Postprandial C-Peptide to Glucose Ratio as a Marker of β Cell Function: Implication for the Management of Type 2 Diabetes

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Yoshifumi Saisho

2016-05-01

Full Text Available C-peptide is secreted from pancreatic β cells at an equimolar ratio to insulin. Since, in contrast to insulin, C-peptide is not extracted by the liver and other organs, C-peptide reflects endogenous insulin secretion more accurately than insulin. C-peptide is therefore used as a marker of β cell function. C-peptide has been mainly used to assess the presence of an insulin-dependent state for the diagnosis of type 1 diabetes. However, recent studies have revealed that β cell dysfunction is also a core deficit of type 2 diabetes, and residual β cell function is a key factor in achieving optimal glycemic control in patients with type 2 diabetes. This review summarizes the role of C-peptide, especially the postprandial C-peptide to glucose ratio which likely better reflects maximum β cell secretory capacity compared with the fasting ratio in assessing β cell function, and discusses perspectives on its clinical utility for managing glycemic control in patients with type 2 diabetes.

Preserved glucagon-like peptide-1 responses to oral glucose, but reduced incretin effect, insulin secretion and sensitivity in young Asians with type 2 diabetes mellitus

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Yeow, Toh Peng; Pacini, Giovanni; Tura, Andrea

2017-01-01

are scarce. We examined the insulin resistance, β-cell function (BC), glucagon-like peptide (GLP)-1 hormone and incretin effect in Asian YT2DM. RESEARCH DESIGN AND METHODS: This case-control study recruited 25 Asian YT2DM and 15 healthy controls, matched for gender, ethnicity and body mass index. Serum......OBJECTIVE: Youth onset type 2 diabetes mellitus (YT2DM) is a globally rising phenomenon with substantial Asians representation. The understanding of its pathophysiology is derived largely from studies in the obese African-American and Caucasian populations, while studies on incretin effect...... glucose, insulin, C peptide and GLP-1 were sampled during 2-hour oral glucose tolerance tests (OGTTs) and 1-hour intravenous glucose tolerance tests (IVGTTs). Insulin sensitivity was derived from the Quantitative Insulin Sensitivity Check Index (QUICKI), Oral Glucose Insulin Sensitivity Index (OGIS...

Automatic computation of radioimmunoassay data. Insulin and C-peptide

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Toyota, T; Kudo, M; Abe, K [Hirosaki Univ., Aomori (Japan). School of Medicine; Kawamata, F; Uehata, S

1975-09-01

Radioimmunoassay provided dose response curves which showed linearity by the use of logistic transformation (Rodbard). This transformation which was applicable to radioimmunoassay should be useful for the computer processing of insulin and C-peptide assay. In the present studies, standard curves were analysed by testing the fit of analytic functions to radioimmunoassay of insulin and C-peptides. A program for use in combination with the double antibody technique was made by Dr. Kawamata. This approach was evidenced to be useful in order to allow automatic computation of data derived from the double antibody assays of insulin and C-peptides. Automatic corrected calculations of radioimmunoassay data of insulin was found to be satisfactory.

Evaluation of fasting state-/oral glucose tolerance test-derived measures of insulin release for the detection of genetically impaired β-cell function.

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Silke A Herzberg-Schäfer

Full Text Available BACKGROUND: To date, fasting state- and different oral glucose tolerance test (OGTT-derived measures are used to estimate insulin release with reasonable effort in large human cohorts required, e.g., for genetic studies. Here, we evaluated twelve common (or recently introduced fasting state-/OGTT-derived indices for their suitability to detect genetically determined β-cell dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 1364 White European individuals at increased risk for type 2 diabetes was characterized by OGTT with glucose, insulin, and C-peptide measurements and genotyped for single nucleotide polymorphisms (SNPs known to affect glucose- and incretin-stimulated insulin secretion. One fasting state- and eleven OGTT-derived indices were calculated and statistically evaluated. After adjustment for confounding variables, all tested SNPs were significantly associated with at least two insulin secretion measures (p≤0.05. The indices were ranked according to their associations' statistical power, and the ranks an index obtained for its associations with all the tested SNPs (or a subset were summed up resulting in a final ranking. This approach revealed area under the curve (AUC(Insulin(0-30/AUC(Glucose(0-30 as the best-ranked index to detect SNP-dependent differences in insulin release. Moreover, AUC(Insulin(0-30/AUC(Glucose(0-30, corrected insulin response (CIR, AUC(C-Peptide(0-30/AUC(Glucose(0-30, AUC(C-Peptide(0-120/AUC(Glucose(0-120, two different formulas for the incremental insulin response from 0-30 min, i.e., the insulinogenic indices (IGI(2 and IGI(1, and insulin 30 min were significantly higher-ranked than homeostasis model assessment of β-cell function (HOMA-B; p<0.05. AUC(C-Peptide(0-120/AUC(Glucose(0-120 was best-ranked for the detection of SNPs involved in incretin-stimulated insulin secretion. In all analyses, HOMA-β displayed the highest rank sums and, thus, scored last. CONCLUSIONS/SIGNIFICANCE: With AUC(Insulin(0

C-Peptide, Baseline and Postprandial Insulin Resistance after a Carbohydrate-Rich Test Meal - Evidence for an Increased Insulin Clearance in PCOS Patients?

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Stassek, J; Erdmann, J; Ohnolz, F; Berg, F D; Kiechle, M; Seifert-Klauss, V

2017-01-01

Introduction Known characteristics of patients with PCOS include infertility, menstrual disorders, hirsutism and also often insulin resistance. These symptoms increase with increasing body weight. In the LIPCOS study ( L ifestyle I ntervention for Patients with Polycystic Ovary Syndrome [ PCOS ]) long-term changes of the PCOS in dependence on pregnancy and parenthood were systematically assessed. In the framework of the LIPCOS study, PCOS patients were given a standardised carbohydrate-rich test meal in order to examine glucose homeostasis and insulin secretion. The results were compared with those of a eumenorrhoeic control group who all had corresponding BMI values and corresponding ages. Methods and Patients 41 PCOS patients (without diabetes) and 68 controls received a standardised carbohydrate-rich test meal (260 kcal, 62 % carbohydrates, 32 % fat, 6 % proteins) in order to generate a submaximal insulin and glucose stimulation. The values were determined at baseline and postprandial after 60, 120 and 180 minutes. In addition, the corresponding C-peptide levels were recorded. Results In the PCOS patients (n = 41), the insulin secretion test after a standardised test meal showed almost identical baseline and postprandial insulin levels when compared with those of the age- and BMI-matched eumenorrhoeic controls (n = 68). In the PCOS patients, the baseline and postprandial glucose levels were significantly elevated (92.88 ± 10.28 [PCOS] vs. 85.07 ± 9.42 mg/dL [controls]; p PCOS patients formally exhibit a higher fasting insulin resistance than controls. In spite of the higher stimulated C-peptide levels, the insulin levels did not increase more strongly with increasing glucose levels than in controls which may be indicative of a higher insulin clearance in PCOS patients.

Effect of gestational age and blood glucose on C-peptide excretion rate and clearance in neonates.

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Salis, Emma R; Soelbeck, Mikkel K; Reith, David M; Wheeler, Benjamin J; Broadbent, Roland S; Medlicott, Natalie J

2016-01-01

The aim of this study was to measure urinary C-peptide concentrations, and then calculate C-peptide clearance (Cl), and excretion rate (UER) in neonates. In addition, the effect of gestational age (GA) and blood glucose levels (BGL) on C-peptide UER were investigated. Insulin concentrations in plasma and C-peptide concentrations were measured in plasma and urine, in 20 neonates. Chemiluminescent immunoassays were used for insulin and C-peptide measurements, with urine diluted to 40% with bovine serum albumin 1% in phosphate buffered saline. Urine volume and time of collection were recorded and used to calculate UER and Cl. The mean Cl of C-peptide was 0.309 ± 0.329 mL/min/kg, and UER was 0.0329 ± 0.0342 pmol/min/kg. Correlations between Cl or UER and GA were not significant (P > 0.05). No significant correlation was shown between Cl or UER and BGL (P > 0.05). Both Cl and UER were highly variable in neonates, but were not correlated with GA. Additionally, BGL did not appear to affect C-peptide UER and Cl. As GA and BGL did not appear to affect Cl and UER, urinary C-peptide may provide a non-invasive method of measuring insulin production in neonates. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Gastro-Resistant Insulin Receptor-Binding Peptide from Momordica charantia Improved the Glucose Tolerance in Streptozotocin-Induced Diabetic Mice via Insulin Receptor Signaling Pathway.

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Lo, Hsin-Yi; Li, Chia-Cheng; Chen, Feng-Yuan; Chen, Jaw-Chyun; Hsiang, Chien-Yun; Ho, Tin-Yun

2017-10-25

Momordica charantia is a commonly used food and has been used for the management of diabetes. Our previous study has identified an insulin receptor (IR)-binding protein (mcIRBP) from Momordica charantia. Here we identified the gastro-resistant hypoglycemic bioactive peptides from protease-digested mcIRBP. By in vitro digestion and IR kinase activity assay, we found that a 9-amino-acid-residue peptide, mcIRBP-9, was a gastro-resistant peptide that enhanced IR kinase activities. mcIRBP-9 activated IR signaling transduction pathway, which resulted in the phosphorylation of IR, the translocation of glucose transporter 4, and the uptake of glucose in cells. Intraperitoneal and oral administration of mcIRBP-9 stimulated the glucose clearance by 30.91 ± 0.39% and 32.09 ± 0.38%, respectively, in streptozotocin-induced diabetic mice. Moreover, a pilot study showed that daily ingestion of mcIRBP-9 for 30 days decreased the fasting blood glucose levels and glycated hemoglobin (HbA1c) levels by 23.62 ± 6.14% and 24.06 ± 1.53%, respectively. In conclusion, mcIRBP-9 is a unique gastro-resistant bioactive peptide generated after the digestion of mcIRBP. Furthermore, oral administration of mcIRBP-9 improves both the glucose tolerance and the HbA1c levels in diabetic mice via targeting IR signaling transduction pathway.

Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

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Smith, G D; Amos, T A; Mahler, R; Peters, T J

1987-01-01

Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes melli...

A high-throughput mass spectrometry assay to simultaneously measure intact insulin and C-peptide.

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Taylor, Steven W; Clarke, Nigel J; Chen, Zhaohui; McPhaul, Michael J

2016-04-01

Measurements of fasting levels of insulin and C-peptide are useful in documenting insulin resistance and may help predict development of diabetes mellitus. However, the specific insulin and C-peptide levels associated with specific degrees of insulin resistance have not been defined, owing to marked variability among immunoassays and lack of standardization. Herein, we describe a multiplexed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for intact insulin and C-peptide. Insulin and C-peptide were enriched from patient sera using monoclonal antibodies immobilized on magnetic beads and processed on a robotic liquid handler. Eluted peptides were analyzed by LC-MS/MS. Bovine insulin and a stable isotopically-labeled (13C/15N) C-peptide were utilized as internal standards. The assay had an analytical measurement range of 3 to 320 μIU/ml (18 to 1920 pmol/l) for insulin and 0.11 to 27.2 ng/ml (36 to 9006 pmol/l) for C-peptide. Intra- and inter-day assay variation was less than 11% for both peptides. Of the 5 insulin analogs commonly prescribed to treat diabetes, only the recombinant drug insulin lispro caused significant interference for the determination of endogenous insulin. There were no observed interferences for C-peptide. We developed and validated a high-throughput, quantitative, multiplexed LC-MS/MS assay for intact insulin and C-peptide. Copyright © 2016 Elsevier B.V. All rights reserved.

Alteration of postprandial glucose and insulin concentrations with meal frequency and composition.

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Kanaley, Jill A; Heden, Timothy D; Liu, Ying; Fairchild, Timothy J

2014-11-14

A frequent eating pattern may alter glycaemic control and augment postprandial insulin concentrations in some individuals due to the truncation of the previous postprandial period by a subsequent meal. The present study examined glucose, insulin, C-peptide and glucose-dependent insulinotropic peptide (GIP) responses in obese individuals when meals were ingested in a high-frequency pattern (every 2 h, 6M) or in a low-frequency pattern (every 4 h, 3M) over 12 h. It also examined these postprandial responses to high-frequency, high-protein meals (6MHP). In total, thirteen obese subjects completed three 12 h study days during which they consumed 6276 kJ (1500 kcal): (1) 3M - 15 % protein and 65 % carbohydrate; (2) 6M - 15 % protein and 65 % carbohydrate; (3) 6MHP - 45 % protein and 35 % carbohydrate. Blood samples were collected every 10 min and analysed for glucose, insulin, C-peptide and GIP. Insulin total AUC (tAUC) and peak insulin concentrations (Pmeal frequency or composition. In obese subjects, ingestion of meals in a low-frequency pattern does not alter glucose tAUC, but increases postprandial insulin responses. The substitution of carbohydrates with protein in a frequent meal pattern results in tighter glycaemic control and reduced postprandial insulin responses.

Correlation of the secretion of insulin and C-peptide in cancer patients

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Modnikov, O P; Lomtev, N G [Kirgizskij Nauchno-Issledovatel' skij Inst. Onkologii i Radiologii, Frunze (USSR)

1983-08-01

Insulin and C-peptide levels were studied with a radioimmunoassay in the peripheral blood serum of 44 patients with gastric and cervical cancer and 22 healthy persons. Hyperfunction of the pancreatic insular apparatus was shown in cancer patients which was expressed in a statistically significant increase in the C-peptide level. In gastric cancer patients hyperfunction of the insular apparatus was accompanied by hypoinsulinemia, and in cervical cancer patients by hormoinsulinemia. An analysis has shown that the ratio insulin/C-peptide in gastric and cervical cancer patients was about the same and significantly lower than the control. A conclusion has been made that in spite of difference in the initial insulin concentration, the same phenomenon - acceleration of the metabolic clearance of insulin - occurs in patients with cancer of the above sites. The C-peptide level decreased, the ratio insulin/C-peptide increased, i.e. hyperfunction of the insular apparatus disappeared and the metabolic clearance of insulin slowed down.

Correlation of the sectetion of insulin and C-peptide in cancer patients

International Nuclear Information System (INIS)

Modnikov, O.P.; Lomtev, N.G.

1983-01-01

Insulin and C-peptide levels were studied with a radioimmunoassay in the peripheral blood serum of 44 patients with gastric and cervical cancer and 22 healthy persons. Hyperfunction of the pancreatic insular apparatus was shown in cancer patients which was expressed in a statistically significant increase in the C-peptide level. In gastric cancer patients hyperfunction of the insular apparatus was accompanied by hypoinsulinemia, and in cervical cancer patients by hormoinsulinemia. An analysis has shown that the ratio insulin/C-peptide in gastric and cervical cancer patients was about the same and significantly lower than the control. A conclusion has been made that in spite of difference in the initial insulin concentration, the same phenomenon - acceleration of the metabolic clearance of insulin - occurs in patients with cancer of the above sites. The C-peptide level decreased, the ratio insulin/C-peptide increased, i.e. hyperfunction of the insular apparatus disappeared and the metabolic clearance of insulin slowed down

Determining pancreatic β-cell compensation for changing insulin sensitivity using an oral glucose tolerance test

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Solomon, Thomas; Malin, Steven K; Karstoft, Kristian

2014-01-01

Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index...

Assessment of insulin action in insulin-dependent diabetes mellitus using [6(14)C]glucose, [3(3)H]glucose, and [2(3)H]glucose. Differences in the apparent pattern of insulin resistance depending on the isotope used

International Nuclear Information System (INIS)

Bell, P.M.; Firth, R.G.; Rizza, R.A.

1986-01-01

To determine whether [2(3)H], [3(3)H], and [6(14)C]glucose provide an equivalent assessment of glucose turnover in insulin-dependent diabetes mellitus (IDDM) and nondiabetic man, glucose utilization rates were measured using a simultaneous infusion of these isotopes before and during hyperinsulinemic euglycemic clamps. In the nondiabetic subjects, glucose turnover rates determined with [6(14)C]glucose during insulin infusion were lower (P less than 0.02) than those determined with [2(3)H]glucose and higher (P less than 0.01) than those determined with [3(3)H]glucose. In IDDM, glucose turnover rates measured with [6(14)C]glucose during insulin infusion were lower (P less than 0.05) than those determined with [2(3)H]glucose, but were not different from those determined with [3(3)H]glucose. All three isotopes indicated the presence of insulin resistance. However, using [3(3)H]glucose led to the erroneous conclusion that glucose utilization was not significantly decreased at high insulin concentrations in the diabetic patients. [6(14)C] and [3(3)H]glucose but not [2(3)H]glucose indicated impairment in insulin-induced suppression of glucose production. These results indicate that tritiated isotopes do not necessarily equally reflect the pattern of glucose metabolism in diabetic and nondiabetic man

C peptide and insulin releasing RIA test for the investigation of β cell function in diabetic patients

International Nuclear Information System (INIS)

Shi Ailan; Zhu Chengmo; Wang Qiyu; Wang Ping

1993-01-01

Results of C-peptide releasing RIA test in 15 normals, and 100 diabetes were summarized and compared with glucose tolerance test and serum insulin for investigating the characteristics in different types of diabetes and evaluating the functional state of islet β cell. In 36 cases of IDDM the fasting blood sugar was significantly increased, and further elevated after eating of bread, but its peak time delay in 2 hours (normalin 1 hour). The level of basal C-peptide is very low, but shows slightly weak on no response after bread stimulating test, all of this denotes that β cell function of islets severely injured. The increasing of fasting blood sugar in 64 cases of NIDDM was lower than those of IDDM. Fasting C-peptide and insulin was normal or increased, their peak value increased after bread stimulation with peak time delayed also at 2 hours. Above results demonstrated that the function of islets B cell decreased but not fully deprived. It is concluded that C-peptide and insulin stimulating test, together with OGTT can accurately assess the islets β cell function, and also have important significance in the pathogenesis, classification and staging, prognostic evaluation and monitoring of therapeutic effects in diabetes

The role of insulin C-peptide in the coevolution analyses of the insulin signaling pathway: a hint for its functions.

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Shuai Wang

Full Text Available As the linker between the A chain and B chain of proinsulin, C-peptide displays high variability in length and amino acid composition, and has been considered as an inert byproduct of insulin synthesis and processing for many years. Recent studies have suggested that C-peptide can act as a bioactive hormone, exerting various biological effects on the pathophysiology and treatment of diabetes. In this study, we analyzed the coevolution of insulin molecules among vertebrates, aiming at exploring the evolutionary characteristics of insulin molecule, especially the C-peptide. We also calculated the correlations of evolutionary rates between the insulin and the insulin receptor (IR sequences as well as the domain-domain pairs of the ligand and receptor by the mirrortree method. The results revealed distinctive features of C-peptide in insulin intramolecular coevolution and correlated residue substitutions, which partly supported the idea that C-peptide can act as a bioactive hormone, with significant sequence features, as well as a linker assisting the formation of mature insulin during synthesis. Interestingly, the evolution of C-peptide exerted the highest correlation with that of the insulin receptor and its ligand binding domain (LBD, implying a potential relationship with the insulin signaling pathway.

Enhanced glucagon-like peptide-1 (GLP-1) response to oral glucose in glucose-intolerant HIV-infected patients on antiretroviral therapy

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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...

Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

Science.gov (United States)

Smith, G D; Amos, T A; Mahler, R; Peters, T J

1987-01-01

Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes. This response seems to reflect decreased degradation of insulin rather than increased pancreatic output. These observations suggest that treatment with chloroquine or suitable analogues may be a new approach to the management of diabetes. PMID:3103729

Pengaruh Transplantasi Allograf Pancreatic Stem Cell terhadap Kadar Insulin dan C-Peptide Tikus Putih Penderita Diabetes Melitus Tipe I

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Boedi Setiawan

2016-09-01

Full Text Available Diabetes mellitus is one of the degenerative diseases in which the therapy still remains unresolved and is still a serious threat to the global health, including to the health of Indonesian people. The aim of this study was to describe the level of insulin and C-peptide in diabetes mellitus type I white rats treated with pancreatic stem cell allograft through intrapancreatic laparotomy. This study was conducted at the Institute of Tropical Diseases, Universitas Airlangga, Surabaya in a 6 month period (July–December 2014. Twelve male white rats Rattus novergicus Wistar strain, were randomly divided into two groups. The first group (P0 was injected by alloxan, 150 mg/kg body weight, without stem cell therapy. Another group was injected by alloxan, 150 mg/kg body weight, and was treated with 1x106/kg body weight pancreatic stem cell throughintrapancreatic laparotomy (P1. The experiment was finalized on the 31th day of the experiment. The results showed that the blood glucose levels at the end of experiment were highly significantly different p<0.01 between the treatment group that received stem cell therapy (P1 and P0 positive control, although the average value of blood glucose levels was not as normal as on the first day. C-peptide and insulin levels of P0 and P1 group differed significantly (p<0.01. It can be concluded that stem cell therapy through intrapancreatic laparotomy can reduce blood glucose levels and increase the levels of C-peptide and insulin.

Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I.

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Fernandez, Ana M; Hernandez-Garzón, Edwin; Perez-Domper, Paloma; Perez-Alvarez, Alberto; Mederos, Sara; Matsui, Takashi; Santi, Andrea; Trueba-Saiz, Angel; García-Guerra, Lucía; Pose-Utrilla, Julia; Fielitz, Jens; Olson, Eric N; Fernandez de la Rosa, Ruben; Garcia Garcia, Luis; Pozo, Miguel Angel; Iglesias, Teresa; Araque, Alfonso; Soya, Hideaki; Perea, Gertrudis; Martin, Eduardo D; Torres Aleman, Ignacio

2017-01-01

Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes. © 2017 by the American Diabetes Association.

Effects of Clear Kefir on Biomolecular Aspects of Glycemic Status of Type 2 Diabetes Mellitus (T2DM Patients in Bandung, West Java [Study on Human Blood Glucose, c Peptide and Insulin

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Judiono J

2014-08-01

Full Text Available Background: Diabetes Mellitus (DM triggers an excessive reaction of free-radicals. It increases reactive oxygen species and reduces antioxidants status as well as the β cell damage. Clear kefir was used for DM therapies, however it limited biomolecular exploration of its bioactive roles. Research aimed to investigate the effects of clear kefir on the biomolecular nature of the glycemic status of T2DM in Bandung. Methods: The randomized pretest-posttest control group was conducted by 106 T2DM patients. Research was done in several hospitals in Bandung and Cimahi, West Java from 2012–2013. Samples were divided randomly into three groups: (1 T2DM with HbA1c 7 fed standard diet and supplemented 200 ml/day by clear kefir, (3 T2DM with HbA1c was fed a standard diet as a control group. Dose response was obtained from a preeliminary vivo study, and then converted to human dosage by year 2011. Intervention was effectively done for 30 days. HbA1c was measured by HPLC. Fasting blood glucose (FBG and Postprandial blood glucose levels (PBG were measured by enzymes levels. C Peptide and insulin were measured by Elisa. Data was analyzed by a statictics programme by significance p<0,05. Study was approved by ethic committee. Results : HbA1c was significantly reduced in delta level (p<0.01 and FBG (p<0.015 among kefir groups. PBG was not significantly reduced among groups. C-Peptide was significantly increased in delta level, except in control group (p<0.014. Insulin was reduced significantly, except in control group (p<0.003. Conclusions : Supplementation of clear kefir reduced blood glucose levels (HbA1c, FBG, PBG and increased c-peptide. Clear kefir’s biomolecular mechanisms and chemistry characterization is a challenge for future studies.

Unprecedented high insulin secretion in a healthy human subject after intravenous glucagon-like peptide-1

DEFF Research Database (Denmark)

Knop, Filip K; Lund, Asger; Madsbad, Sten

2014-01-01

BACKGROUND: The gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are released in response to ingestion of nutrients. Both hormones are highly insulinotropic in strictly glucose-dependent fashions and glucagon-like peptide-1 is often referred...... to as one of the most insulinotropic substances known. CASE PRESENTATION: Plasma insulin and C-peptide concentrations were measured in a healthy Caucasian male (age: 53 years; body mass index: 28.6 kg/m2; fasting plasma glucose: 5.7 mM; 2 h plasma glucose value following 75 g-oral glucose tolerance test: 3...

Glucose metabolism in pigs expressing human genes under an insulin promoter.

Science.gov (United States)

Wijkstrom, Martin; Bottino, Rita; Iwase, Hayoto; Hara, Hidetaka; Ekser, Burcin; van der Windt, Dirk; Long, Cassandra; Toledo, Frederico G S; Phelps, Carol J; Trucco, Massimo; Cooper, David K C; Ayares, David

2015-01-01

Xenotransplantation of porcine islets can reverse diabetes in non-human primates. The remaining hurdles for clinical application include safe and effective T-cell-directed immunosuppression, but protection against the innate immune system and coagulation dysfunction may be more difficult to achieve. Islet-targeted genetic manipulation of islet-source pigs represents a powerful tool to protect against graft loss. However, whether these genetic alterations would impair islet function is unknown. On a background of α1,3-galactosyltransferase gene-knockout (GTKO)/human (h)CD46, additional genes (hCD39, human tissue factor pathway inhibitor, porcine CTLA4-Ig) were inserted in different combinations under an insulin promoter to promote expression in islets (confirmed by immunofluorescence). Seven pigs were tested for baseline and glucose/arginine-challenged levels of glucose, insulin, C-peptide, and glucagon. This preliminary study did not show definite evidence of β-cell deficiencies, even when three transgenes were expressed under the insulin promoter. Of seven animals, all were normoglycemic at fasting, and five of seven had normal glucose disposal rates after challenge. All animals exhibited insulin, C-peptide, and glucagon responses to both glucose and arginine challenge; however, significant interindividual variation was observed. Multiple islet-targeted transgenic expression was not associated with an overtly detrimental effect on islet function, suggesting that complex genetic constructs designed for islet protection warrants further testing in islet xenotransplantation models. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Acute but not chronic activation of brain glucagon-like peptide-1 receptors enhances glucose-stimulated insulin secretion in mice.

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Tudurí, E; Beiroa, D; Porteiro, B; López, M; Diéguez, C; Nogueiras, R

2015-08-01

To investigate the role of brain glucagon-like peptide-1 (GLP-1) in pancreatic β-cell function. To determine the role of brain GLP-1 receptor (GLP-1R) on β-cell function, we administered intracerebroventricular (i.c.v.) infusions of GLP-1 or the specific GLP-1 antagonist exendin-9 (Ex-9), in both an acute and a chronic setting. We observed that acute i.c.v. GLP-1 infusion potentiates glucose-stimulated insulin secretion (GSIS) and improves glucose tolerance, whereas central GLP-1R blockade with Ex-9 impaired glucose excursion after a glucose load. Sustained activation of central nervous system GLP-1R, however, did not produce any effect on either GSIS or glucose tolerance. Similarly, ex vivo GSIS performed in islets from mice chronically infused with i.c.v. GLP-1 resulted in no differences compared with controls. In addition, in mice fed a high-fat diet we observed that acute i.c.v. GLP-1 infusion improved glucose tolerance without changes in GSIS, while chronic GLP-1R activation had no effect on glucose homeostasis. Our results indicate that, under non-clamped conditions, brain GLP-1 plays a functional neuroendocrine role in the acute regulation of glucose homeostasis in both lean and obese rodents. © 2015 John Wiley & Sons Ltd.

Variables associated with persistence of C-Peptide secretion among patients with Type 1 diabetes mellitus

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Ibrahim Abbood Zaboon

2017-01-01

Full Text Available Background: C-peptide is a reliable method for estimating the beta-cell residual function. The objective of this study to assess the variables associated with persistence of C-peptide secretion among patients with Type 1 diabetes mellitus (T1DM. Patients and Methods: This was a cross-sectional study conducted from October 2015 to September 2016. This study enrolled patients with T1DM with at least 1 year or more duration. Random C-peptide with concomitant plasma glucose at least 144 mg/dl (8 mmol/l was measured and at this cutoff considered as a stimulated value. Variables that were assessed were age at the time of enrollment, age at the diagnosis of diabetes, gender, family history of diabetes, duration of diabetes, frequency of insulin per day, insulin dose (units/kg/day, type of insulin, devices delivery, body mass index (BMI at enrollment, blood pressure, glucose (plasma, lipid profile, glycated hemoglobin (HbA1c, thyrotropin (TSH, and antibodies to glutamic acid decarboxylase (GAD65, thyroid peroxidase antibodies (anti-TPO, and tissue transglutaminase antibodies-IgA (anti-TTG-IgA. Results: A total 324 patients were included in the study. A higher level of C-peptide has been seen if the disease acquired at the age of 18 years and older with detectable C-peptide observed among 17.7% of those diagnosed at age <18 years versus 31.7% for those aged 18 years or above. The more the duration of diabetes, the more is the loss of C-peptide. On logistic regression analysis, only duration of diabetes <6 years, and insulin dose <1 U/kg/day were statistically significantly associated with the detectable level of C-peptide in this cohort of T1DM. Conclusion: Diagnosis of TIDM at a late age, positive family history of diabetes, those requiring <1 U of insulin per kg per day, and higher fasting glucose was associated with higher and more detectable C-peptide. On multivariable analysis, the only duration of diabetes <6 years and insulin dose <1 U of insulin

CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle.

Science.gov (United States)

Witczak, Carol A; Jessen, Niels; Warro, Daniel M; Toyoda, Taro; Fujii, Nobuharu; Anderson, Mark E; Hirshman, Michael F; Goodyear, Laurie J

2010-06-01

Studies using chemical inhibitors have suggested that the Ca(2+)-sensitive serine/threonine kinase Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of both insulin- and contraction-stimulated glucose uptake in skeletal muscle. However, due to nonspecificity of these inhibitors, the specific role that CaMKII may play in the regulation of glucose uptake is not known. We sought to determine whether specific inhibition of CaMKII impairs insulin- and/or contraction-induced glucose uptake in mouse skeletal muscle. Expression vectors containing green fluorescent protein conjugated to a CaMKII inhibitory (KKALHRQEAVDCL) or control (KKALHAQERVDCL) peptide were transfected into tibialis anterior muscles by in vivo electroporation. After 1 wk, muscles were assessed for peptide expression, CaMK activity, insulin- and contraction-induced 2-[(3)H]deoxyglucose uptake, glycogen concentrations, and changes in intracellular signaling proteins. Expression of the CaMKII inhibitory peptide decreased muscle CaMK activity approximately 35% compared with control peptide. Insulin-induced glucose uptake was not changed in muscles expressing the inhibitory peptide. In contrast, expression of the inhibitory peptide significantly decreased contraction-induced muscle glucose uptake (approximately 30%). Contraction-induced decreases in muscle glycogen were not altered by the inhibitory peptide. The CaMKII inhibitory peptide did not alter expression of the glucose transporter GLUT4 and did not impair contraction-induced increases in the phosphorylation of AMP-activated protein kinase (Thr(172)) or TBC1D1/TBC1D4 on phospho-Akt substrate sites. These results demonstrate that CaMKII does not regulate insulin-stimulated glucose uptake in skeletal muscle. However, CaMKII plays a critical role in the regulation of contraction-induced glucose uptake in mouse skeletal muscle.

Intraportal injection of insulin-producing cells generated from human bone marrow mesenchymal stem cells decreases blood glucose level in diabetic rats.

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Tsai, Pei-Jiun; Wang, Hwai-Shi; Lin, Chi-Hung; Weng, Zen-Chung; Chen, Tien-Hua; Shyu, Jia-Fwu

2014-01-01

We studied the process of trans-differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) into insulin-producing cells. Streptozotocin (STZ)-induced diabetic rat model was used to study the effect of portal vein transplantation of these insulin-producing cells on blood sugar levels. The BM-MSCs were differentiated into insulin-producing cells under defined conditions. Real-time PCR, immunocytochemistry and glucose challenge were used to evaluate in vitro differentiation. Flow cytometry showed that hBM-MSCs were strongly positive for CD44, CD105 and CD73 and negative for hematopoietic markers CD34, CD38 and CD45. Differentiated cells expressed C-peptide as well as β-cells specific genes and hormones. Glucose stimulation increased C-peptide secretion in these cells. The insulin-producing, differentiated cells were transplanted into the portal vein of STZ-induced diabetic rats using a Port-A catheter. The insulin-producing cells were localized in the liver of the recipient rat and expressed human C-peptide. Blood glucose levels were reduced in diabetic rats transplanted with insulin-producing cells. We concluded that hBM-MSCs could be trans-differentiated into insulin-producing cells in vitro. Portal vein transplantation of insulin-producing cells alleviated hyperglycemia in diabetic rats.

Expression and Purification of C-Peptide Containing Insulin Using Pichia pastoris Expression System

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Mohammed N. Baeshen

2016-01-01

Full Text Available Increase in the incidence of Insulin Dependent Diabetes Mellitus (IDDM among people from developed and developing countries has created a large global market for insulin. Moreover, exploration of new methods for insulin delivery including oral or inhalation route which require very high doses would further increase the demand of cost-effective recombinant insulin. Various bacterial and yeast strains have been optimized to overproduce important biopharmaceuticals. One of the approaches we have taken is the production of recombinant human insulin along with C-peptide in yeast Pichia pastoris. We procured a cDNA clone of insulin from Origene Inc., USA. Insulin cDNA was PCR amplified and cloned into yeast vector pPICZ-α. Cloned insulin cDNA was confirmed by restriction analysis and DNA sequencing. pPICZ-α-insulin clone was transformed into Pichia pastoris SuperMan5 strain. Several Zeocin resistant clones were obtained and integration of insulin cDNA in Pichia genome was confirmed by PCR using insulin specific primers. Expression of insulin in Pichia clones was confirmed by ELISA, SDS-PAGE, and Western blot analysis. In vivo efficacy studies in streptozotocin induced diabetic mice confirmed the activity of recombinant insulin. In conclusion, a biologically active human proinsulin along with C-peptide was expressed at high level using Pichia pastoris expression system.

Glucose uptake and pulsatile insulin infusion: euglycaemic clamp and [3-3H]glucose studies in healthy subjects

International Nuclear Information System (INIS)

Schmitz, O.; Arnfred, J.; Hother Nielsen, O.; Beck-Nielsen, H.; Oerskov, H.

1986-01-01

To test the hypothesis that insulin has a greater effect on glucose metabolism when given as pulsatile than as continuous infusion, a 354-min euglycaemic clamp study was carried out in 8 healthy subjects. At random order soluble insulin was given intravenously either at a constant rate of 0.45mU/kg · min or in identical amounts in pulses of 1 1 / 2 to 2 1 / 4 min followed by intervals of 10 1 / 2 to 9 3 / 4 min. Average serum insulin levels were similar during the two infusion protocols, but pulsatile administration induced oscillations ranging between 15 and 62 μU/ml. Glucose uptake expressed as metabolic clearance rate (MCR) for glucose was significantly increased during pulsatile insulin delivery as compared with continuous administration (270-294 min: 8.7±0.7 vs 6.8±0.9 ml/kg · min, P 3 H]glucose infusion technique was suppressed to insignificant values. Finally, the effect of insulin on endogenous insulin secretion and lipolysis as assessed by changes in serum C-peptide and serum FFA was uninfluenced by the infusion mode. In conclusion, insulin infusion resulting in physiological serum insulin levels enhances glucose uptake in peripheral tissues in healthy subjects to a higher degree when given in a pulsed pattern mimicking that of the normal endocrine pancreas than when given as a continuous infusion. (author)

Differential effects of glucagon-like peptide-1 on microvascular recruitment and glucose metabolism in short- and long-term Insulin resistance

DEFF Research Database (Denmark)

Sjøberg, Kim Anker; Rattigan, Stephen; Jeppesen, Jacob Fuglsbjerg

2015-01-01

Acute infusion of glucagon-like-peptide-1 (GLP-1) has potent effects on blood flow distribution through the microcirculation in healthy humans and rats. High fat diet induces impairments in insulin-mediated microvascular recruitment (MVR) and muscle glucose uptake, and here we examined whether......-mediated glucose uptake in skeletal muscle by 90% (Prights...

The effect of oral and intravenous dextrose on C-peptide secretion in ponies.

Science.gov (United States)

de Laat, M A; van Haeften, J J; Sillence, M N

2016-02-01

Managing equine hyperinsulinemia is crucial for preventing laminitis, but our understanding of the mechanisms involved in insulin dysregulation in this species is incomplete. C-peptide is co-secreted with insulin but is resistant to hepatic metabolism and can be used to study insulin dysregulation. This study examined C-peptide secretion in serial blood samples collected after oral and i.v. dextrose (0.75 g/kg) administration to 9 ponies (BCS, 7.1 ± 0.5). The ponies were designated as hyperinsulinemic (HI) or normoinsulinemic (NI) responders before the study, using oral glucose tests and fasted glucose-to-insulin ratios, and responses were compared between the 2 groups. C-peptide concentrations increased ( dextrose, with similar area under the concentration-time curve (AUC) for both tests and a significant correlation with AUC. The AUC was similar in HI and NI ponies after i.v. dextrose, indicating similar pancreatic capacity for both groups. However, for oral dextrose, the AUC and the AUC were markedly higher ( < 0.05) in the HI ponies, indicating a greater secretion rate of these peptides. Slower insulin clearance might have also contributed to the larger AUC in HI ponies, but this hypothesis requires further investigation with specific measures of hepatic insulin clearance.

Radioimmunoassay of seric C-peptide. Practical value in the study of insulin secretion. Results of 140 stimulation tests

International Nuclear Information System (INIS)

Wafflart, Jean.

1977-10-01

C-peptide, which appears as a by-product of insulin synthesis, is secreted with this latter in equimolar quantities but is not degraded in the liver. It thus reflects indirectly the insulin secreted. After the structure of C-peptide was determined in 1971 by OYER it was synthesized by YANAIHARA and a radioimmunoassay was developed by KANEKO in 1974. This work was made possible by the recent commercialisation of a Japanese analysis kit, the 'DAIICHI' kit, and its availability through GUERBET TESTS. Part one describes the structural, physiological and immuno properties of C-peptide and its method of determination. Part two is devoted to a review of foreign publications on the practical interest of the C-peptide measurement. Part three gives the results of 140 oral or venous stimulation tests where blood sugar, blood insulin and C-peptide are measured in parallel. The different diabetic pathologies are explored and compared against normal subjects. The purpose of this work is to establish the value of C-peptide as a reflection of insulin secretion on the one hand, and that of a parallel insulin and C-peptide determination on the other [fr

Mathematical Modelling of Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide-1 following Ingestion of Glucose

DEFF Research Database (Denmark)

Røge, Rikke M; Bagger, Jonatan I; Alskär, Oskar

2017-01-01

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting ...

