberto; Rubichi, Sandro; Iani, Cristina; Nicoletti, Roberto

    2018-04-01

    This study investigated whether the visual and auditory Simon effects could be accounted for by the same mechanism. In a single experiment, we performed a detailed comparison of the visual and the auditory Simon effects arising in behavioural responses and in pupil dilation, a psychophysiological measure considered as a marker of the cognitive effort induced by conflict processing. To address our question, we performed sequential and distributional analyses on both reaction times and pupil dilation. Results confirmed that the mechanisms underlying the visual and auditory Simon effects are functionally equivalent in terms of the interaction between unconditional and conditional response processes. The two modalities, however, differ with respect to the strength of their activation and inhibition. Importantly, pupillary data mirrored the pattern observed in behavioural data for both tasks, adding physiological evidence to the current literature on the processing of visual and auditory information in a conflict task.

  4. PHYSIOLOGICAL AND MEDICAL EFFECTS OF PLANT FLAVONOID QUERCETIN

    Directory of Open Access Journals (Sweden)

    Aneta Štochmaľová

    2013-02-01

    Full Text Available Flavonoid compounds in vegetable-based diets bring a significant contribution to the role of fruits and vegetables as health-promoting foods. This review summarizes the available data concerning physiological and therapeutical effect of plan flavonoid quercetin. Quercetin has a number of beneficial influence on health because of their antioxidant, anti-inflammatory, anti-proliferative, anti-carcinogenic and anti-diabetes properties. Effects of quercetin have been explained by its interference with cellular enzymes, receptors, transporters and signal transduction systems. Despite the available data reviewed here, the targets, effects, absorption, metabolism and areas of practical application of quercetin are still poorly understood, therefore further studies in this areas are required.

  5. Effects of Harmful Algae on the Physiology of Fishes

    DEFF Research Database (Denmark)

    Svendsen, Morten Bo Søndergaard

    Blooms of harmful planktonic algae causing adverse effects in aquatic environments are a global problem, causing both human morbidity and killing aquatic lifeforms worldwide. Focusing on fish kills, it is largely unknown what mechanisms of the fish’s physiology are affected during exposure...... is deemed unlikely on basis of rainbow trout (Onchorhyncus mykiss) not recovering. The specific toxicity of Pseudochattonella spp. is unknown, but by studying the effects of Pseudochattonella spp. on fish during a natural bloom occurring at a trout farm an adverse outcome could be created. The adverse...... Alexandrium monilatum has been studied intensively the effects of Alexandrium monilatum on fish is largely unknown. In the Chesapeake Bay, Eastern U.S.A., fishes are further challenged in late summer by an oxygen squeeze from deep part of the water column, limiting their utilizable habitat to mid...

  6. Metabolic effects of physiological levels of caffeine in myotubes.

    Science.gov (United States)

    Schnuck, Jamie K; Gould, Lacey M; Parry, Hailey A; Johnson, Michele A; Gannon, Nicholas P; Sunderland, Kyle L; Vaughan, Roger A

    2018-02-01

    Caffeine has been shown to stimulate multiple major regulators of cell energetics including AMP-activated protein kinase (AMPK) and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). Additionally, caffeine induces peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial biogenesis. While caffeine enhances oxidative metabolism, experimental concentrations often exceed physiologically attainable concentrations through diet. This work measured the effects of low-level caffeine on cellular metabolism and gene expression in myotubes, as well as the dependence of caffeine's effects on the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPARβ/δ). C2C12 myotubes were treated with various doses of caffeine for up to 24 h. Gene and protein expression were measured via qRT-PCR and Western blot, respectively. Cellular metabolism was determined via oxygen consumption and extracellular acidification rate. Caffeine significantly induced regulators of mitochondrial biogenesis and oxidative metabolism. Mitochondrial staining was suppressed in PPARβ/δ-inhibited cells which was rescued by concurrent caffeine treatment. Caffeine-treated cells also displayed elevated peak oxidative metabolism which was partially abolished following PPARβ/δ inhibition. Similar to past observations, glucose uptake and GLUT4 content were elevated in caffeine-treated cells, however, glycolytic metabolism was unaltered following caffeine treatment. Physiological levels of caffeine appear to enhance cell metabolism through mechanisms partially dependent on PPARβ/δ.

  7. Physiologic effects of intravenous fluid administration in healthy volunteers

    DEFF Research Database (Denmark)

    Holte, Kathrine; Jensen, Peter; Kehlet, Henrik

    2003-01-01

    Dose regimens in perioperative fluid management are rarely evidence based. Therefore, we investigated responses to an IV fluid infusion in healthy volunteers to assess basic physiologic effects of a fluid infusion per se. In a prospective, double-blinded, cross-randomized study, 12 healthy...... volunteers with a median age of 63 yr (range, 59-67 yr) received an infusion of lactated Ringer's solution 40 mL/kg (median, 2820 mL) or 5 mL/kg (median, 353 mL; background infusion) in random order on two separate occasions. The study was designed to mimic the perioperative course with preoperative fasting...... by fluid administration. These findings may serve as a basis for clinical studies applying the same type of fluid in different amounts to determine the optimal amount of perioperative fluid in various surgical procedures. IMPLICATIONS: Infusion of 40 mL/kg of lactated Ringer's solution in volunteers led...

  8. Deleterious effects of tributyltin on porcine vascular stem cells physiology.

    Science.gov (United States)

    Bernardini, Chiara; Zannoni, Augusta; Bertocchi, Martina; Bianchi, Francesca; Salaroli, Roberta; Botelho, Giuliana; Bacci, Maria Laura; Ventrella, Vittoria; Forni, Monica

    2016-01-01

    The vascular functional and structural integrity is essential for the maintenance of the whole organism and it has been demonstrated that different types of vascular progenitor cells resident in the vessel wall play an important role in this process. The purpose of the present research was to observe the effect of tributyltin (TBT), a risk factor for vascular disorders, on porcine Aortic Vascular Precursor Cells (pAVPCs) in term of cytotoxicity, gene expression profile, functionality and differentiation potential. We have demonstrated that pAVPCs morphology deeply changed following TBT treatment. After 48h a cytotoxic effect has been detected and Annexin binding assay demonstrated that TBT induced apoptosis. The transcriptional profile of characteristic pericyte markers has been altered: TBT 10nM substantially induced alpha-SMA, while, TBT 500nM determined a significant reduction of all pericyte markers. IL-6 protein detected in the medium of pAVPCs treated with TBT at both doses studied and with a dose response. TBT has interfered with normal pAVPC functionality preventing their ability to support a capillary-like network. In addition TBT has determined an increase of pAVPC adipogenic differentiation. In conclusion in the present paper we have demonstrated that TBT alters the vascular stem cells in terms of structure, functionality and differentiating capability, therefore effects of TBT in blood should be deeply explored to understand the potential vascular risk associated with the alteration of vascular stem cell physiology. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. The effect of pneumatic tourniquets on skeletal muscle physiology.

    Science.gov (United States)

    Patterson, S; Klenerman, L; Biswas, M; Rhodes, A

    1981-01-01

    The effect of 3- and 5-hour pneumatic tourniquets on skeletal muscle physiology was investigated. Maximum isometric tension development, contraction and half relaxation times were measured in the muscles lying immediately under and distal to the tourniquet. On release of the tourniquet no consistent difference between control and experimental muscles was observed with respect to contraction and half relaxation times; however, there was a marked reduction in maximum isometric tension development. On the sixth day after release of a 5-hour tourniquet, isometric tension was reduced to 2--20 per cent of the control value in the distal muscle and to 40--60 per cent of the control value in the compressed muscle. Six days after a 3-hour tourniquet the compressed muscle tension was reduced to approximately 80 per cent of the control value whilst in the distal muscle, tension development varied from normal to 64 per cent of the control value. Thus it is shown that the effect on muscle contraction after a 3-hour tourniquet is not immediately reversed by the restoration of the blood supply. A reduction in muscle strength follows which may take a week or more to recover.

  10. Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease

    DEFF Research Database (Denmark)

    Junker, Anders E; Gluud, Lise L; van Hall, Gerrit

    2016-01-01

    BACKGROUND & AIMS: We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS: On two separate days 10 non-diabetic...... patients with liver biopsy-verified NAFLD (NAFLD activity score 2.5±1.0) and 10 matched controls underwent a 2-hour intravenous infusions of GLP-1 (0.8 pmol × kg(-1) × min(-1)) and placebo. Since GLP-1-mediated glucagon suppression has been shown to be glucose-dependent, plasma glucose was clamped...

  11. Physiological effects of increased foraging effort in a small passerine.

    Science.gov (United States)

    Yap, Kang Nian; Kim, Oh Run; Harris, Karilyn C; Williams, Tony D

    2017-11-15

    Foraging to obtain food, either for self-maintenance or at presumably elevated rates to provide for offspring, is thought to be an energetically demanding activity but one that is essential for fitness (higher reproductive success and survival). Nevertheless, the physiological mechanisms that allow some individuals to support higher foraging performance, and the mechanisms underlying costs of high workload, remain poorly understood. We experimentally manipulated foraging behaviour in zebra finches ( Taeniopygia guttata ) using the technique described by Koetsier and Verhulst (2011) Birds in the 'high foraging effort' (HF) group had to obtain food either while flying/hovering or by making repeated hops or jumps from the ground up to the feeder, behaviour typical of the extremely energetically expensive foraging mode observed in many free-living small passerines. HF birds made significantly more trips to the feeder per 10 min, whereas control birds spent more time (perched) at the feeder. Despite this marked change in foraging behaviour, we documented few short- or long-term effects of 'training' (3 days and 90 days of 'training', respectively) and some of these effects were sex specific. There were no effects of treatment on basal metabolic rate, haematocrit, haemoglobin or plasma glycerol, triglyceride and glucose levels, and masses of kidney, crop, large intestine, small intestine, gizzard and liver. HF females had higher masses of flight muscle, leg muscle, heart and lung compared with controls. In contrast, HF males had lower heart mass than controls and there were no differences for other organs. When both sexes were pooled, there were no effects of treatment on body composition. Finally, birds in the HF treatment group had higher levels of reactive oxygen metabolites (dROMs) and, consequently, although treatment did not affect total anti-oxidant capacity, birds in the HF treatment group had higher oxidative stress. © 2017. Published by The Company of

  12. The physiology and pharmacology of incretins in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2008-01-01

    Two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1, help control blood glucose levels by affecting plasma insulin levels in response to oral glucose intake - this is known as the incretin effect. Incretins increase plasma insulin by a numbe...

