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Sample records for rapid-acting insulin analogues

  1. The Insuline Analogues

    OpenAIRE

    Garrido Carrasco, Elizabeth; Servicio de Endocrinología, Hospital Nacional Edgardo Rebagliati Martins, Lima, Perú

    2014-01-01

    Insulin analogues are a new pharmaceutical family, designed to overcome deficiencies that still exist with the rDNA insulin. There are rapid-acting insulin analogues such as lispro insulin and insulin aspart. They avoid postprandial and nocturnal hypoglycemia. There are also intermediate-acting insulin analogues like NPL and Mix 25 (a mixture between NPL and lispro), which join the neutral protamine insulin length of action and the fast onset of the rapid-acting analogue lispro. Finally, ther...

  2. Carcinogenicity of insulin analogues

    NARCIS (Netherlands)

    Braak, Sebastiaan Johannes ter

    2015-01-01

    There is epidemiological evidence that the use of some insulin analogues by diabetic patients is correlated with an increased cancer risk. In vitro exposure experiments revealed that insulin glargine (LANTUS) was the only commercial insulin analogue with an increased mitogenic potential. In the

  3. The cost effectiveness of rapid-acting insulin aspart compared with human insulin in type 2 diabetes patients: an analysis from the Japanese third-party payer perspective.

    Science.gov (United States)

    Pollock, R F; Valentine, W J; Pilgaard, T; Nishimura, H

    2011-01-01

    The Nippon Ultra-Rapid Insulin and Diabetic Complication Evaluation Study (NICE Study) (NCT00575172) was a 5-year, open-label, randomised controlled trial which compared cardiovascular outcomes in Japanese type 2 diabetes patients intensively treated with regular human insulin or insulin aspart (NovoRapid; Novo Nordisk A/S, Bagsvaerd, Denmark), a rapid-acting insulin analogue. The aim of the present analysis was to evaluate the cost effectiveness of insulin aspart versus regular human insulin from the perspective of a Japanese third-party healthcare payer. A discrete event-simulation model was developed in Microsoft Excel to assess the within-trial cost effectiveness and make longer-term clinical projections in patients treated with regular human insulin or insulin aspart. In addition to severe hypoglycaemia, the model captured myocardial and cerebral infarction events and percutaneous coronary intervention and coronary artery bypass graft procedures. Within-trial mortality, incidence of severe hypoglycaemia and cardiovascular event probabilities were derived from the annual rates observed during the trial period, while post-trial outcomes were calculated using the event rates from the trial, adjusted for increasing patient age. Event costs were accounted from the healthcare payer perspective and expressed in 2008 Japanese yen (JPY), while health-related quality of life (HRQoL) was captured using event and state utilities. Future costs and clinical benefits were discounted at 3% annually. Life expectancy, quality-adjusted life expectancy, cardiovascular event rates and costs were evaluated over 5- and 10-year time horizons and sensitivity analyses were performed to assess variability in model outcomes. Over 5 years of treatment, insulin aspart dominated human insulin both in incremental life expectancy and in incremental quality-adjusted life-years (QALYS). Insulin aspart was associated with a small improvement in discounted life expectancy of 0.005 years (4.688 vs

  4. Needle-free jet injection of rapid-acting insulin improves early postprandial glucose control in patients with diabetes

    NARCIS (Netherlands)

    Engwerda, E.E.; Tack, C.J.J.; Galan, B.E. de

    2013-01-01

    OBJECTIVE: Clamp studies have shown that the absorption and action of rapid-acting insulin are faster with injection by a jet injector than with administration by conventional pen. To determine whether these pharmacokinetic changes also exist in patients with diabetes and benefit postprandial

  5. Análogos de insulina Insulin analogues

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    Manuel E. Licea Puig

    2006-12-01

    diabetes mellitus (DM. The recombinant technology of deoxyribonucleic acid (DNA has allowed the development of human insulin; however, this has not totally solved the problems related to immunogenecity, among other problems. Therefore, the new technologies are applied to create insulin analogues. It is our purpose to review relevant pharmacological and clinical aspects related to the insulin analogues, as well as their usefulness in the treatment of DM. The insulin analogues result from biochemical modifications of human insulin. These modifications of the insulin molecule alter not only the absorption, but also the beginning and duration of the action, which offer advantages over the conventional insulins. At present, there are three rapid acting insulin analogues: insulin lispro, insulin aspart and glulisine; and three long acting analogues; glargine, detemir and albulin. Albulin is the latest long acting analogue reported. At present, it is being subjected to various in vitro and in vivo studies. Besides, there have been developed diverse formulations where the rapid acting insulin analogues are premixed with the long acting analogues. The rapid acting insulin analogues have showed a modest global benefit against the conventional insulins in type 1 diabetics. The long acting analogues focus their attention in those persons with DM with nocturnal hypoglycemic episodes. Longer term studies are necessary to confirm the safety and benefits of these preparations, as well as to determine their effect on the micro- and macroangiopathic complications of DM.