Cholinergic signaling mediates the effects of xenin-25 on secretion of pancreatic polypeptide but not insulin or glucagon in humans with impaired glucose tolerance.

Directory of Open Access Journals (Sweden)

Songyan Wang

Full Text Available We previously demonstrated that infusion of an intestinal peptide called xenin-25 (Xen amplifies the effects of glucose-dependent insulinotropic polypeptide (GIP on insulin secretion rates (ISRs and plasma glucagon levels in humans. However, these effects of Xen, but not GIP, were blunted in humans with type 2 diabetes. Thus, Xen rather than GIP signaling to islets fails early during development of type 2 diabetes. The current crossover study determines if cholinergic signaling relays the effects of Xen on insulin and glucagon release in humans as in mice. Fasted subjects with impaired glucose tolerance were studied. On eight separate occasions, each person underwent a single graded glucose infusion- two each with infusion of albumin, Xen, GIP, and GIP plus Xen. Each infusate was administered ± atropine. Heart rate and plasma glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide (PP levels were measured. ISRs were calculated from C-peptide levels. All peptides profoundly increased PP responses. From 0 to 40 min, peptide(s infusions had little effect on plasma glucose concentrations. However, GIP, but not Xen, rapidly and transiently increased ISRs and glucagon levels. Both responses were further amplified when Xen was co-administered with GIP. From 40 to 240 min, glucose levels and ISRs continually increased while glucagon concentrations declined, regardless of infusate. Atropine increased resting heart rate and blocked all PP responses but did not affect ISRs or plasma glucagon levels during any of the peptide infusions. Thus, cholinergic signaling mediates the effects of Xen on insulin and glucagon release in mice but not humans.

Sensitivity and reproducibility of urinary C-peptide as estimate of islet B-cell function in insulin-treated diabetes

DEFF Research Database (Denmark)

Gjessing, H J; Matzen, L E; Faber, O K

1989-01-01

The aims of the present study were to evaluate the ability of urinary C-peptide determination to demonstrate presence of residual insulin secretion, and to evaluate the reproducibility of urinary C-peptide excretion in 125 insulin-treated diabetic patients. C-peptide was determined in two...

Glucagon-like peptide-2, but not glucose-dependent insulinotropic polypeptide, stimulates glucagon release in patients with type 1 diabetes

DEFF Research Database (Denmark)

Christensen, Mikkel; Knop, Filip K; Vilsbøll, Tina

2010-01-01

This study investigated the glucagon-releasing properties of the hormones glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) in 8 patients with type 1 diabetes mellitus (T1DM) without paracrine intraislet influence of insulin (C-peptide negative following a 5 g...... intravenous arginine stimulation; on study days only treated with basal insulin substitution). On 3 study days, 180-minute two-step glucose clamps were performed. Plasma glucose (PG) was clamped at fasting values, with a mean of 7.4+/-0.5 mM in the first 90 min (period 1) and raised 1.5 times the fasting...

Measurement of insulin and C-peptide excitatory test levels in gestational diabetes mellitus

International Nuclear Information System (INIS)

Du Tongxin; Wang Zizheng

2001-01-01

To investigate the function of islet β cells in patients with gestational diabetes mellitus (GDM), serum insulin and C-peptide (C-P) excitatory test levels were measured dynamically by radioimmunoassay in 41 patients with GDM and 30 normal pregnant controls. The results showed that there were significant difference in insulin and C-peptide excitatory test levels between normal pregnancy for 32-40 weeks and patients with GDM (P < 0.001). The secretory peak of insulin occurred at 60 min in normal pregnancy, while at 120 min in patients with GDM, and the recovery postponed in patients with GDM. The peak time for C-P was just as same as that of insulin, but the peak error for C-P between normal pregnant controls and patients with GDM was more larger than that for insulin and it recovered more slowly. It suggested that majority of islet β cells in patients with GDM were good enough for response to islet resistance factors and big stress from pregnancy, and also suggested a relation between pregnancy and islet β cells function

Insulin hypersecretion together with high luteinizing hormone concentration augments androgen secretion in oral glucose tolerance test in women with polycystic ovarian disease.

Science.gov (United States)

Anttila, L; Koskinen, P; Jaatinen, T A; Erkkola, R; Irjala, K; Ruutiainen, K

1993-08-01

Female hyperandrogenism is often associated with hyperinsulinaemia and insulin resistance. We evaluated the hormone responses in an oral glucose tolerance test to investigate the interactions of gonadotrophins, insulin, C-peptide and androgens in women with polycystic ovarian disease (PCOD). In 28 patients with ultrasonographically diagnosed PCOD, hyperinsulinaemia and insulin resistance were mainly associated with obesity. Both basal and cumulative sum of insulin to C-peptide ratios were high in obese subjects, suggesting decreasing hepatic removal of insulin caused by obesity. Nevertheless, in some lean PCOD women, despite normal fasting insulin concentrations, insulin hypersecretion existed. The mean concentration of testosterone decreased significantly during the oral glucose tolerance test both in PCOD and control women, and of androstenedione in the PCOD patients only. However, an increase in androgen responses was found in a subgroup of PCOD patients, who had both elevated luteinizing hormone (LH) concentrations and hyperinsulinaemic response to oral glucose. In the remaining PCOD patients an inverse correlation between LH and insulin was found. The patients with hyperinsulinaemia together with LH hypersecretion may represent a subgroup of PCOD with deranged regulation of androgen secretion.

Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance.

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Haselton, Aaron; Sharmin, Effat; Schrader, Janel; Sah, Megha; Poon, Peter; Fridell, Yih-Woei C

2010-08-01

In Drosophila melanogaster (D. melanogaster), neurosecretory insulin-like peptide-producing cells (IPCs), analogous to mammalian pancreatic beta cells are involved in glucose homeostasis. Extending those findings, we have developed in the adult fly an oral glucose tolerance test and demonstrated that IPCs indeed are responsible for executing an acute glucose clearance response. To further develop D. melanogaster as a relevant system for studying age-associated metabolic disorders, we set out to determine the impact of adult-specific partial ablation of IPCs (IPC knockdown) on insulin-like peptide (ILP) action, metabolic outcomes and longevity. Interestingly, while IPC knockdown flies are hyperglycemic and glucose intolerant, these flies remain insulin sensitive as measured by peripheral glucose disposal upon insulin injection and serine phosphorylation of a key insulin-signaling molecule, Akt. Significant increases in stored glycogen and triglyceride levels as well as an elevated level of circulating lipid measured in adult IPC knockdown flies suggest profound modulation in energy metabolism. Additional physiological outcomes measured in those flies include increased resistance to starvation and impaired female fecundity. Finally, increased life span and decreased mortality rates measured in IPC knockdown flies demonstrate that it is possible to modulate ILP action in adult flies to achieve life span extension without insulin resistance. Taken together, we have established and validated an invertebrate genetic system to further investigate insulin action, metabolic homeostasis and regulation of aging regulated by adult IPCs.

A novel Alaska pollack-derived peptide, which increases glucose uptake in skeletal muscle cells, lowers the blood glucose level in diabetic mice.

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Ayabe, Tatsuhiro; Mizushige, Takafumi; Ota, Wakana; Kawabata, Fuminori; Hayamizu, Kohsuke; Han, Li; Tsuji, Tomoko; Kanamoto, Ryuhei; Ohinata, Kousaku

2015-08-01

We found that the tryptic digest of Alaska pollack protein exhibits a glucose-lowering effect in KK-Ay mice, a type II diabetic model. We then searched for glucose-lowering peptides in the digest. Ala-Asn-Gly-Glu-Val-Ala-Gln-Trp-Arg (ANGEVAQWR) was identified from a peak of the HPLC fraction selected based on the glucose-lowering activity in an insulin resistance test using ddY mice. ANGEVAQWR (3 mg kg(-1)) decreased the blood glucose level after intraperitoneal administration. Among its fragment peptides, the C-terminal tripeptide, Gln-Trp-Arg (QWR, 1 mg kg(-1)), lowered the blood glucose level, suggesting that the C-terminal is critical for glucose-lowering activity. QWR also enhanced glucose uptake into C2C12, a mouse skeletal muscle cell line. QWR did not induce the phosphorylation of serine/threonine protein kinase B (Akt) and adenosine monophosphate-activated protein kinase (AMPK). We also demonstrated that QWR lowered the blood glucose level in NSY and KK-Ay, type II diabetic models.

Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass

DEFF Research Database (Denmark)

Dirksen, Carsten; Bojsen-Møller, Kirstine N; Jørgensen, Nils Bruun

2013-01-01

Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon-like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones...

Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

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Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

2016-11-01

Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concentrations in healthy subjects

DEFF Research Database (Denmark)

Hlebowicz, Joanna; Hlebowicz, Anna; Lindstedt, Sandra

2009-01-01

glucose, plasma concentrations of insulin and incretin hormones [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)], the ghrelin response, and satiety in healthy subjects. DESIGN: GER was measured by using real-time ultrasonography after ingestion of rice pudding...... with and without 1 or 3 g cinnamon. Fifteen healthy subjects were assessed in a crossover trial. RESULTS: The addition of 1 or 3 g cinnamon had no significant effect on GER, satiety, glucose, GIP, or the ghrelin response. The insulin response at 60 min and the area under the curve (AUC) at 120 min were...... cinnamon (P = 0.0082 and P = 0.0138, respectively, after Bonferroni correction). CONCLUSIONS: Ingestion of 3 g cinnamon reduced postprandial serum insulin and increased GLP-1 concentrations without significantly affecting blood glucose, GIP, the ghrelin concentration, satiety, or GER in healthy subjects...

Connecting peptide (c-peptide) and the duration of diabetes mellitus ...

African Journals Online (AJOL)

Objective: C-peptide is derived from proinsulin and it is secreted in equimolar concentration with insulin. Plasma C-peptide is more stable than insulin and it provides an indirect measure of insulin secretory reserve and beta cell function. To determine relationship between C-peptide and duration of diabetes mellitus, age, ...

Using Glucose Tolerance Tests to Model Insulin Secretion and Clearance

Directory of Open Access Journals (Sweden)

Anthony Shannon

2005-04-01

Full Text Available The purpose of the studies described in this paper is to develop theoretically and to validate experimentally mathematical compartment models which can be used to predict plasma insulin levels in patients with diabetes mellitus (DM. In the case of Type 2 Diabetes Mellitus (T2DM, the C-peptide levels in the plasma were measured as part of routine glucose tolerance tests in order to estimate the prehepatic insulin secretion rates. In the case of Type 1 Diabetes Mellitus (T1DM, a radioactive labelled insulin was used to measure the absorption rate of insulin after a subcutaneous injection of insulin. Both models gave close fits between theoretical estimates and experimental data, and, unlike other models, it is not necessary to seed these models with initial estimates.

Glucokinase, the pancreatic glucose sensor, is not the gut glucose sensor

DEFF Research Database (Denmark)

Murphy, R; Tura, A; Clark, P M

2008-01-01

AIMS/HYPOTHESIS: The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic peptide (GIP) are released from intestinal endocrine cells in response to luminal glucose. Glucokinase is present in these cells and has been proposed as a glucose sensor. The physiological...... role of glucokinase can be tested using individuals with heterozygous glucokinase gene (GCK) mutations. If glucokinase is the gut glucose sensor, GLP-1 and GIP secretion during a 75 g OGTT would be lower in GCK mutation carriers compared with controls. METHODS: We compared GLP-1 and GIP concentrations...... measured at five time-points during a 75 g OGTT in 49 participants having GCK mutations with those of 28 familial controls. Mathematical modelling of glucose, insulin and C-peptide was used to estimate basal insulin secretion rate (BSR), total insulin secretion (TIS), beta cell glucose sensitivity...

C-Peptide Is a Sensitive Indicator for the Diagnosis of Metabolic Syndrome in Subjects from Central Mexico.

Science.gov (United States)

Gonzalez-Mejia, M Elba; Porchia, Leonardo M; Torres-Rasgado, Enrique; Ruiz-Vivanco, Guadalupe; Pulido-Pérez, Patricia; Báez-Duarte, Blanca G; Pérez-Fuentes, Ricardo

2016-05-01

Metabolic Syndrome (MetS) is associated with elevated risk for developing diabetes and cardiovascular disease. A key component of MetS is the development of insulin resistance (IR). The homeostatic model assessment (HOMA) model can determine IR by using insulin or C-peptide concentrations; however, the efficiency of insulin and C-peptide to determine MetS has not been compared. The aim of the study was to compare the efficiency of C-peptide and insulin to determine MetS in Mexicans. Anthropometrics, glucose, insulin, C-peptide, triglycerides, and high-density lipoproteins were determined in 156 nonpregnant females and 114 males. Subjects were separated into normal or positive for MetS. IR was determined by the HOMA2 calculator using insulin or C-peptide. Correlations were calculated using the Spearman correlation coefficient (ρ). Differences between correlations were determined by calculating Steiger's Z. The sensitivity was determined by the area under receiver operating characteristics curve (AUC) analysis. Independent of the MetS definition [Adult Treatment Panel III (ATP III), International Diabetes Federation (IDF), or World Health Organization (WHO)], C-peptide and insulin were significantly higher in MetS subjects (P indicator of MetS. Since C-peptide has recently emerged as a biomolecule with significant importance for inflammatory diseases, monitoring C-peptide levels will aid clinicians in preventing MetS.

Diagnostic value of C-peptide determination

International Nuclear Information System (INIS)

Kober, G.; Rainer, O.H.

1983-01-01

C-peptide and insulin serum determinations were performed in 94 glucagon-stimulated diabetics and in 15 healthy persons. A minimal increase of 1.5 ng C-peptide/ml serum after glucagon injection (1 mg i.v.) was found to be a useful parameter for the differentiation of insulin dependent and non-insulin dependent diabetics. The maximal response to glucagon occurred during the first 10-minutes after the injection (blood was drawn at 2-minutes intervals). Serum insulin levels and basal C-peptide concentrations were of no value in predicting insulin-dependency. Basal C-peptide levels were significantly different from control in juvenile insulin dependent diabetics (decrease) only. (Author)

Kinetics of circulating endogenous insulin, C-peptide, and proinsulin in fasting nondiabetic man

DEFF Research Database (Denmark)

Henriksen, Jens Henrik Sahl; Tronier, B; Bülow, J B

1987-01-01

Plasma concentrations of insulin, C-peptide, and proinsulin were measured in different vascular beds in order to determine renal, hepatic, and systemic kinetics of the endogenous peptides in the fasting condition. Nineteen nondiabetic subjects were studied, two were normal, nine had minor vascular...

Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagons, lactate and TNF-alfa in patients with HIV-lipodystrophy

DEFF Research Database (Denmark)

Haugaard, Steen B; Andersen, Ove; Pedersen, SB

2006-01-01

with the remaining HIV-infected patients (all Ptriglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients.......OBJECTIVES: We examined whether insulin-resistant lipodystrophic HIV-infected patients with known high fasting prehepatic insulin secretion rates (FISRs) displayed alterations in first-phase prehepatic insulin response to intravenous glucose (ISREG0-10 min). METHODS: Eighteen normoglycaemic...... lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp...

Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagon, lactate and TNF-alpha in patients with HIV-lipodystrophy

DEFF Research Database (Denmark)

Haugaard, S B; Andersen, O; Pedersen, S B

2006-01-01

with the remaining HIV-infected patients (all Ptriglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients.......OBJECTIVES: We examined whether insulin-resistant lipodystrophic HIV-infected patients with known high fasting prehepatic insulin secretion rates (FISRs) displayed alterations in first-phase prehepatic insulin response to intravenous glucose (ISREG0-10 min). METHODS: Eighteen normoglycaemic...... lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp...

Diminished hepatic insulin removal in obesity

International Nuclear Information System (INIS)

Cano, I.; Salvador, J.; Rodriguez, R.; Arraiza, M.C.; Goena, M.; Barberia, J.J.; Moncada, E.

1986-01-01

Peripheral insulin and C-peptide levels during oral glucose load were measured in 20 obese and 23 normal weight nondiabetic subjects. The fasting C-peptide to insulin molar ratios (Cp/I), as well as the relation between incremental areas of the two polypeptides (ACp-AI)/ACp, were used as relative measures of the hepatic insulin extraction (HIE). The insulin and C-peptide basal levels as well as incremental areas under plasma curves were higher in the obese subjects (P<0.001). HIE was lower in obeses than in controls assessed in the fasting state (P<0.05), as well as after glucose load (P<0.001). Nevertheless, obeses and controls with similar insulin fasting levels showed identical hepatic insulin extraction in fasting or after glucose load. HIE was independent of obesity degree, but was related to insulin basal levels (r=-0.60, P<0.01). This study suggests the hypothesis that the decreased hepatic insulin extraction in obeses is a result of the chronically increased insulin delivery to the liver and is not a consequence of obesity, although a contributory role cannot be ruled out

Diminished hepatic insulin removal in obesity

Energy Technology Data Exchange (ETDEWEB)

Cano, I; Salvador, J; Rodriguez, R; Arraiza, M C; Goena, M; Barberia, J J; Moncada, E

1986-01-01

Peripheral insulin and C-peptide levels during oral glucose load were measured in 20 obese and 23 normal weight nondiabetic subjects. The fasting C-peptide to insulin molar ratios (Cp/I), as well as the relation between incremental areas of the two polypeptides (ACp-AI)/ACp, were used as relative measures of the hepatic insulin extraction (HIE). The insulin and C-peptide basal levels as well as incremental areas under plasma curves were higher in the obese subjects (P<0.001). HIE was lower in obeses than in controls assessed in the fasting state (P<0.05), as well as after glucose load (P<0.001). Nevertheless, obeses and controls with similar insulin fasting levels showed identical hepatic insulin extraction in fasting or after glucose load. HIE was independent of obesity degree, but was related to insulin basal levels (r=-0.60, P<0.01). This study suggests the hypothesis that the decreased hepatic insulin extraction in obeses is a result of the chronically increased insulin delivery to the liver and is not a consequence of obesity, although a contributory role cannot be ruled out.

Clinical significance of determination of serum C-peptide levels

International Nuclear Information System (INIS)

Wang Guohong; Xu Ruiji; Zhang Zhongshu; Wang Xiaoji

2006-01-01

Objective: To study the clinical meanings of changes of serum C-peptide levels and insulin/C-peptide ratio. Methods: Serum insulin and C-peptide levels were determined with RIA in 171 patients with DM-2 of all ages (31-50, n= 50, 51-60, n=60, over 60, n=61) and 50 patients with renal insufficiency. The insulin/C-peptide ratio were calculated. Results: The serum C-peptide and insulin levels in patients with renal insufficiency were significantly higher than those in diabetics of all age groups and the insulin/C-peptide ratio were significantly lower than those in diabetics (P 0.05), but the serum C-peptide levels increased as the age of patients increased with decrease of insulin/C-peptide ratio (P<0.01). Conclusion: Abnormal changes of C-peptide levels and insulin/C-peptide ratio in diabetics (the age-factor corrected) might reflect renal dysfunction. (authors)

Stimulation of the endogenous incretin glucose-dependent insulinotropic peptide by enteral dextrose improves glucose homeostasis and inflammation in murine endotoxemia.

Science.gov (United States)

Shah, Faraaz Ali; Singamsetty, Srikanth; Guo, Lanping; Chuan, Byron W; McDonald, Sherie; Cooper, Bryce A; O'Donnell, Brett J; Stefanovski, Darko; Wice, Burton; Zhang, Yingze; O'Donnell, Christopher P; McVerry, Bryan J

2018-03-01

Loss of glucose homeostasis during sepsis is associated with increased organ dysfunction and higher mortality. Novel therapeutic strategies to promote euglycemia in sepsis are needed. We have previously shown that early low-level intravenous (IV) dextrose suppresses pancreatic insulin secretion and induces insulin resistance in septic mice, resulting in profound hyperglycemia and worsened systemic inflammation. In this study, we hypothesized that administration of low-level dextrose via the enteral route would stimulate intestinal incretin hormone production, potentiate insulin secretion in a glucose-dependent manner, and thereby improve glycemic control in the acute phase of sepsis. We administered IV or enteral dextrose to 10-week-old male C57BL/6J mice exposed to bacterial endotoxin and measured incretin hormone release, glucose disposal, and proinflammatory cytokine production. Compared with IV administration, enteral dextrose increased circulating levels of the incretin hormone glucose-dependent insulinotropic peptide (GIP) associated with increased insulin release and insulin sensitivity, improved mean arterial pressure, and decreased proinflammatory cytokines in endotoxemic mice. Exogenous GIP rescued glucose metabolism, improved blood pressure, and increased insulin release in endotoxemic mice receiving IV dextrose, whereas pharmacologic inhibition of GIP signaling abrogated the beneficial effects of enteral dextrose. Thus, stimulation of endogenous GIP secretion by early enteral dextrose maintains glucose homeostasis and attenuates the systemic inflammatory response in endotoxemic mice and may provide a therapeutic target for improving glycemic control and clinical outcomes in patients with sepsis. Published by Elsevier Inc.

Binding Mode of Insulin Receptor and Agonist Peptide

Institute of Scientific and Technical Information of China (English)

无

2006-01-01

Insulin is a protein hormone secreted by pancreatic β cells. One of its main functions is to keep the balance of glucose inside the body by regulating the absorption and metabolism of glucose in the periphery tissue, as well as the production and storage of hepatic glycogen. The insulin receptor is a transmembrane glycoprotein in which two α subunits with a molecular weight of 135 kD and twoβ subunits with a molecular weight of 95 kD are joined by a disulfide bond to form a β-α-α-β structure. The extracellular α subunit, especially, its three domains near the N-terminal are partially responsible for signal transduction or ligand-binding, as indicated by the experiments. The extracellular α subunits are involved in binding the ligands. The experimental results indicate that the three domains of the N-terminal of the α subunits are the main determinative parts of the insulin receptor to bind the insulin or mimetic peptide.We employed the extracellular domain (PDBID: 1IGR) of the insulin-like growth factor-1 receptor (IGF-1 R ) as the template to simulate and optimize the spatial structures of the three domains in the extracellular domain of the insulin receptor, which includes 468 residues. The work was accomplished by making use of the homology program in the Insight Ⅱ package on an Origin3800 server. The docking calculations of the insulin receptor obtained by homology with hexapeptides were carried out by means of the program Affinity. The analysis indicated that there were hydrogen bonding, and electrostatic and hydrophobic effects in the docking complex of the insulin receptor with hexapeptides.Moreover, we described the spatial orientation of a mimetic peptide with agonist activity in the docking complex. We obtained a rough model of binding of DLAPSQ or STIVYS with the insulin receptor, which provides the powerful theoretical support for designing the minimal insulin mimetic peptide with agonist activity, making it possible to develop oral small

Generation of glucose-responsive, insulin-producing cells from human umbilical cord blood-derived mesenchymal stem cells.

Science.gov (United States)

Prabakar, Kamalaveni R; Domínguez-Bendala, Juan; Molano, R Damaris; Pileggi, Antonello; Villate, Susana; Ricordi, Camillo; Inverardi, Luca

2012-01-01

We sought to assess the potential of human cord blood-derived mesenchymal stem cells (CB-MSCs) to derive insulin-producing, glucose-responsive cells. We show here that differentiation protocols based on stepwise culture conditions initially described for human embryonic stem cells (hESCs) lead to differentiation of cord blood-derived precursors towards a pancreatic endocrine phenotype, as assessed by marker expression and in vitro glucose-regulated insulin secretion. Transplantation of these cells in immune-deficient animals shows human C-peptide production in response to a glucose challenge. These data suggest that human cord blood may be a promising source for regenerative medicine approaches for the treatment of diabetes mellitus.

Purification and characterization of insulin and the C-peptide of proinsulin from Przewalski's horse, zebra, rhino, and tapir (Perissodactyla).

Science.gov (United States)

Henry, J S; Lance, V A; Conlon, J M

1993-02-01

Within the order Perissodactyla, the primary structure of insulin has been strongly conserved. Insulin from Przewalski's horse and the mountain zebra (suborder Hippomorpha) is the same as that from the domestic horse and differs from insulin from the white rhinoceros and mountain tapir (suborder Ceratomorpha) by a single substitution (Gly-->Ser) at position 9 in the A-chain. A second molecular form of Przewalski's horse insulin isolated in this study was shown to represent the gamma-ethyl ester of the Glu17 residue of the A-chain. This component was probably formed during the extraction of the pancreas with acidified ethanol. The amino acid sequence of the C-peptide of proinsulin has been less well conserved. Zebra C-peptide comprises 31 amino acid residues and differs from Przewalski's horse and domestic horse C-peptide by one substitution (Gln30-->Pro). Rhino C-peptide was isolated only in a truncated form corresponding to residues (1-23) of intact C-peptide. Its amino acid sequence contains three substitutions compared with the corresponding region of horse C-peptide. It is postulated that the substitution (Pro23-->Thr) renders rhino C-peptide more liable to proteolytic cleavage by a chymotrypsin-like enzyme than horse C-peptide. C-peptide could not be identified in the extract of tapir pancreas, suggesting that proteolytic degradation may have been more extensive than in the rhino. In contrast to the ox and pig (order Artiodactyla), there was no evidence for the expression of more than one proinsulin gene in the species of Perissodactyla examined.

Diagnostic value of C-peptide determination. [Radioimmunoassay

Energy Technology Data Exchange (ETDEWEB)

Kober, G; Rainer, O H [Landeskrankenhaus Klagenfurt (Austria). Nuklearmedizinische Abt.

1983-01-01

C-peptide and insulin serum determinations were performed in 94 glucagon-stimulated diabetics and in 15 healthy persons. A minimal increase of 1.5 ng C-peptide/ml serum after glucagon injection (1 mg i.v.) was found to be a useful parameter for the differentiation of insulin dependent and non-insulin dependent diabetics. The maximal response to glucagon occurred during the first 10-minutes after the injection (blood was drawn at 2-minutes intervals). Serum insulin levels and basal C-peptide concentrations were of no value in predicting insulin-dependency. Basal C-peptide levels were significantly different from control in juvenile insulin dependent diabetics (decrease) only.

Fall in C-Peptide During First 4 Years From Diagnosis of Type 1 Diabetes: Variable Relation to Age, HbA1c, and Insulin Dose.

Science.gov (United States)

Hao, Wei; Gitelman, Steven; DiMeglio, Linda A; Boulware, David; Greenbaum, Carla J

2016-10-01

We aimed to describe the natural history of residual insulin secretion in Type 1 Diabetes TrialNet participants over 4 years from diagnosis and relate this to previously reported alternative clinical measures reflecting β-cell secretory function. Data from 407 subjects from 5 TrialNet intervention studies were analyzed. All subjects had baseline stimulated C-peptide values of ≥0.2 nmol/L from mixed-meal tolerance tests (MMTTs). During semiannual visits, C-peptide values from MMTTs, HbA1c, and insulin doses were obtained. The percentage of individuals with stimulated C-peptide of ≥0.2 nmol/L or detectable C-peptide of ≥0.017 nmol/L continued to diminish over 4 years; this was markedly influenced by age. At 4 years, only 5% maintained their baseline C-peptide secretion. The expected inverse relationships between C-peptide and HbA1c or insulin doses varied over time and with age. Combined clinical variables, such as insulin-dose adjusted HbA1c (IDAA1C) and the relationship of IDAA1C to C-peptide, also were influenced by age and time from diagnosis. Models using these clinical measures did not fully predict C-peptide responses. IDAA1C ≤9 underestimated the number of individuals with stimulated C-peptide ≥0.2 nmol/L, especially in children. Current trials of disease-modifying therapy for type 1 diabetes should continue to use C-peptide as a primary end point of β-cell secretory function. Longer duration of follow-up is likely to provide stronger evidence of the effect of disease-modifying therapy on preservation of β-cell function. © 2016 by the American Diabetes Association.

Correlations between fasting plasma C-peptide, glucagon-stimulated plasma C-peptide, and urinary C-peptide in insulin-treated diabetics

DEFF Research Database (Denmark)

Gjessing, H J; Matzen, L E; Frøland, A

1987-01-01

This study correlated fasting plasma C-peptide (CP), plasma CP 6 min after stimulation with 1 mg glucagon i.v., and the mean of three 24-h urinary excretions of C-peptide (UCP)/creatinine in 132 insulin-treated diabetics. Patients were divided into three groups: group 1, stimulated CP less than 0.......06 nM (n = 51); group 2, stimulated CP 0.06-0.60 nM (n = 48); and group 3, stimulated CP greater than 0.60 nM (n = 33). In all patients fasting CP was closely correlated to stimulated CP (r = .988, P less than .001), whereas the correlations between UCP and both fasting CP (r = .904, P less than .001......) and stimulated CP r = .902, P less than .001) were slightly less pronounced. The associations between UCP and both fasting CP (r = .716, P less than .001) and stimulated CP (r = .731, P less than .001) were modest in group 2, and even more so in group 3 (r = .557, P less than .001 and r = .641, P less than .001...

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

International Nuclear Information System (INIS)

Naidoo, C.

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, 125 I-insulin binding to the solubilized erythrocyte membrane receptor and 125 I-insulin binding to fibroblasts in culture

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

Energy Technology Data Exchange (ETDEWEB)

Naidoo, C

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, /sup 125/I-insulin binding to the solubilized erythrocyte membrane receptor and /sup 125/I-insulin binding to fibroblasts in culture.

Elevated C-peptide and insulin predict increased risk of colorectal adenomas in normal mucosa

International Nuclear Information System (INIS)

Vidal, Adriana C; Keku, Temitope O; Lund, Pauline Kay; Hoyo, Cathrine; Galanko, Joseph; Burcal, Lauren; Holston, Rachel; Massa, Berri; Omofoye, Oluwaseun; Sandler, Robert S

2012-01-01

Lower concentrations of the insulin–like growth factor binding protein-1 (IGFBP-1) and elevated concentrations of insulin or C-peptide have been associated with an increase in colorectal cancer risk (CRC). However few studies have evaluated IGFBP-1 and C-peptide in relation to adenomatous polyps, the only known precursor for CRC. Between November 2001 and December 2002, we examined associations between circulating concentrations of insulin, C-peptide, IGFBP-1 and apoptosis among 190 individuals with one or more adenomatous polyps and 488 with no adenomatous polyps using logistic regression models. Individuals with the highest concentrations of C-peptide were more likely to have adenomas (OR = 2.2, 95% CI 1.4-4.0) than those with the lowest concentrations; associations that appeared to be stronger in men (OR = 4.4, 95% CI 1.7-10.9) than women. Individuals with high insulin concentrations also had a higher risk of adenomas (OR = 3.5, 95% CI 1.7-7.4), whereas higher levels of IGFBP-1 were associated with a reduced risk of adenomas in men only (OR = 0.3, 95% CI 0.1-0.7). Overweight and obese individuals with higher C-peptide levels (>1 st Q) were at increased risk for lower apoptosis index (OR = 2.5, 95% CI 0.9-7.1), an association that remained strong in overweight and obese men (OR = 6.3, 95% CI 1.0-36.7). Higher levels of IGFBP-1 in overweight and obese individuals were associated with a reduced risk of low apoptosis (OR = 0.3, 95% CI 0.1-1.0). Associations between these peptides and the apoptosis index in overweight and obese individuals, suggest that the mechanism by which C-peptide could induce adenomas may include its anti-apoptotic properties. This study suggests that hyperinsulinemia and IGF hormones predict adenoma risk, and that outcomes associated with colorectal carcinogenesis maybe modified by gender

Role of C-peptide in Altered Lipid Profile among Apparently Healthy Adults of Vijayapura City, Karnataka

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Chandrahas M.Kulkarni

2016-04-01

Full Text Available Background: C-peptide is produced in equimolar concentration during insulin production as inactive molecule by beta islet cells of Langerhans. C-peptide is most useful biomarker of endogenous insulin production. Aim and Objectives: To predict metabolic syndrome in advance by estimation of C-peptide and lipid profile in healthy adults. Material and Methods: Serum C-peptide, fasting blood glucose and lipid profile of 128 healthy individuals were estimated. Adults in the age group of 18 to 60 years of both sexes were included in study. Results: C-peptide levels were increased in 27%, Serum cholesterol in 30%, LDL Cholesterol in 55% and triglyceride levels in 21% of healthy individuals. Significant correlation was observed between C peptide, age, serum cholesterol, LDL and cholesterol LDL ratio in male subjects only. In our study group most of the subjects (both males and females fell in overweight group. Conclusion: Cpeptide level and lipid profile may be considered as useful biomarkers to predict type 2 diabetes mellitus in advance, possibly due to insulin resistance.

B-type natriuretic peptide (BNP) affects the initial response to intravenous glucose: a randomised placebo-controlled cross-over study in healthy men.

Science.gov (United States)

Heinisch, B B; Vila, G; Resl, M; Riedl, M; Dieplinger, B; Mueller, T; Luger, A; Pacini, G; Clodi, M

2012-05-01

B-type natriuretic peptide (BNP) is a hormone released from cardiomyocytes in response to cell stretching and elevated in heart failure. Recent observations indicate a distinct connection between chronic heart failure and diabetes mellitus. This study investigated the role of BNP on glucose metabolism. Ten healthy volunteers (25 ± 1 years; BMI 23 ± 1 kg/m(2); fasting glucose 4.6 ± 0.1 mmol/l) were recruited to a participant-blinded investigator-open placebo-controlled cross-over study, performed at a university medical centre. They were randomly assigned (sequentially numbered opaque sealed envelopes) to receive either placebo or 3 pmol kg(-1) min(-1) BNP-32 intravenously during 4 h on study day 1 or 2. One hour after beginning the BNP/placebo infusion, a 3 h intravenous glucose tolerance test (0.33 g/kg glucose + 0.03 U/kg insulin at 20 min) was performed. Plasma glucose, insulin and C-peptide were frequently measured. Ten volunteers per group were analysed. BNP increased the initial glucose distribution volume (13 ± 1% body weight vs 11 ± 1%, p < 0.002), leading to an overall reduction in glucose concentration (p < 0.001), particularly during the initial 20 min of the test (p = 0.001), accompanied by a reduction in the initial C-peptide levels (1.42 ± 0.13 vs 1.62 ± 0.10 nmol/l, p = 0.015). BNP had no impact on beta cell function, insulin clearance or insulin sensitivity and induced no adverse effects. Intravenous administration of BNP increases glucose initial distribution volume and lowers plasma glucose concentrations following a glucose load, without affecting beta cell function or insulin sensitivity. These data support the theory that BNP has no diabetogenic properties, but improves metabolic status in men, and suggest new questions regarding BNP-induced differences in glucose availability and signalling in various organs/tissues. ClinicalTrials.gov: NCT01324739 The study was funded by Jubilée Fonds of the Austrian National Bank (OeNB-Fonds).

Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes

DEFF Research Database (Denmark)

Meier, Juris J; Weyhe, Dirk; Michaely, Mark

2004-01-01

of GLP-1 (1.2 pmol x kg x min) and placebo over 8 hrs, each administered in randomized order in the fasting state. C-reactive protein concentrations of 4.9+/-4.2 mg/dL indicated a systemic inflammation. Blood was drawn in 30-min intervals for glucose (glucose oxidase), insulin, C-peptide, glucagon...... practicability and the risk of hypoglycemia. Therefore, the glucose-lowering effect of the incretin hormone glucagon-like peptide 1 (GLP-1) was investigated in patients with type 2 diabetes after major surgery. DESIGN: Randomised clinical study. SETTING: A surgical unit of a university hospital. PATIENTS......, and GLP-1 (specific immunoassays). Statistics were done with repeated-measures analysis of variance and Duncan's post hoc tests. MAIN RESULTS: During the intravenous infusion of GLP-1, plasma glucose concentrations were significantly lowered, reaching the normoglycemic fasting glucose range within 150...

Glucose tolerance, insulin release, and insulin binding to monocytes in kidney transplant recipients

International Nuclear Information System (INIS)

Briggs, W.A.; Wielechowski, K.S.; Mahajan, S.K.; Migdal, S.D.; McDonald, F.D.

1982-01-01

In order to evaluate glucose tolerance following renal transplantation, intravenous glucose tolerance tests (IVGTT), with evaluation of hormonal responses to the intravenous glucose load and percent specific 125 I-insulin binding to peripheral blood monocytes, were studied in eight clinically stable kidney transplant recipients. For comparison purposes, identical studies were done in eight control subjects and seven clinically stable hemodialysis patients. One transplant recipient was glucose intolerant, with fasting hyperglycemia, elevated HbA1C, and abnormal glucose decay constant. Impaired pancreatic insulin release appeared to be the major factor accounting for his glucose intolerance. The seven glucose-tolerant transplant recipients had significantly increased insulin release during IVGTT compared to control subjects, and significant correlations were found among insulin release, glucose decay constant, and fasting blood sugar in those patients. Insulin binding to monocytes was significantly greater in transplant recipients than control subjects due to an increase in insulin binding capacity per cell. A significant correlation was found between percent specific 125 I-insulin binding and steroid dose, expressed as mg/kg body weight/day, in those patients. Thus, chronic steroid administration does not cause glucose intolerance in transplant recipients who manifest steroid-associated increases in pancreatic insulin release and cellular insulin binding capacity

Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia

DEFF Research Database (Denmark)

Green, Charlotte J; Henriksen, Tora I; Pedersen, Bente K

2012-01-01

Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the......Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose...

Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice.

Science.gov (United States)

Coomans, Claudia P; Biermasz, Nienke R; Geerling, Janine J; Guigas, Bruno; Rensen, Patrick C N; Havekes, Louis M; Romijn, Johannes A

2011-12-01

Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated tissue-specific glucose uptake. Tolbutamide, an inhibitor of ATP-sensitive K(+) channels (K(ATP) channels), or vehicle was infused into the lateral ventricle in the basal state and during hyperinsulinemic-euglycemic conditions in postabsorptive, chow-fed C57Bl/6J mice and in postabsorptive C57Bl/6J mice with diet-induced obesity. Whole-body glucose uptake was measured by d-[(14)C]glucose kinetics and tissue-specific glucose uptake by 2-deoxy-d-[(3)H]glucose uptake. During clamp conditions, intracerebroventricular administration of tolbutamide impaired the ability of insulin to inhibit EGP by ∼20%. In addition, intracerebroventricular tolbutamide diminished insulin-stimulated glucose uptake in muscle (by ∼59%) but not in heart or adipose tissue. In contrast, in insulin-resistant mice with diet-induced obesity, intracerebroventricular tolbutamide did not alter the effects of insulin during clamp conditions on EGP or glucose uptake by muscle. Insulin stimulates glucose uptake in muscle in part through effects via K(ATP) channels in the central nervous system, in analogy with the inhibitory effects of insulin on EGP. High-fat diet-induced obesity abolished the central effects of insulin on liver and muscle. These observations stress the role of central insulin resistance in the pathophysiology of diet-induced insulin resistance.