  13. Physiological Effects of Visual Stimulation with Forest Imagery

    Directory of Open Access Journals (Sweden)

    Chorong Song

    2018-01-01

    Full Text Available This study was aimed to clarify the physiological effects of visual stimulation using forest imagery on activity of the brain and autonomic nervous system. Seventeen female university students (mean age, 21.1 ± 1.0 years participated in the study. As an indicator of brain activity, oxyhemoglobin (oxy-Hb concentrations were measured in the left and right prefrontal cortex using near-infrared time-resolved spectroscopy. Heart rate variability (HRV was used as an indicator of autonomic nervous activity. The high-frequency (HF component of HRV, which reflected parasympathetic nervous activity, and the ratio of low-frequency (LF and high-frequency components (LF/HF, which reflected sympathetic nervous activity, were measured. Forest and city (control images were used as visual stimuli using a large plasma display window. After sitting at rest viewing a gray background for 60 s, participants viewed two images for 90 s. During rest and visual stimulation, HRV and oxy-Hb concentration in the prefrontal cortex were continuously measured. Immediately thereafter, subjective evaluation of feelings was performed using a modified semantic differential (SD method. The results showed that visual stimulation with forest imagery induced (1 a significant decrease in oxy-Hb concentrations in the right prefrontal cortex and (2 a significant increase in perceptions of feeling “comfortable,” “relaxed,” and “natural.”

  14. Effect of Compression Garments on Physiological Responses After Uphill Running.

    Science.gov (United States)

    Struhár, Ivan; Kumstát, Michal; Králová, Dagmar Moc

    2018-03-01

    Limited practical recommendations related to wearing compression garments for athletes can be drawn from the literature at the present time. We aimed to identify the effects of compression garments on physiological and perceptual measures of performance and recovery after uphill running with different pressure and distributions of applied compression. In a random, double blinded study, 10 trained male runners undertook three 8 km treadmill runs at a 6% elevation rate, with the intensity of 75% VO2max while wearing low, medium grade compression garments and high reverse grade compression. In all the trials, compression garments were worn during 4 hours post run. Creatine kinase, measurements of muscle soreness, ankle strength of plantar/dorsal flexors and mean performance time were then measured. The best mean performance time was observed in the medium grade compression garments with the time difference being: medium grade compression garments vs. high reverse grade compression garments. A positive trend in increasing peak torque of plantar flexion (60º·s-1, 120º·s-1) was found in the medium grade compression garments: a difference between 24 and 48 hours post run. The highest pain tolerance shift in the gastrocnemius muscle was the medium grade compression garments, 24 hour post run, with the shift being +11.37% for the lateral head and 6.63% for the medial head. In conclusion, a beneficial trend in the promotion of running performance and decreasing muscle soreness within 24 hour post exercise was apparent in medium grade compression garments.

  15. Effects of Long Distance Transportation on Honey Bee Physiology

    Directory of Open Access Journals (Sweden)

    Kiheung Ahn

    2012-01-01

    Full Text Available Despite the requirement of long distance transportation of honey bees used for pollination, we understand little how transportation affects honey bees. Three trials in three different states (CA, GA, and MI were conducted to study the effects of long distance transportation on honey bee physiology. Newly emerged bees from one colony were split into two groups and introduced into a transported (T colony or a stationary (S colony in each trial. Volumes of hypopharyngeal gland acini in T colonies were significantly smaller than S colonies in all three trials. There were no significant differences between S and T colonies in juvenile hormone titers. Protein content in head showed no significant differences between S and T either in 7-day-old or 17-day-old bees of MI trial, but GA trial showed a significant reduction in bees experiencing transportation. Protein content in thorax was only measured in GA trial and was not significantly different between the two groups. Lipid content in abdomen was not significantly different between the S and T colonies in all three trials. This study suggests that bees experiencing transportation have trouble fully developing their food glands and this might affect their ability to nurse the next generation of workers.

  16. Effects of Weightlessness on Human Fluid and Electrolyte Physiology

    Science.gov (United States)

    Leach, Carolyn S.; Johnson, Philip C., Jr.

    1991-01-01

    The changes that occur in human fluid and electrolyte physiology during the acute and adaptive phases of adaptation to spaceflight are summarized. A number of questions remain to be answered. At a time when plasma volume and extracellular fluid volume are contracted and salt and water intake is unrestricted. ADH does not correct the volume deficit and serum sodium decreases. Change in secretion or activity of a natriuretic factor during spaceflight is one possible explanation. Recent identification of a polypeptide hormone produced in cardiac muscle cells which is natiuretic, is hypotensive, and has an inhibitory effect on renin and aldosterone secretion has renewed interest in the role of a natriuretic factor. The role of this atrial natriuretic factor (ANF) in both long- and short-term variation in extracellular volumes and in the inability of the kidney to bring about an escape from the sodium-retaining state accompanying chronic cardiac dysfunction makes it reasonable to look for a role of ANF in the regulation of sodium during exposure to microgravity. Prostaglandin-E is another hormone that may antagonize the action of ADH. Assays of these hormones will be performed on samples from crew members in the future.

  17. [Physiological effects of metsulfuron-methy on Elodea nuttallii].

    Science.gov (United States)

    Pan, Hui-Yun; Li, Xiao-Lu; Xu, Xiao-Hua; Gao, Shi-Xiang

    2008-07-01

    Physiological effects of metsulfuron-methy on Elodea nuttallii was studied. The growth status, the photosynthetic pigments content and activities of anti-oxidation enzymes of Elodea nuttallii were examined with different contents of metsulfuron-methyl in cultural solution. The results showed that metsulfuron-methy could stimulate the sprout bourgeoning but restrained the growth of frond remarkably. At lower concentrations, metsulfuron-methy could increase the content of chlorophyll at the beginning, but inhibited the syntheses of chlorophyll ultimately and reduced the plant's photosynthetic capacity. Activities of CAT and POD increased at first and then decreased, while SOD activities increased all the time. With higher concentration and longer treatment time, the activities of anti-oxidation enzymes would decrease. It is indicated that metsulfuron-methy can arise the formation and accumulation of reactive oxygen species in Elodea nuttalii, and induce activities of anti-oxidation enzymes. When stress intensity exceeds a certain value, the activities of anti-oxidation enzymes will be inhibited and reactive oxygen species can not be removed in time and will finally result in oxidative damages to the plant. This may be an important toxicity mechanism of this kind of herbicide to aquatic plants.

  18. The effect of hysterectomy on ano-rectal physiology.

    LENUS (Irish Health Repository)

    Kelly, J L

    2012-02-03

    Hysterectomy is associated with severe constipation in a subgroup of patients, and an adverse effect on colonic motility has been described in the literature. The onset of irritable bowel syndrome and urinary bladder dysfunction has also been reported after hysterectomy. In this prospective study, we investigated the effect of simple hysterectomy on ano-rectal physiology and bowel function. Thirty consecutive patients were assessed before and 16 weeks after operation. An abdominal hysterectomy was performed in 16 patients, and a vaginal procedure was performed in 14. The parameters measured included the mean resting, and maximal forced voluntary contraction anal pressures, the recto-anal inhibitory reflex, and rectal sensation to distension. In 8 patients, the terminal motor latency of the pudendal nerve was assessed bilaterally. Pre-operatively, 8 patients were constipated. This improved following hysterectomy in 4, worsened in 2, and was unchanged in 2. Symptomatology did not correlate with changes in manometry. Although, the mean resting pressure was reduced after hysterectomy (57 mmHg-53 mmHg, P = 0.0541), the maximal forced voluntary contraction pressure was significantly decreased (115 mmHg-105 mmHg, P = 0.029). This effect was more pronounced in those with five or more previous vaginal deliveries (P = 0.0244, n = 9). There was no significant change in the number of patients with an intact ano-rectal inhibitory reflex after hysterectomy. There was no change in rectal sensation to distension, and the right and left pudendal nerve terminal motor latencies were unaltered at follow-up. Our results demonstrate that hysterectomy causes a decrease in the maximal forced voluntary contraction and pressure, and this appears to be due to a large decrease in a small group of patients with previous multiple vaginal deliveries.

  19. Characterization of the glucagon-like peptide-1 receptor in male mouse brain using a novel antibody and in situ hybridization

    DEFF Research Database (Denmark)

    Jensen, Casper Bo; Pyke, Charles; Rasch, Morten Grønbech

    2017-01-01

    was abundantly expressed in numerous regions including the septal nucleus, the hypothalamus and the brain stem. GLP-1R protein expression was also observed on neuronal projections in brain regions devoid of any mRNA which has not been observed in earlier reports. Taken together, these findings provide new......Glucagon-like peptide-1 (GLP-1) is a physiological regulator of appetite and long-acting GLP-1 receptor agonists (GLP-1RA) lower food intake and bodyweight in both human and animal studies. The effects are mediated through brain GLP-1Rs, and several brain nuclei expressing the GLP-1R may...... be involved. To date, mapping the complete location of GLP-1R protein in the brain has been challenged by lack of good antibodies and the discrepancy between mRNA and protein especially relevant in neuronal axonal processes. Here, we present a novel and specific monoclonal GLP-1R antibody...

  20. Physiological and perceptual effects of precooling in wheelchair basketball athletes

    Science.gov (United States)

    Pumpa, Kate; Knight, Emma; Miller, Joanna

    2016-01-01

    Objective To investigate the physiological and perceptual effects of three precooling strategies during pre-exercise rest in athletes with a spinal cord injury (SCI). Design Randomized, counterbalanced. Participants were precooled, then rested for 60 minutes (22.7 ± 0.2°C, 64.2 ± 2.6%RH). Setting National Wheelchair Basketball Training Centre, Australia. Participants Sixteen wheelchair basketball athletes with a SCI. Interventions Participants were precooled through; 1) 10 minutes of 15.8°C cold water immersion (CWI), 2) ingestion of 6.8 g/kg−1 of slushie (S) from sports drink; 3) ingestion of 6.8 g/kg−1 of slushie with application of iced towels to the legs, torso and back/arms (ST); or 4) ingestion of 6.8 g/kg−1 of room temperature (22.3°C) sports drink (CON). Outcome measures Core temperature (Tgi), skin temperature (Tsk), heart rate (HR), and thermal and gastrointestinal comfort. Results Following CWI, a significant reduction in Tgi was observed compared to CON, with a greatest reduction of 1.58°C occurring 40 minutes post-cooling (95% CI [1.07, 2.10]). A significant reduction in Tgi following ST compared to CON was also observed at 20 minutes (0.56°C; [0.03, 1.09]) and 30 minutes (0.56°C; [0.04, 1.09]) post-cooling. Additionally, a significant interaction between impairment level and time was observed for Tgi and HR, demonstrating athletes with a higher level of impairment experienced a greater reduction in HR and significant decrease in rate of decline in Tgi, compared to lesser impaired athletes. Conclusion CWI and ST can effectively lower body temperature in athletes with a SCI, and may assist in tolerating warm conditions. PMID:27192132

  1. Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits

    Science.gov (United States)

    2012-01-01

    Background Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. Discussion Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. Conclusions We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted. PMID:22891821

  2. Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits

    Directory of Open Access Journals (Sweden)

    Ebdrup Bjørn H

    2012-08-01

    Full Text Available Abstract Background Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1. Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. Discussion Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. Conclusions We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.