  6. Design of ultra-stable insulin analogues for the developing world

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    Michael A Weiss

    2013-01-01

    Full Text Available The engineering of insulin analogues illustrates the application of structure-based protein design to clinical medicine. Such design has traditionally been based on structures of wild-type insulin hexamers in an effort to optimize the pharmacokinetic (PK and pharmacodynamic properties of the hormone. Rapid-acting insulin analogues (in chronological order of their clinical introduction, Humalog ® [Eli Lilly & Co.], Novolog ® [Novo-Nordisk], and Apidra ® [Sanofi-Aventis] exploit the targeted destabilization of subunit interfaces to facilitate capillary absorption. Conversely, long-acting insulin analogues exploit the stability of the insulin hexamer and its higher-order self-assembly within the subcutaneous depot to enhance basal glycemic control. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus ® ; Sanofi-Aventis or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir ® ; Novo-Nordisk. Such molecular engineering has often encountered a trade-off between PK goals and product stability. Given the global dimensions of the diabetes pandemic and complexity of an associated cold chain of insulin distribution, we envisage that concurrent engineering of ultra-stable protein analogue formulations would benefit the developing world, especially for patients exposed to high temperatures with inconsistent access to refrigeration. We review the principal mechanisms of insulin degradation above room temperature and novel molecular approaches toward the design of ultra-stable rapid-acting and basal formulations.

  7. Differences in bioactivity between human insulin and insulin analogues approved for therapeutic use- compilation of reports from the past 20 years

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    Werner Haim

    2011-06-01

    Full Text Available Abstract In order to provide comprehensive information on the differences in bioactivity between human insulin and insulin analogues, published in vitro comparisons of human insulin and the rapid acting analogues insulin lispro (Humalog®, insulin aspart ( NovoRapid®, insulin glulisine (Apidra®, and the slow acting analogues insulin glargine (Lantus®, and insulin detemir (Levemir® were gathered from the past 20 years (except for receptor binding studies. A total of 50 reports were retrieved, with great heterogeneity among study methodology. However, various differences in bioactivity compared to human insulin were obvious (e.g. differences in effects on metabolism, mitogenesis, apoptosis, intracellular signalling, thrombocyte function, protein degradation. Whether or not these differences have clinical bearings (and among which patient populations remains to be determined.

  8. Engineering of insulin receptor isoform-selective insulin analogues

    National Research Council Canada - National Science Library

    Glendorf, Tine; Stidsen, Carsten E; Norrman, Mathias; Nishimura, Erica; Sørensen, Anders R; Kjeldsen, Thomas

    2011-01-01

    .... The aim of this study was to investigate the importance of the C-terminus of the B chain in IR isoform binding in order to explore the possibility of engineering tissue-specific/liver-specific insulin analogues...

  9. Effects of metformin on body weight in patients with type 2 diabetes mellitus,receiving insulin analogue treatment

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    T I Romantsova

    2013-03-01

    Full Text Available Aims. To study the dynamics of body weight, waist circumference, blood lipid and insulin demand in patients with type 2 diabetes mellitus (T2DM during first year of combined treatment with metformin and insulin analogues, compared with insulin analogue monotherapy.Materials and Methods. We examined 78 patients with T2DM on newly initiated insulin therapy, including 54 females and 24 males. Median age was 56 [51.0; 64.0] years, median disease duration – 9 [6.8;14.0] years. Participants were subdivided in two groups. First group was comprised of 48 subjects (33 females and 15 males, who received monotherapy with insulin analogues (glargine, de- temir, biphasic Aspart 30 and Humalog Mix 25 or rapid-acting lispro and aspart. Second group included 30 patients (18 females and12 males, who were treated with combined therapy (insulin analogues plus metformin. We measured HbA1c, plasma lipid composition, BMI, waist circumference and insulin demand initially and after one year of follow-up.Results. We showed that combined therapy vs. insulin monotherapy allows better glycemic compensation while reducing insulin demand and lowering risks for weight gain.Conclusions. Combined insulin analogue plus metformin treatment delivers better metabolic control in patients with T2DM and is as- sociated with lower risks for body weight gain and increase in insulin demand against monotherapy with insulin analogues.