Study on the insulin resistance and β-cell function in individuals with normal and those with abnormal glucose metabolism

International Nuclear Information System (INIS)

Wei Zikun

2006-01-01

Objective: To study the insulin resistance and β-cell function in individuals with normal glucose tolerance (NGT) and those with glucose metabolism dysfunction. Methods: Insulin resistance and β-cell function were studied with oral glucose tolerance test and the following parameters: 2h insulin/2h plasma glucose (2hIns/2hPG), insulin resistance index (IRI), insulin sensitivity index (ISI) and 30 min net increment of insulin/30min net increment of glucose (AI 30 /AG 30 ) were examined in 44 individuals with NGT, 45 subjects with impaired glucose tolerance (IGT), 66 recently diagnosed diabetics and 175 well-established diabetics. Results: The insulin resistance index (IRI) increased progressively from that in NGT individuals to that in recently diabetics (20 ± 1. 5→3.1 ± 1.6→4.1 ± 1.8), while the 2hIns/2hPG, ΔI 30 /ΔG 30 and ISI decreased progressively with significant differences between those in successive groups (P 30 /ΔG 30 and ISI kept decreasing (values in patients with disease history less than 3 yrs vs those in patients with disease over 3yrs: 2.9 ± 3.2 vs 2.4 + 2.3, 30.2 + 1.1 vs 23.4 ± 2.3, P 30 /ΔG 30 were significantly correlated with ISI (F =96.3, 58.4 and 47.5 respectively). For principal component analysis display, the cumulative contribution rate of four parameters (2hIns/2hPG, ISI, ΔI 30 /ΔG 30 and 2h C-peptide) exceeded 85% (86.5%). Conclusion: As the dysfunction of glucose metabolism proceeded from IGT to well established diabetes, the IR increased first with decrease of β-cell secretion followed. The parameters 2hIns/2hPG, ISI, 2h C-peptide ΔI 30 /ΔG 30 were especially useful for the investigation . (authors)

The interaction of insulin, glucose, and insulin-glucose mixtures with a phospholipid monolayer.

Science.gov (United States)

Shigenobu, Hayato; McNamee, Cathy E

2012-12-15

We determined how glucose or insulin interacts with a phospholipid monolayer at the air/water interface and explained these mechanisms from a physico-chemical point of view. The 1,2-dipalmitoyl-2-sn-glycero-3-phosphatidylcholine (DPPC) monolayer at an air/water interface acted as a model membrane, which allowed the effect of the molecular packing density in the monolayer on the interactions to be determined. The interaction of glucose, insulin, and a mixture of glucose and insulin to the DPPC monolayer were investigated via surface pressure-area per molecule Langmuir isotherms and fluorescence microscopy. Glucose adsorbed to the underside of the DPPC monolayer, while insulin was able to penetrate through the monolayer when the phospholipid molecules were not densely packed. The presence of a mixture of insulin and glucose affected the molecular packing in the DPPC monolayer differently than the pure insulin or glucose solutions, and the glucose-insulin mixture was seen to be able to penetrate through the monolayer. These results indicated that glucose and insulin interact with one another, giving a material that may then transported through a pore in the monolayer or through the spaces between the molecules of the monolayer. Copyright © 2012 Elsevier Inc. All rights reserved.

The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype

DEFF Research Database (Denmark)

Vilsbøll, Tina; Knop, F K; Krarup, T

2003-01-01

[maturity-onset diabetes of the young (MODY)3]; and 5) newly diagnosed type 1 diabetic patients. All participants underwent three hyperglycemic clamps (2 h, 15 mM) with continuous infusion of saline, 1 pmol GLP-1 (7-36)amide/kg body weight.min or 4 pmol GIP pmol/kg body weight.min. The early-phase (0-20 min......The effect of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1), is preserved in typical middle-aged, obese, insulin-resistant type 2 diabetic patients, whereas a defective amplification of the so-called late-phase plasma insulin response (20-120 min) to glucose by the other...... incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2...

Sup(13)C NMR studies of glucose disposal in normal and non-insulin-dependent diabetic humans

International Nuclear Information System (INIS)

Shulman, G.I.; Rothman, D.L.; Shulman, R.G.

1990-01-01

To examine the extent to which the defect in insulin action in subjects with non-insulin-dependent diabetes mellitus (NIDDM) can be accounted for by impairment of muscle glycogen synthesis, we performed combined hyperglycemic-hyperinsulinemic clamp studies with [ 13 C]glucose in five subjects with NIDDM and in six age- and weight-matched healthy subjects. The rate of incorporation of intravenously infused [1- 13 C]glucose into muscle glycogen was measured directly in the gastrocnemius muscle by means of a nuclear magnetic resonance (NMR) spectrometer with a 15.5 min time resolution and a 13 C surface coil. The steady-state plasma concentrations of insulin and glucose were similar in both study groups. The mean (±SE) rate of glycogen synthesis, as determined by 13 C NMR, was 78±28 and 183±39 μmol-glucosyl units (kg muscle tissue (wet mass)) -1 min -1 in the diabetic and normal subjects, respectively. The mean glucose uptake was markedly reduced in the diabetic as compared with the normal subjects. The mean rate of non-oxidative glucose metabolism was 22±4 μmol kg -1 min -1 in the diabetic subjects and 42±4 μmol kg -1 min -1 in the normal subjects. When these rates are extrapolated to apply to the whole body, the synthesis of muscle glycogen would account for most of the total-body glucose uptake and all of the non-oxidative glucose metabolism in both normal and diabetic subjects. We conclude that muscle glycogen synthesis is the principal pathway of glucose disposal in both normal and diabetic subjects and that defects in muscle glycogen synthesis have a dominant role in the insulin resistance that occurs in persons with NIDDM. (author)

Short-term glucagon stimulation test of C-peptide effect on glucose utilization in patients with type 1 diabetes mellitus.

Science.gov (United States)

Mojto, Viliam; Rausova, Zuzana; Chrenova, Jana; Dedik, Ladislav

2015-12-01

This work aimed to evaluate the use of a four-point glucagon stimulation test of C-peptide effect on glucose utilization in type 1 diabetic patients using a new mathematical model. A group of 32 type 1 diabetic patients and a group of 10 healthy control subjects underwent a four-point glucagon stimulation test with blood sampling at 0, 6, 15 and 30 min after 1 mg glucagon bolus intravenous administration. Pharmacokinetic and pharmacokinetic/pharmacodynamic models of C-peptide effect on glucose utilization versus area under curve (AUC) were used. A two-sample t test and ANOVA with Bonferroni correction were used to test the significance of differences between parameters. A significant difference between control and patient groups regarding the coefficient of whole-body glucose utilization and AUC C-peptide/AUC glucose ratio (p ≪ 0.001 and p = 0.002, respectively) was observed. The high correlation (r = 0.97) between modeled coefficient of whole-body glucose utilization and numerically calculated AUC C-peptide/AUC glucose ratio related to entire cohort indicated the stability of used method. The short-term four-point glucagon stimulation test allows the numerically calculated AUC C-peptide/AUC glucose ratio and/or the coefficient of whole-body glucose utilization calculated from model to be used to diagnostically identify type 1 diabetic patients.

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.

D-[U-11C]glucose uptake and metabolism in the brain of insulin-dependent diabetic subjects

International Nuclear Information System (INIS)

Gutniak, M.; Blomqvist, G.; Widen, L.; Stone-Elander, S.; Hamberger, B.; Grill, V.

1990-01-01

We used D-[U-11C]glucose to evaluate transport and metabolism of glucose in the brain in eight nondiabetic and six insulin-dependent diabetes mellitus (IDDM) subjects. IDDM subjects were treated by continuous subcutaneous insulin infusion. Blood glucose was regulated by a Biostator-controlled glucose infusion during a constant insulin infusion. D-[U-11C]-glucose was injected for positron emission tomography studies during normoglycemia as well as during moderate hypoglycemia [arterial plasma glucose 2.74 +/- 0.14 in nondiabetic and 2.80 +/- 0.26 mmol/l (means +/- SE) in IDDM subjects]. Levels of free insulin were constant and similar in both groups. The tracer data were analyzed using a three-compartment model with a fixed correction for 11CO2 egression. During normoglycemia the influx rate constant (k1) and blood-brain glucose flux did not differ between the two groups. During hypoglycemia k1 increased significantly and similarly in both groups (from 0.061 +/- 0.007 to 0.090 +/- 0.006 in nondiabetic and from 0.061 +/- 0.006 to 0.093 +/- 0.013 ml.g-1.min-1 in IDDM subjects). During normoglycemia the tracer-calculated metabolism of glucose was higher in the whole brain in the nondiabetic than in the diabetic subjects (22.0 +/- 1.9 vs. 15.6 +/- 1.1 mumol.100 g-1.min-1, P less than 0.01). During hypoglycemia tracer-calculated metabolism was decreased by 40% in nondiabetic subjects and by 28% in diabetic subjects. The results indicate that uptake of glucose is normal, but some aspect of glucose metabolism is abnormal in a group of well-controlled IDDM subjects

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.

Dessert Formulation Using Sucralose and Dextrin Affects Favorably Postprandial Response to Glucose, Insulin, and C-Peptide in Type 2 Diabetic Patients

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Argyri, Konstantina; Sotiropoulos, Alexios; Psarou, Eirini; Papazafiropoulou, Athanasia; Zampelas, Antonios; Kapsokefalou, Maria

2013-01-01

BACKGROUND: Dessert compositions may conform to diabetic diet when it contains low sugar or artificial sweetener to replace sugar. However, it is still questionable whether glycemic control in type 2 diabetes patients is improved by the use of diet-conforming dessert compositions. OBJECTIVE: To compare, in type 2 diabetes patients, the glycemic, insulin, and C-peptide responses to seven modified dessert compositions for diabetics (D-dessert) with the response to seven similar desserts of non-...

Effects of Glucose with Casein Peptide Supplementation on Post-Exercise Muscle Glycogen Resynthesis in C57BL/6J Mice

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Yutaka Matsunaga

2018-06-01

Full Text Available Numerous studies have reported that post-exercise ingestion of carbohydrates with protein supplementation can enhance glycogen recovery. However, few reports have focused on the degrees of degradation of the ingested proteins due to post-exercise glycogen resynthesis. Accordingly, the aim of this study was to clarify the effects of differences in protein degradation on muscle glycogen recovery. Male seven-week-old C57BL/6J mice performed a single bout of 60-min treadmill running exercise and were then orally administered glucose (Glu; 1.5 mg/g body weight (BW, glucose with casein peptide (Glu + Pep; 1.5 + 0.5 mg/g BW or its constituent amino acid mixture (Glu + AA; 1.5 + 0.5 mg/g BW. At 120 min after supplementation, the soleus muscle glycogen content in the Glu and Glu + AA groups was significantly higher than that immediately after exercise; however, no such difference was observed in the Glu + Pep group. Blood substrate concentration and insulin signaling did not differ among the three groups. Furthermore, energy expenditure during the recovery period in the Glu + Pep group was significantly higher than that in the Glu and Glu + AA groups. These findings suggest that post-exercise co-ingestion of glucose and casein peptide might delay glycogen resynthesis, at least in part through increased energy expenditure caused by casein peptide ingestion.

Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides

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Rehfeld, J F

2011-01-01

and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by islet...... cell hyperplasia and increased insulin secretion. Conventionally, the effect of gastrointestinal hormones on insulin secretion (the incretin effect) has been defined and quantified in relation to oral versus intravenous glucose loadings. Under these unphysiological conditions, the release of gastrin...

Impaired glucose-induced glucagon suppression after partial pancreatectomy

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Schrader, Henning; Menge, Bjoern A; Breuer, Thomas G K

2009-01-01

INTRODUCTION: The glucose-induced decline in glucagon levels is often lost in patients with type 2 diabetes. It is unclear whether this is due to an independent defect in alpha-cell function or secondary to the impairment in insulin secretion. We examined whether a partial pancreatectomy in humans...... would also impair postchallenge glucagon concentrations and, if so, whether this could be attributed to the reduction in insulin levels. PATIENTS AND METHODS: Thirty-six patients with pancreatic tumours or chronic pancreatitis were studied before and after approximately 50% pancreatectomy with a 240-min...... oral glucose challenge, and the plasma concentrations of glucose, insulin, C-peptide, and glucagon were determined. RESULTS: Fasting and postchallenge insulin and C-peptide levels were significantly lower after partial pancreatectomy (P

Effects of genetic variants in ADCY5, GIPR, GCKR and VPS13C on early impairment of glucose and insulin metabolism in children.

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Jan Windholz

Full Text Available OBJECTIVE: Recent genome-wide association studies identified novel candidate genes for fasting and 2 h blood glucose and insulin levels in adults. We investigated the role of four of these loci (ADCY5, GIPR, GCKR and VPS13C in early impairment of glucose and insulin metabolism in children. RESEARCH DESIGN AND METHODS: We genotyped four variants (rs2877716; rs1260326; rs10423928; rs17271305 in 638 Caucasian children with detailed metabolic testing including an oGTT and assessed associations with measures of glucose and insulin metabolism (including fasting blood glucose, insulin levels and insulin sensitivity/secretion indices by linear regression analyses adjusted for age, sex, BMI-SDS and pubertal stage. RESULTS: The major allele (C of rs2877716 (ADCY5 was nominally associated with decreased fasting plasma insulin (P = 0.008, peak insulin (P = 0.009 and increased QUICKI (P = 0.016 and Matsuda insulin sensitivity index (P = 0.013. rs17271305 (VPS13C was nominally associated with 2 h blood glucose (P = 0.009, but not with any of the insulin or insulin sensitivity parameters. We found no association of the GIPR and GCKR variants with parameters of glucose and insulin metabolism. None of the variants correlated with anthropometric traits such as height, WHR or BMI-SDS, which excluded potential underlying associations with obesity. CONCLUSIONS: Our data on obese children indicate effects of genetic variation within ADCY5 in early impairment of insulin metabolism and VPS13C in early impairment of blood glucose homeostasis.

Urinary C-peptide: a useful tool for evaluating the endogenous insulin reserve in cohort and longitudinal studies of diabetes in childhood.

Science.gov (United States)

de Beaufort, C E; den Boer, N C; Bruining, G J; Eilers, G A; van Strik, R; Weterings, T

1988-09-01

Increasing research into the remission phase of type I diabetes mellitus stresses the importance of a non-traumatic and reliable method for the evaluation of endogenous insulin production. We compared 24-h urinary C-peptide excretion (UCE) with plasma C-peptide values before and after stimulation with 1 mg glucagon in 24 type I diabetic children. Fasting plasma C-peptide values and stimulated plasma C-peptide values showed a linear correlation with 24 h UCE. Mean plasma C-peptide levels correlated inversely with the exogenous insulin dose. A slightly better correlation was found between the exogenous insulin dose and 24 h UCE. Control data of 24 h UCE were obtained from healthy siblings. A linear correlation with age was found up to 10 years of age above which UCE values seem to reach a plateau. This effect of age, as well as the frequency of sampling was taken into account in the derivation of 95% reference intervals for UCE. The measurement of 24 h UCE appears to be a useful parameter to assess endogenous insulin production in diabetic children, provided that age is taken into account.

Use of anesthesia dramatically alters the oral glucose tolerance and insulin secretion in C57Bl/6 mice

DEFF Research Database (Denmark)

Windeløv, Johanne A; Pedersen, Jens; Holst, Jens J

2016-01-01

Evaluation of the impact of anesthesia on oral glucose tolerance in mice. Anesthesia is often used when performing OGTT in mice to avoid the stress of gavage and blood sampling, although anesthesia may influence gastrointestinal motility, blood glucose, and plasma insulin dynamics. C57Bl/6 mice...... in the time frame -15 to +150 min. Plasma insulin concentration was measured at time 0 and 20 min. All four anesthetic regimens resulted in impaired glucose tolerance compared to saline/no anesthesia. (1) hypnorm/midazolam increased insulin concentrations and caused an altered glucose tolerance; (2) ketamine...... regimens altered the oral glucose tolerance, and we conclude that anesthesia should not be used when performing metabolic studies in mice....

Observations on the presence of insulin resistance in patients with essential hypertension and coronary heart disease

International Nuclear Information System (INIS)

Zhu Mei; Wu Guo

2006-01-01

Objective: To investigate the presence of insulin resistance in patients with essential hypertension (EH) and coronary heart disease (CHD). Methods: Fasting and 2h post oral 75g glucose blood sugar (with oxidase method), insulin and C-peptide (with RIA) levels were examined in 52 patients with EH, 40 patients with CHD and 35 controls. Results: The fasting and 2h post o- ral glucose serum levels of glucose, insulin and C-peptide in the patients were significantly higher than those in the controls (P < 0.01), suggesting presence of impaired glucose tolerance and insulin resistance. Conclusion: Impaired glucose tolerance due to insulin resistance was demonstrated in the studied patients with EH or CHD. (authors)

Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study

DEFF Research Database (Denmark)

Laakso, M; Zilinskaite, J; Hansen, T

2008-01-01

AIMS/HYPOTHESIS: We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. METHODS: Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic...

Low-cost production of proinsulin in tobacco and lettuce chloroplasts for injectable or oral delivery of functional insulin and C-peptide.

Science.gov (United States)

Boyhan, Diane; Daniell, Henry

2011-06-01

Current treatment for type I diabetes includes delivery of insulin via injection or pump, which is highly invasive and expensive. The production of chloroplast-derived proinsulin should reduce cost and facilitate oral delivery. Therefore, tobacco and lettuce chloroplasts were transformed with the cholera toxin B subunit fused with human proinsulin (A, B, C peptides) containing three furin cleavage sites (CTB-PFx3). Transplastomic lines were confirmed for site-specific integration of transgene and homoplasmy. Old tobacco leaves accumulated proinsulin up to 47% of total leaf protein (TLP). Old lettuce leaves accumulated proinsulin up to 53% TLP. Accumulation was so stable that up to ~40% proinsulin in TLP was observed even in senescent and dried lettuce leaves, facilitating their processing and storage in the field. Based on the yield of only monomers and dimers of proinsulin (3 mg/g leaf, a significant underestimation), with a 50% loss of protein during the purification process, one acre of tobacco could yield up to 20 million daily doses of insulin per year. Proinsulin from tobacco leaves was purified up to 98% using metal affinity chromatography without any His-tag. Furin protease cleaved insulin peptides in vitro. Oral delivery of unprocessed proinsulin bioencapsulated in plant cells or injectable delivery into mice showed reduction in blood glucose levels similar to processed commercial insulin. C-peptide should aid in long-term treatment of diabetic complications including stimulation of nerve and renal functions. Hyper-expression of functional proinsulin and exceptional stability in dehydrated leaves offer a low-cost platform for oral and injectable delivery of cleavable proinsulin. © 2010 The Authors. Plant Biotechnology Journal © 2010 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.

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Min He

Full Text Available BACKGROUND: Glucagon-like peptide-1 (GLP-1 is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg for 12 weeks. Body weight, body mass index (BMI, food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various

Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

DEFF Research Database (Denmark)

Richter, Erik; Hansen, B F; Hansen, S A

1988-01-01

in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.......The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing...

Insulin-like peptide 5 is a microbially regulated peptide that promotes hepatic glucose production

DEFF Research Database (Denmark)

Lee, Ying Shiuan; De Vadder, Filipe; Tremaroli, Valentina

2016-01-01

expression in the brain was higher in CONV-R versus GF mice. We also observed that colonic Insl5 expression was suppressed by increasing the energy supply in GF mice by colonization or high-fat feeding. We did not observe any differences in food intake, gut transit or oral glucose tolerance between Insl5......-/- and wild-type mice. However, we showed impaired intraperitoneal glucose tolerance in Insl5-/- mice. We also observed improved insulin tolerance and reduced hepatic glucose production in Insl5-/- mice. CONCLUSIONS: We have shown that colonic Insl5 expression is regulated by the gut microbiota and energy...... availability. We propose that INSL5 is a hormone that could play a role in promoting hepatic glucose production during periods of energy deprivation....

Changes in Gastrointestinal Hormone Responses, Insulin Sensitivity, and Beta-Cell Function Within 2 Weeks After Gastric Bypass in Non-diabetic Subjects

DEFF Research Database (Denmark)

Jacobsen, Siv Hesse; Olesen, S C; Dirksen, C

2012-01-01

measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY(3-36) (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin......, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance. RESULTS: Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated...... postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after...

Insulin release by glucagon and secretin

DEFF Research Database (Denmark)

Kofod, Hans; Andreu, D; Thams, P

1988-01-01

Secretin and glucagon potentiate glucose-induced insulin release. We have compared the effects of secretin and glucagon with that of four hybrid molecules of the two hormones on insulin release and formation of cyclic AMP (cAMP) in isolated mouse pancreatic islets. All six peptides potentiated...... the release of insulin at 10 mM D-glucose, and their effects were indistinguishable with respect to the dynamics of release, dose-response relationship, and glucose dependency. However, measurements of cAMP accumulation in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-4) M...... potentiating effects of secretin and glucagon on glucose-induced insulin release, their modes of action may be different....

Continuous glucose monitoring, oral glucose tolerance, and insulin - glucose parameters in adolescents with simple obesity.

Science.gov (United States)

El Awwa, A; Soliman, A; Al-Ali, M; Yassin, M; De Sanctis, V

2012-09-01

In obese adolescents pancreatic beta-cells may not be able to cope with insulin resistance leading to hyperglycemia and type2 diabetes (T2DM To assess oral glucose tolerance, 72-h continuous blood glucose concentrations (CGM) and calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) in 13 adolescents with simple obesity (BMI SDS=4 ± 1.06). OGTT performed in 13 obese adolescents (13.47 ± 3 years) revealed 3 cases (23%) with impaired fasting glucose (IFG: fasting glucose >5.6 mmol/L), 4 cases (30%) with impaired glucose tolerance (IGT: 2h blood glucose >7.8 continuous glucose monitoring system ( CGMS), IFG was detected in 4 cases, the maximum serum blood glucose (BG : 2h or more after meal) was >7.8 and 11.1 mmol/L (diabetes) in one case (7.6%). Five cases had a minimum BG recorded of 2.6 and QUICKI values obese adolescents, CGMS is superior to OGTT and HbA1C in detecting glycemic abnormalities, which appears to be secondary to insulin resistance.

Nicotinamide induces differentiation of embryonic stem cells into insulin-secreting cells

International Nuclear Information System (INIS)

Vaca, Pilar; Berna, Genoveva; Araujo, Raquel; Carneiro, Everardo M.; Bedoya, Francisco J.; Soria, Bernat; Martin, Franz

2008-01-01

The poly(ADP-ribose) polymerase (PARP) inhibitor, nicotinamide, induces differentiation and maturation of fetal pancreatic cells. In addition, we have previously reported evidence that nicotinamide increases the insulin content of cells differentiated from embryonic stem (ES) cells, but the possibility of nicotinamide acting as a differentiating agent on its own has never been completely explored. Islet cell differentiation was studied by: (i) X-gal staining after neomycin selection; (ii) BrdU studies; (iii) single and double immunohistochemistry for insulin, C-peptide and Glut-2; (iv) insulin and C-peptide content and secretion assays; and (v) transplantation of differentiated cells, under the kidney capsule, into streptozotocin (STZ)-diabetic mice. Here we show that undifferentiated mouse ES cells treated with nicotinamide: (i) showed an 80% decrease in cell proliferation; (ii) co-expressed insulin, C-peptide and Glut-2; (iii) had values of insulin and C-peptide corresponding to 10% of normal mouse islets; (iv) released insulin and C-peptide in response to stimulatory glucose concentrations; and (v) after transplantation into diabetic mice, normalized blood glucose levels over 7 weeks. Our data indicate that nicotinamide decreases ES cell proliferation and induces differentiation into insulin-secreting cells. Both aspects are very important when thinking about cell therapy for the treatment of diabetes based on ES cells

Immunological half-life of porcine proinsulin C-peptide

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Oyama, H; Horino, M; Matsumura, S [Kawasaki Medical Coll., Kurashiki (Japan). Div. of Endocrinology; Kobayshi, K; Suetsugu, N [Yamaguchi Univ., Ube (Japan). School of Medicine

1975-11-01

Immunological half-lifes of injected porcine C-peptide and insulin with RIA were studied and calculated as 9.8 and 8.0 minutes. Higher circulating levels of C-peptide as compared to insulin in normal young swines lead to speculation about a longer half-life of C-peptide. This hypothesis was verified in this study. Immunological half-lifes of porcine proinsulin and insulin in the pig were 20 and 6 minutes, respectively.

Identification of the bioactive and consensus peptide motif from Momordica charantia insulin receptor-binding protein.

Science.gov (United States)

Lo, Hsin-Yi; Li, Chia-Cheng; Ho, Tin-Yun; Hsiang, Chien-Yun

2016-08-01

Many food bioactive peptides with diverse functions have been discovered by studying plant proteins. We have previously identified a 68-residue insulin receptor (IR)-binding protein (mcIRBP) from Momordica charantia that exhibits hypoglycemic effects in mice via interaction with IR. By in vitro digestion, we found that mcIRBP-19, spanning residues 50-68 of mcIRBP, enhanced the binding of insulin to IR, stimulated the phosphorylation of PDK1 and Akt, induced the expression of glucose transporter 4, and stimulated both the uptake of glucose in cells and the clearance of glucose in diabetic mice. Furthermore, mcIRBP-19 homologs were present in various plants and shared similar β-hairpin structures and IR kinase-activating abilities to mcIRBP-19. In conclusion, our findings suggested that mcIRBP-19 is a blood glucose-lowering bioactive peptide that exhibits IR-binding potentials. Moreover, we newly identified novel IR-binding bioactive peptides in various plants which belonged to different taxonomic families. Copyright © 2016 Elsevier Ltd. All rights reserved.

An acute bout of whole body passive hyperthermia increases plasma leptin, but does not alter glucose or insulin responses in obese type 2 diabetics and healthy adults.

Science.gov (United States)

Rivas, Eric; Newmire, Dan E; Crandall, Craig G; Hooper, Philip L; Ben-Ezra, Vic

2016-07-01

Acute and chronic hyperthermic treatments in diabetic animal models repeatedly improve insulin sensitivity and glycemic control. Therefore, the purpose of this study was to test the hypothesis that an acute 1h bout of hyperthermic treatment improves glucose, insulin, and leptin responses to an oral glucose challenge (OGTT) in obese type 2 diabetics and healthy humans. Nine obese (45±7.1% fat mass) type 2 diabetics (T2DM: 50.1±12y, 7.5±1.8% HbA1c) absent of insulin therapy and nine similar aged (41.1±13.7y) healthy non-obese controls (HC: 33.4±7.8% fat mass, Pwhole body passive hyperthermia treatment via head-out hot water immersion (1h resting in 39.4±0.4°C water) that increased internal temperature above baseline by ∆1.6±0.4°C or a control resting condition. Twenty-four hours post treatments, a 75g OGTT was administered to evaluate changes in plasma glucose, insulin, C-peptide, and leptin concentrations. Hyperthermia itself did not alter area under the curve for plasma glucose, insulin, or C-peptide during the OGTT in either group. Fasting absolute and normalized (kg·fat mass) plasma leptin was significantly increased (P<0.01) only after the hyperthermic exposure by 17% in T2DM and 24% in HC groups (P<0.001) when compared to the control condition. These data indicate that an acute hyperthermic treatment does not improve glucose tolerance 24h post treatment in moderate metabolic controlled obese T2DM or HC individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Integrated model of insulin and glucose kinetics describing both hepatic glucose and pancreatic insulin regulation

DEFF Research Database (Denmark)

Erlandsen, Mogens; Martinussen, Christoffer; Gravholt, Claus Højbjerg

2018-01-01

AbstractBackground and objectives Modeling of glucose kinetics has to a large extent been based on models with plasma insulin as a known forcing function. Furthermore, population-based statistical methods for parameter estimation in these models have mainly addressed random inter-individual varia......AbstractBackground and objectives Modeling of glucose kinetics has to a large extent been based on models with plasma insulin as a known forcing function. Furthermore, population-based statistical methods for parameter estimation in these models have mainly addressed random inter......-individual variations and not intra-individual variations in the parameters. Here we present an integrated whole-body model of glucose and insulin kinetics which extends the well-known two-compartment glucose minimal model. The population-based estimation technique allow for quantification of both random inter......- and intra-individual variation in selected parameters using simultaneous data series on glucose and insulin. Methods We extend the two-compartment glucose model into a whole-body model for both glucose and insulin using a simple model for the pancreas compartment which includes feedback of glucose on both...

The changes in levels of C-P and insulin in glucose tolerance test in rats with experimental non-insulin dependent diabetes mellitus

International Nuclear Information System (INIS)

Liu Xinqiu; Lei Ming

2001-01-01

The changes in levels of C-P and insulin were investigated in the GT test in rats with non-insulin dependent diabetes mellitus. In order to establish a model of non-insulin dependent diabetes mellitus (NIDDM), the authors injected rats with small dose streptozocoi (i.v.). Two weeks after the injection, the rats developed impaired glucose tolerance (IGT). Then, they were fed with high energy diet for eight weeks to form NIDDM. The results showed that the highest peak time of C-P and insulin in NIDDM was remarkably later than that in normal subjects, the highest peak time was in two hours (P < 0.05). The data suggest that level of C-P could accurately respond to level of insulin, and this experimental non-insulin dependent diabetes mellitus model is ideal

Glucagon-like peptide-1, glucose homeostasis and diabetes

DEFF Research Database (Denmark)

Holst, Jens Juul; Deacon, Carolyn F; Vilsbøll, Tina

2008-01-01

Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor beta-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects...... as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here....

The association between newborn regional body composition and cord blood concentrations of C-peptide and insulin-like growth factor I

DEFF Research Database (Denmark)

Carlsen, Emma M; Renault, Kristina M; Jensen, Rikke B

2015-01-01

BACKGROUND: Third trimester fetal growth is partially regulated by C-peptide and insulin-like growth factor I (IGF-I). Prenatal exposures including maternal obesity and high gestational weight gain as well as high birth weight have been linked to subsequent metabolic disease. We evaluated...... with both C-peptide (p tissue accumulation was associated with cord blood C-peptide and IGF-I. Total and abdominal fat masses were related to C-peptide but not to IGF-I. Thus, newborn adiposity is partially mediated through C-peptide and early...

Pregnancy-induced rise in serum C-peptide concentrations in women with type 1 diabetes

DEFF Research Database (Denmark)

Nielsen, Lene Ringholm; Rehfeld, Jens F; Pedersen-Bjergaard, Ulrik

2009-01-01

OBJECTIVE: The purpose of this study was to investigate whether pregnancy induces increased insulin production as a marker of improved beta-cell function in women with long-term type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a prospective study of 90 consecutive pregnant women with type 1.......85). Multivariate regression analysis revealed a positive association between the absolute increase in C-peptide concentrations during pregnancy and decreased A1C from 8 to 33 weeks (P = 0.003). CONCLUSIONS: A pregnancy-induced increase in C-peptide concentrations in women with long-term type 1 diabetes...... in 35 women. RESULTS: C-peptide concentrations gradually increased throughout pregnancy regardless of serum glucose concentrations in the 90 women with a median duration of diabetes of 17 years (range 1-36 years). Among 35 women with paired recordings of stimulated C-peptide, C-peptide production...

Nanoparticle Delivered Human Biliverdin Reductase-Based Peptide Increases Glucose Uptake by Activating IRK/Akt/GSK3 Axis: The Peptide Is Effective in the Cell and Wild-Type and Diabetic Ob/Ob Mice

Directory of Open Access Journals (Sweden)

Peter E. M. Gibbs

2016-01-01

Full Text Available Insulin’s stimulation of glucose uptake by binding to the IRK extracellular domain is compromised in diabetes. We have recently described an unprecedented approach to stimulating glucose uptake. KYCCSRK (P2 peptide, corresponding to the C-terminal segment of hBVR, was effective in binding to and inducing conformational change in the IRK intracellular kinase domain. Although myristoylated P2, made of L-amino acids, was effective in cell culture, its use for animal studies was unsuitable. We developed a peptidase-resistant formulation of the peptide that was efficient in both mice and cell culture systems. The peptide was constructed of D-amino acids, in reverse order, and blocked at both termini. Delivery of the encapsulated peptide to HepG2 and HSKM cells was confirmed by its prolonged effect on stimulation of glucose uptake (>6 h. The peptide improved glucose clearance in both wild-type and Ob/Ob mice; it lowered blood glucose levels and suppressed glucose-stimulated insulin secretion. IRK activity was stimulated in the liver of treated mice and in cultured cells. The peptide potentiated function of IRK’s downstream effector, Akt-GSK3-(α,β axis. Thus, P2-based approach can be used for improving glucose uptake by cells. Also, it allows for screening peptides in vitro and in animal models for treatment of diabetes.

Characterization of an insulin-like growth factor-I/somatomedin-C radioimmunoassay specific for the C-peptide region

International Nuclear Information System (INIS)

Hintz, R.L.; Liu, F.; Seegan, G.

1982-01-01

Insulin-like growth factor-I (IGF-I) and somatomedin-C (SM-C) have been shown to be functionally identical by a number of criteria. We have synthesized the 12 amino acid C-peptide region of IGF-I (Gly-Tyr-Gly-Ser-Ser-Ser-Arg-Arg-Ala-Pro-Glu-Thr) and developed a RIA based on antibodies against this synthetic peptide. IGF-I and SM-C were indistinguishable in this RIA. No other peptides competed for this antiserum. The SM-C/IGF-I values of acid-chromatographed serum were strongly age dependent. The mean of children 1-5 yr old was 0.67 +/- 0.033 U/ml (mean +/- sD; n = 23), whereas the mean of children 12-17 yr old was 2.01 +/- 0.66 U/ml (n = 39) and the mean of 38 adults 26-85 yr old was 1.05 +/- 0.34. The SM-C/IGF-I values measured by this RIA were also growth hormone dependent. Thus, this region-specific RIA provides a clinically useful assessment of serum SM-C/IGF-I levels

Effects of ambient temperature on glucose tolerance and insulin sensitivity test outcomes in normal and obese C57 male mice.

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Dudele, Anete; Rasmussen, Gitte Marie; Mayntz, David; Malte, Hans; Lund, Sten; Wang, Tobias

2015-05-01

Mice are commonly used as animal models to study human metabolic diseases, but experiments are typically performed at room temperature, which is far below their thermoneutral zone and is associated with elevated heart rate, food intake, and energy expenditure. We set out to study how ambient temperature affects glucose tolerance and insulin sensitivity in control and obese male mice. Adult male C57BL/6J mice were housed at room temperature (23°C) for 6 weeks and fed either control or high fat diet. They were then fasted for 6 h before glucose or insulin tolerance tests were performed at 15, 20, 25, or 30°C. To ensure that behavioral thermoregulation did not counterbalance the afflicted ambient temperatures, oxygen consumption was determined on mice with the same thermoregulatory opportunities as during the tests. Decreasing ambient temperatures increased oxygen consumption and body mass loss during fasting in both groups. Mice fed high fat diet had improved glucose tolerance at 30°C and increased levels of fasting insulin followed by successive decrease of fasting glucose. However, differences between control and high-fat diet mice were present at all temperatures. Ambient temperature did not affect glucose tolerance in control group and insulin tolerance in either of the groups. Ambient temperature affects glucose metabolism in mice and this effect is phenotype specific. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Chapter 10: Glucose control: insulin therapy*

African Journals Online (AJOL)

Insulin and its analogues lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits ... control on 2 or 3 oral glucose lowering drugs.

Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease.

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Christine Bernsmeier

Full Text Available The incretins glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD. However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH patients and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001. In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

 Pleiotropic action of proinsulin C-peptid

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Michał Usarek

2012-03-01

Full Text Available  Proinsulin C-peptide, released in equimolar amounts with insulin by pancreatic β cells, since its discovery in 1967 has been thought to be devoid of biological functions apart from correct insulin processing and formation of disulfide bonds between A and B chains. However, in the last two decades research has brought a substantial amount of data indicating a crucial role of C-peptide in regulating various processes in different types of cells and organs. C-peptide acts presumably via either G-protein-coupled receptor or directly inside the cell, after being internalized. However, a receptor binding this peptide has not been identified yet. This peptide ameliorates pathological changes induced by type 1 diabetes mellitus, including glomerular hyperfiltration, vessel endothelium inflammation and neuron demyelinization. In diabetic patients and diabetic animal models, C-peptide substitution in physiological doses improves the functional and structural properties of peripheral neurons and protects against hyperglycemia-induced apoptosis, promoting neuronal development, regeneration and cell survival. Moreover, it affects glycogen synthesis in skeletal muscles. In vitro C-peptide promotes disaggregation of insulin oligomers, thus enhancing its bioavailability and effects on metabolism. There are controversies concerning the biological action of C-peptide, particularly with respect to its effect on Na /K -ATPase activity. Surprisingly, the excess of circulating peptide associated with diabetes type 2 contributes to atherosclerosis development. In view of these observations, long-term, large-scale clinical investigations using C-peptide physiological doses need to be conducted in order to determine safety and health outcomes of long-term administration of C-peptide to diabetic patients.

Effects of an oral insulin nanoparticle administration on hepatic glucose metabolism assessed by 13C and 2H isotopomer analysis

NARCIS (Netherlands)

Reis, C.P.; Neufeld, R.; Veiga, F.; Figueiredo, I.V.; Jones, J.; Soares, A.F.; Nunes, P.M.; Damg\\'e, C.; Carvalho, R.A.

2012-01-01

The purpose of this study was to evaluate hepatic glucose metabolism of diabetic induced rats after a daily oral load of insulin nanoparticles over 2 weeks. After the 2-week treatment, an oral glucose tolerance test was performed with [U-��C] glucose and �H2O. Plasma glucose �H and ��C enrichments

Insulin dynamics and biochemical markers for predicting impaired glucose tolerance in obese Thai youth.