  3. Effect of Compression Garments on Physiological Responses After Uphill Running

    Directory of Open Access Journals (Sweden)

    Struhár Ivan

    2018-03-01

    Full Text Available Limited practical recommendations related to wearing compression garments for athletes can be drawn from the literature at the present time. We aimed to identify the effects of compression garments on physiological and perceptual measures of performance and recovery after uphill running with different pressure and distributions of applied compression. In a random, double blinded study, 10 trained male runners undertook three 8 km treadmill runs at a 6% elevation rate, with the intensity of 75% VO2max while wearing low, medium grade compression garments and high reverse grade compression. In all the trials, compression garments were worn during 4 hours post run. Creatine kinase, measurements of muscle soreness, ankle strength of plantar/dorsal flexors and mean performance time were then measured. The best mean performance time was observed in the medium grade compression garments with the time difference being: medium grade compression garments vs. high reverse grade compression garments. A positive trend in increasing peak torque of plantar flexion (60o·s-1, 120o·s-1 was found in the medium grade compression garments: a difference between 24 and 48 hours post run. The highest pain tolerance shift in the gastrocnemius muscle was the medium grade compression garments, 24 hour post run, with the shift being +11.37% for the lateral head and 6.63% for the medial head. In conclusion, a beneficial trend in the promotion of running performance and decreasing muscle soreness within 24 hour post exercise was apparent in medium grade compression garments.

  4. Two component systems: physiological effect of a third component.

    Directory of Open Access Journals (Sweden)

    Baldiri Salvado

    Full Text Available Signal transduction systems mediate the response and adaptation of organisms to environmental changes. In prokaryotes, this signal transduction is often done through Two Component Systems (TCS. These TCS are phosphotransfer protein cascades, and in their prototypical form they are composed by a kinase that senses the environmental signals (SK and by a response regulator (RR that regulates the cellular response. This basic motif can be modified by the addition of a third protein that interacts either with the SK or the RR in a way that could change the dynamic response of the TCS module. In this work we aim at understanding the effect of such an additional protein (which we call "third component" on the functional properties of a prototypical TCS. To do so we build mathematical models of TCS with alternative designs for their interaction with that third component. These mathematical models are analyzed in order to identify the differences in dynamic behavior inherent to each design, with respect to functionally relevant properties such as sensitivity to changes in either the parameter values or the molecular concentrations, temporal responsiveness, possibility of multiple steady states, or stochastic fluctuations in the system. The differences are then correlated to the physiological requirements that impinge on the functioning of the TCS. This analysis sheds light on both, the dynamic behavior of synthetically designed TCS, and the conditions under which natural selection might favor each of the designs. We find that a third component that modulates SK activity increases the parameter space where a bistable response of the TCS module to signals is possible, if SK is monofunctional, but decreases it when the SK is bifunctional. The presence of a third component that modulates RR activity decreases the parameter space where a bistable response of the TCS module to signals is possible.

  5. Physiological aspects of energy metabolism and gastrointestinal effects of carbohydrates.

    Science.gov (United States)

    Elia, M; Cummings, J H

    2007-12-01

    short-chain fatty acids. The exact amounts and types of carbohydrate that reach the caecum are unknown, but are probably between 20 and 40 g/day in countries with 'westernized' diets, whereas they may reach 50 g/day where traditional staples are largely cereal or diets are high in fruit and vegetables. Non-starch polysaccharides clearly affect bowel habit and so, to a lesser extent, does resistant starch. However, the short-chain carbohydrates, which are also found in breast milk, have little if any laxative role, although do effect the balance of the flora. This latter property has led to the term 'prebiotic', which is defined as the capacity to increase selectively the numbers of bifidobacteria and lactobacilli without growth of other genera. This now well-established physiological property has not so far led through to clear health benefits, but current studies are focused on their potential to prevent diarrhoeal illnesses, improve well-being and immunomodulation, particularly in atopic children and on increased calcium absorption.

  6. Emotional intelligence buffers the effect of physiological arousal on dishonesty

    NARCIS (Netherlands)

    Pittarello, Andrea; Conte, Beatrice; Caserotti, Marta; Scrimin, Sara; Rubaltelli, Enrico

    We studied the emotional processes that allow people to balance two competing desires: benefitting from dishonesty and keeping a positive self-image. We recorded physiological arousal (skin conductance and heart rate) during a computer card game in which participants could cheat and fail to report a

  7. water deficit effects on morpho-physiologicals parameters in durum ...

    African Journals Online (AJOL)

    S. Chahbar

    1 sept. 2016 ... ABSTRACT. Various morpho-physiological characters r rate water loss, stomatal density, stomata genotypes under two hydrous conditions strategies develops by each genotype have present an appreciable variability intrasp related to the adaptation to the water defici for relative water content who is ...

  8. Effects of low temperature and drought on the physiological and ...

    African Journals Online (AJOL)

    To find out how oil palm adapts to the environmental conditions, the dynamics of a series of important physiological components derived from the leaves of potted oil palm seedlings under drought stress (DS) (water with holding) and low temperature stress (LTS) (10°C) were studied. The results showed that low temperature ...

  9. The effects of incretin hormones on cerebral glucose metabolism in health and disease

    DEFF Research Database (Denmark)

    Nilsson, Malin; Gjedde, Albert; Brock, Birgitte

    2017-01-01

    Incretin hormones, notably glucagon-like peptide-1 (GLP-1), are gluco-regulatory hormones with pleiotropic effects also in the central nervous system. Apart from a local production of GLP-1, systemic administration of the hormone has been shown to influence a number of cerebral pathologies......, including neuroinflammation. Given the brains massive dependence on glucose as its major fuel, we here review the mechanistics of cerebral glucose transport and metabolism, focusing on the deleterious effects of both hypo- and hyperglycaemia. GLP-1, when administered as long-acting analogues...... or intravenously, appears to decrease transport of glucose in normoglycaemic conditions, without affecting the total cerebral glucose content. During hypoglycaemia this effect seems abated, whereas during hyperglycaemia GLP-1 regulates cerebral glucose metabolism towards stable levels resembling normoglycaemia...

  10. Aroma Effects on Physiologic and Cognitive Function Following Acute Stress: A Mechanism Investigation

    OpenAIRE

    Chamine, Irina; Oken, Barry S.

    2016-01-01

    Objective: Aromas may improve physiologic and cognitive function after stress, but associated mechanisms remain unknown. This study evaluated the effects of lavender aroma, which is commonly used for stress reduction, on physiologic and cognitive functions. The contribution of pharmacologic, hedonic, and expectancy-related mechanisms of the aromatherapy effects was evaluated.

  11. Effect of gamma irradiation on the physiological activity of Korean soybean fermented foods, Chungkookjang and Doenjang

    International Nuclear Information System (INIS)

    Byun, M.-W.; Son, J.-H.; Yook, H.-S.; Jo, Cheorun; Kim, D.-H.

    2002-01-01

    Effects of gamma irradiation on the physiological activity of Korean soybean fermented foods were investigated. Chungkookjang, the whole cooked soybean product and Doenjang, soybean paste were purchased and irradiated at 5, 10 and 20 kGy of absorbed doses. The physiological activity was evaluated by angiotensin converting enzyme inhibition, xanthine oxidase inhibition, tyrosinase inhibition and radical scavenging ability and results indicated that at 10 kGy or below did not show any significant change on physiological activities by irradiation

  12. The physiological effect of cobalt on watermelon cultivation

    International Nuclear Information System (INIS)

    Yao Naihua; Jin Yafang; Sun Yaochen; Huang Yiming

    1993-01-01

    Cobalt has essential physiological action on both animals and plants. For the latter it can raise plant's nitrogen-fixing ability and saccharine content. Spray of cobalt mixed with other nutritive elements can improve the germinatit of seeds and the yield of fruit. For specifying the nutritive function of cobalt upon watermelon, isotope 60 Co was mixed into a complex leaf nutritive aqua and the regularity of transferring and absorbing cobalt in the watermelon's body was investigated

  13. Geo-Effective Heliophysical Variations and Human Physiological State

    Science.gov (United States)

    Dimitrova, S.

    2006-03-01

    A group of 86 volunteers was examined on each working day in autumn 2001 and in spring 2002. These periods were chosen because of maximal expected geomagnetic activity. There were 26 persons in the group on a drug treatment, mainly because of hypertension. Systolic and diastolic blood pressure and heart rate were registered. Pulse pressure was calculated. Data about subjective psycho-physiological complaints of the persons examined were also gathered. Altogether 2799 recordings were obtained and analyzed. MANOVA was employed to check the significance of the influence of three factors on the physiological parameters under consideration. The factors were as follows: 1) geomagnetic activity estimated by H-component of the local geomagnetic field and divided into five levels; 2) gender - males and females; 3) presence of medication. Post hoc analysis was performed to elicit the significance of differences in the factors' levels. The average arterial blood pressure, pulse pressure and the percentage of the persons in the group with subjective psycho-physiological complaints were found to increase significantly with the increase of geomagnetic activity. The maximal increment of systolic and diastolic blood pressure was 10-11% and for pulse pressure 13.6%. Analyses revealed that females and persons on a medication were more sensitive to the increase of geomagnetic activity than respectively males and persons with no medication.

  14. The effect of endogenously released glucose, insulin, glucagon-like peptide 1, ghrelin on cardiac output, heart rate, stroke volume, and blood pressure.

    Science.gov (United States)

    Hlebowicz, Joanna; Lindstedt, Sandra; Björgell, Ola; Dencker, Magnus

    2011-12-29

    Ingestion of a meal increases the blood flow to the gastrointestinal organs and affects the heart rate (HR), blood pressure and cardiac output (CO), although the mechanisms are not known. The aim of this study was to evaluate the effect of endogenously released glucose, insulin, glucagon-like peptide 1 (GLP-1), ghrelin on CO, HR, stroke volume (SV), and blood pressure. Eleven healthy men and twelve healthy women ((mean ± SEM) aged: 26 ± 0.2 y; body mass index: 21.8 ± 0.1 kg/m(2))) were included in this study. The CO, HR, SV, systolic and diastolic blood pressure, antral area, gastric emptying rate, and glucose, insulin, GLP-1 and ghrelin levels were measured. The CO and SV at 30 min were significantly higher, and the diastolic blood pressure was significantly lower, than the fasting in both men and women (P blood pressure (P = 0.021, r = -0.681), and the change in SV (P = 0.008, r = -0.748) relative to the fasting in men. The insulin 0-30 min AUC was significantly correlated to the CO 0-30 min AUC (P = 0.002, r = 0.814) in men. Significant correlations were also found between the 0-120 min ghrelin and HR AUCs (P = 0.007, r = 0.966) in men. No statistically significant correlations were seen in women. Physiological changes in the levels of glucose, insulin, GLP-1 and ghrelin may influence the activity of the heart and the blood pressure. There may also be gender-related differences in the haemodynamic responses to postprandial changes in hormone levels. The results of this study show that subjects should not eat immediately prior to, or during, the evaluation of cardiovascular interventions as postprandial affects may affect the results, leading to erroneous interpretation of the cardiovascular effects of the primary intervention. NCT01027507.

  15. The effect of salinity on the growth, morphology and physiology of ...

    African Journals Online (AJOL)

    The salinity of water and soil decreases the growth and yield of agricultural products. Salinity affects many physiological and morphological processes of plant by influencing soil solution osmotic potential and ion absorption and accumulation of minerals. To evaluate the effect of salinity on some physiological and ...

  16. Young Children's Reasoning about the Effects of Emotional and Physiological States on Academic Performance

    Science.gov (United States)

    Amsterlaw, Jennifer; Lagattuta, Kristin Hansen; Meltzoff, Andrew N.