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Tirabanchasak, Sirapassorn; Siripunthana, Sukumarn; Supornsilchai, Vichit; Wacharasindhu, Suttipong; Sahakitrungruang, Taninee

2015-09-01

Subjects with impaired glucose tolerance (IGT) are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. The predictors of IGT in obese youth are not well described. We studied 115 obese Thai children who underwent an oral glucose tolerance test (OGTT). Plasma glucose and insulin levels were calculated for assessment of β-cell function. Hemoglobin A1c (HbA1c), lipid profile, and clinical parameters were also used to determine predictors of IGT. We found that three patients had T2DM and 30 subjects had IGT. IGT patients had significantly higher fasting glucose (FG), 1-h postload glucose, 2-h postload insulin, and lower whole-body insulin sensitivity indices than in normal glucose tolerance subjects whereas other indices were comparable. By ROC curve analyses, 1-h postload glucose was the best predictor of IGT, but FG or HbA1c represented a poor diagnostic tool for prediabetes screening. Subjects with 1-h OGTT glucose > 155 mg/dL had significantly lower high-density lipoprotein levels, lower insulin sensitivity, and more insulin resistance than those with 1-h postload glucose of ≤ 155 mg/dL. Abnormal glucose tolerance is highly prevalent in obese Thai youth. Several fasting indices and HbA1c fail to predict IGT. An 1-h OGTT glucose of > 155 mg/dL appears to be more associated with adverse insulin dynamics and metabolic profile than 2-h postload glucose.

Pathological consequences of C-peptide deficiency ininsulin-dependent diabetes mellitus

Institute of Scientific and Technical Information of China (English)

Ahmad Ghorbani; Reza Shafiee-Nick

2015-01-01

Diabetes is associated with several complicationssuch as retinopathy, nephropathy, neuropathy andcardiovascular diseases. Currently, insulin is the mainused medication for management of insulin-dependentdiabetes mellitus （type-1 diabetes）. In this metabolicsyndrome, in addition to decrease of endogenous insulin,the plasma level of connecting peptide （C-peptide） is alsoreduced due to beta cell destruction. Studies in the pastdecade have shown that C-peptide is much more than abyproduct of insulin biosynthesis and possess differentbiological activities. Therefore, it may be possible thatC-peptide deficiency be involved, at least in part, in thedevelopment of different complications of diabetes. It hasbeen shown that a small level of remaining C-peptide isassociated with significant metabolic benefit. The purposeof this review is to describe beneficial effects of C-peptidereplacement on pathological features associated withinsulin-dependent diabetes. Also, experimental andclinical findings on the effects of C-peptide on wholebodyglucose utilization, adipose tissue metabolism andtissues blood flow are summarized and discussed. Thehypoglycemic, antilipolytic and vasodilator effects ofC-peptide suggest that it may contribute to fine-tuningof the tissues metabolism under different physiologic orpathologic conditions. Therefore, C-peptide replacementtogether with the classic insulin therapy may prevent,retard, or ameliorate diabetic complications in patientswith type-1 diabetes.

Effects of Curcuma longa (turmeric) on postprandial plasma glucose and insulin in healthy subjects.

Science.gov (United States)

Wickenberg, Jennie; Ingemansson, Sandra Lindstedt; Hlebowicz, Joanna

2010-10-12

Previous animal studies have shown that Curcuma (C.) longa lowers plasma glucose. C. longa may thus be a promising ingredient in functional foods aimed at preventing type 2 diabetes. The purpose of the study is to study the effect of C. longa on postprandial plasma glucose, insulin levels and glycemic index (GI) in healthy subjects. Fourteen healthy subjects were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT) was administered together with capsules containing a placebo or C. longa. Finger-prick capillary and venous blood samples were collected before, and 15, 30, 45, 60, 90, and 120 min after the start of the OGTT to measure the glucose and insulin levels, respectively. The ingestion of 6 g C. longa had no significant effect on the glucose response. The change in insulin was significantly higher 30 min (P = 0.03) and 60 min (P = 0.041) after the OGTT including C. longa. The insulin AUCs were also significantly higher after the ingestion of C. longa, 15 (P = 0.048), 30 (P = 0.035), 90 (P = 0.03), and 120 (P = 0.02) minutes after the OGTT. The ingestion of 6 g C. longa increased postprandial serum insulin levels, but did not seem to affect plasma glucose levels or GI, in healthy subjects. The results indicate that C. longa may have an effect on insulin secretion.

Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance

Science.gov (United States)

Hirvonen, Jussi; Virtanen, Kirsi A.; Nummenmaa, Lauri; Hannukainen, Jarna C.; Honka, Miikka-Juhani; Bucci, Marco; Nesterov, Sergey V.; Parkkola, Riitta; Rinne, Juha; Iozzo, Patricia; Nuutila, Pirjo

2011-01-01

OBJECTIVE Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance. RESEARCH DESIGN AND METHODS We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [18F]fluorodeoxyglucose (for brain glucose metabolism) and [15O]H2O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling. RESULTS The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group. CONCLUSIONS We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance. PMID:21270256

Serum proatrial natriuretic peptide concentrations during oral glucose-induced acute hyperinsulinemia in lean and obese men

DEFF Research Database (Denmark)

Asferg, Camilla L; Nielsen, Søren J; Andersen, Ulrik B

2018-01-01

Atrial natriuretic peptide (ANP) is primarily seen as a hormone involved in salt and water homeostasis and blood pressure regulation. Evidence supports a link between metabolism and ANP. Circulating ANP concentrations are low in obese individuals with insulin resistance and hyperinsulinemia....... The dynamic relationship between insulin and ANP has been sparsely studied. We therefore measured circulating concentrations of midregional proatrial natriuretic peptide (MR-proANP), a stable marker of ANP secretion, and insulin in lean and obese men during an oral glucose challenge. One hundred and three...... obese men (body mass index (BMI) ≥30.0 kg/m2) were compared with 27 lean men (BMI = 20.0-24.9 kg/m2). During a 75 g oral glucose challenge, circulating concentrations of MR-proANP and insulin were measured at baseline and every half hour for 2 h. Fasting MR-proANP concentrations were lower in the obese...

Fixed ratio combinations of glucagon like peptide 1 receptor agonists with basal insulin: a systematic review and meta-analysis.

Science.gov (United States)

Liakopoulou, Paraskevi; Liakos, Aris; Vasilakou, Despoina; Athanasiadou, Eleni; Bekiari, Eleni; Kazakos, Kyriakos; Tsapas, Apostolos

2017-06-01

Basal insulin controls primarily fasting plasma glucose but causes hypoglycaemia and weight gain, whilst glucagon like peptide 1 receptor agonists induce weight loss without increasing risk for hypoglycaemia. We conducted a systematic review and meta-analysis of randomised controlled trials to investigate the efficacy and safety of fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists. We searched Medline, Embase, and the Cochrane Library as well as conference abstracts up to December 2016. We assessed change in haemoglobin A 1c , body weight, and incidence of hypoglycaemia and gastrointestinal adverse events. We included eight studies with 5732 participants in the systematic review. Switch from basal insulin to fixed ratio combinations with a glucagon like peptide 1 receptor agonist was associated with 0.72% reduction in haemoglobin A 1c [95% confidence interval -1.03 to -0.41; I 2  = 93%] and 2.35 kg reduction in body weight (95% confidence interval -3.52 to -1.19; I 2  = 93%), reducing also risk for hypoglycaemia [odds ratio 0.70; 95% confidence interval 0.57 to 0.86; I 2  = 85%] but increasing incidence of nausea (odds ratio 6.89; 95% confidence interval 3.73-12.74; I 2  = 79%). Similarly, switching patients from treatment with a glucagon like peptide 1 receptor agonist to a fixed ratio combination with basal insulin was associated with 0.94% reduction in haemoglobin A 1c (95% confidence interval -1.11 to -0.77) and an increase in body weight by 2.89 kg (95% confidence interval 2.17-3.61). Fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists improve glycaemic control whilst balancing out risk for hypoglycaemia and gastrointestinal side effects.

Involvement of insulin-degrading enzyme in insulin- and atrial natriuretic peptide-sensitive internalization of amyloid-β peptide in mouse brain capillary endothelial cells.

Science.gov (United States)

Ito, Shingo; Ohtsuki, Sumio; Murata, Sho; Katsukura, Yuki; Suzuki, Hiroya; Funaki, Miho; Tachikawa, Masanori; Terasaki, Tetsuya

2014-01-01

Cerebral clearance of amyloid-β peptide (Aβ), which is implicated in Alzheimer's disease, involves elimination across the blood-brain barrier (BBB), and we previously showed that an insulin-sensitive process is involved in the case of Aβ1-40. The purpose of this study was to clarify the molecular mechanism of the insulin-sensitive Aβ1-40 elimination across mouse BBB. An in vivo cerebral microinjection study demonstrated that [125I]hAβ1-40 elimination from mouse brain was inhibited by human natriuretic peptide (hANP), and [125I]hANP elimination was inhibited by hAβ1-40, suggesting that hAβ1-40 and hANP share a common elimination process. Internalization of [125I]hAβ1-40 into cultured mouse brain capillary endothelial cells (TM-BBB4) was significantly inhibited by either insulin, hANP, other natriuretic peptides or insulin-degrading enzyme (IDE) inhibitors, but was not inhibited by phosphoramidon or thiorphan. Although we have reported the involvement of natriuretic peptide receptor C (Npr-C) in hANP internalization, cells stably expressing Npr-C internalized [125I]hANP but not [125I]hAβ1-40, suggesting that there is no direct interaction between Npr-C and hAβ1-40. IDE was detected in plasma membrane of TM-BBB4 cells, and internalization of [125I]hAβ1-40 by TM-BBB4 cells was reduced by IDE-targeted siRNAs. We conclude that elimination of hAβ1-40 from mouse brain across the BBB involves an insulin- and ANP-sensitive process, mediated by IDE expressed in brain capillary endothelial cells.

Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle

DEFF Research Database (Denmark)

Deshmukh, Atul S

2016-01-01

transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type...... 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle....

Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.

Science.gov (United States)

Benzler, J; Ganjam, G K; Legler, K; Stöhr, S; Krüger, M; Steger, J; Tups, A

2013-05-01

The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3β (Ser9), which are important

Brain natriuretic peptide and insulin resistance in older adults.

Science.gov (United States)

Kim, F; Biggs, M L; Kizer, J R; Brutsaert, E F; de Filippi, C; Newman, A B; Kronmal, R A; Tracy, R P; Gottdiener, J S; Djoussé, L; de Boer, I H; Psaty, B M; Siscovick, D S; Mukamal, K J

2017-02-01

Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established. N-terminal of the pro hormone brain natriuretic peptide (NT-pro BNP) was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance. Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP). In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. © 2016 Diabetes UK.

Indomethacin treatment prevents high fat diet-induced obesity and insulin resistance but not glucose intolerance in C57BL/6J Mice

DEFF Research Database (Denmark)

Fjære, Even; Aune, Ulrike Liisberg; Røen, Kristin

2014-01-01

Chronic low grade inflammation is closely linked to obesity-associated insulin resistance. To examine how administration of the anti-inflammatory compound indomethacin, a general cyclooxygenase inhibitor, affected obesity development and insulin sensitivity, we fed obesity-prone male C57BL/6J mice...... a high fat/high sucrose (HF/HS) diet or a regular diet supplemented or not with indomethacin (±INDO) for 7 weeks. Development of obesity, insulin resistance, and glucose intolerance was monitored, and the effect of indomethacin on glucose-stimulated insulin secretion (GSIS) was measured in vivo...... and in vitro using MIN6 β-cells. We found that supplementation with indomethacin prevented HF/HS-induced obesity and diet-induced changes in systemic insulin sensitivity. Thus, HF/HS+INDO-fed mice remained insulin-sensitive. However, mice fed HF/HS+INDO exhibited pronounced glucose intolerance. Hepatic glucose...

Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers

DEFF Research Database (Denmark)

Nauck, Michael A; Heimesaat, Markus M; Behle, Kai

2002-01-01

and neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of C-peptide kinetics). At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P......Glucagon-like peptide 1 (GLP-1) and analogues are being evaluated as a new therapeutic principle for the treatment of type 2 diabetes. GLP-1 suppresses glucagon secretion, which could lead to disturbances of hypoglycemia counterregulation. This has, however, not been tested. Nine healthy volunteers.......97). The other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses...

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.

Sex-Related Differences in the Effects of the Mediterranean Diet on Glucose and Insulin Homeostasis

Directory of Open Access Journals (Sweden)

Alexandra Bédard

2014-01-01

Full Text Available Objective. To document sex differences in the impact of the Mediterranean diet (MedDiet on glucose/insulin homeostasis and to verify whether these sex-related effects were associated with changes in nonesterified fatty acids (NEFA. Methods. All foods were provided to 38 men and 32 premenopausal women (24–53 y during 4 weeks. Variables were measured during a 180 min OGTT before and after the MedDiet. Results. A sex-by-time interaction for plasma insulin iAUC was found (men: −17.8%, P=0.02; women: +9.4%, P=0.63; P for sex-by-time interaction = 0.005. A sex-by-time interaction was also observed for insulin sensitivity (Cederholm index, P=0.03, for which only men experienced improvements (men: +8.1%, P=0.047; women: −5.9%, P=0.94. No sex difference was observed for glucose and C-peptide responses. Trends toward a decrease in NEFA AUC (P=0.06 and an increase in NEFA suppression rate (P=0.06 were noted, with no sex difference. Changes in NEFA were not associated with change in insulin sensitivity. Conclusions. Results suggest that the more favorable changes in glucose/insulin homeostasis observed in men compared to women in response to the MedDiet are not explained by sex differences in NEFA response. This clinical trial is registered with clinicaltrials.gov NCT01293344.

Sex-Related Differences in the Effects of the Mediterranean Diet on Glucose and Insulin Homeostasis

Science.gov (United States)

Bédard, Alexandra; Corneau, Louise; Lamarche, Benoît; Dodin, Sylvie; Lemieux, Simone

2014-01-01

Objective. To document sex differences in the impact of the Mediterranean diet (MedDiet) on glucose/insulin homeostasis and to verify whether these sex-related effects were associated with changes in nonesterified fatty acids (NEFA). Methods. All foods were provided to 38 men and 32 premenopausal women (24–53 y) during 4 weeks. Variables were measured during a 180 min OGTT before and after the MedDiet. Results. A sex-by-time interaction for plasma insulin iAUC was found (men: −17.8%, P = 0.02; women: +9.4%, P = 0.63; P for sex-by-time interaction = 0.005). A sex-by-time interaction was also observed for insulin sensitivity (Cederholm index, P = 0.03), for which only men experienced improvements (men: +8.1%, P = 0.047; women: −5.9%, P = 0.94). No sex difference was observed for glucose and C-peptide responses. Trends toward a decrease in NEFA AUC (P = 0.06) and an increase in NEFA suppression rate (P = 0.06) were noted, with no sex difference. Changes in NEFA were not associated with change in insulin sensitivity. Conclusions. Results suggest that the more favorable changes in glucose/insulin homeostasis observed in men compared to women in response to the MedDiet are not explained by sex differences in NEFA response. This clinical trial is registered with clinicaltrials.gov NCT01293344. PMID:25371817

Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study

DEFF Research Database (Denmark)

Zander, Mette; Madsbad, Sten; Madsen, Jan Lysgaard

2002-01-01

subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week 0) and at weeks 1 and 6, they underwent beta-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and free fatty acids, and appetite and side-effect ratings on 100 mm visual...... analogue scales; at weeks 0 and 6 they also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A(1c), and fructosamine. The primary endpoints were haemoglobin A(1c) concentration, 8-h profile of glucose concentration in plasma, and beta......-cell function (defined as the first-phase response to glucose and the maximum insulin secretory capacity of the cell). Analyses were per protocol. FINDINGS: One patient assigned saline was excluded because no veins were accessible. In the remaining nine patients in that group, no significant changes were...

Effects of Curcuma longa (turmeric on postprandial plasma glucose and insulin in healthy subjects

Directory of Open Access Journals (Sweden)

Ingemansson Sandra

2010-10-01

Full Text Available Abstract Background Previous animal studies have shown that Curcuma (C. longa lowers plasma glucose. C. longa may thus be a promising ingredient in functional foods aimed at preventing type 2 diabetes. The purpose of the study is to study the effect of C. longa on postprandial plasma glucose, insulin levels and glycemic index (GI in healthy subjects. Methods Fourteen healthy subjects were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT was administered together with capsules containing a placebo or C. longa. Finger-prick capillary and venous blood samples were collected before, and 15, 30, 45, 60, 90, and 120 min after the start of the OGTT to measure the glucose and insulin levels, respectively. Results The ingestion of 6 g C. longa had no significant effect on the glucose response. The change in insulin was significantly higher 30 min (P = 0.03 and 60 min (P = 0.041 after the OGTT including C. longa. The insulin AUCs were also significantly higher after the ingestion of C. longa, 15 (P = 0.048, 30 (P = 0.035, 90 (P = 0.03, and 120 (P = 0.02 minutes after the OGTT. Conclusions The ingestion of 6 g C. longa increased postprandial serum insulin levels, but did not seem to affect plasma glucose levels or GI, in healthy subjects. The results indicate that C. longa may have an effect on insulin secretion. Trial registration number NCT01029327

Gastrin-Releasing Peptide and Glucose Metabolism Following Pancreatitis.

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Pendharkar, Sayali A; Drury, Marie; Walia, Monika; Korc, Murray; Petrov, Maxim S

2017-08-01

Gastrin-releasing peptide (GRP) is a pluripotent peptide that has been implicated in both gastrointestinal inflammatory states and classical chronic metabolic diseases such as diabetes. Abnormal glucose metabolism (AGM) after pancreatitis, an exemplar inflammatory disease involving the gastrointestinal tract, is associated with persistent low-grade inflammation and altered secretion of pancreatic and gut hormones as well as cytokines. While GRP is involved in secretion of many of them, it is not known whether GRP has a role in AGM. Therefore, we aimed to investigate the association between GRP and AGM following pancreatitis. Fasting blood samples were collected to measure GRP, blood glucose, insulin, amylin, glucagon, pancreatic polypeptide (PP), somatostatin, cholecystokinin, gastric-inhibitory peptide (GIP), gastrin, ghrelin, glicentin, glucagon-like peptide-1 and 2, oxyntomodulin, peptide YY (PYY), secretin, vasoactive intestinal peptide, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein (MCP)-1, and interleukin-6. Modified Poisson regression analysis and linear regression analyses were conducted. Four statistical models were used to adjust for demographic, metabolic, and pancreatitis-related risk factors. A total of 83 individuals after an episode of pancreatitis were recruited. GRP was significantly associated with AGM, consistently in all four models (P -trend < 0.05), and fasting blood glucose contributed 17% to the variance of GRP. Further, GRP was significantly associated with glucagon (P < 0.003), MCP-1 (P < 0.025), and TNF-α (P < 0.025) - consistently in all four models. GRP was also significantly associated with PP and PYY in three models (P < 0.030 for both), and with GIP and glicentin in one model (P = 0.001 and 0.024, respectively). Associations between GRP and other pancreatic and gut hormones were not significant. GRP is significantly increased in patients with AGM after pancreatitis and is associated with increased levels of pro

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...

Glucagon-insulin interaction on fat cell metabolism using c14 glucose

International Nuclear Information System (INIS)

Zewail, M.A.; Nielsen, J.H.

1984-01-01

Glucagon is known to stimulate the lipolysis in isolated fat cells from young rats, but not in fat cells from old heavy rate (Manganiello 1972). Insulin is known to counteract the lipolytic effect and to stimulate the synthesis of fatty acids from glucose. However, little is known about the interaction between the two hormones on the glucose metabolism. Experiments based on the use of various inhibitors of lipolysis have however, clearly shown that glucagon can also stimulate the entry and overall oxidation of glucose by mechanism which is distinct from its lipolysis stimulating mechanism (M. Blecher et al. 1969). Fat cells from old heavy rats are known to be less responsive to both the lipogenic action of insulin and the lipolytic action of glucagon than fat cells from young lean rats (E.G. Hansen, Nielsen and Gliemann, 1974). The aim of the present study was to see how glucagon affects glucose metabolism in fat cells, and whether this effect was dependent on the lipolytic action of glucagon

The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype

DEFF Research Database (Denmark)

Vilsbøll, Tina; Knop, F K; Krarup, T

2003-01-01

diabetic patients. We studied (six in each group): 1) patients with diabetes mellitus secondary to chronic pancreatitis; 2) lean type 2 diabetic patients (body mass index ... incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is seen in these patients. The aim of the present investigation was to evaluate plasma insulin and C-peptide responses to GLP-1 and GIP in five groups of diabetic patients with etiology and phenotype distinct from the obese type 2...

Clinical significance of the radioimmunological determination of C-peptide

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Dudczak, R.; Waldhaeusl, W.

1979-01-01

The aim of this study was to investigate the relationship of metabolic control to insulinogenic reserve in insulin-dependent diabetics. Thus, the secretory reserve of the pancreatic beta cell was estimated in insulin-dependent diabetics by measuring changes in peripheral serum immunoreactive C-peptide (IRCP) concentrations in response to intravenous arginine (n = 19; 0.5 g/kg,t = 30 min) or glibenclamide-glucose (n = 6; 2 mg HB 419 - 0.33 g/kg intravenously). In the majority of ''stable'' diabetics a small secretory reserve of the beta cell was demonstrated, but both the absolute and relative increase in IRCP was reduced after intravenous arginine or glibenclamide-glucose in comparison with normal controls. In ''unstable'' diabetics a decreased basal concentration of IRCP, significantly smaller than that seen in ''stable'' diabetics (p < 0.01), was accompanied by a complete lack of IRCP release on intravenous arginine administration. Thus, we conclude that the radioimmunological determination of IRCP is of clinical interest in assessing the residual secretory capacity of the beta cell in insulin-dependent diabetics. In revealing a lack of insulin this diagnostic tool seems to detect a group of potentially ''unstable'' diabetics in need of strict observation, which would minimize the risks of bad metabolic control. (author)

Clinical significance of the radioimmunological determination of C-peptide

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Dudczak, R; Waldhaeusl, W [Vienna Univ. (Austria). 1. Medizinische Klinik

1979-10-12

The aim of this study was to investigate the relationship of metabolic control to insulinogenic reserve in insulin-dependent diabetics. Thus, the secretory reserve of the pancreatic beta cell was estimated in insulin-dependent diabetics by measuring changes in peripheral serum immunoreactive C-peptide (IRCP) concentrations in response to intravenous arginine (n = 19; 0.5 g/kg,t = 30 min) or glibenclamide-glucose (n = 6; 2 mg HB 419 - 0.33 g/kg intravenously). In the majority of stable diabetics a small secretory reserve of the beta cell was demonstrated, but both the absolute and relative increase in IRCP was reduced after intravenous arginine or glibenclamide-glucose in comparison with normal controls. In unstable diabetics a decreased basal concentration of IRCP, significantly smaller than that seen in stable diabetics (p < 0.01), was accompanied by a complete lack of IRCP release on intravenous arginine administration. Thus, we conclude that the radioimmunological determination of IRCP is of clinical interest in assessing the residual secretory capacity of the beta cell in insulin-dependent diabetics. In revealing a lack of insulin this diagnostic tool seems to detect a group of potentially unstable diabetics in need of strict observation, which would minimize the risks of bad metabolic control.

Effect of Artemisia dracunculus Administration on Glycemic Control, Insulin Sensitivity, and Insulin Secretion in Patients with Impaired Glucose Tolerance.

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Méndez-Del Villar, Miriam; Puebla-Pérez, Ana M; Sánchez-Peña, María J; González-Ortiz, Luis J; Martínez-Abundis, Esperanza; González-Ortiz, Manuel

2016-05-01

To evaluate the effect of Artemisia dracunculus on glycemic control, insulin sensitivity, and insulin secretion in patients with impaired glucose tolerance (IGT). A randomized, double blind, placebo-controlled clinical trial was performed in 24 patients with diagnosis of IGT. Before and after the intervention, glucose and insulin levels were measured every 30 min for 2 h after a 75-g dextrose load, along with glycated hemoglobin A1c (A1C) and lipid profile. Twelve patients received A. dracunculus (1000 mg) before breakfast and dinner for 90 days; the remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first phase of insulin secretion, and insulin sensitivity were calculated. Wilcoxon signed-rank, Mann-Whitney U, and chi-square tests were used for statistical analyses. The institutional ethics committee approved the protocol. After A. dracunculus administration, there were significant decreases in systolic blood pressure (SBP; 120.0 ± 11.3 vs. 113.0 ± 11.2 mmHg, P AUC of insulin (56,136.0 ± 27,426.0 vs. 44,472.0 ± 23,370.0 pmol/L, P AUC of insulin, and total insulin secretion with a significant increase in HDL-C levels.

Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes

International Nuclear Information System (INIS)

Carter-Su, C.; Okamoto, K.

1987-01-01

The ability of glucocorticoids to modify the effect of insulin on glucose (L-1- 3 H(N)]glucose and D-[ 14 C-U]glucose) transport was investigated in both intact isolated rat adipocytes and in membranes isolated from hormone-treated adipocytes. In intact adipocytes, dexamethasone, a potent synthetic glucocorticoid, inhibited insulin-stimulated 3-O-methylglucose transport at all concentrations of insulin tested. Insulin sensitivity, as well as the maximal response to insulin, was decreased by dexamethasone in the absence of a change in 125 I insulin binding. The inhibition was observed regardless of which hormone acted first, was blocked by actinomycin D, and resulted from a decrease in V/sub max/ rather than an increase in K/sub t/ of transport. In plasma membranes isolated from insulin-treated adipocytes, glucose transport activity and the amount of glucose transporter covalently labeled with [ 3 H]cytochalasin B were increased in parallel in a dose-dependent fashion. The amount of labeled transporter in a low-density microsomal fraction (LDMF) was decreased in a reciprocal fashion. In contrast, addition of dexamethasone to insulin-stimulated cells caused decreases in both transport activity and amount of labeled transporter in the plasma membranes. This was accompanied by a small increase in the amount of [ 3 H]cytochalasin B incorporated into the glucose transporter in the LDMF. These results are consistent with both insulin and glucocorticoids altering the distribution of glucose transporters between the plasma membrane and LDMF, in opposite directions

Elevated 1-hour postload plasma glucose levels identify subjects with normal glucose tolerance but impaired β-cell function, insulin resistance, and worse cardiovascular risk profile: the GENFIEV study.

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Bianchi, Cristina; Miccoli, Roberto; Trombetta, Maddalena; Giorgino, Francesco; Frontoni, Simona; Faloia, Emanuela; Marchesini, Giulio; Dolci, Maria A; Cavalot, Franco; Cavallo, Gisella; Leonetti, Frida; Bonadonna, Riccardo C; Del Prato, Stefano

2013-05-01

In subjects with normal glucose tolerance (NGT) 1-hour postload plasma glucose (1-h oral glucose tolerance test [OGTT]) of >155 mg/dL predicts type 2 diabetes (T2DM) and is associated with subclinical atherosclerosis. The purpose of this study was to evaluate β-cell function, insulin resistance, and cardiovascular risk profile in subjects with NGT with a 1-h OGTT glucose of >155 mg/dL. The GENFIEV (Genetics, PHYsiopathology, and Evolution of Type 2 diabetes) study is a multicenter study recruiting individuals at high risk of T2DM. A total of 926 subjects underwent a 75-g OGTT for assessment of plasma glucose and C-peptide for mathematical modeling of β-cell function (derivative and proportional control). Fasting insulin, lipid profile, and clinical parameters were determined as well. A 1-hour OGTT glucose of >155 mg/dL was found in 39% of subjects with NGT, 76% with impaired fasting glucose (IFG), 90% with impaired glucose tolerance (IGT), and 99% and 98% with IFG + IGT or newly diagnosed T2DM, respectively. Among subjects with NGT (n = 474), those with 1-hour OGTT glucose of >155 mg/dL were more insulin-resistant and had worse β-cell function than those with 1-hour OGTT glucose of ≤155 mg/dL. Moreover, glycosylated hemoglobin, blood pressure, low-density lipoprotein cholesterol, and triglycerides were higher in subjects with NGT with 1-hour OGTT glucose of >155 mg/dL, whereas high-density lipoprotein cholesterol was lower compared with that in subjects with NGT with 1-hour OGTT glucose of ≤155 mg/dL. Compared with subjects with IGT, those with NGT with 1-hour OGTT glucose of >155 mg/dL had comparable cardiovascular risk profile and insulin resistance but slightly better β-cell function. Among subjects with NGT, those with 1-hour OGTT glucose of >155 mg/dL showed lower insulin sensitivity, impaired β-cell function, and worse cardiovascular risk profile and therefore are at greater risk of developing T2DM and cardiovascular disease.

Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

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Chih-Ting Su

2016-11-01

Full Text Available Insulin antibodies (IA associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA found in insulin autoimmune syndrome (IAS, which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%, high insulin concentration (111.9 IU/mL and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly.

Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes.

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Nuttall, Frank Q; Almokayyad, Rami M; Gannon, Mary C

2015-02-01

Hyperglycemia improves when patients with type 2 diabetes are placed on a weight-loss diet. Improvement typically occurs soon after diet implementation. This rapid response could result from low fuel supply (calories), lower carbohydrate content of the weight-loss diet, and/or weight loss per se. To differentiate these effects, glucose, insulin, C-peptide and glucagon were determined during the last 24 h of a 3-day period without food (severe calorie restriction) and a calorie-sufficient, carbohydrate-free diet. Seven subjects with untreated type 2 diabetes were studied. A randomized-crossover design with a 4-week washout period between arms was used. Results from both the calorie-sufficient, carbohydrate-free diet and the 3-day fast were compared with the initial standard diet consisting of 55% carbohydrate, 15% protein and 30% fat. The overnight fasting glucose concentration decreased from 196 (standard diet) to 160 (carbohydrate-free diet) to 127 mg/dl (fasting). The 24 h glucose and insulin area responses decreased by 35% and 48% on day 3 of the carbohydrate-free diet, and by 49% and 69% after fasting. Overnight basal insulin and glucagon remained unchanged. Short-term fasting dramatically lowered overnight fasting and 24 h integrated glucose concentrations. Carbohydrate restriction per se could account for 71% of the reduction. Insulin could not entirely explain the glucose responses. In the absence of carbohydrate, the net insulin response was 28% of the standard diet. Glucagon did not contribute to the metabolic adaptations observed. Published by Elsevier Inc.

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

Science.gov (United States)

Xiao, Changting; Dash, Satya; Stahel, Priska; Lewis, Gary F

2018-03-14

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m 2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP. © 2018 John Wiley & Sons Ltd.

SAD-A potentiates glucose-stimulated insulin secretion as a mediator of glucagon-like peptide 1 response in pancreatic β cells.

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Nie, Jia; Lilley, Brendan N; Pan, Y Albert; Faruque, Omar; Liu, Xiaolei; Zhang, Weiping; Sanes, Joshua R; Han, Xiao; Shi, Yuguang

2013-07-01

Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic β cells, which can be restored by glucagon-like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet β cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreas and brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca(2+)-dependent signaling pathways in islet β cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet β cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet β cells.

Quantification of beta-cell function during IVGTT in Type II and non-diabetic subjects: assessment of insulin secretion by mathematical methods

DEFF Research Database (Denmark)

Kjems, L L; Vølund, A; Madsbad, Sten

2001-01-01

AIMS/HYPOTHESIS: We compared four methods to assess their accuracy in measuring insulin secretion during an intravenous glucose tolerance test in patients with Type II (non-insulin-dependent) diabetes mellitus and with varying beta-cell function and matched control subjects. METHODS: Eight control...... subjects and eight Type II diabetic patients underwent an intravenous glucose tolerance test with tolbutamide and an intravenous bolus injection of C-peptide to assess C-peptide kinetics. Insulin secretion rates were determined by the Eaton deconvolution (reference method), the Insulin SECretion method...... (ISEC) based on population kinetic parameters as well as one-compartment and two-compartment versions of the combined model of insulin and C-peptide kinetics. To allow a comparison of the accuracy of the four methods, fasting rates and amounts of insulin secreted during the first phase (0-10 min...

Pancreatic Endoderm-Derived From Diabetic Patient-Specific Induced Pluripotent Stem Cell Generates Glucose-Responsive Insulin-Secreting Cells.

Science.gov (United States)

Rajaei, Bahareh; Shamsara, Mehdi; Amirabad, Leila Mohammadi; Massumi, Mohammad; Sanati, Mohammad Hossein

2017-10-01

Human-induced pluripotent stem cells (hiPSCs) can potentially serve as an invaluable source for cell replacement therapy and allow the creation of patient- and disease-specific stem cells without the controversial use of embryos and avoids any immunological incompatibility. The generation of insulin-producing pancreatic β-cells from pluripotent stem cells in vitro provides an unprecedented cell source for personal drug discovery and cell transplantation therapy in diabetes. A new five-step protocol was introduced in this study, effectively induced hiPSCs to differentiate into glucose-responsive insulin-producing cells. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, primitive gut-tube endoderm, posterior foregut, pancreatic endoderm, and endocrine precursor. Each stage of differentiation were characterized by stage-specific markers. The produced cells exhibited many properties of functional β-cells, including expression of critical β-cells transcription factors, the potency to secrete C-peptide in response to high levels of glucose and the presence of mature endocrine secretory granules. This high efficient differentiation protocol, established in this study, yielded 79.18% insulin-secreting cells which were responsive to glucose five times higher than the basal level. These hiPSCs-derived glucose-responsive insulin-secreting cells might provide a promising approach for the treatment of type I diabetes mellitus. J. Cell. Physiol. 232: 2616-2625, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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...

The clinical significance of detecting serum glutamic acid decarboxylase antibody (GAD), C-peptide and insulin in diabetics

International Nuclear Information System (INIS)

Zheng Tingliang; Zhang Jinchi; Yao Yingfei; Chen Linxing; Huang Hua

2005-01-01

Objective: To explore the clinical significance of detecting serum glutamic acid decarboxylase (GAD) antibody, C-peptide (CP) and insulin (INS) in the classification of diabetic patients. Methods: Serum GAD antibody, CP and INS concentration were determined with RIA in 27 patients with type 1 diabetes mellitus (DM1) and 49 patients with type 2 diabetes mellitus (DM2). Sugar-electrode-method was used to detect the concentrations of fasting plasma glucose (FPG) in these patients. Results: The positive rate of GAD antibody in DM1 patients (66.7%) were significantly higher than that in DM2 group (8.2%) (P<0.01), The levels of CP and INS were lower in DM1 group than those in DM2 group as well (P<0.01). Conclusion: GAD antibody is a valuable marker to predict the impairment of β-cell GAD antibody levels, together with CP /FPG and INS/FPG ratios, might be useful in determining the type of DM and guiding the therapy. (authors)

Hydroxylamine enhances glucose uptake in C2C12 skeletal muscle cells through the activation of insulin receptor substrate 1.

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Kimura, Taro; Kato, Eisuke; Machikawa, Tsukasa; Kimura, Shunsuke; Katayama, Shinji; Kawabata, Jun

2014-02-28

Diabetes mellitus is a global disease, and the number of patients with it is increasing. Of various agents for treatment, those that directly act on muscle are currently attracting attention because muscle is one of the main tissues in the human body, and its metabolism is decreased in type II diabetes. In this study, we found that hydroxylamine (HA) enhances glucose uptake in C2C12 myotubes. Analysis of HA's mechanism revealed the involvement of IRS1, PI3K and Akt that is related to the insulin signaling pathway. Further investigation about the activation mechanism of insulin receptor or IRS1 by HA may provide a way to develop a novel anti-diabetic agent alternating to insulin. Copyright © 2014 Elsevier Inc. All rights reserved.

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

Valine Pyrrolidide Preserves Intact Glucose-Dependent Insulinotropic Peptide and Improves Abnormal Glucose Tolerance in Minipigs With Reduced β-Cell Mass

OpenAIRE

Larsen, Marianne Olholm; Rolin, Bidda; Ribel, Ulla; Wilken, Michael; Deacon, Carolyn F.; Svendsen, Ove; Gotfredsen, Carsten F.; Carr, Richard David

2003-01-01

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation.However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced β-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)–treated min...

Decreased serum betatrophin levels correlate with improved fasting plasma glucose and insulin secretion capacity after Roux-en-Y gastric bypass in obese Chinese patients with type 2 diabetes: a 1-year follow-up.

Science.gov (United States)

Guo, Kaifeng; Yu, Haoyong; Lu, Junxi; Bao, Yuqian; Chen, Haibing; Jia, Weiping

2016-08-01

There is increasing evidence that serum betatrophin levels, a hormone derived from adipose tissue and liver, are elevated in type 2 diabetes (T2D). To investigate the relationships among betatrophin and metabolic control, insulin resistance, and pancreatic β-cell function in obese Chinese patients with T2D who underwent Roux-en-Y gastric bypass (RYGB). University hospital, China. This 1-year follow-up study included 34 obese individuals with T2D (18 males, 16 females) who underwent RYGB in our hospital. Anthropometric results, glucose levels, lipid profiles, and serum betatrophin levels were determined before and 1 year after RYGB. The serum betatrophin level decreased significantly after RYGB (72.0 ng/mL [33.4-180.9] versus 35.7 ng/mL [14.8-103.3]); Pfasting plasma glucose and negatively correlated with the changes in the 2-hour C-peptide/fasting C-peptide and homeostasis model of assessment of β-cell function (Pfasting plasma glucose (β = .586, Pfasting C-peptide (β = -.309, P = .021). Circulating betatrophin might be involved in the regulation of glucose control and insulin secretion in obese Chinese with T2D soon after RYGB. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

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.

Korean Red Ginseng Improves Glucose Control in Subjects with Impaired Fasting Glucose, Impaired Glucose Tolerance, or Newly Diagnosed Type 2 Diabetes Mellitus

OpenAIRE

Bang, Hyangju; Kwak, Jung Hyun; Ahn, Hyeon Yeong; Shin, Dong Yeob; Lee, Jong Ho

2014-01-01

This study was designed to evaluate the effect of Korean red ginseng (KRG) supplementation on glucose control in subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or newly diagnosed type 2 diabetes mellitus (T2DM). The study was a 12-week randomized, double-blinded, placebo-controlled (5 g of KRG [n=21] or placebo [n=20] in tablet form) trial. Glucose-related biomarkers, including serum and whole blood levels of glucose, insulin, and C-peptide, were measured by 2...