    2009-01-01

    This study assessed young children's understanding of the effects of emotional and physiological states on cognitive performance. Five, 6-, 7-year-olds, and adults (N = 96) predicted and explained how children experiencing a variety of physiological and emotional states would perform on academic tasks. Scenarios included: (a) negative and positive…

  17. Effect of physiological factors on dose due to organically bound tritium

    International Nuclear Information System (INIS)

    Trivedi, A.

    1998-01-01

    The International Commission on Radiological Protection (ICRP) recommends the understanding of the effect of age, anatomical and physiological data on the doses in order to prescribe dose coefficient for radionuclides. The published data on OBT dose fraction after acute or chronic intakes of HTO are evaluated to examine the variation of OBT dose with the age and physiology of occupational workers. (author)

  18. Acute and phase-shifting effects of ocular and extraocular light in human circadian physiology

    NARCIS (Netherlands)

    Rüger, Melanie; Gordijn, Marijke C.M.; Beersma, Domien G.M.; de Vries, Bonnie; Daan, Serge

    2003-01-01

    Light can influence physiology and performance of humans in two distinct ways. It can acutely change the level of physiological and behavioral parameters, and it can induce a phase shift in the circadian oscillators underlying variations in these levels. Until recently, both effects were thought to

  19. Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion

    DEFF Research Database (Denmark)

    Hansen, Morten; Scheltema, Matthijs J; Sonne, David P

    2016-01-01

    AIMS: In patients with type 2 diabetes, rectal administration of bile acids increases glucagon-like peptide-1 (GLP-1) secretion and reduces plasma glucose. In addition, oral bile acid sequestrants (BASs) reduce blood glucose by an unknown mechanism. In this study we evaluated the effects...... of the primary human bile acid, chenodeoxycholic acid (CDCA), and the BAS, colesevelam, instilled into the stomach, on plasma levels of GLP-1, glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin as well as gastric emptying, gallbladder volume, appetite......, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which in turn may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans....

  20. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure

    DEFF Research Database (Denmark)

    Halbirk, Mads; Nørrelund, Helene; Møller, Niels

    2010-01-01

    effects of 48-h GLP-1 infusions in patients with congestive HF. In a randomized, double-blind crossover design, 20 patients without diabetes and with HF with ischemic heart disease, EF of 30 +/- 2%, New York Heart Association II and III (n = 14 and 6) received 48-h GLP-1 (0.7 pmol.kg(-1).min(-1......)) and placebo infusion. At 0 and 48 h, LVEF, diastolic function, tissue Doppler regional myocardial function, exercise testing, noninvasive cardiac output, and brain natriuretic peptide (BNP) were measured. Blood pressure, heart rate, and metabolic parameters were recorded. Fifteen patients completed...... patients. GLP-1 infusion increased circulating insulin levels and reduced plasma glucose concentration but had no major cardiovascular effects in patients without diabetes but with compensated HF. The impact of minor increases in heart rate and diastolic blood pressure during GLP-1 infusion requires...

  1. Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and "isoglycemic" intravenous glucose

    DEFF Research Database (Denmark)

    Vardarli, Irfan; Arndt, Elisabeth; Deacon, Carolyn F

    2014-01-01

    ,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased...... by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly...... the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic...

  2. A novel exendin-4 human serum albumin fusion protein, E2HSA, with an extended half-life and good glucoregulatory effect in healthy rhesus monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ling; Wang, Lin; Meng, Zhiyun; Gan, Hui; Gu, Ruolan; Wu, Zhuona; Gao, Lei; Zhu, Xiaoxia; Sun, Wenzhong; Li, Jian; Zheng, Ying; Dou, Guifang, E-mail: douguifang@vip.163.com

    2014-03-07

    Highlights: • E2HSA has an extended half-life and good plasma stability. • E2HSA could improve glucose-dependent insulin secretion. • E2HSA has excellent glucoregulatory effects in vivo. • E2HSA could potentially be used as a new long-acting GLP-1 receptor agonist for type 2 diabetes management. - Abstract: Glucagon-like peptide-1 (GLP-1) has attracted considerable research interest in terms of the treatment of type 2 diabetes due to their multiple glucoregulatory functions. However, the short half-life, rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native incretin hormone. Therefore, efforts are being made to develop the long-acting incretin mimetics via modifying its structure. Here we report a novel recombinant exendin-4 human serum albumin fusion protein E2HSA with HSA molecule extends their circulatory half-life in vivo while still retaining exendin-4 biological activity and therapeutic properties. In vitro comparisons of E2HSA and exendin-4 showed similar insulinotropic activity on rat pancreatic islets and GLP-1R-dependent biological activity on RIN-m5F cells, although E2HSA was less potent than exendin-4. E2HSA had a terminal elimation half-life of approximate 54 h in healthy rhesus monkeys. Furthermore, E2HSA could reduce postprandial glucose excursion and control fasting glucose level, dose-dependent suppress food intake. Improvement in glucose-dependent insulin secretion and control serum glucose excursions were observed during hyperglycemic clamp test (18 h) and oral glucose tolerance test (42 h) respectively. Thus the improved physiological characterization of E2HSA make it a new potent anti-diabetic drug for type 2 diabetes therapy.

  3. Physiological effects of light on the human circadian pacemaker

    Science.gov (United States)

    Shanahan, T. L.; Czeisler, C. A.

    2000-01-01

    The physiology of the human circadian pacemaker and its influence and on the daily organization of sleep, endocrine and behavioral processes is an emerging interest in science and medicine. Understanding the development, organization and fundamental properties underlying the circadian timing system may provide insight for the application of circadian principles to the practice of clinical medicine, both diagnostically (interpretation of certain clinical tests are dependent on time of day) and therapeutically (certain pharmacological responses vary with the time of day). The light-dark cycle is the most powerful external influence acting upon the human circadian pacemaker. It has been shown that timed exposure to light can both synchronize and reset the phase of the circadian pacemaker in a predictable manner. The emergence of detectable circadian rhythmicity in the neonatal period is under investigation (as described elsewhere in this issue). Therefore, the pattern of light exposure provided in the neonatal intensive care setting has implications. One recent study identified differences in both amount of sleep time and weight gain in infants maintained in a neonatal intensive care environment that controlled the light-dark cycle. Unfortunately, neither circadian phase nor the time of day has been considered in most clinical investigations. Further studies with knowledge of principles characterizing the human circadian timing system, which governs a wide array of physiological processes, are required to integrate these findings with the practice of clinical medicine.

  4. Innocence and resisting confession during interrogation: effects on physiologic activity.

    Science.gov (United States)

    Guyll, Max; Madon, Stephanie; Yang, Yueran; Lannin, Daniel G; Scherr, Kyle; Greathouse, Sarah

    2013-10-01

    Innocent suspects may not adequately protect themselves during interrogation because they fail to fully appreciate the danger of the situation. This experiment tested whether innocent suspects experience less stress during interrogation than guilty suspects, and whether refusing to confess expends physiologic resources. After experimentally manipulating innocence and guilt, 132 participants were accused and interrogated for misconduct, and then pressured to confess. Systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), respiratory sinus arrhythmia (RSA), and preejection period (PEP) responses quantified stress reactions. As hypothesized, the innocent evidenced smaller stress responses to interrogation for SBP, DBP, HR, and RSA than did the guilty. Furthermore, innocents who refused to confess exhibited greater sympathetic nervous system activation, as evidenced by shorter PEPs, than did innocent or guilty confessors. These findings suggest that innocent suspects underestimate the threat of interrogation and that resisting pressures to confess can diminish suspects' physiologic resources and lead to false confessions. PsycINFO Database Record (c) 2013 APA, all rights reserved

  5. Presbypropria: the effects of physiological ageing on proprioceptive control.

    Science.gov (United States)

    Boisgontier, Matthieu P; Olivier, Isabelle; Chenu, Olivier; Nougier, Vincent

    2012-10-01

    Several changes in the human sensory systems, like presbycusis or presbyopia, are well-known to occur with physiological ageing. A similar change is likely to occur in proprioception, too, but there are strong and unexplained discrepancies in the literature. It was proposed that assessment of the attentional cost of proprioceptive control could provide information able to unify these previous studies. To this aim, 15 young adults and 15 older adults performed a position matching task in single and dual-task paradigms with different difficulty levels of the secondary task (congruent and incongruent Stroop-type tasks) to assess presumed age-related deficits in proprioceptive control. Results showed that proprioceptive control was as accurate and as consistent in older as in young adults for a single proprioceptive task. However, performing a secondary cognitive task and increasing the difficulty of this secondary task evidenced both a decreased matching performance and/or an increased attentional cost of proprioceptive control in older adults as compared to young ones. These results advocated for an impaired proprioception in physiological ageing.

  6. Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects

    DEFF Research Database (Denmark)

    Meier, Juris J; Kemmeries, Guido; Holst, Jens Juul

    2005-01-01

    . On separate occasions, the prokinetic drugs metoclopramide (10 mg), domperidone (10 mg), cisapride (10 mg, all at -30 min per oral), or erythromycin (200 mg intravenously from -30 to -15 min) were administered in addition to GLP-1. A liquid test meal (50 g sucrose and 8% mixed amino acids in 400 ml......, we aimed to antagonize the deceleration of gastric emptying by GLP-1 to study its effects on insulin secretion after a meal. Nine healthy male volunteers (age 25 +/- 4 years, BMI 25.0 +/- 4.9 kg/m2) were studied with an infusion of GLP-1 (0.8 pmol.kg(-1).min(-1) from -30 to 240 min) or placebo...... technique. Statistical analyses were performed using repeated-measures ANOVA and Duncan's post hoc test. GLP-1 significantly decelerated the velocity of gastric emptying (P drugs used had no effect. Postprandial...