Estimation of Insulin Resistance in Mexican Adults by the [13C]Glucose Breath Test Corrected for Endogenous Total CO2 Production

Directory of Open Access Journals (Sweden)

Erika Ibarra-Pastrana

2012-01-01

Full Text Available Objective. To evaluate the efficacy of the [13C]glucose breath test for measuring insulin resistance in Mexican adults with different glycemic states. Research Design and Methods. Fifty-eight adults underwent a [13C]glucose breath test with simultaneous measurement of total CO2 production by indirect calorimetry, at baseline and 90 minutes after the ingestion of 15 g of dextrose and 25 mg of [13C]glucose. HOMA was used as a marker of insulin resistance. Results. We found an inverse correlation between HOMA and the breath test δ13CO2 (‰, r=-0.41 (P=0.001. After adjusting for total CO2 production, correlations between HOMA and fasting glucose were less strong but remained significant. An ROC curve was constructed using δ13CO2 (‰ and HOMA values; the cut-off point was 9.99‰ δ13CO2, corresponding to a sensitivity of 80.0 (95% CI: 51.9, 95.7 and a specificity of 67.4 (95% CI: 51.5, 80.9. Conclusions. The [13C]glucose breath test is a simple noninvasive procedure but was not sufficiently robust for an accurate diagnosis of insulin resistance. Our findings suggest that the test might be helpful in identifying individuals who are not IR, which in turn may contribute to improved diabetes prevention.

Development of glucose-responsive 'smart' insulin systems.

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Rege, Nischay K; Phillips, Nelson F B; Weiss, Michael A

2017-08-01

The complexity of modern insulin-based therapy for type I and type II diabetes mellitus and the risks associated with excursions in blood-glucose concentration (hyperglycemia and hypoglycemia) have motivated the development of 'smart insulin' technologies (glucose-responsive insulin, GRI). Such analogs or delivery systems are entities that provide insulin activity proportional to the glycemic state of the patient without external monitoring by the patient or healthcare provider. The present review describes the relevant historical background to modern GRI technologies and highlights three distinct approaches: coupling of continuous glucose monitoring (CGM) to deliver devices (algorithm-based 'closed-loop' systems), glucose-responsive polymer encapsulation of insulin, and molecular modification of insulin itself. Recent advances in GRI research utilizing each of the three approaches are illustrated; these include newly developed algorithms for CGM-based insulin delivery systems, glucose-sensitive modifications of existing clinical analogs, newly developed hypoxia-sensitive polymer matrices, and polymer-encapsulated, stem-cell-derived pancreatic β cells. Although GRI technologies have yet to be perfected, the recent advances across several scientific disciplines that are described in this review have provided a path towards their clinical implementation.

Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

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Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

2017-10-01

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk. Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer. Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio ( P trend = 0.55 and P trend = 0.27, respectively). Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development. Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR . ©2017 American Association for Cancer Research.

Effect of HCV on fasting glucose, fasting insulin and peripheral insulin resistance in first 5 years of infection.

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Ahmed, Naeema; Rashid, Amir; Naveed, Abdul Khaliq; Bashir, Qudsia

2016-02-01

To assess the effects of hepatitis C virus infection in the first 5 years on fasting glucose, fasting insulin and peripheral insulin resistance. The case-control study was conducted at the Army Medical College, Rawalpindi, from December 2011 to November 2012, and comprised subjects recruited from a government hospital in Rawalpindi. The subjects included known cases of hepatitis C virus infection for at least 5 years, and normal healthy controls. Fasting blood samples of all the subjects were collected and analysed for serum fasting insulin and serum fasting glucose levels. Homeostatic model assessment-Insulin resistance was calculated SPSS 11 was used for statistical analysis. Of the 30 subjects, 20(66.6%) were cases, while 10(33.3%) were controls. Serum fasting glucose mean level in cases was 89.55±9.53 compared to 84.40±9.80 in the controls (p=0.188). The mean serum fasting insulin in controls was 7.52±3.23 and 6.79±3.30 in cases (p=0.567). Homeostatic model assessment-Insulin resistance level in controls was 1.60±0.76 and In the cases it was 1.49±0.74 (p=0.695). Peripheral insulin resistance and development of type 2 diabetes as a complication of hepatitis C virus infection was not likely at least within the first five years of infection.

Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass

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Larsen, Marianne Olholm; Rolin, Bidda; Ribel, Ulla

2003-01-01

levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral......The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation. However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment...... glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 +/- 42 to 192 +/- 108; P

BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes.

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Xu, Qi; Luo, Jiao; Wu, Ning; Zhang, Renshuai; Shi, Dayong

2018-01-01

Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Orosomucoid binds insulin and IGF1 and reduces hormone stimulated protein synthesis and glucose metabolism in C2C12 myotubes

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Previous research has indicated that orosomuciod (ORM1) may enhance insulin response in 3T3-L1 adipocytes. The present study was undertaken to determine if ORM1 can modify muscle metabolism by examining glucose oxidation and protein synthesis in the C2C12 muscle cell line. Cells were used for expe...

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

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Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte R

2005-01-01

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic...... endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting...... insulin (130%, P Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P

High serum fasting peptide YY (3-36) is associated with obesity-associated insulin resistance and type 2 diabetes.

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Ukkola, Olavi H; Puurunen, Veli-Pekka; Piira, Olli-Pekka; Niva, Jarkko T; Lepojärvi, E Samuli; Tulppo, Mikko P; Huikuri, Heikki V

2011-10-10

We studied whether serum fasting levels of active form of peptide YY (PYY), PYY(3-36), are associated with obesity and related phenotypes. The study population consisted of 428 patients with coronary artery disease and diagnosed type 2 diabetes and 440 patients with coronary artery disease but without evidence of diabetes from the ARTEMIS study. The patients were recruited from the consecutive series of patients undergoing coronary angiography in the Oulu University Hospital. The patients without diabetes underwent a 2-hour oral glucose tolerance test. PYY(3-36) levels were analyzed by human PYY(3-36) specific radioimmunoassay. Result suggested that when PYY(3-36) tertiles were considered, high serum fasting PYY(3-36) concentration was associated with high body mass index, waist circumference, hemoglobin A1c, fasting blood glucose, leptin, triglyceride (p for all p ≤ 0.001), serum insulin (p=0.013) and with a low high-density lipoprotein cholesterol (p=0.004) concentrations in the analyses adjusted for age, sex and study group. The link high PYY(3-36)-high insulin level was evident in subjects with normal glucose tolerance (pfasting glucose, impaired glucose tolerance and normal glucose tolerance (pfasting PYY(3-36) concentrations in type 2 diabetic subjects are high. Although high PYY(3-36) is strongly linked to obesity and associated insulin resistance, the relation between PYY(3-36) and type 2 diabetes is independent of body fatness. Copyright © 2011 Elsevier B.V. All rights reserved.

The minor C-allele of rs2014355 in ACADS is associated with reduced insulin release following an oral glucose load

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Hornbak, Malene; Banasik, Karina; Justesen, Johanne Marie

2011-01-01

-aged Danish individuals (nACADS=4,324; nACADM=4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (nACADS=8,313; nACADM=8,344). Results In glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following...... an oral glucose load (per allele effect (beta)=-3.8% (-6.3%;-1.3%), P=0.003), reduced incremental area under the insulin curve (beta=-3.6% (-6.3%;-0.9%), P=0.009), reduced acute insulin response (beta=-2.2% (-4.2%;0.2%), P=0.03), and with increased insulin sensitivity ISIMatsuda (beta= 2.9% (0.5%;5.2%), P...

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

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Nicolai J. Wewer Albrechtsen

2017-11-01

Full Text Available Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61 appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.

Hepatitis C virus eradication by direct antiviral agents improves glucose tolerance and reduces post-load insulin resistance in nondiabetic patients with genotype 1.

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Salomone, Federico; Catania, Maurizio; Montineri, Arturo; Bertino, Gaetano; Godos, Justyna; Rizzo, Leonardo; Magrì, Giovanni; Li Volti, Giovanni

2017-12-19

Genotype 1 chronic hepatitis C is associated with an impairment of glucose homoeostasis, especially in the advanced stages of the disease. Glucose tolerance is an independent predictor of liver-related mortality in patients with cirrhosis because of chronic hepatitis C. However, no study has demonstrated so far weather hepatitis C virus clearance affects glucose tolerance. To this aim, we performed a prospective study assessing the effects of direct antiviral agents treatment in nondiabetic cirrhotic patients with genotypes 1a/1b and impaired glucose tolerance based on a 75-g oral glucose tolerance test. Impaired glucose tolerance was diagnosed by a 2-hour plasma glucose between 140 and 199 mg/dL. Insulin resistance was estimated by the oral glucose insulin sensitivity index, an oral glucose tolerance test-derived measure. After meeting the inclusion criteria, the study population included 32 outpatients (26/6 genotypes 1b/1a; age 62 ± 7.4 years; 18 males) with compensated Child-A cirrhosis. All patients achieved a sustained virological response following direct antiviral agents treatment. After viral eradication, we did not observe change in fasting plasma glucose (103.5 ± 7.1 vs 102.8 ± 7.2 mg/dL, P = .15) but 2-hour plasma glucose was reduced (165.2 ± 22.7 vs 138.5 ± 21.3 mg/dL, P Hepatitis C virus eradication led also to a significant reduction in HbA1c (6.1 ± 0.2% vs 5.7 ± 0.3%, P resistance as assessed by the oral glucose insulin sensitivity index (6.92 ± 1.56 vs 9.52 ± 1.39 mg/kg/min, P  .5). Our results indicate that hepatitis C virus eradication may early improve glucose tolerance in patients with hepatitis C virus-related cirrhosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients

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Toft-Nielsen, M B; Madsbad, Sten; Holst, J J

1999-01-01

OBJECTIVE: The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore......, previously shown to lower blood glucose effectively in type 2 diabetic patients. Fasting plasma glucose (day 2) decreased from 14.1 +/- 0.9 (saline) to 12.2 +/- 0.7 mmol/l (GLP-1), P = 0.009, and 24-h mean plasma glucose decreased from 15.4 +/- 1.0 to 13.0 +/- 1.0 mmol/l, P = 0.0009. Fasting and total area...... under the curve for insulin and C-peptide levels were significantly higher during the GLP-1 administration, whereas glucagon levels were unchanged. Neither triglycerides nor free fatty acids were affected. GLP-1 administration decreased hunger and prospective food intake and increased satiety, whereas...

Interaction between exogenous insulin, endogenous insulin, and glucose in type 2 diabetes patients.

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Janukonyté, Jurgita; Parkner, Tina; Bruun, Niels Henrik; Lauritzen, Torsten; Christiansen, Jens Sandahl; Laursen, Torben

2015-05-01

Little is known about the influence of exogenous insulin and actual glucose levels on the release of endogenous insulin in insulin-treated type 2 diabetes mellitus (T2DM) patients. This study investigated the interaction among serum endogenous insulin (s-EI), serum exogenous insulin aspart (s-IAsp), and blood glucose levels in an experimental short-term crossover design. Eight T2DM patients (63.52 years old; range, 49-69 years; mean body mass index, 28.8±3.8 kg/m(2)) were randomized to treatment with individual fixed doses of insulin aspart (0.5-1.5 IU/h) as a continuous subcutaneous insulin infusion (CSII) during a 10-h period on two occasions with different duration of hyperglycemia: (1) transient hyperglycemia for 2 h (visit TH) and (2) continuous hyperglycemia for 12 h (visit CH). During steady state the variances of plasma glucose (p-glucose), s-IAsp, and s-EI were equal within visit TH and within visit CH, but variances were significantly higher during visit CH compared with visit TH. The s-IAsp reached lower levels at visit CH compared with visit TH (test for slope=1, P=0.005). The s-EI depended on p-glucose in a nonlinear fashion during the first 100 min of both visits when s-IAsp was undetectable (adjusted R(2)=0.9). A complex but statistically significant interaction among s-IAsp, s-EI, p-glucose, and patients was observed during measurable s-IAsp levels (adjusted R(2)=0.70). Endogenous and exogenous insulin showed higher variation during continuous hyperglycemia. Significantly lower levels of exogenous insulin were observed following CSII during continuous hyperglycemia compared with transient hyperglycemia. Endogenous insulin levels could in a complex way be explained by an individual interaction among p-glucose and serum exogenous insulin, if present.

Deteriorated glucose metabolism with a high-protein, low-carbohydrate diet in db mice, an animal model of type 2 diabetes, might be caused by insufficient insulin secretion.

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Arimura, Emi; Pulong, Wijang Pralampita; Marchianti, Ancah Caesarina Novi; Nakakuma, Miwa; Abe, Masaharu; Ushikai, Miharu; Horiuchi, Masahisa

2017-02-01

We previously showed the deleterious effects of increased dietary protein on renal manifestations and glucose metabolism in leptin receptor-deficient (db) mice. Here, we further examined its effects on glucose metabolism, including urinary C-peptide. We also orally administered mixtures corresponding to low- or high-protein diets to diabetic mice. In diet experiments, under pair-feeding (equivalent energy and fat) conditions using a metabolic cage, mice were fed diets with different protein content (L diet: 12 % protein, 71 % carbohydrate, 17 % fat; H diet: 24 % protein, 59 % carbohydrate, 17 % fat) for 15 days. In oral administration experiments, the respective mixtures (L mixture: 12 % proline, 71 % maltose or starch, 17 % linoleic acid; H mixture: 24 % proline, 59 % maltose or starch, 17 % linoleic acid) were supplied to mice. Biochemical parameters related to glucose metabolism were measured. The db-H diet mice showed significantly higher water intake, urinary volume, and glucose levels than db-L diet mice but similar levels of excreted urinary C-peptide. In contrast, control-H diet mice showed significantly higher C-peptide excretion than control-L diet mice. Both types of mice fed H diet excreted high levels of urinary albumin. When maltose mixtures were administered, db-L mixture mice showed significantly higher blood glucose after 30 min than db-H mixture mice. However, db mice administered starch-H mixture showed significantly higher blood glucose 120-300 min post-administration than db-L mixture mice, although both groups exhibited similar insulin levels. High-protein, low-carbohydrate diets deteriorated diabetic conditions and were associated with insufficient insulin secretion in db mice. Our findings may have implications for dietary management of diabetic symptoms in human patients.

Influence of insulin on beta-endorphin plasma levels in obese and normal weight subjects.

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Brunani, A; Pincelli, A I; Pasqualinotto, L; Tibaldi, A; Baldi, G; Scacchi, M; Fatti, L M; Cavagnini, F

1996-08-01

To establish the possible role of hyperinsulinemia in the elevation of plasma beta-endorphin (beta-EP) levels observed in obese patients after an oral glucose load. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Two groups of six (age: 22-39 y, BMI: 30-48 kg/m2) and eight obese men (age: 18-37 y, BMI: 35-45 kg/m2), respectively, and five normal weight healthy men (age: 22-30 y, BMI 22-23 kg/m2). Glucose, insulin and beta-EP levels at baseline and every 30 min until 180 min during the OGTT; glucose, insulin, C-peptide and beta-EP concentrations at baseline and in steady state condition (i.e. during the last 30 min of insulin infusion) in the euglycemic-hyperinsulinemic clamp studies. In the six obese patients undergoing the OGTT a significant elevation of beta-EP plasma levels was observed between 60 and 90 min after glucose ingestion. In the clamp studies no significant differences in beta-EP plasma levels, blood glucose and serum insulin were observed between obese and normal weight subjects both at baseline and at steady state. A markedly diminished insulin sensitivity along with a lower inhibition of C-peptide during insulin infusion was observed in obese patients compared to control subjects. A rise in serum insulin levels unaccompanied by a concomitant increase in blood glucose concentration is unable to elicit a beta-EP response in obese patients.

Restitution of defective glucose-stimulated insulin secretion in diabetic GK rat by acetylcholine uncovers paradoxical stimulatory effect of beta-cell muscarinic receptor activation on cAMP production.

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Dolz, Manuel; Bailbé, Danielle; Giroix, Marie-Hélène; Calderari, Sophie; Gangnerau, Marie-Noelle; Serradas, Patricia; Rickenbach, Katharina; Irminger, Jean-Claude; Portha, Bernard

2005-11-01

Because acetylcholine (ACh) is a recognized potentiator of glucose-stimulated insulin release in the normal beta-cell, we have studied ACh's effect on islets of the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes. We first verified that ACh was able to restore the insulin secretory glucose competence of the GK beta-cell. Then, we demonstrated that in GK islets 1) ACh elicited a first-phase insulin release at low glucose, whereas it had no effect in Wistar; 2) total phospholipase C activity, ACh-induced inositol phosphate production, and intracellular free calcium concentration ([Ca2+]i) elevation were normal; 3) ACh triggered insulin release, even in the presence of thapsigargin, which induced a reduction of the ACh-induced [Ca2+]i response (suggesting that ACh produces amplification signals that augment the efficacy of elevated [Ca2+]i on GK exocytosis); 4) inhibition of protein kinase C did not affect [Ca2+]i nor the insulin release responses to ACh; and 5) inhibition of cAMP-dependent protein kinases (PKAs), adenylyl cyclases, or cAMP generation, while not affecting the [Ca2+]i response, significantly lowered the insulinotropic response to ACh (at low and high glucose). In conclusion, ACh acts mainly through activation of the cAMP/PKA pathway to potently enhance Ca2+-stimulated insulin release in the GK beta-cell and, in doing so, normalizes its defective glucose responsiveness.

Combining insulins for optimal blood glucose control in type 1 and 2 diabetes: focus on insulin glulisine

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Heather Ulrich

2007-07-01

lispro or RHI in type 1 or 2 DM and it has been shown to be as safe and effective when used in a continuous subcutaneous insulin infusion (CSII. In summary, insulin glulisine is a safe, effective, and well tolerated rapid-acting insulin analogue across all BMIs and a worthy option for prandial glucose control in type 1 or 2 DM.Keywords: glycemic control, glycosylated hemoglobin A1c (HbA1c, rapid-acting insulin analogues, type 1 diabetes mellitus, type 2 diabetes mellitus, insulin glulisine, body mass index (BMI

Elastin-derived peptides are new regulators of insulin resistance development in mice

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Blaise, Sébastien; Romier, Béatrice; Kawecki, Charlotte

2013-01-01

. In the current study, we show that elastin-derived peptides (EDPs) may be involved in the development of insulin resistance (IRES) in mice. In chow-fed mice, acute or chronic intravenous injections of EDPs induced hyperglycemic effects associated with glucose uptake reduction and IRES in skeletal muscle, liver......, and adipose tissue. Based on in vivo, in vitro, and in silico approaches, we propose that this IRES is due to interaction between the insulin receptor (IR) and the neuraminidase-1 subunit of the elastin receptor complex triggered by EDPs. This interplay was correlated with decreased sialic acid levels...

Enhanced glucose tolerance in pancreatic-derived factor (PANDER knockout C57BL/6 mice

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Shari L. Moak

2014-11-01

Full Text Available Pancreatic-derived factor (PANDER; also known as FAM3B is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. PANDER has been hypothesized to regulate fasting and fed glucose homeostasis, hepatic lipogenesis and insulin signaling, and to serve a potential role in the onset or progression of type 2 diabetes (T2D. Despite having potentially pivotal pleiotropic roles in glycemic regulation and T2D, there has been limited generation of stable animal models for the investigation of PANDER function, and there are no models on well-established genetic murine backgrounds for T2D. Our aim was to generate an enhanced murine model to further elucidate the biological function of PANDER. Therefore, a pure-bred PANDER knockout C57BL/6 (PANKO-C57 model was created and phenotypically characterized with respect to glycemic regulation and hepatic insulin signaling. The PANKO-C57 model exhibited an enhanced metabolic phenotype, particularly with regard to enhanced glucose tolerance. Male PANKO-C57 mice displayed decreased fasting plasma insulin and C-peptide levels, whereas leptin levels were increased as compared with matched C57BL/6J wild-type mice. Despite similar peripheral insulin sensitivity between both groups, hepatic insulin signaling was significantly increased during fasting conditions, as demonstrated by increased phosphorylation of hepatic PKB/Akt and AMPK, along with mature SREBP-1 expression. Insulin stimulation of PANKO-C57 mice resulted in increased hepatic triglyceride and glycogen content as compared with wild-type C57BL/6 mice. In summary, the PANKO-C57 mouse represents a suitable model for the investigation of PANDER in multiple metabolic states and provides an additional tool to elucidate the biological function and potential role in T2D.

Insulin Stimulates S100B Secretion and These Proteins Antagonistically Modulate Brain Glucose Metabolism.

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Wartchow, Krista Minéia; Tramontina, Ana Carolina; de Souza, Daniela F; Biasibetti, Regina; Bobermin, Larissa D; Gonçalves, Carlos-Alberto

2016-06-01

Brain metabolism is highly dependent on glucose, which is derived from the blood circulation and metabolized by the astrocytes and other neural cells via several pathways. Glucose uptake in the brain does not involve insulin-dependent glucose transporters; however, this hormone affects the glucose influx to the brain. Changes in cerebrospinal fluid levels of S100B (an astrocyte-derived protein) have been associated with alterations in glucose metabolism; however, there is no evidence whether insulin modulates glucose metabolism and S100B secretion. Herein, we investigated the effect of S100B on glucose metabolism, measuring D-(3)H-glucose incorporation in two preparations, C6 glioma cells and acute hippocampal slices, and we also investigated the effect of insulin on S100B secretion. Our results showed that: (a) S100B at physiological levels decreases glucose uptake, through the multiligand receptor RAGE and mitogen-activated protein kinase/ERK signaling, and (b) insulin stimulated S100B secretion via PI3K signaling. Our findings indicate the existence of insulin-S100B modulation of glucose utilization in the brain tissue, and may improve our understanding of glucose metabolism in several conditions such as ketosis, streptozotocin-induced dementia and pharmacological exposure to antipsychotics, situations that lead to changes in insulin signaling and extracellular levels of S100B.

Gastric emptying, glucose responses, and insulin secretion after a liquid test meal

DEFF Research Database (Denmark)

Willms, B; Werner, J; Holst, J J

1996-01-01

yr; body mass index, 30.0 +/- 5.2 kg/m2; hemoglobin A1c, 10.5 +/- 1.2%) were studied in the fasting state (plasma glucose, 11.1 +/- 1.1 mmol/L). A liquid meal of 400 mL containing 8% amino acids and 50 g sucrose (327 Kcal) was administered at time zero by a nasogastric tube. Gastric volume......The aim of the study was to investigate whether inhibition of gastric emptying of meals plays a role in the mechanism of the blood glucose-lowering action of glucagon-like peptide-1-(7-36) amide [GLP-1-(7-36) amide] in type 2 diabetes. Eight poorly controlled type 2 diabetic patients (age, 58 +/- 6...... to normal fasting values (5.4 +/- 0.7 mmol/L) within 3-4 h, whereas insulin was stimulated in most, but not all, patients, and glucagon remained at the basal level or was slightly suppressed. In conclusion, GLP-1-(7-36) amide inhibits gastric emptying in type 2 diabetic patients. Together...

Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes

DEFF Research Database (Denmark)

Meier, Juris J; Gallwitz, Baptist; Salmen, Stefan

2003-01-01

in the fasting state and after a solid test meal (containing [(13)C]octanoic acid). Blood was drawn for glucose, insulin, C-peptide, glucagon, and GLP-1 determinations. The gastric emptying rate was calculated from the (13)CO(2) excretion rates in breath samples. Statistics were determined using repeated......The effects of different i.v. doses of glucagon-like peptide 1 (GLP-1) on glucose homeostasis and gastric emptying were compared in patients with type 2 diabetes. Twelve patients with type 2 diabetes received three different infusion rates of GLP-1 (0.4, 0.8, and 1.2 pmol/kg x min) or placebo...... ingestion (P = 0.0031 and 0.0074, respectively). Glucagon secretion was suppressed with GLP-1. Gastric emptying was decelerated by GLP-1 in a dose-dependent fashion (P

Intracellular Signalling by C-Peptide

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Claire E. Hills

2008-01-01

Full Text Available C-peptide, a cleavage product of the proinsulin molecule, has long been regarded as biologically inert, serving merely as a surrogate marker for insulin release. Recent findings demonstrate both a physiological and protective role of C-peptide when administered to individuals with type I diabetes. Data indicate that C-peptide appears to bind in nanomolar concentrations to a cell surface receptor which is most likely to be G-protein coupled. Binding of C-peptide initiates multiple cellular effects, evoking a rise in intracellular calcium, increased PI-3-kinase activity, stimulation of the Na+/K+ ATPase, increased eNOS transcription, and activation of the MAPK signalling pathway. These cell signalling effects have been studied in multiple cell types from multiple tissues. Overall these observations raise the possibility that C-peptide may serve as a potential therapeutic agent for the treatment or prevention of long-term complications associated with diabetes.

Percentiles of fasting serum insulin, glucose, HbA1c and HOMA-IR in pre-pubertal normal weight European children from the IDEFICS cohort.

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Peplies, J; Jiménez-Pavón, D; Savva, S C; Buck, C; Günther, K; Fraterman, A; Russo, P; Iacoviello, L; Veidebaum, T; Tornaritis, M; De Henauw, S; Mårild, S; Molnár, D; Moreno, L A; Ahrens, W

2014-09-01

The aim of this study is to present age- and sex-specific reference values of insulin, glucose, glycosylated haemoglobin (HbA1c) and the homeostasis model assessment to quantify insulin resistance (HOMA-IR) for pre-pubertal children. The reference population consists of 7074 normal weight 3- to 10.9-year-old pre-pubertal children from eight European countries who participated in at least one wave of the IDEFICS ('identification and prevention of dietary- and lifestyle-induced health effects in children and infants') surveys (2007-2010) and for whom standardised laboratory measurements were obtained. Percentile curves of insulin (measured by an electrochemiluminescence immunoassay), glucose, HbA1c and HOMA-IR were calculated as a function of age stratified by sex using the general additive model for location scale and shape (GAMLSS) method. Levels of insulin, fasting glucose and HOMA-IR continuously show an increasing trend with age, whereas HbA1c shows an upward trend only beyond the age of 8 years. Insulin and HOMA-IR values are higher in girls of all age groups, whereas glucose values are slightly higher in boys. Median serum levels of insulin range from 17.4 and 13.2 pmol l(-1) in 3-HOMA-IR, median values range from 0.5 and 0.4 in 3-<3.5-year-old girls and boys to 1.7 and 1.4 in 10.5-<11-year-old girls and boys, respectively. Our study provides the first standardised reference values for an international European children's population and provides the, up to now, largest data set of healthy pre-pubertal children to model reference percentiles for markers of insulin resistance. Our cohort shows higher values of Hb1Ac as compared with a single Swedish study while our percentiles for the other glucose metabolic markers are in good accordance with previous studies.

Theoretical and Computational Studies of Peptides and Receptors of the Insulin Family

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Harish Vashisth

2015-02-01

Full Text Available Synergistic interactions among peptides and receptors of the insulin family are required for glucose homeostasis, normal cellular growth and development, proliferation, differentiation and other metabolic processes. The peptides of the insulin family are disulfide-linked single or dual-chain proteins, while receptors are ligand-activated transmembrane glycoproteins of the receptor tyrosine kinase (RTK superfamily. Binding of ligands to the extracellular domains of receptors is known to initiate signaling via activation of intracellular kinase domains. While the structure of insulin has been known since 1969, recent decades have seen remarkable progress on the structural biology of apo and liganded receptor fragments. Here, we review how this useful structural information (on ligands and receptors has enabled large-scale atomically-resolved simulations to elucidate the conformational dynamics of these biomolecules. Particularly, applications of molecular dynamics (MD and Monte Carlo (MC simulation methods are discussed in various contexts, including studies of isolated ligands, apo-receptors, ligand/receptor complexes and intracellular kinase domains. The review concludes with a brief overview and future outlook for modeling and computational studies in this family of proteins.

Effects of prepartum fat supplementation on plasma concentrations of glucagon-like peptide-1, peptide YY, adropin, insulin, and leptin in periparturient dairy cows.

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Zapata, Rizaldy C; Salehi, Reza; Ambrose, Divakar J; Chelikani, Prasanth K

2015-10-01

Dietary fat supplementation during the periparturient period is one strategy to increase energy intake and attenuate the degree of negative energy balance during early lactation; however, little is known of the underlying hormonal and metabolic adaptations. We evaluated the effects of prepartum fat supplementation on energy-balance parameters and plasma concentrations of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), adropin, insulin, leptin, glucose, nonesterified fatty acid, and β-hydroxybutyric acid in dairy cows. Twenty-four pregnant dairy cows were randomized to diets containing either rolled canola or sunflower seed at 8% of dry matter, or no oilseed supplementation, during the last 5 wk of gestation and then assigned to a common lactation diet postpartum. Blood samples were collected at -2, +2, and +14 h relative to feeding, at 2 wk after the initiation of the diets, and at 2 wk postpartum. Dietary canola and sunflower supplementation alone did not affect energy balance, body weight, and plasma concentrations of glucagon-like peptide-1, PYY, adropin, insulin, leptin, nonesterified fatty acid, and β-hydroxybutyric acid; however, canola decreased and sunflower tended to decrease dry matter intake. We also observed that the physiological stage had a significant, but divergent, effect on circulating hormones and metabolite concentrations. Plasma glucagon-like peptide-1, PYY, adropin, nonesterified fatty acid, and β-hydroxybutyric acid concentrations were greater postpartum than prepartum, whereas glucose, insulin, leptin, body weight, and energy balance were greater prepartum than postpartum. Furthermore, the interaction of treatment and stage was significant for leptin and adropin, and tended toward significance for PYY and insulin; only insulin exhibited an apparent postprandial increase. Postpartum PYY concentrations exhibited a strong negative correlation with body weight, suggesting that PYY may be associated with body weight regulation during

The effect of endogenously released glucose, insulin, glucagon-like peptide 1, ghrelin on cardiac output, heart rate, stroke volume, and blood pressure

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Hlebowicz Joanna

2011-12-01

Full Text Available Abstract Background 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. Methods Eleven healthy men and twelve healthy women ((mean ± SEM aged: 26 ± 0.2 y; body mass index: 21.8 ± 0.1 kg/m2 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. Results 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 P = 0.015, r = 0.946, and between ghrelin levels and HR (P = 0.013, r = 0.951 at 110 min. Significant correlations were also found between the change in glucose level at 30 min and the change in systolic 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. Conclusions 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

The fluctuation of blood glucose, insulin and glucagon concentrations before and after insulin therapy in type 1 diabetes

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Arif, Idam; Nasir, Zulfa

2015-09-01

A dynamical-systems model of plasma glucose, insulin and glucagon concentrations has been developed to investigate the effects of insulin therapy on blood glucose, insulin and glucagon regulations in type 1 diabetic patients. Simulation results show that the normal regulation of blood glucose concentration depends on insulin and glucagon concentrations. On type 1 diabetic case, the role of insulin on regulating blood glucose is not optimal because of the destruction of β cells in pancreas. These β cells destructions cause hyperglycemic episode affecting the whole body metabolism. To get over this, type 1 diabetic patients need insulin therapy to control the blood glucose level. This research has been done by using rapid acting insulin (lispro), long-acting insulin (glargine) and the combination between them to know the effects of insulin therapy on blood glucose, insulin and glucagon concentrations. Simulation results show that these different types of insulin have different effects on blood glucose concentration. Insulin therapy using lispro shows better blood glucose control after consumption of meals. Glargin gives better blood glucose control between meals and during sleep. Combination between lispro and glargine shows better glycemic control for whole day blood glucose level.

Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation.

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Frank, N; Hermida, P; Sanchez-Londoño, A; Singh, R; Gradil, C M; Uricchio, C K

2017-07-01

Octreotide is a somatostatin analog that suppresses insulin secretion. We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Twelve horses, N = 5, ID = 7. Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1.0 μg/kg IV) was then administered, and blood was collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minute, and 2, 3, 4, 6, 8, 12, and 24 hour for measurement of glucose and insulin concentrations. Area under the curve (AUC) values were calculated. Mean AUC values for glucose and insulin did not differ between normal (n = 5) and ID (n = 7) groups after octreotide injection. Significant time (P glucose and insulin concentrations. A group × time interaction (P = .091) was detected for insulin concentrations after administration of octreotide, but the group (P = .33) effect was not significant. Octreotide suppresses insulin secretion, resulting in hyperglycemia, and then concentrations increase above baseline as glycemic control is restored. Our hypothesis that octreotide causes insulin concentrations to decrease in horses was supported, but differences between N and ID groups did not reach statistical significance when blood glucose and insulin responses were compared. The utility of an octreotide response test remains to be determined. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Validation of methods for measurement of insulin secretion in humans in vivo

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Kjems, L L; Christiansen, E; Vølund, A

2000-01-01

To detect and understand the changes in beta-cell function in the pathogenesis of type 2 diabetes, an accurate and precise estimation of prehepatic insulin secretion rate (ISR) is essential. There are two common methods to assess ISR, the deconvolution method (by Eaton and Polonsky)-considered th......To detect and understand the changes in beta-cell function in the pathogenesis of type 2 diabetes, an accurate and precise estimation of prehepatic insulin secretion rate (ISR) is essential. There are two common methods to assess ISR, the deconvolution method (by Eaton and Polonsky...... of these mathematical techniques for quantification of insulin secretion have been tested in dogs, but not in humans. In the present studies, we examined the validity of both methods to recover the known infusion rates of insulin and C-peptide mimicking ISR during an oral glucose tolerance test. ISR from both......, and a close agreement was found for the results of an oral glucose tolerance test. We also studied whether C-peptide kinetics are influenced by somatostatin infusion. The decay curves after bolus injection of exogenous biosynthetic human C-peptide, the kinetic parameters, and the metabolic clearance rate were...

Lixisenatide as add-on therapy to basal insulin

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Brown DX

2013-12-01

Full Text Available Dominique Xavier Brown, Emma Louise Butler, Marc Evans Diabetes Department, University Hospital Llandough, Cardiff, UK Abstract: Many patients with type 2 diabetes mellitus do not achieve target glycosylated hemoglobin A1c levels despite optimally titrated basal insulin and satisfactory fasting plasma glucose levels. Current evidence suggests that HbA1c levels are dictated by both basal glucose and postprandial glucose levels. This has led to a consensus that postprandial glucose excursions contribute to poor glycemic control in these patients. Lixisenatide is a once-daily, prandial glucagon-like peptide 1 (GLP-1 receptor agonist with a four-fold affinity for the GLP-1 receptor compared with native GLP-1. Importantly, lixisenatide causes a significant delay in gastric emptying time, an important determinant of the once-daily dosing regimen. An exendin-4 mimetic with six lysine residues removed at the C-terminal, lixisenatide has pronounced postprandial glucose-lowering effects, making it a novel incretin agent for use in combination with optimally titrated basal insulin. Lixisenatide exerts profound effects on postprandial glucose through established mechanisms of glucose-dependent insulin secretion and glucagon suppression in combination with delayed gastric emptying. This review discusses the likely place that lixisenatide will occupy in clinical practice, given its profound effects on postprandial glucose and potential to reduce glycemic variability. Keywords: lixisenatide, add-on therapy, insulin, GLP-1 receptor agonist, postprandial glucose, pharmacodynamics

Neuronal Cbl Controls Biosynthesis of Insulin-Like Peptides in Drosophila melanogaster

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Yu, Yue; Sun, Ying; He, Shengqi; Yan, Cheng; Rui, Liangyou; Li, Wenjun

2012-01-01

The Cbl family proteins function as both E3 ubiquitin ligases and adaptor proteins to regulate various cellular signaling events, including the insulin/insulin-like growth factor 1 (IGF1) and epidermal growth factor (EGF) pathways. These pathways play essential roles in growth, development, metabolism, and survival. Here we show that in Drosophila melanogaster, Drosophila Cbl (dCbl) regulates longevity and carbohydrate metabolism through downregulating the production of Drosophila insulin-like peptides (dILPs) in the brain. We found that dCbl was highly expressed in the brain and knockdown of the expression of dCbl specifically in neurons by RNA interference increased sensitivity to oxidative stress or starvation, decreased carbohydrate levels, and shortened life span. Insulin-producing neuron-specific knockdown of dCbl resulted in similar phenotypes. dCbl deficiency in either the brain or insulin-producing cells upregulated the expression of dilp genes, resulting in elevated activation of the dILP pathway, including phosphorylation of Drosophila Akt and Drosophila extracellular signal-regulated kinase (dERK). Genetic interaction analyses revealed that blocking Drosophila epidermal growth factor receptor (dEGFR)-dERK signaling in pan-neurons or insulin-producing cells by overexpressing a dominant-negative form of dEGFR abolished the effect of dCbl deficiency on the upregulation of dilp genes. Furthermore, knockdown of c-Cbl in INS-1 cells, a rat β-cell line, also increased insulin biosynthesis and glucose-stimulated secretion in an ERK-dependent manner. Collectively, these results suggest that neuronal dCbl regulates life span, stress responses, and metabolism by suppressing dILP production and the EGFR-ERK pathway mediates the dCbl action. Cbl suppression of insulin biosynthesis is evolutionarily conserved, raising the possibility that Cbl may similarly exert its physiological actions through regulating insulin production in β cells. PMID:22778134

Effects of the dipeptidyl peptidase-IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance

DEFF Research Database (Denmark)

Rosenstock, Julio; Foley, James E; Rendell, Marc

2008-01-01

OBJECTIVE: This study was conducted to determine the effects of vildagliptin on incretin hormone levels, islet function, and postprandial glucose control in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A 12-week, double-blind, randomized, parallel-group study...... comparing vildagliptin (50 mg q.d.) and placebo was conducted in 179 subjects with IGT (2-h glucose 9.1 mmol/l, A1C 5.9%). Plasma levels of intact glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide, and glucagon were measured during standard meal tests...... performed at baseline and at week 12. Insulin secretory rate (ISR) was estimated by C-peptide deconvolution. The between-group differences (vildagliptin - placebo) in the adjusted mean changes from baseline to end point in the total and incremental (Delta) area under the curve (AUC)(0-2 h...

Characterization of the intravenous glucose tolerance test and the combined glucose-insulin test in donkeys.