  7. Transcriptional effects of 1,25 dihydroxyvitamin D3 physiological and supra-physiological concentrations in breast cancer organotypic culture

    International Nuclear Information System (INIS)

    Milani, Cintia; Góes, João Carlos Guedes Sampaio; Nonogaki, Suely; Tamura, Rodrigo Esaki; Folgueira, Maria Aparecida Azevedo Koike; Katayama, Maria Lucia Hirata; Lyra, Eduardo Carneiro de; Welsh, JoEllen; Campos, Laura Tojeiro; Brentani, M Mitzi; Maciel, Maria do Socorro; Roela, Rosimeire Aparecida; Valle, Paulo Roberto del

    2013-01-01

    Vitamin D transcriptional effects were linked to tumor growth control, however, the hormone targets were determined in cell cultures exposed to supra physiological concentrations of 1,25(OH) 2 D 3 (50-100nM). Our aim was to evaluate the transcriptional effects of 1,25(OH) 2 D 3 in a more physiological model of breast cancer, consisting of fresh tumor slices exposed to 1,25(OH) 2 D 3 at concentrations that can be attained in vivo. Tumor samples from post-menopausal breast cancer patients were sliced and cultured for 24 hours with or without 1,25(OH) 2 D 3 0.5nM or 100nM. Gene expression was analyzed by microarray (SAM paired analysis, FDR≤0.1) or RT-qPCR (p≤0.05, Friedman/Wilcoxon test). Expression of candidate genes was then evaluated in mammary epithelial/breast cancer lineages and cancer associated fibroblasts (CAFs), exposed or not to 1,25(OH) 2 D 3 0.5nM, using RT-qPCR, western blot or immunocytochemistry. 1,25(OH) 2 D 3 0.5nM or 100nM effects were evaluated in five tumor samples by microarray and seven and 136 genes, respectively, were up-regulated. There was an enrichment of genes containing transcription factor binding sites for the vitamin D receptor (VDR) in samples exposed to 1,25(OH) 2 D 3 near physiological concentration. Genes up-modulated by both 1,25(OH) 2 D 3 concentrations were CYP24A1, DPP4, CA2, EFTUD1, TKTL1, KCNK3. Expression of candidate genes was subsequently evaluated in another 16 samples by RT-qPCR and up-regulation of CYP24A1, DPP4 and CA2 by 1,25(OH) 2 D 3 was confirmed. To evaluate whether the transcripitonal targets of 1,25(OH) 2 D 3 0.5nM were restricted to the epithelial or stromal compartments, gene expression was examined in HB4A, C5.4, SKBR3, MDA-MB231, MCF-7 lineages and CAFs, using RT-qPCR. In epithelial cells, there was a clear induction of CYP24A1, CA2, CD14 and IL1RL1. In fibroblasts, in addition to CYP24A1 induction, there was a trend towards up-regulation of CA2, IL1RL1, and DPP4. A higher protein expression of CD14 in

  8. Effects of maxillary sinus floor elevation surgery on maxillary sinus physiology

    NARCIS (Netherlands)

    Timmenga, NM; Raghoebar, GM; Liem, RSB; van Weissenbruch, R; Manson, WL; Vissink, A

    In a prospective study, the effects of elevation surgery of the maxillary sinus floor on maxillary sinus physiology were assessed. Seventeen consecutive patients without preoperative anamnestic, clinical and radiological signs of maxillary sinusitis underwent sinus floor elevation surgery with iliac

  9. Digestive physiology of the pig symposium: secretion of gastrointestinal hormones and eating control.

    Science.gov (United States)

    Steinert, R E; Feinle-Bisset, C; Geary, N; Beglinger, C

    2013-05-01

    Nutrient ingestion triggers numerous changes in gastrointestinal (GI) peptide hormone secretion that affect appetite and eating. Evidence for these effects comes from research in laboratory animals, healthy humans, and, increasingly, obese patients after Roux-en-Y gastric bypass (RYGB) surgery, which has marked effects on GI hormone function and is currently the most effective therapy for morbid obesity. Increases in cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine (PYY) and decreases in ghrelin secretion after meals are triggered by changes in the nutrient content of the intestine. One apparent physiological function of each is to initiate a reflex-like feedback control of eating. Here we briefly review this function, with an emphasis on the controls of their secretion. Each is secreted from enteroendocrine cells that are directly or indirectly affected by caloric load, macronutrient composition, and other characteristics of ingested food such as fatty acid chain length. In addition, digestive hydrolysis is a critical mechanism that controls their secretion. Although there are relatively few data in agricultural animals, the generally consistent results across widely divergent mammals suggests that most of the processes described are also likely to be relevant to GI hormone functions and eating in agricultural animals.

  10. Modeling Variable Phanerozoic Oxygen Effects on Physiology and Evolution.

    Science.gov (United States)

    Graham, Jeffrey B; Jew, Corey J; Wegner, Nicholas C

    2016-01-01

    Geochemical approximation of Earth's atmospheric O2 level over geologic time prompts hypotheses linking hyper- and hypoxic atmospheres to transformative events in the evolutionary history of the biosphere. Such correlations, however, remain problematic due to the relative imprecision of the timing and scope of oxygen change and the looseness of its overlay on the chronology of key biotic events such as radiations, evolutionary innovation, and extinctions. There are nevertheless general attributions of atmospheric oxygen concentration to key evolutionary changes among groups having a primary dependence upon oxygen diffusion for respiration. These include the occurrence of Devonian hypoxia and the accentuation of air-breathing dependence leading to the origin of vertebrate terrestriality, the occurrence of Carboniferous-Permian hyperoxia and the major radiation of early tetrapods and the origins of insect flight and gigantism, and the Mid-Late Permian oxygen decline accompanying the Permian extinction. However, because of variability between and error within different atmospheric models, there is little basis for postulating correlations outside the Late Paleozoic. Other problems arising in the correlation of paleo-oxygen with significant biological events include tendencies to ignore the role of blood pigment affinity modulation in maintaining homeostasis, the slow rates of O2 change that would have allowed for adaptation, and significant respiratory and circulatory modifications that can and do occur without changes in atmospheric oxygen. The purpose of this paper is thus to refocus thinking about basic questions central to the biological and physiological implications of O2 change over geological time.

  11. Glucagon-like peptide-1 does not have acute effects on central or renal hemodynamics in patients with type 2 diabetes without nephropathy

    DEFF Research Database (Denmark)

    Asmar, Ali; Simonsen, Lene; Asmar, Meena

    2016-01-01

    effects of GLP-1 in patients with type 2 diabetes under fixed sodium intake. During a 3-hour infusion of GLP-1 (1.5 pmol kg(-1) min(-1)) or saline, intra-arterial blood pressure and heart rate were measured continuously, concomitantly with cardiac output estimated by pulse contour analysis. Renal plasma...... infusion, systolic and diastolic blood pressure and cardiac output remained unchanged, whereas heart rate increased significantly. Arterio-venous gradients for GLP-1 exceeded glomerular filtrations significantly, but renal plasma flow and glomerular filtration rate as well as renal sodium and lithium...... flow, glomerular filtration rate, and uptake/release of hormones and ions were measured using Fick's Principle after catheterization of a renal vein. Urine collection was conducted throughout the experiments at voluntary voiding, and patients remained supine during the experiments. During the GLP-1...

  12. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations

    DEFF Research Database (Denmark)

    Nauck, M A; Bartels, E; Orskov, C

    1993-01-01

    . The combination of GIP and GLP-1 led to B-cell responses that were significantly higher than those with either hormone alone (additive mode of cooperation). Plasma GIP concentrations were similar after endogenous secretion (oral glucose) and i.v. infusion, while exogenously administered GLP-1 led to plasma levels...

  13. Prediction of the effect on antihyperglycaemic action of sitagliptin by plasma active form glucagon-like peptide-1.

    Science.gov (United States)

    Kushiyama, Akifumi; Kikuchi, Takako; Tanaka, Kentaro; Tahara, Tazu; Takao, Toshiko; Onishi, Yukiko; Yoshida, Yoko; Kawazu, Shoji; Iwamoto, Yasuhiko

    2016-06-10

    To investigate whether active glucagon-like peptide-1 (GLP-1) is a prediction Factor of Effect of sitagliptin on patients with type 2 diabetes mellitus (GLP-1 FEST:UMIN000010645). Seventy-six patients with type 2 diabetes, who had insufficient glycemic control [Hemoglobin A1c (HbA1c) ≥ 7%] in spite of treatment with metformin and/or sulfonylurea, were included in the investigation. Patients were divided into three groups by tertiles of fasting plasma active GLP-1 level, before the administration of 50 mg sitagliptin. At baseline, body mass index, serum UA, insulin and HOMA-IR were higher in the high active GLP-1 group than in the other two groups. The high active GLP-1 group did not show any decline of HbA1c (7.6% ± 1.4% to 7.5% ± 1.5%), whereas the middle and low groups indicated significant decline of HbA1c (7.4 ± 0.7 to 6.8 ± 0.6 and 7.4 ± 1.2 to 6.9 ± 1.3, respectively) during six months. Only the low and middle groups showed a significant increment of active GLP-1, C-peptide level, a decreased log and proinsulin/insulin ratio after administration. In logistic analysis, the low or middle group is a significant explanatory variable for an HbA1c decrease of ≥ 0.5%, and its odds ratio is 4.5 (1.40-17.6) (P = 0.01) against the high active GLP-1 group. This remains independent when adjusted for HbA1c level before administration, patients' medical history, medications, insulin secretion and insulin resistance. Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin.

  14. Effect of heat on firefighters' work performance and physiology.

    Science.gov (United States)

    Larsen, Brianna; Snow, Rodney; Aisbett, Brad

    2015-10-01

    Wildland firefighters often perform their duties under both hot and mild ambient temperatures. However, the direct impact of different ambient temperatures on firefighters' work performance has not been quantified. This study compared firefighters' work performance and physiology during simulated wildland firefighting work in hot (HOT; 32°C, 43% RH) and temperate (CON; 19°C, 56% RH) conditions. Firefighters (n=38), matched and allocated to either the CON (n=18) or HOT (n=20) condition, performed simulated self-paced wildland fire suppression tasks (e.g., hose rolling/dragging, raking) in firefighting clothing for six hours, separated by dedicated rest breaks. Task repetitions were counted (and converted to distance or area). Core temperature (Tc), skin temperature (Tsk), and heart rate were recorded continuously throughout the protocol. Urine output was measured before and during the protocol, and urine specific gravity (USG) analysed, to estimate hydration. Ad libitum fluid intake was also recorded. There were no differences in overall work output between conditions for any physical task. Heart rate was higher in the HOT (55±2% HRmax) compared to the CON condition (51±2% HRmax) for the rest periods between bouts, and for the static hose hold task (69±3% HRmax versus 65±3% HRmax). Tc and Tsk were 0.3±0.1°C and 3.1±0.2°C higher in the HOT compared to the CON trial. Both pre- and within- shift fluid intake were increased two-fold in the heat, and participants in the heat recorded lower USG results than their CON counterparts. There was no difference between the CON and HOT conditions in terms of their work performance, and firefighters in both experimental groups increased their work output over the course of the simulated shift. Though significantly hotter, participants in the heat also managed to avoid excessive cardiovascular and thermal strain, likely aided by the frequent rest breaks in the protocol, and through doubling their fluid intake. Therefore

  15. PANCREATIC AND EXTRA-PANCREATIC EFFECTS OF INCRETINS AND PERSPECTIVES FOR STUDYING ENTEROINSULIN HORMONAL SYSTEM DURING GESTATIONAL DISORDER OF CARBOHYDRATE METABOLISM

    Directory of Open Access Journals (Sweden)

    T. V. Saprina

    2013-01-01

    Full Text Available The absence of an ideal medicine for the treatment of patients with type 2 diabetes, that would be able to provide not only high quality and constant monitoring of glycemia without increasing body weight, with no risk of hypoglycemia, with no negative impact on the heart, kidneys, liver, but could also ensure the preservation of the secretory function of β-cells, makes scientists continue to search for new opportunities to influence the occurrence and progression of T2D.Gastric inhibitory polypeptide (GIP and glucagon-like peptide-1 (GLP-1 are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β-cells. Within the pancreas, GIP and GLP-1 together promote β-cell proliferation and inhibit apoptosis, thereby expanding pancreatic β-cell mass, while GIP enhances postprandial glucagon response and GLP-1 suppresses it. In adipose tissues, GIP but not GLP-1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP-1 inhibits bone absorption. In the brain, both GIP and GLP-1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP-1 and their insulinotropic effects on β-cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects.Enteroinsulin hormones' role in the development of gestational disorder of carbohydrate metabolism is poorly understood.In a review article we analyze the publications that summarize what is known about the pancreatic and extra-pancreatic GIP and GLP-1-effects compared with healthy subjects and type 2 diabetes patients. The aspects of gestational diabetes pathophysiology and the perspectives for studying enteroinsulin hormonal system during pregnancy are also discussed in the article.