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Mendoza, F J; Aguilera-Aguilera, R; Gonzalez-De Cara, C A; Toribio, R E; Estepa, J C; Perez-Ecija, A

2015-12-01

Glucose-insulin dynamic challenges such as the intravenous glucose tolerance test (IVGTT) and combined glucose-insulin test (CGIT) have not been described in donkeys. The objectives of this study were (1) to characterize the IVGTT and CGIT in healthy adult donkeys, and (2) to establish normal glucose-insulin proxies. Sixteen donkeys were used and body morphometric variables obtained each. For the IVGTT, glucose (300 mg/kg) was given IV. For the CGIT, glucose (150 mg/kg) followed by recombinant insulin (0.1 IU/kg) were administered IV. Blood samples for glucose and insulin determinations were collected over 300 min. In the IVGTT the positive phase lasted 160.9 ± 13.3 min, glucose concentration peaked at 323.1 ± 9.2 mg/dL and declined at a rate of 1.28 ± 0.15 mg/dL/min. The glucose area under the curve (AUC) was 21.4 ± 1.9 × 10(3) mg/dL/min and the insulin AUC was 7.2 ± 0.9 × 10(3) µIU/mL/min. The positive phase of the CGIT curve lasted 44 ± 3 min, with a glucose clearance rate of 2.01 ± 0.18 mg/dL/min. The negative phase lasted 255.9 ± 3 min, decreasing glucose concentration at rate of -0.63 ± 0.06 mg/dL/min, and reaching a nadir (33.1 ± 3.6 mg/dL) at 118.3 ± 6.3 min. The glucose and insulin AUC values were 15.2 ± 0.9 × 10(3) mg/dL/min and 13.2 ± 0.9 × 10(3) µIU/mL/min. This is the first study characterizing CGIT and IVGTT, and glucose-insulin proxies in healthy adult donkeys. Distinct glucose dynamics, when compared with horses, support the use of species-specific protocols to assess endocrine function. Copyright © 2015 Elsevier Ltd. All rights reserved.

Calcitonin gene-related peptide: neuroendocrine communication between the pancreas, gut, and brain in regulation of blood glucose.

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Pendharkar, Sayali A; Walia, Monika; Drury, Marie; Petrov, Maxim S

2017-11-01

Calcitonin gene-related peptide (CGRP), a ubiquitous neuropeptide, plays a diverse and intricate role in chronic low-grade inflammation, including conditions such as obesity, type 2 diabetes, and diabetes of the exocrine pancreas. Diabetes of exocrine pancreas is characterised by chronic hyperglycemia and is associated with persistent low-grade inflammation and altered secretion of certain pancreatic and gut hormones. While CGRP may regulate glucose homeostasis and the secretion of pancreatic and gut hormones, its role in chronic hyperglycemia after acute pancreatitis (CHAP) is not known. The aim of this study was to investigate the association between CGRP and CHAP. Fasting blood samples were collected to measure insulin, HbA1c, CGRP, amylin, C-peptide, glucagon, pancreatic polypeptide (PP), somatostatin, gastric inhibitory peptide, glicentin, glucagon-like peptide-1 and 2, and oxyntomodulin. Modified Poisson regression analysis and linear regression analyses were conducted. Five statistical models were used to adjust for demographic, metabolic, and pancreatitis-related risk factors. A total of 83 patients were recruited. CGRP was significantly associated with CHAP in all five models (P-trend <0.005). Further, it was significantly associated with oxyntomodulin (P<0.005) and glucagon (P<0.030). Oxyntomodulin and glucagon independently contributed 9.7% and 7%, respectively, to circulating CGRP variance. Other pancreatic and gut hormones were not significantly associated with CGRP. CGRP is involved in regulation of blood glucose in individuals after acute pancreatitis. This may have translational implications in prevention and treatment of diabetes of the exocrine pancreas.

Effects of turtle oil on insulin sensitivity and glucose metabolism in insulin resistant cell model

International Nuclear Information System (INIS)

Bai Jing; Tian Yaping; Guo Duo

2007-01-01

To evaluate the effects of turtle oil on insulin sensitivity and glucose metabolism in an insulin-resistant (IR) cell model which was established by the way of high concentration of insulin induction with HepG 2 cell in vitro culture. The IR cells were treated by turtle oil, the glucose consumption and 3 H-D-glucose incorporation rate in IR cells were detected by the way of glucose oxidase and 3 H-D-glucose incorporation assay respectively. The state of cell proliferation was tested by MTT method. The results showed that the incorporation rate of 3 H-D-glucose in IR cells was significantly lower than that in the control cells(P 3 H-D-glucose incorporation rate in either IR cells or control cells was increased with the increase of insulin concentration. Moreover, the 3 H-D-glucose incorporation rate of IR cells increased slower than that of control cells. The MTT assay showed that turtle oil can promote the proliferation of IR cell and control cell. The glucose uptake and glucose consumption in IR cell which treated with turtle oil was significantly increase than that in the control cells (P<0.05). Turtle oil can improve the insulin sensitivity and glucose metabolism in the IR cell model. (authors)

Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects

DEFF Research Database (Denmark)

Greenfield, Jerry R; Farooqi, I Sadaf; Keogh, Julia M

2008-01-01

objective was to determine whether glutamine increases circulating GLP-1 and GIP concentrations in vivo and, if so, whether this is associated with an increase in plasma insulin. DESIGN: We recruited 8 healthy normal-weight volunteers (LEAN), 8 obese individuals with type 2 diabetes or impaired glucose...... plasma insulin concentrations. Glutamine stimulated glucagon secretion in all 3 study groups. CONCLUSION: Glutamine effectively increases circulating GLP-1, GIP, and insulin concentrations in vivo and may represent a novel therapeutic approach to stimulating insulin secretion in obesity and type 2......BACKGROUND: Incretin hormones, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in meal-related insulin secretion. We previously demonstrated that glutamine is a potent stimulus of GLP-1 secretion in vitro. OBJECTIVE: Our...

Effects of dapagliflozin on insulin-requirement, glucose excretion and ß-hydroxybutyrate levels are not related to baseline HbA1c in youth with type 1 diabetes.

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Biester, Torben; Aschemeier, Baerbel; Fath, Maryam; Frey, Marcel; Scheerer, Markus F; Kordonouri, Olga; Danne, Thomas

2017-11-01

Youth with type 1 diabetes (T1D) infrequently achieve HbA1c targets. Therefore, this placebo-controlled, randomized, crossover study was set up to assess the safety, effect and pharmacokinetics of a single dose of 10 mg dapagliflozin (DAPA) as add-on to insulin in relationship to HbA1c in youth. A total of 33 youths (14 males, median age 16 years, diabetes duration 8 years) were included and stratified into 3 baseline HbA1c categories (9.0; n = 11 each). During the study period of 24 hours, intravenous insulin administration and glucose-infusion kept blood glucose levels at 160 to 220 mg/dL. DAPA reduced mean insulin dose by 13.6% ( P  HbA1c. Six independent episodes in 6 patients with plasma ß-hydroxybutyrate levels between ≥0.6 and HbA1c levels, for adjunct SGLT2-inhibitor therapy in the paediatric age group by lowering insulin dose and increasing glucose excretion. © 2017 John Wiley & Sons Ltd.

Production of peptide antisera specific for mouse and rat proinsulin C-peptide 2

DEFF Research Database (Denmark)

Blume, N; Madsen, O D; Kofod, Hans

1990-01-01

for antibody binding to the immunizing antigen. Antisera to C-peptide 2, stained islet beta-cells on mouse and rat, but not monkey pancreas sections in immunocytochemical analysis. Preabsorption to the synthetic C-peptide 2, but not the synthetic mouse and rat C-peptide 1 abolished staining. In conclusion we......Mice and rats have two functional non-allelic insulin genes. By using a synthetic peptide representing a common sequence in mouse and rat C-peptide 2 as antigen, we have produced rabbit antisera specific for an epitope which is not present in mouse or rat C-peptide 1. Long-term immunization did...... not seem to increase the end point titre as tested in direct ELISA. The specificity of the antiserum was determined by competitive ELISA and histochemistry on pancreas sections. Only the synthetic C-peptide 2, but not the homologous synthetic C-peptide 1 from mouse and rat competed efficiently in ELISA...

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.

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Softic, Samir; Gupta, Manoj K; Wang, Guo-Xiao; Fujisaka, Shiho; O'Neill, Brian T; Rao, Tata Nageswara; Willoughby, Jennifer; Harbison, Carole; Fitzgerald, Kevin; Ilkayeva, Olga; Newgard, Christopher B; Cohen, David E; Kahn, C Ronald

2017-11-01

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

Professional continuous glucose monitoring for the identification of type 1 diabetes mellitus among subjects with insulin therapy.

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Chen, Yin-Chun; Huang, Yu-Yao; Li, Hung-Yuan; Liu, Shih-Wei; Hsieh, Sheng-Hwu; Lin, Chia-Hung

2015-01-01

The identification of type 1 diabetes in diabetic subjects receiving insulin therapy is sometimes difficult. The purpose of this study is to evaluate whether results of professional continuous glucose monitoring can improve the identification of type 1 diabetes.From 2007 to 2012, 119 adults receiving at least twice-daily insulin therapy and professional continuous glucose monitoring were recruited. Type 1 diabetes was diagnosed by endocrinologists according to American Diabetes Association standards, including a very low C-peptide level (diabetic ketoacidosis. Continuous glucose monitoring was applied for 3 days.Among 119 subjects, 86 were diagnosed with type 1 diabetes. Subjects with type 1 diabetes were younger (33.8 vs 52.3 years old, P 1), had lower body mass index (BMI, 21.95 vs 24.42, P = 0.003), lower serum creatinine (61.77  vs 84.65 μmol/L, P = 0.001), and higher estimated glomerular filtration rate (108.71 vs 76.48 mg/mL/min/1.73m2, P 1) than subjects with type 2 diabetes. Predictive scores for identification of type 1 diabetes were constructed, including age, BMI, average mean amplitude of glucose excursion in days 2 and 3, and the area under the curve of nocturnal hyperglycemic and hypoglycemic states. The area under the receiver operating characteristic curve was 0.90. With the cutoff of 0.58, the sensitivity was 86.7% and the specificity was 80.8%. The good performance was validated by the leave-one-out method (sensitivity 83.3%, specificity 73.1%).Professional continuous glucose monitoring is a useful tool that improves identification of type 1 diabetes among diabetic patients receiving insulin therapy.

Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion.

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Houtz, Jessica; Borden, Philip; Ceasrine, Alexis; Minichiello, Liliana; Kuruvilla, Rejji

2016-11-07

Insulin secretion by pancreatic islet β cells is critical for glucose homeostasis, and a blunted β cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve growth factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet β cells. High glucose rapidly enhances NGF secretion and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF or TrkA, or acute disruption of TrkA signaling, impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate β cell dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance.

Science.gov (United States)

Yang, Sae Jeong; Kim, Tae Nyun; Baik, Sei Hyun; Kim, Tae Sun; Lee, Kwan Woo; Nam, Moonsuk; Park, Yong Soo; Woo, Jeong-Teak; Kim, Young Seol; Kim, Sung-Hoon

2013-05-01

The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM). A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose ≥ 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281). The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index β-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p ≤ 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p insulin secretion status than the 3-hour abnormal levels group. Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both β-cell dysfunction and insulin resistance.

Effects of Oral Glucose Load on Endothelial Function and on Insulin and Glucose Fluctuations in Healthy Individuals

Directory of Open Access Journals (Sweden)

A. Major-Pedersen

2008-01-01

Full Text Available Background/aims. Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order to better understand and cope with the postprandial state in insulin resistant individuals. Methods. We assessed post-oral glucose load endothelial function (flow mediated dilation, plasma insulin, and blood glucose in 9 healthy subjects. Results. The largest increases in delta FMD values (fasting FMD value subtracted from postprandial FMD value occurred at 3 hours after both glucose or placebo load, respectively: 4.80±1.41 (P = .009 and 2.34±1.47 (P = .15. Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. Conclusion. Oral glucose load does not induce endothelial dysfunction in healthy individuals with mean insulin and glucose values of 5.6 mmol/L and 27.2 mmol/L, respectively, 2 hours after glucose load.

Dynamic Metabolomics Reveals that Insulin Primes the Adipocyte for Glucose Metabolism

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James R. Krycer

2017-12-01

Full Text Available Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis. Integrating dynamic metabolomics and phosphoproteomics data revealed that insulin-dependent phosphorylation of anabolic enzymes occurred prior to substrate accumulation. Indeed, glycogen synthesis was activated independently of glucose supply. We refer to this phenomenon as metabolic priming, whereby insulin signaling creates a demand-driven system to “pull” glucose into specific anabolic pathways. This complements the supply-driven regulation of anabolism by substrate accumulation and highlights an additional role for insulin action in adipocyte glucose metabolism.

MKR mice have increased dynamic glucose disposal despite metabolic inflexibility, and hepatic and peripheral insulin insensitivity.

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Vaitheesvaran, B; LeRoith, D; Kurland, I J

2010-10-01

Recent work has shown that there can be significant differences when glucose disposal is assessed for high-fat induced insulin resistance by static clamp methods vs dynamic assessment during a stable isotope i.p. glucose tolerance test. MKR mice, though lean, have severe insulin resistance and decreased muscle fatty acid oxidation. Our goal was to assess dynamic vs static glucose disposal in MKR mice, and to correlate glucose disposal and muscle-adipose-liver flux interactions with metabolic flexibility (indirect calorimetry) and muscle characteristics. Stable isotope flux phenotyping was performed using [6,6-(2)H(2)]glucose, [U-(13)C(6)]glucose and [2-(13)C]glycerol. Muscle triacylglycerol (TAG) and diacylglycerol (DAG) content was assessed by thin layer chromatography, and histological determination of fibre type and cytochrome c activity performed. Metabolic flexibility was assessed by indirect calorimetry. Indirect calorimetry showed that MKR mice used more glucose than FVB/N mice during fasting (respiratory exchange ratio [RER] 0.88 vs 0.77, respectively). Compared with FVB/N mice, MKR mice had faster dynamic glucose disposal, despite increased whole-muscle DAG and TAG, and similar hepatic glucose production with higher fasting insulin and unchanged basal glucose. Fed MKR muscle had more glycogen, and increased levels of GLUT1 and GLUT4 than FVB/N muscle. Histology indicated that MKR soleus had mildly decreased cytochrome c activity overall and more type II (glycolytic) fibres compared with that in FVB/N mice. MKR muscle adapts to using glucose, with more type II fibres present in red muscle. Fasting RER is elevated and glucose disposal during an i.p. glucose tolerance test is accelerated despite increased muscle DAG and TAG. Metabolic inflexibility may result from the compensatory use of fuel that can be best utilised for energy requirements; static vs dynamic glucose disposal assessments may measure complementary aspects of metabolic flexibility and insulin

Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin

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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...

Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

International Nuclear Information System (INIS)

Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya; Hirose, Takahisa; Kawamori, Ryuzo; Fujitani, Yoshio; Watada, Hirotaka

2009-01-01

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

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Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan); Fujitani, Yoshio, E-mail: fujitani@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan)

2009-12-18

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

Association of fasting glucagon and proinsulin concentrations with insulin resistance

DEFF Research Database (Denmark)

Ferrannini, E; Muscelli, E; Natali, A

2007-01-01

AIMS/HYPOTHESIS: Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. METHODS: We measured IR [by a euglycaemic......, controlling for known determinants of insulin sensitivity (i.e. sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin...

The Role of Taste in Cephalic Phase of Insulin Secretion

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M. Dušková

2013-01-01

Full Text Available The effect of a short gustatory signal of a sweet solution was tested on 15 young male volunteers. The experiment consisted of mouth rinsing with either a sucrose or aspartate solution or pure water as a placebo. Blood was then taken in short intervals of 0, 5, 10, 15 and 20 min. Blood glucose, C-peptide, insulin and cortisol were determined. While C-peptide and glucose were unaffected, a short-term increase in insulin was observed after the sucrose, but not after the aspartate or placebo. The increase in insulin was significant, though it amounted to only 0.5 mIU/l and lasted approx. 15 min reaching then the starting value. The decline of cortisol level within 20 min of the experiment was approx. 40 nmol/l, although it was also observed after aspartate or placebo mouth rinsing and was probably caused by stress factors or anticipation. In conclusion, the contribution of taste to the cephalic phase of insulin secretion is small yet significant, and mouth rinsing with 5% sucrose causes an insulin increase of just under 1 IU/l, which returns to starting level within 15 min.

Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion

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Maria L. Mizgier

2017-01-01

Full Text Available Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines. We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS. In conditioned media from human myotubes incubated with/without insulin (100 nmol/L for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets (p<0.05. Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets.

Insulin resistance in human subjects having impaired glucose regulation

International Nuclear Information System (INIS)

Khan, S.H.; Khan, F.A.; Ijaz, A.

2007-01-01

To determine insulin resistance in human subjects having impaired glucose regulation (IGR) by Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). A total of 100 subjects with impaired glucose regulation were selected for evaluation of metabolic syndrome as per the criteria of National Cholesterol Education Program, Adult Treatment Panel III (NCEP, ATP III), along with 47 healthy age and gender-matched controls. Physical examination to determine blood pressure and waist circumference was carried out and so was sampling for plasma glucose, serum triglycerides, HDL-cholesterol and insulin. Insulin resistance was calculated by the HOMA-IR. Finally, subjects with and without metabolic syndrome were compared with controls (n=47), using one-way ANOVA for studying insulin resistance between groups, with Tukey's post-hoc comparison. The frequency of finding metabolic syndrome in cases of IGR remained 47%. The insulin resistance demonstrated stepwise worsening from control population (mean=1.54, 95 % CI: 1.77 - 2.37) to subjects suffering from only IGR (mean=2.07, 95 % CI: 1.77- 2.37) to metabolic syndrome (mean=2.67, 95 %, CI: 2.34 - 3.00) (p < 0.001). Patients with impaired glucose regulation may have significant insulin resistance. It is, thus, recommended that a vigorous search be made to measure insulin resistance in all cases diagnosed to have impaired glucose regulation. (author)

The effect of glucagon-like peptide I (GLP-I) on glucose elimination in healthy subjects depends on the pancreatic glucoregulatory hormones

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Toft-Nielson, M; Madsbad, Sten; Holst, J J

1996-01-01

Glucagon-like peptide I (GLP-I) decreases plasma glucose in type II diabetic patients and in healthy subjects indirectly by stimulation of insulin and inhibition of glucagon secretion, whereby the hepatic glucose production decreases. However, recent studies indicate that GLP-I may also directly...... min, a 25-g intravenous glucose tolerance test (IVGTT) was carried out, and plasma concentrations of glucose, insulin, glucagon, and GLP-I were measured during the following 2 h. IVGTT together with GLP-I infusion significantly elevated insulin during 500 microgram/h SS but not during 1,000 microgram....../h SS. Plasma glucagon was strongly depressed in all experiments. During 500 microgram/h SS, the glucose disappearance constant, Kg, was 0.49 +/- 0.03% per minute with GLP-I and 0.39 +/- 0.04% per minute with saline (n = 8, P = 0.004). With 1,000 microgram/h SS, Kg was 0.42 +/- 0.03% per minute with GLP...

Insulin, concanavalin A, EGF, IFG-I and vanadate activate de novo phosphatidic acid and diacylglycerol synthesis, C-kinase, and glucose transport in BC3H-1 myocytes

International Nuclear Information System (INIS)

Cooper, D.R.; Hernandez, H.; Konda, T.S.; Standaert, M.S.; Pollet, R.J.; Farese, R.V.

1987-01-01

The authors have reported that insulin stimulates de novo synthesis of phosphatidic acid (PA) which is metabolized directly to diacylglycerol (DG) in BS3H-1 myocytes; this is accompanied by increases in C-kinase activity in membrane and cytosolic extracts. This pathway may be involved in stimulating glucose transport and other metabolic processes. In this study, the authors have compared the effects of concanavalin A, EGF, IGF-I and sodium orthovanadate to insulin on PA/DG synthesis, C-kinase activity and glucose transport. All were found to be effective in stimulating glucose transport. Additionally, all activators rapidly increased the incorporation of [ 3 H]glycerol into DG and total glycerolipids, although none were as effective as insulin, which increased [ 3 H]DG 400% in 1 minute. Increased incorporation into phospholipids and triacylglycerols and to a lesser extent monoacylglycerol was also noted. They examined effects of concanavalin A and EGF on C-kinase activity and found that both agonists, like insulin, increase C-kinase activity in cytosolic and/or membrane fractions. Their findings raise the possibility that activation of receptors having associated tyrosine kinase activity may provoke some cellular responses through de novo PA/GD synthesis and C-kinase activation

Short-acting glucagon-like peptide-1 receptor agonists as add-on to insulin therapy in type 1 diabetes

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Albèr, Anders; Brønden, Andreas; Knop, Filip K

2017-01-01

emptying in patients with type 1 diabetes, which could translate into effective lowering of postprandial glucose excursions; however, these observations regarding short-acting GLP-1RAs are all derived from small open-label trials and should thus be interpreted with caution. In the present paper we review......A large proportion of patients with type 1 diabetes do not reach their glycaemic target of glycated hemoglobin (HbA1c) type 1 diabetes are overweight and obese. Treatment of type 1 diabetes is based on insulin therapy......, which is associated with well-described and unfortunate adverse effects such as hypoglycaemia and increased body weight. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are the focus of increasing interest as a possible adjunctive treatment to insulin in type 1 diabetes because...

Exercise Protects Against Defective Insulin Signaling and Insulin Resistance of Glucose Transport in Skeletal Muscle of Angiotensin II-Infused Rat

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Juthamard Surapongchai

2018-04-01

Full Text Available Objectives: The present study investigated the impact of voluntary exercise on insulin-stimulated glucose transport and the protein expression and phosphorylation status of the signaling molecules known to be involved in the glucose transport process in the soleus muscle as well as other cardiometabolic risks in a rat model with insulin resistance syndrome induced by chronic angiotensin II (ANGII infusion.Materials and Methods: Male Sprague-Dawley rats were assigned to sedentary or voluntary wheel running (VWR groups. Following a 6-week period, rats in each group were subdivided and subcutaneously administered either normal saline or ANGII at 100 ng/kg/min for 14 days. Blood pressure, glucose tolerance, insulin-stimulated glucose transport and signaling proteins, including insulin receptor (IR, insulin receptor substrate 1 (IRS-1, Akt, Akt substrate of 160 kDa (AS160, AMPKα, c-Jun NH2-terminal kinase (JNK, p38 MAPK, angiotensin converting enzyme (ACE, ANGII type 1 receptor (AT1R, ACE2, Mas receptor (MasR and oxidative stress marker in the soleus muscle, were evaluated.Results: Exercise protected against the insulin resistance of glucose transport and defective insulin signaling molecules in the soleus muscle; this effect was associated with a significant increase in AMPK Thr172 (43% and decreases in oxidative stress marker (31% and insulin-induced p38 MAPK Thr180/Tyr182 (45% and SAPK/JNK Thr183/Tyr185 (25%, without significant changes in expression of AT1R, AT2R, ACE, ACE2, and MasR when compared to the sedentary rats given ANGII infusion. At the systemic level, VWR significantly decreased body weight, fat weight, and systolic blood pressure as well as improved serum lipid profiles.Conclusion: Voluntary exercise can alleviate insulin resistance of glucose transport and impaired insulin signaling molecules in the soleus muscle and improve whole-body insulin sensitivity in rats chronically administered with ANGII.

Simulation and qualitative analysis of glucose variability, mean glucose, and hypoglycemia after subcutaneous insulin therapy for stress hyperglycemia.

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Strilka, Richard J; Stull, Mamie C; Clemens, Michael S; McCaver, Stewart C; Armen, Scott B

2016-01-27

The critically ill can have persistent dysglycemia during the "subacute" recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial. Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation. Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, "rebound hyperglycemia" was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes. Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose

Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients

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Creutzfeldt, W O; Kleine, N; Willms, B

1996-01-01

. kg-1 . min-1 GLP-1 or placebo was infused intravenously in the morning (plasma glucose 13.7 +/- 0.9 mmol/l; plasma insulin 26 +/- 4 pmol/l). Glucose (glucose oxidase method), insulin, C-peptide, glucagon, GLP-1, cortisol, growth hormone (immunoassays), triglycerides, cholesterol, and nonesterified......OBJECTIVE: Glucagon-like peptide I(7-36) amide (GLP-1) is a physiological incretin hormone that, in slightly supraphysiological doses, stimulates insulin secretion, lowers glucagon concentrations, and thereby normalizes elevated fasting plasma glucose concentrations in type II diabetic patients...... fatty acids (enzymatic tests) were measured. RESULTS: Glucagon was reduced from approximately 8 to 4 pmol/l, and plasma glucose was lowered from 13.4 +/- 1.0 to 10.0 +/- 1.2 mmol/l with GLP-1 administration (plasma concentrations approximately 100 pmol, P

Enhancement of glucose uptake in muscular cell by soybean charged peptides isolated by electrodialysis with ultrafiltration membranes (EDUF): activation of the AMPK pathway.

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Roblet, Cyril; Doyen, Alain; Amiot, Jean; Pilon, Geneviève; Marette, André; Bazinet, Laurent

2014-03-15

Soy peptides consumption has been associated with beneficial effects in type 2 diabetes patients. However, the peptide fractions responsible for these effects, and their mechanisms of action, have not been identified yet. In this study, we have isolated soybean peptides by electrodialysis with an ultrafiltration membrane (EDUF) at 50 V/100 kDa, and tested them for their capacity to improve glucose uptake in L6 muscle cells. We observed that these fractions were able to significantly enhance glucose uptake in the presence of insulin. The reported bioactivity would be due to the low molecular weight peptides (300-500 Da) recovered. Moreover, we observed that an enhancement of glucose uptake was correlated to the activation of the AMPK enzyme, well known for its capacity to increase glucose uptake in muscle cells. To our knowledge, this is the first time that bioactive peptides with glucose uptake activity have been isolated from a complex soy matrix, and that the implication of AMPK in it is demonstrated. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of oral glucose load on endothelial function and on insulin and glucose fluctuations in healthy individuals

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Major-Pedersen, A; Ihlemann, N; Hermann, T S

2008-01-01

to better understand and cope with the postprandial state in insulin resistant individuals. METHODS: We assessed post-oral glucose load endothelial function (flow mediated dilation), plasma insulin, and blood glucose in 9 healthy subjects. RESULTS: The largest increases in delta FMD values (fasting FMD......BACKGROUND/AIMS: Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order...... value subtracted from postprandial FMD value) occurred at 3 hours after both glucose or placebo load, respectively: 4.80 +/- 1.41 (P = .009) and 2.34 +/- 1.47 (P = .15). Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. CONCLUSION: Oral glucose load does not induce...

Bovine α-Lactalbumin Hydrolysates (α-LAH Ameliorate Adipose Insulin Resistance and Inflammation in High-Fat Diet-Fed C57BL/6J Mice

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Jing Gao

2018-02-01

Full Text Available Obesity-induced adipose inflammation has been demonstrated to be a key cause of insulin resistance. Peptides derived from bovine α-lactalbumin have been shown to inhibit the activities of dipeptidyl peptidase IV (DPP-IV and angiotensin converting enzyme (ACE, scavenge 2,2′-azinobis [3-ethylbenzothiazoline-6-sulfonate] (ABTS+ radical and stimulate glucagon-like peptide-2 secretion. In the present study, the effects of bovine α-lactalbumin hydrolysates (α-LAH on adipose insulin resistance and inflammation induced by high-fat diet (HFD were investigated. The insulin resistance model was established by feeding C57BL/6J mice with HFD (60% kcal from fat for eight weeks. Then, the mice were fed with HFD and bovine α-LAH of different doses (100 mg/kg b.w., 200 mg/kg b.w. and 400 mg/kg b.w. for another 12 weeks to evaluate its protective effects against HFD-induced insulin resistance. The oral glucose tolerance test (OGTT and intraperitoneal insulin tolerance test (ipITT were conducted after intervention with α-LAH for 10 weeks and 11 weeks, respectively. Results showed that bovine α-LAH significantly reduced body weight, blood glucose, serum insulin, and HOMA-IR (homeostatic model assessment of insulin resistance levels, lowered the area-under-the-curve (AUC during OGTT and ipITT, and downregulated inflammation-related gene [tumor necrosis factor (TNF-α, interleukin (IL-6, monocyte chemoattractant protein (MCP-1] expression in adipose tissues of HFD-fed C57BL/6J mice. Furthermore, bovine α-LAH also suppressed insulin receptor substrate 1 (IRS-1 serine phosphorylation (Ser307, Ser612, enhanced protein kinase B (known as Akt phosphorylation, and inhibited the activation of inhibitor of kappaB kinase (IKK and mitogen activated protein kinase (MAPK signaling pathways in adipose tissues of HFD-fed C57BL/6J mice. These results suggested that bovine α-LAH could ameliorate adipose insulin resistance and inflammation through IKK and MAPK signaling

The Association between Newborn Regional Body Composition and Cord Blood Concentrations of C-Peptide and Insulin-Like Growth Factor I.

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Emma M Carlsen

Full Text Available Third trimester fetal growth is partially regulated by C-peptide and insulin-like growth factor I (IGF-I. Prenatal exposures including maternal obesity and high gestational weight gain as well as high birth weight have been linked to subsequent metabolic disease. We evaluated the associations between newborn regional body composition and cord blood levels of C-peptide and IGF-I.We prospectively included obese and normal-weight mothers and their newborns; cord blood was collected and frozen. Analyses of C-peptide and IGF-I were performed simultaneously, after recruitment was completed. Newborn regional body composition was assessed with dual-energy X-ray absorptiometry scanning (DXA within 48 hours of birth.Three hundred thirty-six term infants were eligible to participate in the study; of whom 174 (52% infants had cord blood taken. Total, abdominal and arm and leg fat mass were positively associated with C-peptide (p < 0.001. Arm and leg fat mass was associated with IGF-I concentration: 28 g [95% confidence interval: 4, 53] per doubling of IGF-I. There was no association between total or abdominal fat mass and IGF-I. Fat-free mass was positively associated with both C-peptide (p < 0.001 and IGF-I (p = 0.004.Peripheral fat tissue accumulation was associated with cord blood C-peptide and IGF-I. Total and abdominal fat masses were related to C-peptide but not to IGF-I. Thus, newborn adiposity is partially mediated through C-peptide and early linear growth is associated with IGF-I.

Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

Science.gov (United States)

Blanco, Cynthia L; McGill-Vargas, Lisa L; Gastaldelli, Amalia; Seidner, Steven R; McCurnin, Donald C; Leland, Michelle M; Anzueto, Diana G; Johnson, Marney C; Liang, Hanyu; DeFronzo, Ralph A; Musi, Nicolas

2015-03-01

Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

Zinc Supplementation Does Not Alter Indicators of Insulin Secretion and Sensitivity in Black and White Female Adolescents.

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Lobene, Andrea J; Kindler, Joseph M; Jenkins, Nathan T; Pollock, Norman K; Laing, Emma M; Grider, Arthur; Lewis, Richard D

2017-07-01

Background: Zinc is a micronutrient involved in the production of, and peripheral sensitivity to, pancreatic β cell-derived insulin. To our knowledge, the effect of zinc supplementation on insulin outcomes, and potential risk of diabetes, in otherwise healthy children in the United States has not been investigated. Objective: The objective of this study was to determine the influence of zinc supplementation on insulin outcomes in black and white girls in the early stages of adolescence. A secondary objective was to determine relations between baseline zinc concentrations and insulin outcomes. Methods: Healthy black and white girls aged 9-11 y were randomly assigned to daily supplementation of zinc (9 mg elemental Zn/d; n = 75; blacks: n = 35) or placebo ( n = 72; blacks: n = 32) for 4 wk. Fasting serum insulin, glucose, and C-peptide were assessed at baseline and at 4 wk. C-peptide and glucose values were used to calculate the computer model-derived homeostatic model assessment of insulin resistance (HOMA2-IR). Changes in outcome measures were compared by using repeated-measures, mixed-model ANOVA. Results: Baseline plasma zinc was not correlated with C-peptide ( r = -0.07), insulin ( r = -0.06), or HOMA2-IR ( r = -0.09) (all P > 0.05) after controlling for race and age. Treatment × time interactions for C-peptide and HOMA2-IR were not significant (both P > 0.05). Although the treatment × race × time interactions for C-peptide and HOMA2-IR were not significant (both P = 0.08), black girls who received the placebo experienced slight increases in C-peptide (15.7%) and HOMA2-IR (17.7%) ( P = 0.06). Conclusions: Four weeks of zinc supplementation had no effect on insulin outcomes in healthy black and white early-adolescent girls, although C-peptide and HOMA2-IR tended to increase in black girls who received placebo. Additional trials that are appropriately powered should further explore the effect of zinc on markers of diabetes risk, and whether race affects this

Glucose-Responsive Implantable Polymeric Microdevices for "Smart" Insulin Therapy of Diabetes

Science.gov (United States)

Chu, Michael Kok Loon

Diabetes mellitus is a chronic illness manifested by improper blood glucose management, affecting over 350 million worldwide. As a result, all type 1 patients and roughly 20% of type 2 patients require exogenous insulin therapy to survive. Typically, daily multiple injections are taken to maintain normal glucose levels in response glucose spikes from meals. However, patient compliance and dosing accuracy can fluctuate with variation in meals, exercise, glucose metabolism or stress, leading to poor clinical outcomes. A 'smart', closed-loop insulin delivery system providing on-demand release kinetics responding to circulating glucose levels would be a boon for diabetes patients, replacing constant self monitoring and insulin. This thesis focuses on the development of a novel, 'smart' insulin microdevice that can provide on-demand insulin release in response to blood glucose levels. In the early stage, the feasibility of integrating a composite membrane with pH-responsive nanoparticles embedded in ethylcellulose membrane to provide pH-responsive in vitro release was examined and confirmed using a model drug, vitamin B12. In the second microdevice, glucose oxidase for generating pH signals from glucose oxidation, catalase and manganese dioxide nanoparticles, as peroxide scavengers, were used in a bioinorganic, albumin-based membrane cross-linked with a polydimethylsiloxane (PDMS) grid-microdevice system. This prototype device demonstrated insulin release in response to glucose levels in vitro and regulating plasma glucose in type 1 diabetic rats when implanted intraperitoneally. Advancement allowing for subcutaneous implantation and improved biocompatibility was achieved with surface modification of PDMS microdevices grafted with activated 20 kDa polyethylene glycol (PEG) chains, dramatically reducing immune response and local inflammation. When implanted subcutaneously in diabetic rats, glucose-responsive insulin delivery microdevices showed short and long

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.

Increased response to insulin of glucose metabolism in the 6-day unloaded rat soleus muscle

Science.gov (United States)

Henriksen, Erik J.; Tischler, Marc E.; Johnson, David G.

1986-01-01

Hind leg muscles of female rats were unloaded by tail cast suspension for 6 days. In the fresh-frozen unloaded soleus, the significantly greater concentration of glycogen correlated with a lower activity ratio of glycogen phosphorylase (p less than 0.02). The activity ratio of glycogen synthase also was lower (p less than 0.001), possibly due to the higher concentration of glycogen. In isolated unloaded soleus, insulin (0.1 milliunit/ml) increased the oxidation of D(U-C-14) glucose, release of lactate and pyruvate, incorporation of D-(U-C-14) glucose into glycogen, and the concentration of glucose 6-phosphate more (p less than 0.05) than in the weight-bearing soleus. At physiological doses of insulin, the percent of maximal uptake of 2-deoxy-D-(1,2-H-3) glucose/muscle also was greater in the unloaded soleus. Unloading of the soleus increased, by 50 percent the concentration of insuling receptors, due to no decrease in total receptor number during muscle atrophy. This increase may account for the greater response of glucose metabolism to insulin in this muscle. The extensor digitorum longus, which generally shows little response to unloading, displayed no differential response of glucose metabolism to insulin.

Conjoint regulation of glucagon concentrations via plasma insulin and glucose in dairy cows.

Science.gov (United States)

Zarrin, M; Wellnitz, O; Bruckmaier, R M

2015-04-01

Insulin and glucagon are glucoregulatory hormones that contribute to glucose homeostasis. Plasma insulin is elevated during normoglycemia or hyperglycemia and acts as a suppressor of glucagon secretion. We have investigated if and how insulin and glucose contribute to the regulation of glucagon secretion through long term (48 h) elevated insulin concentrations during simultaneous hypoglycemia or euglycemia in mid-lactating dairy cows. Nineteen Holstein dairy cows were randomly assigned to 3 treatment groups: an intravenous insulin infusion (HypoG, n = 5) to decrease plasma glucose concentrations (2.5 mmol/L), a hyperinsulinemic-euglycemic clamp to study effects of insulin at simultaneously normal glucose concentrations (EuG, n = 6) and a 0.9% saline infusion (NaCl, n = 8). Plasma glucose was measured at 5-min intervals, and insulin and glucose infusion rates were adjusted accordingly. Area under the curve of hourly glucose, insulin, and glucagon concentrations on day 2 of infusion was evaluated by analysis of variance with treatments as fixed effect. Insulin infusion caused an increase of plasma insulin area under the curve (AUC)/h in HypoG (41.9 ± 8.1 mU/L) and EuG (57.8 ± 7.8 mU/L) compared with NaCl (13.9 ± 1.1 mU/L; P insulin infusion induces elevated glucagon concentrations during hypoglycemia, although the same insulin infusion reduces glucagon concentrations at simultaneously normal glucose concentrations. Thus, insulin does not generally have an inhibitory effect on glucagon concentrations. If simultaneously glucose is low and insulin is high, glucagon is upregulated to increase glucose availability. Therefore, insulin and glucose are conjoint regulatory factors of glucagon concentrations in dairy cows, and the plasma glucose status is the key factor to decide if its concentrations are increased or decreased. This regulatory effect can be important for the maintenance of glucose homeostasis if insulin secretion is upregulated by other factors than high

Cdk5 inhibitory peptide (CIP inhibits Cdk5/p25 activity induced by high glucose in pancreatic beta cells and recovers insulin secretion from p25 damage.

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Ya-Li Zheng

Full Text Available Cdk5/p25 hyperactivity has been demonstrated to lead to neuron apoptosis and degenerations. Chronic exposure to high glucose (HG results in hyperactivity of Cdk5 and reduced insulin secretion. Here, we set out to determine whether abnormal upregulation of Cdk5/p25 activity may be induced in a pancreatic beta cell line, Min6 cells. We first confirmed that p25 were induced in overexpressed p35 cells treated with HG and increased time course dependence. Next, we showed that no p25 was detected under short time HG stimulation (4-12 hrs, however was detectable in the long exposure in HG cells (24 hrs and 48 hrs. Cdk5 activity in the above cells was much higher than low glucose treated cells and resulted in more than 50% inhibition of insulin secretion. We confirmed these results by overexpression of p25 in Min6 cells. As in cortical neurons, CIP, a small peptide, inhibited Cdk5/p25 activity and restored insulin secretion. The same results were detected in co-infection of dominant negative Cdk5 (DNCdk5 with p25. CIP also reduced beta cells apoptosis induced by Cdk5/p25. These studies indicate that Cdk5/p25 hyperactivation deregulates insulin secretion and induces cell death in pancreatic beta cells and suggests that CIP may serve as a therapeutic agent for type 2 diabetes.