  16. Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

    Directory of Open Access Journals (Sweden)

    van Gilst Wiek H

    2011-09-01

    Full Text Available Abstract Background Progressive remodeling after myocardial infarction (MI is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4, an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI. Methods Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day. The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL or control (MI. At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed. Results Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p Conclusion Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.

  17. Effect of gamma irradiation on lifespan and offspring physiology of male drosophila melanogaster

    International Nuclear Information System (INIS)

    Hou Jiangyu; Gu Wei; Jiang Fangping; Han Hetong

    2010-01-01

    This study aimed to investigate the effects of γ-rays irradiation on adult longevity and physiological changes in F 1 generation.Male Drosophila melanogaster at 1 ∼ 2 days old were irradiated by γ-rays with doses of 5, 10, 15 and 30 Gy. In all experimental groups, mean lifespan, maximum lifespan and 90% of lethaldeath irradiated flies were reduced(at P 1 generation of irradiated group, body weight increased, but the capacity of physiological stress declined. (authors)

  18. Effect of xylazine sedation on some clinico-physiological and ...

    African Journals Online (AJOL)

    Xylazine is classified pharmacologically as an effective sedative, analgesic, muscle relaxant, immobilizing and hypnotic agent in domestic animals (Torre and Erausquine, 1988; Ewing, 1990; Adams, 2001). Xylazine is also known to significantly ameliorate the effects induced by stress stimuli (Ali et al., 2006). It does not ...

  19. Green perspectives for public health: a narrative review on the physiological effects of experiencing outdoor nature.

    Science.gov (United States)

    Haluza, Daniela; Schönbauer, Regina; Cervinka, Renate

    2014-05-19

    Natural environments offer a high potential for human well-being, restoration and stress recovery in terms of allostatic load. A growing body of literature is investigating psychological and physiological health benefits of contact with Nature. So far, a synthesis of physiological health outcomes of direct outdoor nature experiences and its potential for improving Public Health is missing. We were interested in summarizing the outcomes of studies that investigated physiological outcomes of experiencing Nature measuring at least one physiological parameter during the last two decades. Studies on effects of indoor or simulated Nature exposure via videos or photos, animal contact, and wood as building material were excluded from further analysis. As an online literature research delivered heterogeneous data inappropriate for quantitative synthesis approaches, we descriptively summarized and narratively synthesized studies. The procedure started with 1,187 titles. Research articles in English language published in international peer-reviewed journals that investigated the effects of natural outdoor environments on humans by were included. We identified 17 relevant articles reporting on effects of Nature by measuring 20 different physiological parameters. We assigned these parameters to one of the four body systems brain activity, cardiovascular system, endocrine system, and immune function. These studies reported mainly direct and positive effects, however, our analyses revealed heterogeneous outcomes regarding significance of results. Most of the studies were conducted in Japan, based on quite small samples, predominantly with male students as participants in a cross-sectional design. In general, our narrative review provided an ambiguous illustration of the effects outdoor nature exerted on physiological parameters. However, the majority of studies reported significant positive effects. A harmonizing effect of Nature, especially on physiological stress reactions, was

  20. Green Perspectives for Public Health: A Narrative Review on the Physiological Effects of Experiencing Outdoor Nature

    Directory of Open Access Journals (Sweden)

    Daniela Haluza

    2014-05-01

    Full Text Available Natural environments offer a high potential for human well-being, restoration and stress recovery in terms of allostatic load. A growing body of literature is investigating psychological and physiological health benefits of contact with Nature. So far, a synthesis of physiological health outcomes of direct outdoor nature experiences and its potential for improving Public Health is missing. We were interested in summarizing the outcomes of studies that investigated physiological outcomes of experiencing Nature measuring at least one physiological parameter during the last two decades. Studies on effects of indoor or simulated Nature exposure via videos or photos, animal contact, and wood as building material were excluded from further analysis. As an online literature research delivered heterogeneous data inappropriate for quantitative synthesis approaches, we descriptively summarized and narratively synthesized studies. The procedure started with 1,187 titles. Research articles in English language published in international peer-reviewed journals that investigated the effects of natural outdoor environments on humans by were included. We identified 17 relevant articles reporting on effects of Nature by measuring 20 different physiological parameters. We assigned these parameters to one of the four body systems brain activity, cardiovascular system, endocrine system, and immune function. These studies reported mainly direct and positive effects, however, our analyses revealed heterogeneous outcomes regarding significance of results. Most of the studies were conducted in Japan, based on quite small samples, predominantly with male students as participants in a cross-sectional design. In general, our narrative review provided an ambiguous illustration of the effects outdoor nature exerted on physiological parameters. However, the majority of studies reported significant positive effects. A harmonizing effect of Nature, especially on physiological

  1. Effects of immune supplementation and immune challenge on oxidative status and physiology in a model bird: implications for ecologists

    NARCIS (Netherlands)

    Crommenacker, van de J.; Horrocks, N.P.C.; Versteegh, M.A.; Tieleman, B.I.; Komdeur, J.; Matson, K.D.

    2010-01-01

    One route to gain insight into the causes and consequences of ecological differentiation is to understand the underlying physiological mechanisms. We explored the relationships between immunological and oxidative status and investigated how birds cope physiologically with the effects of

  2. Respective effects of sodium and chloride ion on physiological ...

    African Journals Online (AJOL)

    Manure

    strongly suggested that the inhibitory effects of growth, fermentation performance and morphology changes of Z. ... Cell growth was measured by monitoring the optical density of the ... The electronic conductivity was measured by the electrical.

  3. Mercury: Aspects of its ecology and environmental toxicity. [physiological effects of mercury compound contamination of environment

    Science.gov (United States)

    Siegel, S. M.

    1973-01-01

    A study was conducted to determine the effects of mercury pollution on the environment. The possible sources of mercury contamination in sea water are identified. The effects of mercury on food sources, as represented by swordfish, are analyzed. The physiological effects of varying concentrations of mercury are reported. Emphasis is placed on the situation existing in the Hawaiian Islands.

  4. Physiological and psychological effects of walking in stay-in forest therapy.

    Science.gov (United States)

    Park, Bum-Jin; Tsunetsugu, Yuko; Morikawa, Takeshi; Kagawa, Takahide; Lee, Juyoung; Ikei, Harumi; Song, Chorong; Miyazaki, Yoshifumi

    2014-01-01

    To provide scientific evidence of the physiological and psychological effects of forest and urban environments on 47 young male adults undergoing stay-in forest therapy. Field experiments were conducted at four sites in Japan. At each site, 12 subjects participated in the experiment. The experiments were conducted in forest and urban environments, and the subjects' physiological and psychological responses to these environments were compared. On the first day, six subjects were sent to a forest area, and the other six were sent to an urban area as controls. The groups were switched the next day. Heart rate variability and heart rate were measured to assess physiological responses. The semantic differential method for assessing emotions, the reports of "refreshed" feeling, and the Profile of Mood States (POMS) were used to assess psychological responses. The physiological and psychological responses of each subject were recorded during and after walking, and the differences in indices were compared between the two environments. The forest environment was associated with a higher parasympathetic nervous activity, a lower sympathetic nervous activity, and a lower heart rate than the urban environment. The subjective evaluation scores were generally in accordance with the physiological reactions and were significantly higher in the forest environment than in the urban environment. POMS measurements showed that the forest environment was psychologically relaxing and enhanced psychological vigor. This study provided clear scientific evidence of the physiological effects of forest therapy. The results will contribute to the development of forest therapy research and support the inclusion of forest therapy in preventive medicine.

  5. Salt effect on physiological, biochemical and anatomical structures ...

    African Journals Online (AJOL)

    In this study, we evaluated the salt concentration effect on plant growth, mineral composition, antioxidant responses and anatomical structure of two varieties of Origanum majorana after exposure to NaCl treatment. Our results show an inclusive behaviour of the two varieties, since the majority of sodium was exported and ...

  6. The Physiological Effect of Detarium Bread Meal on the Postprandial ...

    African Journals Online (AJOL)

    Objective: This study elicited the effect of Detarium bread meal on the post prandial plasma glucose and insulin levels of non insulin dependent diabetic mellitus (NIDDM) subjects. Subject and Method: This is a clinical study that involved twelve African and Afro-Caribbean men with NIDDM. These men were screened and ...

  7. Respective effects of sodium and chloride ion on physiological ...

    African Journals Online (AJOL)

    Respective effects of sodium and chloride ion on growth, cell morphological changes, membrane disorganization, ion homeostasis, exoenzyme activities and fermentation performance in Zymomonas mobilis232B cultures were presented. In batch cultures containing 0.15 M NaCl, Z. mobilis232B developed filaments, and ...

  8. 11 the effects of environmental assaults on human physiology

    African Journals Online (AJOL)

    admin

    adverse effects of the environment on health. Indeed one of the ... data from Africa on the whole are not available, however in ... morbidity and mortality are malaria, acute respiratory infections and diarrhoeal disease. All three can be linked to unfavourable environmental ... substances and the glomerular filtration rate, which.

  9. Morpho-physiological effects of ibuprofen on Scenedesmus rubescens.

    Science.gov (United States)

    Moro, Isabella; Matozzo, Valerio; Piovan, Anna; Moschin, Emanuela; Vecchia, Francesca Dalla

    2014-09-01

    The pollution of aquatic bodies by drugs is an emerging environmental problem, because of their extensive use in animal and human context. Ibuprofen, 2-[4-(2-methylpropyl)phenyl]propanoic acid, is the non-steroidal anti-inflammatory drug mainly present both in wastewater and in rivers and lakes in Europe. Since in literature there is little information about the effects of ibuprofen on microalgae, in this paper we presented the results on the effects of this molecule at different concentrations (62.5μgL(-1), 250μgL(-1) and 1000μgL(-1)) on cultures of the freshwater microalga Scenedesmus rubescens (P.J.L. Dangeard) E. Kesslet et al. Ibuprofen effects on the alga were assayed at first through analyses of the growth curve. Moreover, analyses of cell morphology, ultrastructure, and photosynthetic pigments were additionally performed. The first negative effect of the drug was on the microalga growth, suggesting a drug action dose-dependent mechanism type, more evident at the concentration of 1000μgL(-1) ibuprofen and in the last phase of the growth curve. In support of this, following ibuprofen exposure, the cells exhibited morphological and ultrastructural alterations, mainly consisting in large cytoplasmic inclusions, probably of lipids and/or carotenoids. The decrease of chlorophyll amounts and, on the contrary, the increase of carotenoids were correlated with a stressful condition induced by drug. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Measuring Effects of Reflection on Learning – A Physiological Study

    NARCIS (Netherlands)

    Qi, Wen; Verpoorten, Dominique; Westera, Wim

    2014-01-01

    As an economical and feasible intervention, reflection demands learners using critical thinking to examine presented information, questioning its validity, and drawing conclusions based on the resulting ideas during a learning process. The aim of this study is to gain insight into the effects

  11. Measuring Effects of Reflectionon Learning: A Physiological Study

    NARCIS (Netherlands)

    Qi, Wen

    2014-01-01

    As an economical and feasible intervention, reflection demands learners using critical thinking to examine presented information, questioning its validity, and drawing conclusions based on the resulting ideas during a learning process. The aim of this study is to gain insight into the effects of

  12. Effect of ultradrying on germination and physiological and ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-02-18

    Feb 18, 2009 ... drying storage of seed has made progress. This paper described the effect of ultra-drying storage on subsequent seed vigor. The objective of this study was to establish a suitable method for storing the seeds of H. persicum, providing a theoretical base for sustaining the biodiversity and conserving the other ...

  13. Physiological effects of ovarian hormones: clinical aspects and compliance

    DEFF Research Database (Denmark)

    Ottesen, B; Pedersen, A T

    1996-01-01

    of osteoporosis and cardiovascular disease are other considerations. Despite the large number of different hormone treatment regimens available, such problems as continued bleeding and concern about side effects engenders low compliance. To enhance compliance, it is important to ensure that post-menopausal women...

  14. Effect of curd suppression in a milk replacer on physiological ...

    African Journals Online (AJOL)

    and therefore had a delaying effect on abomasal emptying rate of these ... prolonged gastric digestion, it is possible that coagulable milk replacers may result in .... alkane yeast meals and soybean meal provided 70-75% of the total protein of ...

  15. Effects of Radon inhalation on physiology and disorders

    International Nuclear Information System (INIS)

    Yamaoka, Kiyonori; Komoto, Yoshiaki

    1998-01-01

    In the first study, we administered Radon (Rn) to rabbits by inhalation and examined changes in the lipid peroxide (thiobarbituric acid reacting substances; TBARS) level, superoxide dismutase (SOD) activity and membrane fluidity in various organs to clarify the therapeutic effects of Rn. In the second study, we sprayed Rn spring water of various concentrations to rabbits to make the animals inhale them, and examined mainly the responses of biogenic amine neurotransmitters for clarifying the effects of Rn inhalation in the neuronal transmitter system. In the third study, indications for treatment at the Misasa Hot Spring, a Rn producing radioactive spring, include hypertension, diabetes mellitus and pain. To clarify its mechanisms of action on these conditions, we evaluated dynamic changes in blood components such as vasoactive substances after Rn inhalation. Vasodilation, alleviation of diabetic symptoms and morphine-like analgesic effects were observed, suggesting that these changes constitute part of the mechanisms of the Rn spring therapy on the above conditions. (J.P.N.)

  16. Physiological effects of some synthetic food colouring additives on rats.

    Science.gov (United States)

    Aboel-Zahab, H; el-Khyat, Z; Sidhom, G; Awadallah, R; Abdel-al, W; Mahdy, K

    1997-11-01

    Three different synthetic chocolate colourant agents (A, B and C) were administered to healthy adult male albino rats for 30 and 60 day periods to evaluate their effects on body weight, blood picture, liver and kidney functions, blood glucose, serum and liver lipids, liver nucleic acids (DNA and RNA), thyroid hormones (T3 and T4) and growth hormone. In addition, histopathological examinations of liver, kidney and stomach sections were studied. These parameters were also investigated 30 days after colourant stoppage (post effect). Ingestion of colourant C (brown HT and indigocarmine) significantly decreased rat body weight, serum cholesterol and HDL-cholesterol fraction, while, T4 hormone, liver RNA content, liver enzymes (S. GOT, S. GPT and alkaline phosphatase), total protein and globulin fractions were significantly elevated. Significant increases were observed in serum total lipids, cholesterol, triglycerides, total protein, globulin and serum transaminases in rats whose diets were supplemented with chocolate colours A and B (sunset yellow, tartrazine, carmoisine and brilliant blue in varying concentrations). Haematological investigations demonstrated selective neutropenia and lymphocytosis with no significant alterations of total white blood cell counts in all rat groups, while haemoglobin concentrations and red blood cell counts were significantly decreased in the rats who were administered food additives A and B. Eosinophilia was noted in rats fed on colourant A only. No changes were recorded for blood glucose, growth hormone and kidney function tests. Histopathological studies showed brown pigment deposition in the portal tracts and Van Küpffer cells of the liver as well as in the interstitial tissue and renal tubular cells of the kidney mainly induced by colourant A. Congested blood vessels and areas of haemorrhage in both liver and renal sections were revealed in those rats who were given colourants B and C. There were no-untoward-effects recorded in the

  17. Effect of rs6923761 gene variant of glucagon-like peptide 1 receptor on metabolic response and weight loss after a 3-month intervention with a hypocaloric diet.

    Science.gov (United States)

    de Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; Lopez, J J; Gomez, E; Torres, B; Soto, G Diaz

    2014-10-01

    Studies of the GLP-1 receptor (GLP-1 R) have been directed at identifying polymorphisms in the GLP-1 R gene that may be a contributing factor in the pathogenesis of obesity and cardiovascular risk factors. Nevertheless, the role of GLP-1 R variants on body weight response after dietary intervention has not been evaluated. We decided to analyze the effects of the rs6923761 GLP-1 R polymorphism on body weight changes and metabolic parameters after 3 months of a hypocaloric diet. A sample of 91 obese subjects was analyzed in a prospective way. The hypocaloric diet had 1,520 calories per day; 52 % of carbohydrates, 25 % of lipids and 23 % of proteins. Distribution of fats was: 50.7 % of monounsaturated fats, 38.5 % of saturated fats and 11.8 % of polyunsaturated fats. In both genotype groups (GG vs. GA + AA), weight, body mass index, fat mass, waist circumference, systolic blood pressure, total cholesterol, LDL cholesterol, leptin, insulin and HOMA levels decreased. No statistical differences were detected in these changes between genotypes. In wild group (GG genotype) (pretreatment and posttreatment), BMI, weight, fat mass, waist circumference and triglyceride levels were higher than (GA + AA) group. Our data showed better anthropometric parameters and triglyceride levels in obese subjects with the mutant allele (A) of rs6923761 GLP-1R polymorphism. A lack of association of this polymorphism with weight loss or biochemical changes after a hypocaloric diet was observed.

  18. SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives.

    Science.gov (United States)

    Gurgle, Holly E; White, Karen; McAdam-Marx, Carrie

    2016-01-01

    Controversy exists regarding the selection of second-line therapy for patients with type 2 diabetes mellitus (T2DM) who are unable to achieve glycemic control with metformin therapy alone. Newer pharmacologic treatments for T2DM include glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Both the classes of medication are efficacious, exhibit positive effects on weight, and are associated with minimal risk of hypoglycemia. The purpose of this review is to compare the clinical trial and real-world effectiveness data of glucagon-like peptide-1 receptor agonists versus sodium-glucose cotransporter 2 inhibitors related to A1c reduction, weight loss, cost-effectiveness, cardiovascular outcomes, and safety in patients with T2DM. This review summarizes comparative evidence for providers who are determining which of the two classes may be the most appropriate for a specific patient.

  19. Geometrical Effects on Nonlinear Electrodiffusion in Cell Physiology

    Science.gov (United States)

    Cartailler, J.; Schuss, Z.; Holcman, D.

    2017-12-01

    We report here new electrical laws, derived from nonlinear electrodiffusion theory, about the effect of the local geometrical structure, such as curvature, on the electrical properties of a cell. We adopt the Poisson-Nernst-Planck equations for charge concentration and electric potential as a model of electrodiffusion. In the case at hand, the entire boundary is impermeable to ions and the electric field satisfies the compatibility condition of Poisson's equation. We construct an asymptotic approximation for certain singular limits to the steady-state solution in a ball with an attached cusp-shaped funnel on its surface. As the number of charge increases, they concentrate at the end of cusp-shaped funnel. These results can be used in the design of nanopipettes and help to understand the local voltage changes inside dendrites and axons with heterogeneous local geometry.

  20. Physiological conditions for the effective interpretation of radiographic images

    International Nuclear Information System (INIS)

    Overington, I.

    1989-01-01

    A wide range of factors influence the ability of the human observer to perceive detail in images. Most of these factors are of some significance in interpretation of one or more types of radiographic image. Human observer performance may be conveniently categorized in terms of multiparametric threshold surfaces, suprathreshold visibility and observer variance. The general multiparametric trends of human threshold performance are discussed, together with the implications for visibility. The importance and implications of observer variance are then explored, with particular reference to their effects on search processes. Finally, attempts are made to highlight the implications of some of the factors on typical radiographic interpretation tasks and on the adequacy of certain types of phantom image used for equipment calibration. (author)

  1. Effect of Soybean on Male Reproductive Physiology in Male Mice

    Directory of Open Access Journals (Sweden)

    M Modaresi

    2011-01-01

    Full Text Available Introduction & Objective: Soybean (Soja hispida Moench is a member of Fabaceae family. It is a species of legume native to East Asia. Soy contains significant amount of all the essential amino acids for humans therefore, is a good source of protein .Soy has an important role in the improvement and treatment of some cancers such as colon, prostate, and breast. The aim of this study was to investigate the effect of soybeans on reproductive system in male mice. Materials & Methods: This experimental study was conducted at Isfahan Payam e Noor University in 2009. In this research, 32 male mice were randomly grouped into four experimental groups. The control group was fed with soy-free basic diet. The experimental groups 1, 2, and 3 were fed with a diet containing 20%, 30% and 50% soy diet respectively.At the end of 9 weeks of treatment, blood samples were collected and serum levels of testosterone, LH and FSH were measured. The collected data was analyzed with SPSS software using one way ANOVA with Dunnett's post test and Duncan test. Results : In the experimental group which received 20% soy diet, the level of testosterone had a meaningful decrease in comparison with the control group (P<0.05, but in the experimental group which received a 50% soy diet, the level of testosterone had a meaningful increase (P<0.05 .The LH level in 30% and 50% groups had a meaningful increase but no significant differences were observed in FSH level & weight of testicles (P<0.05.The number of sperms in all of the treatment regimes had a meaningful decrease (P0.05 Conclusion: Results of this research indicated that the 20, 30, and 50 percent soy diet had a negative effect on the male reproductive system in mice.

  2. Effect of polyethylene coated calcium carbide on physiology, photosynthesis, growth and yield of sweet pepper

    International Nuclear Information System (INIS)

    Ahmed, W.; Yaseen, M.; Arshad, M.; Shahid, M.