Efficacy of 2-hour post glucose insulin levels in predicting insulin resistance in polycystic ovarian syndrome with infertility

Directory of Open Access Journals (Sweden)

Pikee Saxena

2011-01-01

Full Text Available Background : Insulin resistance (IR is central to the pathogenesis of polycystic ovarian syndrome (PCOS, but tests for determining IR are elaborate, tedious and expensive. Aims : To evaluate if "2-hour post-glucose insulin level" is an effective indicator of IR and can aid in diagnosing IR in infertile PCOS women. Settings and Design : Observational study at infertility clinic of a tertiary care center. Materials and Methods : 50 infertile women with PCOS and 20 females with tubal/male factor infertility were evaluated for the presence of IR, as defined by the fasting/2-hour post-glucose insulin levels cutoffs of >25/>41 μU/mL, respectively. The clinical, metabolic and endocrinologic profile was determined in both the groups. Statistical Analysis : Statistical analysis was performed using SPSS (Chicago, IL, USA. Results : Body mass index, post load glucose, insulin, glucose/insulin ratio, area under curve (AUC of glucose and insulin and insulinogenic index were significantly lower in the controls as compared to the PCOS group. "2-hour post-glucose insulin levels" were elevated in 88% of PCOS individuals but were normal in all females not suffering from PCOS. These levels significantly correlated with AUC of glucose and insulin, and insulinogenic index and inversely correlated with 2-hour glucose to insulin ratio (r=0.827, 0.749 and −0.732, respectively. Conclusions : "2-hour post-glucose insulin levels" appears to be a good indicator of IR. It can be a useful tool, especially in low resource setting where a single sample can confirm the diagnosis, thus reducing cost and repeat visits.

Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice

NARCIS (Netherlands)

Coomans, Claudia P.; Biermasz, Nienke R.; Geerling, Janine J.; Guigas, Bruno; Rensen, Patrick C. N.; Havekes, Louis M.; Romijn, Johannes A.

2011-01-01

Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated

Central insulin and leptin-mediated autonomic control of glucose homeostasis.

Science.gov (United States)

Marino, Joseph S; Xu, Yong; Hill, Jennifer W

2011-07-01

Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

TCPTP Regulates Insulin Signalling in AgRP Neurons to Coordinate Glucose Metabolism with Feeding.

Science.gov (United States)

Dodd, Garron T; Lee-Young, Robert S; Brüning, Jens C; Tiganis, Tony

2018-04-30

Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signalling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signalling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons ( Agrp -Cre; Ptpn2 fl/fl ) enhanced insulin sensitivity as assessed by the increased glucose infusion rates and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [ 14 C]-2-deoxy-D-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp -Cre; Ptpn2 fl/fl mice was corrected by IR heterozygosity ( Agrp -Cre; Ptpn2 fl/fl ; Insr fl/+ ), causally linking the effects on glucose metabolism with the IR signalling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signalling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting. © 2018 by the American Diabetes Association.

Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice

NARCIS (Netherlands)

Coomans, C.P.; Biermasz, N.R.; Geerling, J.J.; Guigas, B.; Rensen, P.C.N.; Havekes, L.M.; Romijn, J.A.

2011-01-01

OBJECTIVE - Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated

Protective effect of C-peptide on experimentally induced diabetic nephropathy and the possible link between C-peptide and nitric oxide.

Science.gov (United States)

Elbassuoni, Eman A; Aziz, Neven M; El-Tahawy, Nashwa F

2018-06-01

Diabetic nephropathy one of the major microvascular diabetic complications. Besides hyperglycemia, other factors contribute to the development of diabetic complications as the proinsulin connecting peptide, C-peptide. We described the role of C-peptide replacement therapy on experimentally induced diabetic nephropathy, and its potential mechanisms of action by studying the role of nitric oxide (NO) as a mediator of C-peptide effects by in vivo modulating its production by N G -nitro-l-arginine methyl ester (L-NAME). Renal injury markers measured were serum urea, creatinine, tumor necrosis factor alpha, and angiotensin II, and malondialdehyde, total antioxidant, Bcl-2, and NO in renal tissue. In conclusion, diabetic induction resulted in islet degenerations and decreased insulin secretion with its metabolic consequences and subsequent renal complications. C-Peptide deficiencies in diabetes might have contributed to the metabolic and renal error, since C-peptide treatment to the diabetic rats completely corrected these errors. The beneficial effects of C-peptide are partially antagonized by L-NAME coadministration, indicating that NO partially mediates C-peptide effects.

The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

Science.gov (United States)

2014-01-01

The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies. PMID:24990862

Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance

DEFF Research Database (Denmark)

Jørgensen, N B; Jacobsen, S H; Dirksen, C

2012-01-01

meal before (Pre), 1 wk, 3 mo, and 1 yr after RYGB. Glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), glucose-dependent-insulinotropic polypeptide (GIP), and glucagon concentrations were measured. Insulin resistance (HOMA-IR), ß-cell glucose sensitivity (ß-GS), and disposition index (D......(ß-GS): ß-GS × 1/HOMA-IR) were calculated. Within the first week after RYGB, fasting glucose [T2D Pre: 8.8 ± 2.3, 1 wk: 7.0 ± 1.2 (P ....003)] but not in NGT. HOMA-IR decreased by 50% in both groups. ß-GS increased in T2D [Pre: 1.03 ± 0.49, 1 wk: 1.70 ± 1.2, (P = 0.012)] but did not change in NGT. The increase in DI(ß-GS) was 3-fold in T2D and 1.5-fold in NGT. After RYGB, glucagon secretion was increased in response to the meal. GIP secretion...

Circulating Dopamine and C-Peptide Levels in Fasting Nondiabetic Hypertensive Patients

OpenAIRE

Tomaschitz, Andreas; Ritz, Eberhard; Kienreich, Katharina; Pieske, Burkert; M?rz, Winfried; Boehm, Bernhard O.; Drechsler, Christiane; Meinitzer, Andreas; Pilz, Stefan

2012-01-01

OBJECTIVE Accumulating evidence supports a potential role for dopamine in the regulation of insulin secretion. We examined the association between circulating dopamine and C-peptide concentrations using data from the Graz Endocrine Causes of Hypertension (GECOH) study. RESEARCH DESIGN AND METHODS After 12 h of fasting, we measured plasma dopamine and serum C-peptide levels and established determining factors of insulin secretion in 201 nondiabetic hypertensive patients (mean age 48.1 ? 16.0 y...

Semisolid meal enriched in oat bran decreases plasma glucose and insulin levels, but does not change gastrointestinal peptide responses or short-term appetite in healthy subjects

DEFF Research Database (Denmark)

Juvonen, Kristiina R.; Salmenkallio-Marttila, Marjatta; Lyly, Marika

2011-01-01

types and amounts of DF exert are still poorly understood. METHODS AND RESULTS: We investigated the effects of wheat and oat brans alone and as combination in semisolid food matrix on postprandial appetite profile and gastrointestinal (GI) hormonal responses. Twenty healthy, normal-weight subjects (5...... including 5 g wheat bran DF + 5 g oat bran DF. Blood samples were drawn before and 15, 30, 45, 60, 90, 120 and 180 min after the test meals to determine plasma glucose, ghrelin, peptide YY (PYY) and serum insulin concentrations. Subjective profiles of appetite were assessed using visual analogue scales (VAS...

Differentiation of the insulin-sensitive glucose transporter in 3T3-L1 adipocytes

International Nuclear Information System (INIS)

Frost, S.C.; Baly, D.L.; Cushman, S.W.; Lane, M.D.; Simpson, I.A.

1986-01-01

3T3-L1 fibroblasts differentiate in culture to resemble adipocytes both morphologically and biochemically. Insulin-sensitive glucose transport, as measured by 2-deoxy-[1- 14 C]- glucose uptake in the undifferentiated cell is small (2X). In contrast, the rate of glucose transport in fully differentiated cells is elevated 15-fold over basal in the presence of insulin. To determine if this is due to an increase in the number of transporters/cell or accessibility to the transporters, the number of transporters was measured in subcellular fractions over differentiation using a 3 H-cytochalasin B binding assay. The increase in the rate of insulin-sensitive glucose transport directly parallels an increase in the number of transporters which reside in an insulin-responsive intracellular compartment. This observation was confirmed by identifying the transporters by immunoblotting using an antibody generated against the human erythrocyte transporter. The molecular weight of this transporter increases over differentiation from a single band of 40kDa to a heterogeneous triplet of 40, 44 and 48kDa. These data suggest that the transporter undergoes differential processing and that the functional, insulin-responsive transporter may be different from the insulin-insensitive (basal) transporter

Effects of exercise training on glucose control, lipid metabolism, and insulin sensitivity in hypertriglyceridemia and non-insulin dependent diabetes mellitus.

Science.gov (United States)

Lampman, R M; Schteingart, D E

1991-06-01

Exercise training has potential benefits for patients with hyperlipidemia and/or non-insulin dependent diabetes mellitus. In nondiabetic, nonobese subjects with hypertriglyceridemia, exercise training alone increased insulin sensitivity, improved glucose tolerance, and lowered serum triglyceride and cholesterol levels. These improvements did not occur when exercise training alone was given to similar patients with impaired glucose tolerance. In severely obese (X = 125 kg) subjects without diabetes melitus, a 600 calorie diet alone decreased glucose and insulin concentrations and improved glucose tolerance but did not increase insulin sensitivity. The addition of exercise training improved insulin sensitivity. Obese, non-insulin dependent diabetes mellitus subjects on sulfonylurea therapy alone increased insulin levels but failed to improve insulin sensitivity or glucose levels. In contrast, the addition of exercise training to this medication resulted in improved insulin sensitivity and lowered glucose levels. We conclude that exercise training has major effects on lowering triglyceride levels in hyperlipidemic subjects and can potentiate the effect of diet or drug therapy on glucose metabolism in patients with non-insulin dependent diabetes mellitus.

Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin’s Metabolic Action in the Presence of Insulin Resistance

Science.gov (United States)

Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.

2014-01-01

Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin’s metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy. PMID:24658303

The Proton-Activated Receptor GPR4 Modulates Glucose Homeostasis by Increasing Insulin Sensitivity

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Luca Giudici

2013-11-01

Full Text Available Background: The proton-activated G protein-coupled receptor GPR4 is expressed in many tissues including white adipose tissue. GPR4 is activated by extracellular protons in the physiological pH range (i.e. pH 7.7 - 6.8 and is coupled to the production of cAMP. Methods: We examined mice lacking GPR4 and examined glucose tolerance and insulin sensitivity in young and aged mice as well as in mice fed with a high fat diet. Expression profiles of pro- and anti-inflammatory cytokines in white adipose tissue, liver and skeletal muscle was assessed. Results: Here we show that mice lacking GPR4 have an improved intraperitoneal glucose tolerance test and increased insulin sensitivity. Insulin levels were comparable but leptin levels were increased in GPR4 KO mice. Gpr4-/- showed altered expression of PPARα, IL-6, IL-10, TNFα, and TGF-1β in skeletal muscle, white adipose tissue, and liver. High fat diet abolished the differences in glucose tolerance and insulin sensitivity between Gpr4+/+ and Gpr4-/- mice. In contrast, in aged mice (12 months old, the positive effect of GPR4 deficiency on glucose tolerance and insulin sensitivity was maintained. Liver and adipose tissue showed no major differences in the mRNA expression of pro- and anti-inflammatory factors between aged mice of both genotypes. Conclusion: Thus, GPR4 deficiency improves glucose tolerance and insulin sensitivity. The effect may involve an altered balance between pro- and anti-inflammatory factors in insulin target tissues.

Scoparia dulcis (SDF7) endowed with glucose uptake properties on L6 myotubes compared insulin.

Science.gov (United States)

Beh, Joo Ee; Latip, Jalifah; Abdullah, Mohd Puad; Ismail, Amin; Hamid, Muhajir

2010-05-04

Insulin stimulates glucose uptake and promotes the translocation of glucose transporter 4 (Glut 4) to the plasma membrane on L6 myotubes. The aim of this study is to investigate affect of Scoparia dulcis Linn water extracts on glucose uptake activity and the Glut 4 translocation components (i.e., IRS-1, PI 3-kinase, PKB/Akt2, PKC and TC 10) in L6 myotubes compared to insulin. Extract from TLC fraction-7 (SDF7) was used in this study. The L6 myotubes were treated by various concentrations of SDF7 (1 to 50 microg/ml) and insulin (1 to 100 nM). The glucose uptake activities of L6 myotubes were evaluated using 2-Deoxy-D-glucose uptake assay in with or without fatty acid-induced medium. The Glut 4 translocation components in SDF7-treated L6 myotubes were detected using immunoblotting and quantified by densitometry compared to insulin. Plasma membrane lawn assay and glycogen colorimetry assay were carried out in SDF7- and insulin-treated L6 myotubes in this study. Here, our data clearly shows that SDF7 possesses glucose uptake properties on L6 myotubes that are dose-dependent, time-dependent and plasma membrane Glut 4 expression-dependent. SDF7 successfully stimulates glucose uptake activity as potent as insulin at a maximum concentration of 50 microg/ml at 480 min on L6 myotubes. Furthermore, SDF7 stimulates increased Glut 4 expression and translocation to plasma membranes at equivalent times. Even in the insulin resistance stage (free fatty acids-induced), SDF7-treated L6 myotubes were found to be more capable at glucose transport than insulin treatment. Thus, we suggested that Scoparia dulcis has the potential to be categorized as a hypoglycemic medicinal plant based on its good glucose transport properties. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Insulin-dependent glucose metabolism in dairy cows with variable fat mobilization around calving.

Science.gov (United States)

Weber, C; Schäff, C T; Kautzsch, U; Börner, S; Erdmann, S; Görs, S; Röntgen, M; Sauerwein, H; Bruckmaier, R M; Metges, C C; Kuhla, B; Hammon, H M

2016-08-01

Dairy cows undergo significant metabolic and endocrine changes during the transition from pregnancy to lactation, and impaired insulin action influences nutrient partitioning toward the fetus and the mammary gland. Because impaired insulin action during transition is thought to be related to elevated body condition and body fat mobilization, we hypothesized that over-conditioned cows with excessive body fat mobilization around calving may have impaired insulin metabolism compared with cows with low fat mobilization. Nineteen dairy cows were grouped according to their average concentration of total liver fat (LFC) after calving in low [LLFC; LFC 24.4% total fat/DM; n=10) fat-mobilizing cows. Blood samples were taken from wk 7 antepartum (ap) to wk 5 postpartum (pp) to determine plasma concentrations of glucose, insulin, glucagon, and adiponectin. We applied euglycemic-hyperinsulinemic (EGHIC) and hyperglycemic clamps (HGC) in wk 5 ap and wk 3 pp to measure insulin responsiveness in peripheral tissue and pancreatic insulin secretion during the transition period. Before and during the pp EGHIC, [(13)C6] glucose was infused to determine the rate of glucose appearance (GlucRa) and glucose oxidation (GOx). Body condition, back fat thickness, and energy-corrected milk were greater, but energy balance was lower in HLFC than in LLFC. Plasma concentrations of glucose, insulin, glucagon, and adiponectin decreased at calving, and this was followed by an immediate increase of glucagon and adiponectin after calving. Insulin concentrations ap were higher in HLFC than in LLFC cows, but the EGHIC indicated no differences in peripheral insulin responsiveness among cows ap and pp. However, GlucRa and GOx:GlucRa during the pp EGHIC were greater in HLFC than in LLFC cows. During HGC, pancreatic insulin secretion was lower, but the glucose infusion rate was higher pp than ap in both groups. Plasma concentrations of nonesterified fatty acids decreased during HGC and EGHIC, but in both

Dissociation of in vitro sensitivities of glucose transport and antilipolysis to insulin in NIDDM

International Nuclear Information System (INIS)

Yki-Jaervinen, H.; Kubo, K.; Zawadzki, J.; Lillioja, S.; Young, A.; Abbott, W.; Foley, J.E.

1987-01-01

It is unclear from previous studies whether qualitative or only quantitative differences exist in insulin action in adipocytes obtained from obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) when compared with equally obese nondiabetic subjects. In addition, the role of changes in insulin binding as a cause of insulin resistance in NIDDM is still controversial. The authors compared the sensitivities of [ 14 C]-glucose transport and antilipolysis to insulin and measured [ 125 I]-insulin binding in abdominal adipocytes obtained from 45 obese nondiabetic, obese diabetic, and 15 nonobese female southwestern American Indians. Compared with the nonobese group, the sensitivities of glucose transport antilipolysis were reduced in both the obese nondiabetic and obese diabetic groups. Compared with the obese nondiabetic subjects, the ED 50 for stimulation of glucose transport was higher in the obese patients with NIDDM. In contrast, the ED 50 S for antilipolysis were similar in obese diabetic patients and obese nondiabetic subjects. No differences was found in insulin binding in patients with NIDDM when compared with the equally obese nondiabetic subjects. These data indicate 1) the mechanism of insulin resistance differs in NIDDM and obesity, and 2) the selective loss of insulin sensitivity in NIDDM precludes changes in insulin binding as a cause of insulin resistance in this disorder

Central insulin and leptin-mediated autonomic control of glucose homeostasis

OpenAIRE

Marino, Joseph S.; Xu, Yong; Hill, Jennifer W.

2011-01-01

Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular...

Influence of Flavonoids on Mechanism of Modulation of Insulin Secretion.

Science.gov (United States)

Soares, Juliana Mikaelly Dias; Pereira Leal, Ana Ediléia Barbosa; Silva, Juliane Cabral; Almeida, Jackson R G S; de Oliveira, Helinando Pequeno

2017-01-01

-dependent protein kinase II, GSIS: Glucose-stimulated insulin secretion, Insig-1: Insulin-induced gene 1, IRS-2: Insulin receptor substrate 2, PDX-1: Pancreatic and duodenal homeobox 1, SREBP-1c: Sterol regulatory element binding protein-1c, DMC: Dihydroxy-6'-methoxy-3',5'-dimethylchalcone, GLP-1: Glucagon-like peptide-1, GLP-1R: Glucagon-like peptide 1 receptor.

Insulin binding and glucose transport in adipocytes of acarbose-treated Zucker lean and obese rats.

Science.gov (United States)

Vasselli, J R; Flory, T; Fried, S K

1987-01-01

The intestinal glucosidase inhibitor acarbose was administered as a dietary admix (30 mg/100 g chow diet) to male Zucker obese and lean rats. After 15 weeks, epidiymal fat pads were removed and adipocytes isolated by collagenase digestion. Equilibrium binding of A-14 tyrosine 125I-insulin, and transport of U-14C-glucose was determined was adipocytes incubated for 50 min at 37 degrees C in 0-16000 pM insulin. Insulin binding/cell was enhanced two-fold in lean (P less than 0.01) and obese (n.s.) drug groups. In drug-treated leans, increased sensitivity of glucose transport to submaximally stimulating concentrations of insulin was observed (P less than 0.02). For both genotypes, acarbose mildly decreased insulin levels and body weight gain, although adipocyte size was unaffected. Results indicate that enhanced insulin binding accompanies metabolic improvements induced by acarbose in lean Zucker rats.

Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4.

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Pearson-Leary, J; Jahagirdar, V; Sage, J; McNay, E C

2018-02-15

The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

Closed-loop controlled noninvasive ultrasonic glucose sensing and insulin delivery

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Park, Eun-Joo; Werner, Jacob; Jaiswal, Devina; Smith, Nadine Barrie

2010-03-01

To prevent complications in diabetes, the proper management of blood glucose levels is essential. Previously, ultrasonic transdermal methods using a light-weight cymbal transducer array has been studied for noninvasive methods of insulin delivery for Type-1 diabetes and glucose level monitoring. In this study, the ultrasound systems of insulin delivery and glucose sensing have been combined by a feedback controller. This study was designed to show the feasibility of the feedback controlled ultrasound system for the noninvasive glucose control. For perspective human application, in vivo experiments were performed on large animals that have a similar size to humans. Four in vivo experiments were performed using about 200 lbs pigs. The cymbal array of 3×3 pattern has been used for insulin delivery at 30 kHz with the spatial-peak temporal-peak intensity (Isptp) of 100 mW/cm2. For glucose sensing, a 2×2 array was operated at 20 kHz with Isptp = 100 mW/cm2. Based on the glucose level determined by biosensors after the ultrasound exposure, the ultrasound system for the insulin delivery was automatically operated. The glucose level of 115 mg/dl was set as a reference value for operating the insulin delivery system. For comparison, the glucose levels of blood samples collected from the ear vein were measured by a commercial glucose meter. Using the ultrasound system operated by the close-loop, feed-back controller, the glucose levels of four pigs were determined every 20 minutes and continuously controlled for 120 minutes. In comparison to the commercial glucose meter, the glucose levels determined by the biosensor were slightly higher. The results of in vivo experiments indicate the feasibility of the feedback controlled ultrasound system using the cymbal array for noninvasive glucose sensing and insulin delivery. Further studies on the extension of the glucose control will be continued for the effective method of glucose control.

The Glucose-Insulin Control System

DEFF Research Database (Denmark)

Hallgreen, Christine Erikstrup; Korsgaard, Thomas Vagn; Hansen, RenéNormann N.

2008-01-01

This chapter reviews the glucose-insulin control system. First, classic control theory is described briefly and compared with biological control. The following analysis of the control system falls into two parts: a glucose-sensing part and a glucose-controlling part. The complex metabolic pathways...... are divided into smaller pieces and analyzed via several small biosimulation models that describe events in beta cells, liver, muscle and adipose tissue etc. In the glucose-sensing part, the beta cell are shown to have some characteristics of a classic PID controller, but with nonlinear properties...... control, the analysis shows that the system has many more facets than just keeping the glucose concentration within narrow limits. After glucose enters the cell and is phosphorylated to glucose-6-phosphate, the handling of glucose-6-phosphate is critical for glucose regulation. Also, this handling...

Proximity to Delivery Alters Insulin Sensitivity and Glucose Metabolism in Pregnant Mice.

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Musial, Barbara; Fernandez-Twinn, Denise S; Vaughan, Owen R; Ozanne, Susan E; Voshol, Peter; Sferruzzi-Perri, Amanda N; Fowden, Abigail L

2016-04-01

In late pregnancy, maternal insulin resistance occurs to support fetal growth, but little is known about insulin-glucose dynamics close to delivery. This study measured insulin sensitivity in mice in late pregnancy at day 16 (D16) and near term at D19. Nonpregnant (NP) and pregnant mice were assessed for metabolite and hormone concentrations, body composition by DEXA, tissue insulin signaling protein abundance by Western blotting, glucose tolerance and utilization, and insulin sensitivity using acute insulin administration and hyperinsulinemic-euglycemic clamps with [(3)H]glucose infusion. Whole-body insulin resistance occurred in D16 pregnant dams in association with basal hyperinsulinemia, insulin-resistant endogenous glucose production, and downregulation of several proteins in hepatic and skeletal muscle insulin signaling pathways relative to NP and D19 values. Insulin resistance was less pronounced at D19, with restoration of NP insulin concentrations, improved hepatic insulin sensitivity, and increased abundance of hepatic insulin signaling proteins. At D16, insulin resistance at whole-body, tissue, and molecular levels will favor fetal glucose acquisition, while improved D19 hepatic insulin sensitivity will conserve glucose for maternal use in anticipation of lactation. Tissue sensitivity to insulin, therefore, alters differentially with proximity to delivery in pregnant mice, with implications for human and other species. © 2016 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.

The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity.

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Kelly, Karen R; Brooks, Latina M; Solomon, Thomas P J; Kashyap, Sangeeta R; O'Leary, Valerie B; Kirwan, John P

2009-06-01

Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 +/- 1.5 yr), obese (34.4 +/- 1.7 kg/m(2)) adults with impaired glucose tolerance. In addition to GIP, plasma PYY(3-36), insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in Vo(2 max) (P HYPO (-8.3 +/- 1.1 vs. -2.8 +/- 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO (P = 0.02), as was the glucose-stimulated GIP response (P caloric restriction and exercise reduces the GIP response to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults.

Intragastric administration of leucine or isoleucine lowers the blood glucose response to a mixed-nutrient drink by different mechanisms in healthy, lean volunteers.

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Ullrich, Sina S; Fitzgerald, Penelope Ce; Schober, Gudrun; Steinert, Robert E; Horowitz, Michael; Feinle-Bisset, Christine

2016-11-01

The branched-chain amino acids leucine and isoleucine lower blood glucose after oral glucose ingestion, and the intraduodenal infusion of leucine decreases energy intake in healthy, lean men. We investigated the effects of the intragastric administration of leucine and isoleucine on the gastric emptying of, and blood glucose responses to, a physiologic mixed-macronutrient drink and subsequent energy intake. In 2 separate studies, 12 healthy, lean subjects received on 3 separate occasions an intragastric infusion of 5 g leucine (leucine-5g) or an intragastric infusion of 10 g leucine (leucine-10g), an intragastric infusion of 5 g isoleucine (isoleucine-5g) or an intragastric infusion of 10 g isoleucine (isoleucine-10g), or a control. Fifteen minutes later, subjects consumed a mixed-nutrient drink (400 kcal, 56 g carbohydrates, 15 g protein, and 12 g fat), and gastric emptying ( 13 C-acetate breath test) and blood glucose, plasma insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (leucine study only) were measured for 60 min. Immediately afterward, energy intake from a cold, buffet-style meal was assessed. Compared with the control, leucine-10g decreased the blood glucose area under the curve (AUC) (P blood glucose (P = 0.07), whereas effects of leucine-5g were NS. Leucine-10g, but not leucine-5g, increased plasma insulin and C-peptide AUCs (P blood glucose AUC and peak blood glucose (P blood glucose AUC. Isoleucine did not affect energy intake. In healthy subjects, both leucine and isoleucine reduced blood glucose in response to a mixed-nutrient drink but did not affect subsequent energy intake. The mechanisms underlying glucose lowering appear to differ; leucine stimulated insulin, whereas isoleucine acted insulin independently. These trials were registered at www.anzctr.org.au as 12613000899741 and 12614000837628. © 2016 American Society for Nutrition.

Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats.

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Matveyenko, Aleksey V; Georgia, Senta; Bhushan, Anil; Butler, Peter C

2010-11-01

Embryonic stem cell therapy has been proposed as a therapeutic strategy to restore β-cell mass and function in T1DM. Recently, a group from Novocell (now ViaCyte) reported successful development of glucose-responsive islet-like structures after implantation of pancreatic endoderm (PE) derived from human embryonic stem cells (hESC) into immune-deficient mice. Our objective was to determine whether implantation of hESC-derived pancreatic endoderm from Novocell into athymic nude rats results in development of viable glucose-responsive pancreatic endocrine tissue. Athymic nude rats were implanted with PE derived from hESC either via implantation into the epididymal fat pads or by subcutaneous implantation into TheraCyte encapsulation devices for 20 wk. Blood glucose, weight, and human insulin/C-peptide secretion were monitored by weekly blood draws. Graft β-cell function was assessed by a glucose tolerance test, and graft morphology was assessed by immunohistochemistry and immunofluorescence. At 20 wk postimplantation, epididymal fat-implanted PE progressed to develop islet-like structures in 50% of implants, with a mean β-cell fractional area of 0.8 ± 0.3%. Human C-peptide and insulin were detectable, but at very low levels (C-peptide = 50 ± 26 pmol/l and insulin = 15 ± 7 pmol/l); however, there was no increase in human C-peptide/insulin levels after glucose challenge. There was no development of viable pancreatic tissue or meaningful secretory function when human PE was implanted in the TheraCyte encapsulation devices. These data confirm that islet-like structures develop from hESC differentiated to PE by the protocol developed by NovoCell. However, the extent of endocrine cell formation and secretory function is not yet sufficient to be clinically relevant.

Insulin appearance of subcutaneously infused insulin: influence of the basal rate pulse interval of the infusion pump.

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Birch, K; Hildebrandt, P; Jensen, B M; Kühl, C; Brange, J

1985-05-01

To compare the metabolic control and the pharmacokinetics of infused insulin using an insulin pump (Auto-Syringe AS 6C) which provides the basal rate in pulses every 2-10 min with a pump (Medix Syringe Driver 209) providing the basal rate in pulses every 15-60 min, 6 C-peptide negative diabetic patients received, in random order, identical, but individual, insulin treatment during one 4-day period using the Auto-Syringe pump and another 4-day period using the Medix pump. On the fourth day of each period, blood glucose and plasma-free insulin were estimated every 30 min for 7 hr and every 5 min for the next hour. Plasma-free insulin was significantly higher on 3 time points out of the 26 possible when using the Medix pump, but this was not reflected in the blood glucose concentrations which were similar in the 2 periods. The results indicate that, from a metabolic and pharmacokinetic point of view, insulin pumps working with larger intervals between the basal rate pulses are just as good as the more technically advanced and hence often more expensive pumps which provide the basal rate in more and smaller pulses.

Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance.

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Du, Caiqi; Zhang, Cai; Wu, Wei; Liang, Yan; Wang, Anru; Wu, Shimin; Zhao, Yue; Hou, Ling; Ning, Qin; Luo, Xiaoping

2018-04-25

A novel bioactive peptide, mitochondrial-derived peptide (MOTS-c), has recently attracted attention as a potential prevention or therapeutic option for obesity and type 2 diabetes mellitus (T2DM). MOTS-c profiles have not yet been reported in human obesity and T2DM. We aimed to determine circulating MOTS-c levels in obesity and explore the association between MOTS-c levels and various metabolic parameters. In this case-control study, 40 obese children and adolescents (27 males) and 57 controls (40 males) were recruited in the Hubei Province of China in 2017. Circulating MOTS-c levels were measured, clinical data (e.g., glucose, insulin and lipid profile) were recorded, and anthropometric measurements were performed. Finally, we investigated correlations between MOTS-c levels and related variables. MOTS-c levels were significantly decreased in the obese group compared with the control group (472.61 ± 22.83 ng/mL vs. 561.64 ± 19.19 ng/mL, p c levels were significantly decreased in obese male children and adolescents compared to their counterparts (465.26 ± 24.53 ng/mL vs. 584.07 ± 21.18 ng/mL, p 0.05). Further, MOTS-c levels were negatively correlated with body mass index (BMI), BMI standard deviation score, waist circumference, waist-to-hip ratio, fasting insulin level, HOMA-IR, and HbA1c in the male cohort. Circulating MOTS-c levels were decreased in obese male children and adolescents and correlated with markers of insulin resistance and obesity. This article is protected by copyright. All rights reserved.

Resistant starch and arabinoxylan augment SCFA absorption, but affect postprandial glucose and insulin responses differently - CORRIGENDUM

DEFF Research Database (Denmark)

Ingerslev, Anne Krog; Theil, Peter Kappel; Hedemann, Mette Skou

2015-01-01

The effects of increased colonic fermentation of dietary fibres (DF) on net portal flux (NPF) of carbohydrate-derived metabolites (glucose, SCFA and especially butyrate), hormones (insulin, C-peptide, GLP-1, GIP) and NEFA were studied in a healthy catheterised pig model. Six 59 ± 3.8 kg pigs were...... fitted with catheters in the mesenteric artery, the portal and hepatic vein, and a flowprobe around the portal vein and included in a double 3x3 crossover design with three daily feedings (at 9.00, 14.00 and 19.00 hours). Fasting and 5 hours postprandial blood samples were collected after 7 days...... adaptation to each diet. The pigs were fed a low DF western style control diet (WSD) and two high DF diets; an arabinoxylan (AXD) and a resistant starch (RSD) enriched diet. The NPF of insulin was lower (P = 0.04) in AXD fed pigs (4.6 nmol/h) compared to RSD fed pigs (10.5 nmol/h), despite the lowest NPF...

Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice

DEFF Research Database (Denmark)

Gustavsson, Natalia; Lao, Ye; Maximov, Anton

2008-01-01

and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium...... secretion in pancreatic beta-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic beta-cells. To determine whether synaptotagmin-7 regulates Ca(2+)-dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance...... responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor...

Cephalic phase secretion of insulin and other enteropancreatic hormones in humans

DEFF Research Database (Denmark)

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

2016-01-01

Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic blockade in 10 glucose-clamped healthy men (age: 24.5 ± 0.6 yr, means ± SE; body mass index: 24.0 ± 0.5 kg...... and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min...... and 3.7 ± 21 pg/ml (means ± SE), P phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin....

Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians12

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Fretts, Amanda M; Follis, Jack L; Nettleton, Jennifer A; Lemaitre, Rozenn N; Ngwa, Julius S; Wojczynski, Mary K; Kalafati, Ioanna Panagiota; Varga, Tibor V; Frazier-Wood, Alexis C; Houston, Denise K; Lahti, Jari; Ericson, Ulrika; van den Hooven, Edith H; Mikkilä, Vera; Kiefte-de Jong, Jessica C; Mozaffarian, Dariush; Rice, Kenneth; Renström, Frida; North, Kari E; McKeown, Nicola M; Feitosa, Mary F; Kanoni, Stavroula; Smith, Caren E; Garcia, Melissa E; Tiainen, Anna-Maija; Sonestedt, Emily; Manichaikul, Ani; van Rooij, Frank JA; Dimitriou, Maria; Raitakari, Olli; Pankow, James S; Djoussé, Luc; Province, Michael A; Hu, Frank B; Lai, Chao-Qiang; Keller, Margaux F; Perälä, Mia-Maria; Rotter, Jerome I; Hofman, Albert; Graff, Misa; Kähönen, Mika; Mukamal, Kenneth; Johansson, Ingegerd; Ordovas, Jose M; Liu, Yongmei; Männistö, Satu; Uitterlinden, André G; Deloukas, Panos; Seppälä, Ilkka; Psaty, Bruce M; Cupples, L Adrienne; Borecki, Ingrid B; Franks, Paul W; Arnett, Donna K; Nalls, Mike A; Eriksson, Johan G; Orho-Melander, Marju; Franco, Oscar H; Lehtimäki, Terho; Dedoussis, George V; Meigs, James B; Siscovick, David S

2015-01-01

Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049–ln-pmol/L (95% CI: 0.035, 0.063–ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic

Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.

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García-Cáceres, Cristina; Quarta, Carmelo; Varela, Luis; Gao, Yuanqing; Gruber, Tim; Legutko, Beata; Jastroch, Martin; Johansson, Pia; Ninkovic, Jovica; Yi, Chun-Xia; Le Thuc, Ophelia; Szigeti-Buck, Klara; Cai, Weikang; Meyer, Carola W; Pfluger, Paul T; Fernandez, Ana M; Luquet, Serge; Woods, Stephen C; Torres-Alemán, Ignacio; Kahn, C Ronald; Götz, Magdalena; Horvath, Tamas L; Tschöp, Matthias H

2016-08-11

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB. Copyright © 2016 Elsevier Inc. All rights reserved.

E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

Science.gov (United States)

Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V

2016-01-01

Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

Directory of Open Access Journals (Sweden)

Ha-Na Na

Full Text Available Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR, and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1. In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

Improvement of glycaemic control and elevation of C-peptide following a diet free of dairy products in an insulin-treated, patient with type 2 diabetes with ulcerative colitis.

Science.gov (United States)

Tandeter, Howard

2009-01-01

An insulin-treated patient with type 2 diabetes mellitus started a diet free of dairy products. Unexpectedly, she developed episodes of hypoglycaemia, without any change in her usual medication (insulin NPH at bedtime and Metformin). Laboratory tests showed an improvement of endogenous insulin secretion as demonstrated by the induction of hypoglycaemia and the elevation to normalisation of C-peptide levels. The patient was rechallenged with dairy products, leading to the lowering of the C-peptide levels back to abnormal levels, and an increase in HBA1C levels. The findings in our patient contrast with the insulinotropic effect of milk in healthy subjects described in the literature. The two main "milk debates" on the relation between milk (or its components) and diabetes are presented. Further observations will be needed to clarify the question of whether a diet free of dairy products can improve glycaemic control in other insulin-treated patients with type 2 diabetes.

Comparison of two methods using plasma triglyceride concentration as a surrogate estimate of insulin action in nondiabetic subjects: triglycerides × glucose versus triglyceride/high-density lipoprotein cholesterol.

Science.gov (United States)

Abbasi, Fahim; Reaven, Gerald M

2011-12-01

The objective was to compare relationships between insulin-mediated glucose uptake and surrogate estimates of insulin action, particularly those using fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations. Insulin-mediated glucose uptake was quantified by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test in 455 nondiabetic subjects. Fasting TG, HDL-C, glucose, and insulin concentrations were measured; and calculations were made of the following: (1) plasma concentration ratio of TG/HDL-C, (2) TG × fasting glucose (TyG index), (3) homeostasis model assessment of insulin resistance, and (4) insulin area under the curve (insulin-AUC) during a glucose tolerance test. Insulin-AUC correlated most closely with SSPG (r ∼ 0.75, P index, homeostasis model assessment of insulin resistance, and fasting TG and insulin (r ∼ 0.60, P index correlated with SSPG concentration to a similar degree, and the relationships were comparable to estimates using fasting insulin. The strongest relationship was between SSPG and insulin-AUC. Copyright © 2011 Elsevier Inc. All rights reserved.

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...

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...

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....

Does overnight normalization of plasma glucose by insulin infusion affect assessment of glucose metabolism in Type 2 diabetes?

DEFF Research Database (Denmark)

Staehr, P; Højlund, Kurt; Hother-Nielsen, O

2003-01-01

AIMS: In order to perform euglycaemic clamp studies in Type 2 diabetic patients, plasma glucose must be reduced to normal levels. This can be done either (i) acutely during the clamp study using high-dose insulin infusion, or (ii) slowly overnight preceding the clamp study using a low-dose insulin...... infusion. We assessed whether the choice of either of these methods to obtain euglycaemia biases subsequent assessment of glucose metabolism and insulin action. METHODS: We studied seven obese Type 2 diabetic patients twice: once with (+ ON) and once without (- ON) prior overnight insulin infusion. Glucose...... turnover rates were quantified by adjusted primed-constant 3-3H-glucose infusions, and insulin action was assessed in 4-h euglycaemic, hyperinsulinaemic (40 mU m-2 min-1) clamp studies using labelled glucose infusates (Hot-GINF). RESULTS: Basal plasma glucose levels (mean +/- sd) were 5.5 +/- 0.5 and 10...

Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects

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Onishi, Airin; Fujiwara, Yoshinori; Ishiwata, Kiichi; Ishii, Kenji

2017-01-01

Background Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG) in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD)-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images. Methods Fifty-nine cognitively normal older subjects (age = 75.7 ± 6.4 years) underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR) was calculated. Results Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 ± 8.1 mg/dL, 4.1 ± 1.9 μU/mL, and 1.0 ± 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05), and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4–5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002), and no correlation with plasma insulin levels (r = 0.156, p = 0.12) or HOMA-IR (r = 0.096, p = 0.24). Conclusion This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images. PMID:28715453

Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects.

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Kenji Ishibashi

Full Text Available Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images.Fifty-nine cognitively normal older subjects (age = 75.7 ± 6.4 years underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR was calculated.Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 ± 8.1 mg/dL, 4.1 ± 1.9 μU/mL, and 1.0 ± 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05, and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4-5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002, and no correlation with plasma insulin levels (r = 0.156, p = 0.12 or HOMA-IR (r = 0.096, p = 0.24.This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images.

A hardware acceleration based on high-level synthesis approach for glucose-insulin analysis

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Daud, Nur Atikah Mohd; Mahmud, Farhanahani; Jabbar, Muhamad Hairol

2017-01-01

In this paper, the research is focusing on Type 1 Diabetes Mellitus (T1DM). Since this disease requires a full attention on the blood glucose concentration with the help of insulin injection, it is important to have a tool that able to predict that level when consume a certain amount of carbohydrate during meal time. Therefore, to make it realizable, a Hovorka model which is aiming towards T1DM is chosen in this research. A high-level language is chosen that is C++ to construct the mathematical model of the Hovorka model. Later, this constructed code is converted into intellectual property (IP) which is also known as a hardware accelerator by using of high-level synthesis (HLS) approach which able to improve in terms of design and performance for glucose-insulin analysis tool later as will be explained further in this paper. This is the first step in this research before implementing the design into system-on-chip (SoC) to achieve a high-performance system for the glucose-insulin analysis tool.

Acupuncture Alters Expression of Insulin Signaling Related Molecules and Improves Insulin Resistance in OLETF Rats

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Xin-Yu Huang

2016-01-01

Full Text Available To determine effect of acupuncture on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF rats and to evaluate expression of insulin signaling components. Rats were divided into three groups: Sprague-Dawley (SD rats, OLETF rats, and acupuncture+OLETF rats. Acupuncture was subcutaneously applied to Neiguan (PC6, Zusanli (ST36, and Sanyinjiao (SP6; in contrast, acupuncture to Shenshu (BL23 was administered perpendicularly. For Neiguan (PC6 and Zusanli (ST36, needles were connected to an electroacupuncture (EA apparatus. Fasting blood glucose (FPG was measured by glucose oxidase method. Plasma fasting insulin (FINS and serum C peptide (C-P were determined by ELISA. Protein and mRNA expressions of insulin signaling molecules were determined by Western blot and real-time RT-PCR, respectively. OLETF rats exhibit increased levels of FPG, FINS, C-P, and homeostasis model assessment-estimated insulin resistance (HOMA-IR, which were effectively decreased by acupuncture treatment. mRNA expressions of several insulin signaling related molecules IRS1, IRS2, Akt2, aPKCζ, and GLUT4 were decreased in OLETF rats compared to SD controls. Expression of these molecules was restored back to normal levels upon acupuncture administration. PI3K-p85α was increased in OLETF rats; this increase was also reversed by acupuncture treatment. Acupuncture improves insulin resistance in OLETF rats, possibly via regulating expression of key insulin signaling related molecules.

C-Peptide Is Independently Associated with an Increased Risk of Coronary Artery Disease in T2DM Subjects: A Cross-Sectional Study.

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Lingshu Wang

Full Text Available C-peptide has been reported to be a marker of subclinical atherosclerosis in type 2 diabetes mellitus (T2DM patients, whereas its role in coronary artery disease (CAD has not been clarified, especially in diabetics with differing body mass indices (BMIs.This cross-sectional study included 501 patients with T2DM. First, all subjects were divided into the following two groups: CAD and non-CAD. Then, binary logistic regression was used to determine the risk factors for CAD for all patients. To clarify the role of obesity, we re-divided all subjects into two additional groups (obese and non-obese based on BMI. Finally, binary logistic regression was used to determine the risk factors for CAD for each weight group.The patients with CAD showed a higher BMI and fasting C-peptide level in addition to an increased prevalence of traditional risk factors for CAD, such as hypertension, insulin resistance, higher cholesterol, cysteine-C (Cys-C and lower estimated glomerular filtration rate (eGFR. Logistic regression analysis showed that fasting C-peptide (OR=1.513, p=0.005, insulin treatment (OR=1.832, p=0.027 hypertension (OR=1.987, p=0.016 and hyperlipidemia (OR=4.159, p<0.001 significantly increased the risk of clinical CAD in the T2DM patients independent of age, gender, diabetes duration, smoking and alcohol statuses, fasting insulin and glucose, hypoglycemic episodes, UA and eGFR. Additionally, in both of the obese (OR=1.488, p=0.049 and non-obese (OR=1.686, p=0.037 DM groups, C-peptide was associated with an increased risk of CAD after multiple adjustments.C-peptide is associated with an increased CAD risk in T2DM patients, no matter whether they are obese or not.

High passage MIN6 cells have impaired insulin secretion with impaired glucose and lipid oxidation.

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Kim Cheng

Full Text Available Type 2 diabetes is a metabolic disorder characterized by the inability of beta-cells to secrete enough insulin to maintain glucose homeostasis. MIN6 cells secrete insulin in response to glucose and other secretagogues, but high passage (HP MIN6 cells lose their ability to secrete insulin in response to glucose. We hypothesized that metabolism of glucose and lipids were defective in HP MIN6 cells causing impaired glucose stimulated insulin secretion (GSIS. HP MIN6 cells had no first phase and impaired second phase GSIS indicative of global functional impairment. This was coupled with a markedly reduced ATP content at basal and glucose stimulated states. Glucose uptake and oxidation were higher at basal glucose but ATP content failed to increase with glucose. HP MIN6 cells had decreased basal lipid oxidation. This was accompanied by reduced expressions of Glut1, Gck, Pfk, Srebp1c, Ucp2, Sirt3, Nampt. MIN6 cells represent an important model of beta cells which, as passage numbers increased lost first phase but retained partial second phase GSIS, similar to patients early in type 2 diabetes onset. We believe a number of gene expression changes occurred to produce this defect, with emphasis on Sirt3 and Nampt, two genes that have been implicated in maintenance of glucose homeostasis.

Human c-peptide immunoreactivity (CPR) in blood and urine - evaluation of a radioimmunoassay method and its clinical applications

Energy Technology Data Exchange (ETDEWEB)

Kuzuya, T; Matsuda, A; Saito, T; Yoshida, S

1976-01-01

A double-antibody radioimmunoassay method, using synthetic human connecting peptide as an immunizing antigen and standard, was evaluated for clinical assay of blood and urine samples. Normal fasting blood connecting peptide immunoreacivity (CPR) was 2.45 +- 0.96 ng/ml, increasing promptly after a 50 g oral glucose load, but somewhat slower than insulin. Molar concentration of CPR exceeded that of insulin. CPR responses to glucose were subnormal in diabetics, very low in juvenile-type cases, and often poor in patients on insulin treatment. Fasting CPR levels were elevated in patients on corticosteroid treatment and with uraemia. A patient with insulin 'auto-antibody' had high serum CPR. A considerable amount of CPR appeared in urine. Normal daily excretion of CPR was 1.52 +- 0.55 ..mu..g/kg or 55.1 +- 18.2 ng/mg creatinine. Urine CPR was very low in juvenile-type diabetics, and elevated in patients on corticosteroid treatment. The results confirm that blood and urine CPR are useful measures of the endocrine pancreatic function.

Effect of High Fat and High Sugar Diet on Glucose Tolerance, Insulin Response to Glucose Load and Insulin Sensitivity in Rats

OpenAIRE

岡﨑, 悟

1987-01-01

To investigate the precipitating effects of the westernized diet on diabetes mellitus, glucose tolerance and insulin response to oral glucose load (1.5g/kg body weight) and insulin sensitivity to exogenous insulin (0.2U/kg) were studied in rats fed an experimental diet for 8 weeks. Four experimental diets were used : low fat-no sugar diet (energy ratio of 10% fat, 70% starch, a model of the traditional Japanese diet), high fat-high sugar diet (40% fat, 20% starch, 20% sugar, a model of the we...

A role for polyamines in glucose-stimulated insulin-gene expression.

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Welsh, N

1990-01-01

The aim of the present study was to evaluate the possible role for polyamines in the glucose regulation of the metabolism of insulin mRNA of pancreatic islet cells. For this purpose islets were prepared from adult mice and cultured for 2 days in culture medium RPMI 1640 containing 3.3 mM- or 16.7 mM-glucose with or without the addition of the inhibitors of polyamine biosynthesis difluoromethylornithine (DFMO) and ethylglyoxal bis(guanylhydrazone) (EGBG). Culture at the high glucose concentration increased the islet contents of both insulin mRNA and polyamines. The synthesis of total RNA, total islet polyamines and polyamines associated with islet nuclei was also increased. When the combination of DFMO and EGBG was added in the presence of 16.7 mM-glucose, low contents of insulin mRNA, spermine and spermidine were observed. Total islet polyamine synthesis was also depressed by DFMO + EGBG, unlike islet biosynthesis of polyamines associated with nuclei, which was not equally decreased by the polyamine-synthesis inhibitors. Total RNA synthesis and turnover was not affected by DFMO + EGBG. Finally, actinomycin D attenuated the glucose-induced enhancement of insulin mRNA, and cycloheximide counteracted the insulin-mRNA attenuation induced by inhibition of polyamine synthesis. It is concluded that the glucose-induced increase in insulin mRNA is paralleled by increased contents and rates of polyamine biosynthesis and that an attenuation of the increase in polyamines prevents the increase in insulin mRNA. In addition, the results are compatible with the view that polyamines exert their effects on insulin mRNA mainly by increasing the stability of this messenger. PMID:2241922

The C-terminus of the B-chain of human insulin-like peptide 5 is critical for cognate RXFP4 receptor activity.

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Patil, Nitin A; Bathgate, Ross A D; Kocan, Martina; Ang, Sheng Yu; Tailhades, Julien; Separovic, Frances; Summers, Roger; Grosse, Johannes; Hughes, Richard A; Wade, John D; Hossain, Mohammed Akhter

2016-04-01

Insulin-like peptide 5 (INSL5) is an orexigenic peptide hormone belonging to the relaxin family of peptides. It is expressed primarily in the L-cells of the colon and has a postulated key role in regulating food intake. Its G protein-coupled receptor, RXFP4, is a potential drug target for treating obesity and anorexia. We studied the effect of modification of the C-terminus of the A and B-chains of human INSL5 on RXFP4 binding and activation. Three variants of human INSL5 were prepared using solid phase peptide synthesis and subsequent sequential regioselective disulfide bond formation. The peptides were synthesized as C-terminal acids (both A- and B-chains with free C-termini, i.e., the native form), amides (both chains as the C-terminal amide) and one analog with the C-terminus of its A-chain as the amide and the C-terminus of the B-chain as the acid. The results showed that C-terminus of the B-chain is more important than that of the A-chain for RXFP4 binding and activity. Amidation of the A-chain C-terminus does not have any effect on the INSL5 activity. The difference in RXFP4 binding and activation between the three peptides is believed to be due to electrostatic interaction of the free carboxylate of INSL5 with a positively charged residue (s), either situated within the INSL5 molecule itself or in the receptor extracellular loops.

Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men.

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Heni, Martin; Wagner, Robert; Kullmann, Stephanie; Gancheva, Sofiya; Roden, Michael; Peter, Andreas; Stefan, Norbert; Preissl, Hubert; Häring, Hans-Ulrich; Fritsche, Andreas

2017-07-01

Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive. Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with d-[6,6- 2 H 2 ]glucose infusion to measure endogenous glucose production and glucose disappearance. On two separate days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an intravenous insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by functional MRI. Glucose infusion rates (GIRs) had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean but not in overweight people. The increase in GIRs was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants. By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese people appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis. © 2017 by the American Diabetes Association.

Food fried in extra-virgin olive oil improves postprandial insulin response in obese, insulin-resistant women.

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Farnetti, Sara; Malandrino, Noemi; Luciani, Davide; Gasbarrini, Giovanni; Capristo, Esmeralda

2011-03-01

The benefits of low glycemic load (GL) diets on clinical outcome in several metabolic and cardiovascular diseases have extensively been demonstrated. The GL of a meal can be affected by modulating the bioavailability of carbohydrates or by changing food preparation. We investigated the effect on plasma glucose and insulin response in lean and obese women of adding raw or fried extra-virgin olive oil to a carbohydrate-containing meal. After an overnight fast, 12 obese insulin-resistant women (body mass index [BMI], 32.8 ± 2.2 kg/m(2)) and five lean subjects (BMI, 22.2 ± 1.2 kg/m(2)) were randomly assigned to receive two different meals (designated A and B). Meal A was composed of 60 g of pasta made from wheat flour and 150 g of grilled courgettes with 25 g of uncooked oil. Meal B included 15 g of oil in the 150 g of deep-fried courgettes and 10 g of oil in the 60 g of stir-fried pasta. Both meals included 150 g of apple. Blood samples were collected at baseline and every 30 minutes over a 3-hour post-meal period and were tested for levels of glucose, insulin, C-peptide, and triglycerides. The area under the curve (AUC) values were calculated. In obese women the AUCs for C-peptide were significantly higher after meal A than after meal B at 120 minutes (W [Wilcoxon sign rank test] = 27.5, P = .0020), 150 minutes (W = 26.5, P = .0039), and 180 minutes (W = 26.5, P = .0039). No differences were found in lean subjects. This study demonstrated that in obese, insulin-resistant women, food fried in extra-virgin olive oil significantly reduced both insulin and C-peptide responses after a meal.

Gastric emptying, glucose metabolism and gut hormones: evaluation of a common preoperative carbohydrate beverage.

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Vermeulen, Mechteld A R; Richir, Milan C; Garretsen, Martijn K; van Schie, Annelies; Ghatei, Mohammed A; Holst, Jens J; Heijboer, Annemieke C; Uitdehaag, Bernard M J; Diamant, Michaela; Eekhoff, E Marelise W; van Leeuwen, Paul A M; Ligthart-Melis, Gerdien C

2011-09-01

To study the gastric-emptying rate and gut hormonal response of two carbohydrate-rich beverages. A specifically designed carbohydrate-rich beverage is currently used to support the surgical patient metabolically. Fruit-based beverages may also promote recovery, due to natural antioxidant and carbohydrate content. However, gastric emptying of fluids is influenced by its nutrient composition; hence, safety of preoperative carbohydrate loading should be confirmed. Because gut hormones link carbohydrate metabolism and gastric emptying, hormonal responses were studied. In eight volunteers, gastric emptying rates of both 400 mL of a ready-to-use beverage (A: Nutricia preOp; 50.4 g carbohydrates-mainly polysaccharides; 260 mOsm/kg) and 400 mL over-the-counter fruit-based lemonade (B: Roosvicee Original; 48 g carbohydrates--mainly fruit-associated saccharides; 805 mOsm/kg) were determined scintigraphically (using hepatate Tc-99(m)) according to a crossover design. Plasma glucose, insulin, C-peptide, glucagon-like peptide (GLP-1), peptide YY, total glucagon, and ghrelin were studied. Gastric emptying showed no differences in residual volumes. Earlier onset in emptying for beverage A versus B was observed (trend), with significantly higher glucose, insulin, C-peptide, and glucagon responses at 15-90 min. GLP-1 was inversely related to residual volume. Fruit-based lemonade is a safe alternative for preoperative purposes. It induces a more limited glucose, insulin, and C-peptide response. Later onset in gastric emptying (B versus A: trend), lower glucagon release, and differences in beverage content and osmolarity may have contributed to those differences. Efficient emptying was reflected by early GLP-1 levels. Copyright © 2011 Elsevier Inc. All rights reserved.

Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

NARCIS (Netherlands)

García-Cáceres, Cristina; Quarta, Carmelo; Varela, Luis; Gao, Yuanqing; Gruber, Tim; Legutko, Beata; Jastroch, Martin; Johansson, Pia; Ninkovic, Jovica; Yi, Chun-Xia; Le Thuc, Ophelia; Szigeti-Buck, Klara; Cai, Weikang; Meyer, Carola W.; Pfluger, Paul T.; Fernandez, Ana M.; Luquet, Serge; Woods, Stephen C.; Torres-Alemán, Ignacio; Kahn, C. Ronald; Götz, Magdalena; Horvath, Tamas L.; Tschöp, Matthias H.

2016-01-01

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and

Vitamin C and E chronic supplementation differentially affect hepatic insulin signaling in rats.

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Ali, Mennatallah A; Eid, Rania M H M; Hanafi, Mervat Y

2018-02-01

Vitamin C and vitamin E supplementations and their beneficial effects on type 2 diabetes mellitus (T2DM) have been subjected to countless controversial data. Hence, our aim is to investigate the hepatic molecular mechanisms of any diabetic predisposing risk of the chronic administration of different doses of vitamin E or vitamin C in rats. The rats were supplemented with different doses of vitamin C or vitamin E for eight months. Vitamin C and vitamin E increased fasting blood glucose, insulin, and homeostasis model assessment index for insulin resistance (HOMA). Vitamin C disrupted glucose tolerance by attenuating upstream hepatic insulin action through impairing the phosphorylation and activation of insulin receptor and its subsequent substrates; however, vitamin E showed its effect downstream insulin receptor in the insulin signaling pathway, reducing hepatic glucose transporter-2 (GLUT2) and phosphorylated protein kinase (p-Akt). Moreover, both vitamins showed their antioxidant capabilities [nuclear factor-erythroid-2-related factor 2 (Nrf2), total and reduced glutathione] and their negative effect on Wnt pathway [phosphorylated glycogen synthase kinase-3β (p-GSK-3β)], by altering the previously mentioned parameters, inevitably leading to severe reduction of reactive oxygen species (ROS) below the physiological levels. In conclusion, a detrimental effect of chronic antioxidant vitamins supplementation was detected; leading to insulin resistance and impaired glucose tolerance obviously through different mechanisms. Overall, these findings indicate that the conventional view that vitamins promote health benefits and delay chronic illnesses and aging should be modified or applied with caution. Copyright © 2017. Published by Elsevier Inc.

A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin Resistance Atherosclerosis Study.

Science.gov (United States)

Saad, M F; Anderson, R L; Laws, A; Watanabe, R M; Kades, W W; Chen, Y D; Sands, R E; Pei, D; Savage, P J; Bergman, R N

1994-09-01

An insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis was compared with the glucose clamp in 11 subjects with normal glucose tolerance (NGT), 20 with impaired glucose tolerance (IGT), and 24 with non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity index (SI) was calculated from FSIGTT using 22- and 12-sample protocols (SI(22) and SI(12), respectively). Insulin sensitivity from the clamp was expressed as SI(clamp) and SIP(clamp). Minimal model parameters were similar when calculated with SI(22) and SI(12). SI could not be distinguished from 0 in approximately 50% of diabetic patients with either protocol. SI(22) correlated significantly with SI(clamp) in the whole group (r = 0.62), and in the NGT (r = 0.53), IGT (r = 0.48), and NIDDM (r = 0.41) groups (P SIP(clamp) were expressed in the same units, SI(22) was 66 +/- 5% (mean +/- SE) and 50 +/- 8% lower than SI(clamp) and SIP(clamp), respectively. Thus, minimal model analysis of the insulin-modified FSIGTT provides estimates of insulin sensitivity that correlate significantly with those from the glucose clamp. The correlation was weaker, however, in NIDDM. The insulin-modified FSIGTT can be used as a simple test for assessment of insulin sensitivity in population studies involving nondiabetic subjects. Additional studies are needed before using this test routinely in patients with NIDDM.

An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

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Kyle S. McCommis

2016-08-01

Full Text Available Objective: Transport of pyruvate into the mitochondrial matrix by the Mitochondrial Pyruvate Carrier (MPC is an important and rate-limiting step in its metabolism. In pancreatic β-cells, mitochondrial pyruvate metabolism is thought to be important for glucose sensing and glucose-stimulated insulin secretion. Methods: To evaluate the role that the MPC plays in maintaining systemic glucose homeostasis, we used genetically-engineered Drosophila and mice with loss of MPC activity in insulin-producing cells. Results: In both species, MPC deficiency results in elevated blood sugar concentrations and glucose intolerance accompanied by impaired glucose-stimulated insulin secretion. In mouse islets, β-cell MPC-deficiency resulted in decreased respiration with glucose, ATP-sensitive potassium (KATP channel hyperactivity, and impaired insulin release. Moreover, treatment of pancreas-specific MPC knockout mice with glibenclamide, a sulfonylurea KATP channel inhibitor, improved defects in islet insulin secretion and abnormalities in glucose homeostasis in vivo. Finally, using a recently-developed biosensor for MPC activity, we show that the MPC is rapidly stimulated by glucose treatment in INS-1 insulinoma cells suggesting that glucose sensing is coupled to mitochondrial pyruvate carrier activity. Conclusions: Altogether, these studies suggest that the MPC plays an important and ancestral role in insulin-secreting cells in mediating glucose sensing, regulating insulin secretion, and controlling systemic glycemia. Keywords: Stimulus-coupled secretion, Insulin, β-Cell, Diabetes, Pyruvate, Mitochondria, Drosophila

Differential Effects of Red Meat/Refined Grain Diet and Dairy/Chicken/Nuts/Whole Grain Diet on Glucose, Insulin and Triglyceride in a Randomized Crossover Study.

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Kim, Yoona; Keogh, Jennifer B; Clifton, Peter M

2016-10-30

Epidemiological studies suggest that a diet high in processed meat, with a high glycemic index is associated with an increased risk of type 2 diabetes. It is not clear if this is due to altered insulin sensitivity or an enhanced postprandial glucose. We aimed to compare the acute metabolic response of two different types of meals after ingestion of the matching diet for four weeks. The study was a randomized, crossover acute meal study. Volunteers consumed either a red meat/refined grain meal or a dairy/chicken/nuts/wholegrain meal after four weeks of the matching diet. After a three-week washout period and four weeks of the alternate diet, they consumed the matching meal. The diets differed with respect to both protein and carbohydrate sources. Blood samples were taken for 180 min for the measurement of glucose, insulin, C-peptide and triglyceride. Fifty-one participants (age: 35.1 ± 15.6 years; body mass index: 27.7 ± 6.9 kg/m², 17 with normal and 34 with impaired glucose tolerance) completed two meal tests. The area under the curve ( p glucose tolerance group ( p glucose; the red meat/refined grain diet increased glucose relative to the dairy/chicken/nuts/whole grain diet only in the normal group (+2.5 mmol/L/3 h). The red meat/refined grain diet increased glucose and insulin responses compared with the dairy/chicken/nuts/whole grain diet. This meal pattern would increase pancreatic stress long term and may account for the increased risk of type 2 diabetes with this diet.

Advanced glycation end products impair glucose-induced insulin secretion from rat pancreatic β-cells.

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Hachiya, Hiroyuki; Miura, Yoshikazu; Inoue, Ken-Ichi; Park, Kyung Hwa; Takeuchi, Masayoshi; Kubota, Keiichi

2014-02-01

Advanced glycation end products (AGEs) are derivative compounds generated from non-enzymatic glycosylation and oxidation. In comparison with glucose-derived AGEs (Glu-AGEs), glyceraldehyde-derived AGEs (Glycer-AGEs) have stronger toxicity to living systems. In this study, we compared the effects of Glu-AGE and Glycer-AGE on insulin secretion. Rat pancreatic islets were isolated by collagenase digestion and primary-cultured in the presence of 0.1 mg/ml bovine serum albumin (BSA) or 0.1 mg/ml Glu-AGE or Glycer-AGE-albumin. After 48 h of culture, we performed an insulin secretion test and identified the defects by a battery of rescue experiments [corrected]. Also, mRNA expression of genes associated with insulin secretion was measured. Insulin secretion induced by a high glucose concentration was 164.1 ± 6.0, 124.4 ± 4.4 (P < 0.05) and 119.8 ± 7.1 (P < 0.05) μU/3 islets/h in the presence of BSA, Glu-AGE, and Glycer-AGE, respectively. Inhibition of insulin secretion by Glu-AGE or Glycer-AGE was rescued by a high extracellular potassium concentration, tolbutamide and α-ketoisocaproic acid, but not by glyceraldehyde, dihydroxacetone, methylpyruvate, glucagon-like peptide-1 and acetylcholine. Glu-AGE or Glycer-AGE reduced the expression of the malate dehydrogenase (Mdh1/2) gene, which plays a critical role in the nicotinamide adenine dinucleotide (NADH) shuttle. Despite its reported cytotoxicity, the effects of Glycer-AGE on insulin secretion are similar to those of Glu-AGE. © 2013 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Prediction of Glucose Tolerance without an Oral Glucose Tolerance Test

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Rohit Babbar

2018-03-01

Full Text Available IntroductionImpaired glucose tolerance (IGT is diagnosed by a standardized oral glucose tolerance test (OGTT. However, the OGTT is laborious, and when not performed, glucose tolerance cannot be determined from fasting samples retrospectively. We tested if glucose tolerance status is reasonably predictable from a combination of demographic, anthropometric, and laboratory data assessed at one time point in a fasting state.MethodsGiven a set of 22 variables selected upon clinical feasibility such as sex, age, height, weight, waist circumference, blood pressure, fasting glucose, HbA1c, hemoglobin, mean corpuscular volume, serum potassium, fasting levels of insulin, C-peptide, triglyceride, non-esterified fatty acids (NEFA, proinsulin, prolactin, cholesterol, low-density lipoprotein, HDL, uric acid, liver transaminases, and ferritin, we used supervised machine learning to estimate glucose tolerance status in 2,337 participants of the TUEF study who were recruited before 2012. We tested the performance of 10 different machine learning classifiers on data from 929 participants in the test set who were recruited after 2012. In addition, reproducibility of IGT was analyzed in 78 participants who had 2 repeated OGTTs within 1 year.ResultsThe most accurate prediction of IGT was reached with the recursive partitioning method (accuracy = 0.78. For all classifiers, mean accuracy was 0.73 ± 0.04. The most important model variable was fasting glucose in all models. Using mean variable importance across all models, fasting glucose was followed by NEFA, triglycerides, HbA1c, and C-peptide. The accuracy of predicting IGT from a previous OGTT was 0.77.ConclusionMachine learning methods yield moderate accuracy in predicting glucose tolerance from a wide set of clinical and laboratory variables. A substitution of OGTT does not currently seem to be feasible. An important constraint could be the limited reproducibility of glucose tolerance status during a

Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

DEFF Research Database (Denmark)

Jensen, Christine B; Storgaard, Heidi; Holst, Jens J

2003-01-01

We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp...... Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux......, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but...

A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study.

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Tripathy, Devjit; Cobb, Jeff E; Gall, Walter; Adam, Klaus-Peter; George, Tabitha; Schwenke, Dawn C; Banerji, MaryAnn; Bray, George A; Buchanan, Thomas A; Clement, Stephen C; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Ratner, Robert E; Stentz, Frankie B; Reaven, Peter D; Musi, Nicolas; Ferrannini, Ele; DeFronzo, Ralph A

2015-05-01

The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained. Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P < .001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P < .0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

Glucose turnover and hormonal changes during insulin-induced hypoglycemia in trained humans

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Kjær, Michael; Mikines, K J; Christensen, N J

1984-01-01

Eight athletes (T), studied the third morning after the last exercise session, and seven sedentary males (C) (maximal O2 consumption 65 +/- 4 vs. 49 +/- 4 (SE) ml X kg-1 X min-1, for T and C men, respectively) had insulin infused until plasma glucose, at an insulin level of 1,600 pmol X l-1, was 1...... +/- 6 mU X l-1), and pancreatic polypeptide (361 +/- 84 vs. 180 +/- 29 pmol X l-1) reached higher levels (P less than 0.05) and glucagon (28 +/- 3 vs. 47 +/- 10 pmol X l-1) lower levels in T than in C subjects. Blood pressures changed earlier in athletes during insulin infusion, and early recovery...

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

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Wewer Albrechtsen, Nicolai J.; Kuhre, Rune E.; Hornburg, Daniel

2017-01-01

that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in......Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among...... which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated...

Blueberries’ Impact on Insulin Resistance and Glucose Intolerance

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April J. Stull

2016-11-01

Full Text Available Blueberries are a rich source of polyphenols, which include anthocyanin bioactive compounds. Epidemiological evidence indicates that incorporating blueberries into the diet may lower the risk of developing type 2 diabetes (T2DM. These findings are supported by pre-clinical and clinical studies that have shown improvements in insulin resistance (i.e., increased insulin sensitivity after obese and insulin-resistant rodents or humans consumed blueberries. Insulin resistance was assessed by homeostatic model assessment-estimated insulin resistance (HOMA-IR, insulin tolerance tests, and hyperinsulinemic-euglycemic clamps. Additionally, the improvements in glucose tolerance after blueberry consumption were assessed by glucose tolerance tests. However, firm conclusions regarding the anti-diabetic effect of blueberries cannot be drawn due to the small number of existing clinical studies. Although the current evidence is promising, more long-term, randomized, and placebo-controlled trials are needed to establish the role of blueberries in preventing or delaying T2DM.

Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation

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Reno, Candace M.; Puente, Erwin C.; Sheng, Zhenyu; Daphna-Iken, Dorit; Bree, Adam J.; Routh, Vanessa H.; Kahn, Barbara B.

2017-01-01

GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose. PMID:27797912

Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells.

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Jianhui Liu

Full Text Available Glucose-stimulated insulin secretion (GSIS is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of β-cell failure and one of causes of type 2 diabetes mellitus (T2DM. Although the KATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in β-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in β-cells.

Genetic and phenotypic correlations between surrogate measures of insulin release obtained from OGTT data

DEFF Research Database (Denmark)

Gjesing, Anette Marianne Prior; Ribel-Madsen, Rasmus; Harder, Marie Neergaard

2015-01-01

closely related to fasting insulin with a genetic correlation of 0.85. The effects of 82 selected susceptibility single nucleotide polymorphisms on these insulin secretion indices supported our interpretation of the data and added insight into the biological differences between the examined traits......AIMS/HYPOTHESIS: We examined the extent to which surrogate measures of insulin release have shared genetic causes. METHODS: Genetic and phenotypic correlations were calculated in a family cohort (n = 315) in which beta cell indices were estimated based on fasting and oral glucose-stimulated plasma...... glucose, serum C-peptide and serum insulin levels. Furthermore, we genotyped a large population-based cohort (n = 6,269) for common genetic variants known to associate with type 2 diabetes, fasting plasma glucose levels or fasting serum insulin levels to examine their association with various indices...

Postprandial gut hormone responses and glucose metabolism in cholecystectomized patients

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Sonne, David P; Hare, Kristine J; Martens, Pernille

2013-01-01

-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum......Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We...... examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat...

Analyses of insulin-potentiating fragments of human growth hormone by computative simulation; essential unit for insulin-involved biological responses.

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Ohkura, K; Hori, H

2000-07-01

We analyzed the structural features of insulin-potentiating fragments of human growth hormone by computative simulations. The peptides were designated from the N-terminus sequences of the hormone positions at 1-15 (hGH(1-15); H2N-Phe1-Pro2-Thr3-Ile4-Pro5-Leu6-Ser7-Arg8-L eu9-Phe10-Asp11-Asn12-Ala13-Met14-Leu15 -COOH), 6-13 (hGH(6-13)), 7-13 (hGH(7-13)) and 8-13 (hGH(8-13)), which enhanced insulin-producing hypoglycemia. In these peptide molecules, ionic bonds were predicted to form between 8th-arginyl residue and 11th-aspartic residue, and this intramolecular interaction caused the formation of a macrocyclic structure containing a tetrapeptide Arg8-Leu9-Phe10-Asp11. The peptide positions at 6-10 (hGH(6-10)), 9-13 (hGH(9-13)) and 10-13 (hGH(10-13)) did not lead to a macrocyclic formation in the molecules, and had no effect on the insulin action. Although beta-Ala13hGH(1-15), in which the 13th-alanine was replaced by a beta-alanyl residue, had no effect on insulin-producing hypoglycemia, the macrocyclic region (Arg8-Leu9-Phe10-Asp11) was observed by the computative simulation. An isothermal vibration analysis of both of beta-Ala13hGH(1-15) and hGH(1-15) peptide suggested that beta-Ala13hGH(1-15) is molecule was more flexible than hGH(1-15); C-terminal carboxyl group of Leu15 easily accessed to Arg8 and inhibited the ionic bond formation between Arg8 and Asp11 in beta-Ala13hGH(1-15). The peptide of hGH(8-13) dose-dependently enhanced the insulin-involved fatty acid synthesis in rat white adipocytes, and stabilized the C6-NBD-PC (1-acyl-2-[6-[(7-nitro-2,1,3benzoxadiazol-4-yl)amino]-caproyl]-sn- glycero-3-phosphatidylcholine) model membranes. In contrast, hGH(9-13) had no effect both on the fatty acid synthesis and the membrane stability. In the same culture conditions as the fatty acid synthesis assay, hGH(8-13) had no effect on the transcript levels of glucose transporter isoforms (GLUT 1, 4) and hexokinase isozymes (HK I, II) in rat white adipocytes. Judging from

Effect of glycogen synthase overexpression on insulin-stimulated muscle glucose uptake and storage.

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Fogt, Donovan L; Pan, Shujia; Lee, Sukho; Ding, Zhenping; Scrimgeour, Angus; Lawrence, John C; Ivy, John L

2004-03-01

Insulin-stimulated muscle glucose uptake is inversely associated with the muscle glycogen concentration. To investigate whether this association is a cause and effect relationship, we compared insulin-stimulated muscle glucose uptake in noncontracted and postcontracted muscle of GSL3-transgenic and wild-type mice. GSL3-transgenic mice overexpress a constitutively active form of glycogen synthase, which results in an abundant storage of muscle glycogen. Muscle contraction was elicited by in situ electrical stimulation of the sciatic nerve. Right gastrocnemii from GSL3-transgenic and wild-type mice were subjected to 30 min of electrical stimulation followed by hindlimb perfusion of both hindlimbs. Thirty minutes of contraction significantly reduced muscle glycogen concentration in wild-type (49%) and transgenic (27%) mice, although transgenic mice retained 168.8 +/- 20.5 micromol/g glycogen compared with 17.7 +/- 2.6 micromol/g glycogen for wild-type mice. Muscle of transgenic and wild-type mice demonstrated similar pre- (3.6 +/- 0.3 and 3.9 +/- 0.6 micromol.g(-1).h(-1) for transgenic and wild-type, respectively) and postcontraction (7.9 +/- 0.4 and 7.0 +/- 0.4 micromol.g(-1).h(-1) for transgenic and wild-type, respectively) insulin-stimulated glucose uptakes. However, the [14C]glucose incorporated into glycogen was greater in noncontracted (151%) and postcontracted (157%) transgenic muscle vs. muscle of corresponding wild-type mice. These results indicate that glycogen synthase activity is not rate limiting for insulin-stimulated glucose uptake in skeletal muscle and that the inverse relationship between muscle glycogen and insulin-stimulated glucose uptake is an association, not a cause and effect relationship.

Adipose tissue insulin receptor and glucose transporter 4 expression, and blood glucose and insulin responses during glucose tolerance tests in transition Holstein cows with different body condition.

Science.gov (United States)

Jaakson, H; Karis, P; Ling, K; Ilves-Luht, A; Samarütel, J; Henno, M; Jõudu, I; Waldmann, A; Reimann, E; Pärn, P; Bruckmaier, R M; Gross, J J; Kaart, T; Kass, M; Ots, M

2018-01-01

Glucose uptake in tissues is mediated by insulin receptor (INSR) and glucose transporter 4 (GLUT4). The aim of this study was to examine the effect of body condition during the dry period on adipose tissue mRNA and protein expression of INSR and GLUT4, and on the dynamics of glucose and insulin following the i.v. glucose tolerance test in Holstein cows 21 d before (d -21) and after (d 21) calving. Cows were grouped as body condition score (BCS) ≤3.0 (thin, T; n = 14), BCS = 3.25 to 3.5 (optimal, O; n = 14), and BCS ≥3.75 (overconditioned, OC; n = 14). Blood was analyzed for glucose, insulin, fatty acids, and β-hydroxybutyrate concentrations. Adipose tissue was analyzed for INSR and GLUT4 mRNA and protein concentrations. During the glucose tolerance test 0.15 g/kg of body weight glucose was infused; blood was collected at -5, 5, 10, 20, 30, 40, 50, and 60 min, and analyzed for glucose and insulin. On d -21 the area under the curve (AUC) of glucose was smallest in group T (1,512 ± 33.9 mg/dL × min) and largest in group OC (1,783 ± 33.9 mg/dL × min), and different between all groups. Basal insulin on d -21 was lowest in group T (13.9 ± 2.32 µU/mL), which was different from group OC (24.9 ± 2.32 µU/mL. On d -21 the smallest AUC 5-60 of insulin in group T (5,308 ± 1,214 µU/mL × min) differed from the largest AUC in group OC (10,867 ± 1,215 µU/mL × min). Time to reach basal concentration of insulin in group OC (113 ± 14.1 min) was longer compared with group T (45 ± 14.1). The INSR mRNA abundance on d 21 was higher compared with d -21 in groups T (d -21: 3.3 ± 0.44; d 21: 5.9 ± 0.44) and O (d -21: 3.7 ± 0.45; d 21: 4.7 ± 0.45). The extent of INSR protein expression on d -21 was highest in group T (7.3 ± 0.74 ng/mL), differing from group O (4.6 ± 0.73 ng/mL), which had the lowest expression. The amount of GLUT4 protein on d -21 was lowest in group OC (1.2 ± 0.14 ng/mL), different from group O (1.8 ± 0.14 ng/mL), which had the highest amount

Fall in C-Peptide During First 4 Years From Diagnosis of Type 1 Diabetes: Variable Relation to Age, HbA1c, and Insulin Dose