    2014-01-01

    Polyethylene coated calcium carbide (PCC) is a potent and continuous slowly releasing source of acetylene and ethylene. It potentially improves plant growth by affecting physiology of plant. A pot study was conducted to investigate comparative effects of different rates of PCC on growth and yield attributes of sweet pepper. PCC performed better when applied with soil applied fertilizers. Results revealed that hormonal properties of calcium carbide significantly influenced physiological nutrient use efficiency and vegetative growth by affecting photosynthetic and physiological parameters of sweet pepper. Application of 20 mg PCC kg/sup -1/ soil with soil applied recommended dose of NPK fertilizers significantly improved the net photosynthetic rate by 32%, stomatal conductance by 11%, transpiration rate by 14%, carboxylation efficiency by 47%, physiological water use efficiency by 13%, physiological nitrogen use efficiency by 29% over the control treatment. This improvement in physiological attributes resulted in increase in leaf area by 20%, leaf area index by 78%, total plant dry weight by 35%, flower and fruits by 29% and fruit yield by 24% compared to the treatment of alone recommended dose of NPK fertilizers. Present study suggests that application of PCC particularly at the rate of 20mg PCC kg/sup -1/ soil plus recommended dose of NPK fertilizers improved about 25% sweet pepper production compared to its production in the alone recommended fertilizer treatment. (author)

  3. Physiological effects of weightlessness: countermeasure system development for a long-term Chinese manned spaceflight.

    Science.gov (United States)

    Wang, Linjie; Li, Zhili; Tan, Cheng; Liu, Shujuan; Zhang, Jianfeng; He, Siyang; Zou, Peng; Liu, Weibo; Li, Yinghui

    2018-04-25

    The Chinese space station will be built around 2020. As a national space laboratory, it will offer unique opportunities for studying the physiological effects of weightlessness and the efficacy of the countermeasures against such effects. In this paper, we described the development of countermeasure systems in the Chinese space program. To emphasize the need of the Chinese space program to implement its own program for developing countermeasures, we reviewed the literature on the negative physiological effects of weightlessness, the challenges of completing missions, the development of countermeasure devices, the establishment of countermeasure programs, and the efficacy of the countermeasure techniques in American and Russian manned spaceflights. In addition, a brief overview was provided on the Chinese research and development on countermeasures to discuss the current status and goals of the development of countermeasures against physiological problems associated with weightlessness.

  4. Effects of dietary protein level on growth, health and physiological parameters in growing-furring mink

    DEFF Research Database (Denmark)

    Damgaard, Birthe Marie; Larsen, Peter F.; Clausen, Tove

    2012-01-01

    The aim of the study was to investigate the effects of the dietary protein level and the feeding strategy on growth, health and physiological blood and liver parameters in growing-furring male mink. Effects of dietary protein levels ranging from 22% of metabolizable energy (MEp) to experimental p...

  5. Cytochrome c oxidase inhibition by calcium at physiological ionic composition of the medium: Implications for physiological significance of the effect.

    Science.gov (United States)

    Vygodina, Tatiana V; Mukhaleva, Elizaveta; Azarkina, Natalia V; Konstantinov, Alexander A

    2017-12-01

    Cytochrome c oxidase (CcO) from mammalian mitochondria binds Ca 2+ and Na + in a special cation binding site. Binding of Ca 2+ brings about partial inhibition of the enzyme while Na + competes with Ca 2+ for the binding site and protects the enzyme from the inhibition [Vygodina, T., Kirichenko, A. and Konstantinov, A.A. (2013). Direct Regulation of Cytochrome c oxidase by Calcium Ions. PLoS One 8(9): e74436]. In the original studies, the inhibition was found to depend significantly on the ionic composition of the buffer. Here we describe inhibition of CcO by Ca 2+ in media containing the main ionic components of cytoplasm (150mM KCl, 12mM NaCl and 1mM MgCl 2 ). Under these conditions, Ca 2+ inhibits CcO with effective K i of 20-26μM, that is an order of magnitude higher than determined earlier in the absence of Na + . At physiological value of ionic strength, the inhibition can be observed at any turnover number of CcO, rather than only at low TN (calcium matches closely the known value of "K m " for Ca 2+ -induced activation of the mitochondrial calcium uniporter. The inhibition of CcO by Ca 2+ is proposed to modulate mitochondrial Ca 2+ -uptake via the mitochondrial calcium uniporter, promote permeability transition pore opening and induce reduction of Mia40 in the mitochondrial intermembrane space. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Late effects of 1H irradiation on hippocampal physiology

    Science.gov (United States)

    Kiffer, Frederico; Howe, Alexis K.; Carr, Hannah; Wang, Jing; Alexander, Tyler; Anderson, Julie E.; Groves, Thomas; Seawright, John W.; Sridharan, Vijayalakshmi; Carter, Gwendolyn; Boerma, Marjan; Allen, Antiño R.

    2018-05-01

    NASA's Missions to Mars and beyond will expose flight crews to potentially dangerous levels of charged-particle radiation. Of all charged nuclei, 1H is the most abundant charged particle in both the galactic cosmic ray (GCR) and solar particle event (SPE) spectra. There are currently no functional spacecraft shielding materials that are able to mitigate the charged-particle radiation encountered in space. Recent studies have demonstrated cognitive injuries due to high-dose 1H exposures in rodents. Our study investigated the effects of 1H irradiation on neuronal morphology in the hippocampus of adult male mice. 6-month-old mice received whole-body exposure to 1H at 0.5 and 1 Gy (150 MeV/n; 0.35-0.55 Gy/min) at NASA's Space Radiation Laboratory in Upton, NY. At 9-months post-irradiation, we tested each animal's open-field exploratory performance. After sacrifice, we dissected the brains along the midsagittal plane, and then either fixed or dissected further and snap-froze them. Our data showed that exposure to 0.5 Gy or 1 Gy 1H significantly increased animals' anxiety behavior in open-field testing. Our micromorphometric analyses revealed significant decreases in mushroom spine density and dendrite morphology in the Dentate Gyrus, Cornu Ammonis 3 and 1 of the hippocampus, and lowered expression of synaptic markers. Our data suggest 1H radiation significantly increased exploration anxiety and modulated the dendritic spine and dendrite morphology of hippocampal neurons at a dose of 0.5 or 1 Gy.

  7. Physiological Changes to the Cardiovascular System at High Altitude and Its Effects on Cardiovascular Disease.

    Science.gov (United States)

    Riley, Callum James; Gavin, Matthew

    2017-06-01

    Riley, Callum James, and Matthew Gavin. Physiological changes to the cardiovascular system at high altitude and its effects on cardiovascular disease. High Alt Med Biol. 18:102-113, 2017.-The physiological changes to the cardiovascular system in response to the high altitude environment are well understood. More recently, we have begun to understand how these changes may affect and cause detriment to cardiovascular disease. In addition to this, the increasing availability of altitude simulation has dramatically improved our understanding of the physiology of high altitude. This has allowed further study on the effect of altitude in those with cardiovascular disease in a safe and controlled environment as well as in healthy individuals. Using a thorough PubMed search, this review aims to integrate recent advances in cardiovascular physiology at altitude with previous understanding, as well as its potential implications on cardiovascular disease. Altogether, it was found that the changes at altitude to cardiovascular physiology are profound enough to have a noteworthy effect on many forms of cardiovascular disease. While often asymptomatic, there is some risk in high altitude exposure for individuals with certain cardiovascular diseases. Although controlled research in patients with cardiovascular disease was largely lacking, meaning firm conclusions cannot be drawn, these risks should be a consideration to both the individual and their physician.

  8. Physiological Effects of Nature Therapy: A Review of the Research in Japan.

    Science.gov (United States)

    Song, Chorong; Ikei, Harumi; Miyazaki, Yoshifumi

    2016-08-03

    Humans have evolved into what they are today after the passage of 6-7 million years. If we define the beginning of urbanization as the rise of the industrial revolution, less than 0.01% of our species' history has been spent in modern surroundings. Humans have spent over 99.99% of their time living in the natural environment. The gap between the natural setting, for which our physiological functions are adapted, and the highly urbanized and artificial setting that we inhabit is a contributing cause of the "stress state" in modern people. In recent years, scientific evidence supporting the physiological effects of relaxation caused by natural stimuli has accumulated. This review aimed to objectively demonstrate the physiological effects of nature therapy. We have reviewed research in Japan related to the following: (1) the physiological effects of nature therapy, including those of forests, urban green space, plants, and wooden material and (2) the analyses of individual differences that arise therein. The search was conducted in the PubMed database using various keywords. We applied our inclusion/exclusion criteria and reviewed 52 articles. Scientific data assessing physiological indicators, such as brain activity, autonomic nervous activity, endocrine activity, and immune activity, are accumulating from field and laboratory experiments. We believe that nature therapy will play an increasingly important role in preventive medicine in the future.

  9. Physiological Effects of Nature Therapy: A Review of the Research in Japan

    Directory of Open Access Journals (Sweden)

    Chorong Song

    2016-08-01

    Full Text Available Humans have evolved into what they are today after the passage of 6–7 million years. If we define the beginning of urbanization as the rise of the industrial revolution, less than 0.01% of our species’ history has been spent in modern surroundings. Humans have spent over 99.99% of their time living in the natural environment. The gap between the natural setting, for which our physiological functions are adapted, and the highly urbanized and artificial setting that we inhabit is a contributing cause of the “stress state” in modern people. In recent years, scientific evidence supporting the physiological effects of relaxation caused by natural stimuli has accumulated. This review aimed to objectively demonstrate the physiological effects of nature therapy. We have reviewed research in Japan related to the following: (1 the physiological effects of nature therapy, including those of forests, urban green space, plants, and wooden material and (2 the analyses of individual differences that arise therein. The search was conducted in the PubMed database using various keywords. We applied our inclusion/exclusion criteria and reviewed 52 articles. Scientific data assessing physiological indicators, such as brain activity, autonomic nervous activity, endocrine activity, and immune activity, are accumulating from field and laboratory experiments. We believe that nature therapy will play an increasingly important role in preventive medicine in the future.

  10. Effect of a puzzle on the process of students' learning about cardiac physiology.

    Science.gov (United States)

    Cardozo, Lais Tono; Miranda, Aline Soares; Moura, Maria José Costa Sampaio; Marcondes, Fernanda Klein

    2016-09-01

    The aim of the present study was to evaluate the effects of using a puzzle to learn about cardiac physiology. Students were divided into control and game groups. In class 1, the control group had a 2-h theoretical class about cardiac physiology, including a detailed description of the phases of the cardiac cycle, whereas the game group had a 50-min theoretical class without the description of the cardiac cycle. In class 2, the control group did an assessment exercise before an activity with the cardiac puzzle and the game group answered questions after the above-mentioned activity. While solving the puzzle, the students had to describe the cardiac cycle by relating the concepts of heart morphology and physiology. To evaluate short-term learning, the number of wrong answers and grades in the assessment exercise were compared between the control and game groups. To evaluate medium-term learning, we compared the grades obtained by students of the control and game groups in questions about cardiac physiology that formed part of the academic exam. In the assessment exercise, the game group presented a lower number of errors and higher score compared with the control group. In the academic exam, applied after both groups had used the puzzle, there was no difference in the scores obtained by the control and game groups in questions about cardiac physiology. These results showed a positive effect of the puzzle on students' learning about cardiac physiology compared with those not using the puzzle. Copyright © 2016 The American Physiological Society.

  11. Effect of noisy stimulation on neurobiological sensitization systems and its role for normal and pathological physiology