  10. Engineering of insulin receptor isoform-selective insulin analogues.

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    Tine Glendorf

    Full Text Available BACKGROUND: The insulin receptor (IR exists in two isoforms, A and B, and the isoform expression pattern is tissue-specific. The C-terminus of the insulin B chain is important for receptor binding and has been shown to contact the IR just adjacent to the region where the A and B isoforms differ. The aim of this study was to investigate the importance of the C-terminus of the B chain in IR isoform binding in order to explore the possibility of engineering tissue-specific/liver-specific insulin analogues. METHODOLOGY/PRINCIPAL FINDINGS: Insulin analogue libraries were constructed by total amino acid scanning mutagenesis. The relative binding affinities for the A and B isoform of the IR were determined by competition assays using scintillation proximity assay technology. Structural information was obtained by X-ray crystallography. Introduction of B25A or B25N mutations resulted in analogues with a 2-fold preference for the B compared to the A isoform, whereas the opposite was observed with a B25Y substitution. An acidic amino acid residue at position B27 caused an additional 2-fold selective increase in affinity for the receptor B isoform for analogues bearing a B25N mutation. Furthermore, the combination of B25H with either B27D or B27E also resulted in B isoform-preferential analogues (2-fold preference even though the corresponding single mutation analogues displayed no differences in relative isoform binding affinity. CONCLUSIONS/SIGNIFICANCE: We have discovered a new class of IR isoform-selective insulin analogues with 2-4-fold differences in relative binding affinities for either the A or the B isoform of the IR compared to human insulin. Our results demonstrate that a mutation at position B25 alone or in combination with a mutation at position B27 in the insulin molecule confers IR isoform selectivity. Isoform-preferential analogues may provide new opportunities for developing insulin analogues with improved clinical benefits.

  11. Engineering of Insulin Receptor Isoform-Selective Insulin Analogues

    Science.gov (United States)

    Glendorf, Tine; Stidsen, Carsten E.; Norrman, Mathias; Nishimura, Erica; Sørensen, Anders R.; Kjeldsen, Thomas

    2011-01-01

    Background The insulin receptor (IR) exists in two isoforms, A and B, and the isoform expression pattern is tissue-specific. The C-terminus of the insulin B chain is important for receptor binding and has been shown to contact the IR just adjacent to the region where the A and B isoforms differ. The aim of this study was to investigate the importance of the C-terminus of the B chain in IR isoform binding in order to explore the possibility of engineering tissue-specific/liver-specific insulin analogues. Methodology/Principal Findings Insulin analogue libraries were constructed by total amino acid scanning mutagenesis. The relative binding affinities for the A and B isoform of the IR were determined by competition assays using scintillation proximity assay technology. Structural information was obtained by X-ray crystallography. Introduction of B25A or B25N mutations resulted in analogues with a 2-fold preference for the B compared to the A isoform, whereas the opposite was observed with a B25Y substitution. An acidic amino acid residue at position B27 caused an additional 2-fold selective increase in affinity for the receptor B isoform for analogues bearing a B25N mutation. Furthermore, the combination of B25H with either B27D or B27E also resulted in B isoform-preferential analogues (2-fold preference) even though the corresponding single mutation analogues displayed no differences in relative isoform binding affinity. Conclusions/Significance We have discovered a new class of IR isoform-selective insulin analogues with 2–4-fold differences in relative binding affinities for either the A or the B isoform of the IR compared to human insulin. Our results demonstrate that a mutation at position B25 alone or in combination with a mutation at position B27 in the insulin molecule confers IR isoform selectivity. Isoform-preferential analogues may provide new opportunities for developing insulin analogues with improved clinical benefits. PMID:21625452

  12. Insulin analogues in pregnancy and specific congenital anomalies

    DEFF Research Database (Denmark)

    de Jong, Josta; Garne, Ester; Wender-Ozegowska, Ewa

    2016-01-01

    Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant...... women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we...... included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate...

  13. Metabolic implications when employing heavy pre- and post-exercise rapid-acting insulin reductions to prevent hypoglycaemia in type 1 diabetes patients: a randomised clinical trial.

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    Matthew D Campbell

    Full Text Available To examine the metabolic, gluco-regulatory-hormonal and inflammatory cytokine responses to large reductions in rapid-acting insulin dose administered prandially before and after intensive running exercise in male type 1 diabetes patients.This was a single centre, randomised, controlled open label study. Following preliminary testing, 8 male patients (24±2 years, HbA1c 7.7±0.4%/61±4 mmol.l-1 treated with insulin's glargine and aspart, or lispro attended the laboratory on two mornings at ∼08:00 h and consumed a standardised breakfast carbohydrate bolus (1 g carbohydrate.kg-1BM; 380±10 kcal and self-administered a 75% reduced rapid-acting insulin dose 60 minutes before 45 minutes of intensive treadmill running at 73.1±0.9% VO2peak. At 60 minutes post-exercise, patients ingested a meal (1 g carbohydrate.kg-1BM; 660±21 kcal and administered either a Full or 50% reduced rapid-acting insulin dose. Blood glucose and lactate, serum insulin, cortisol, non-esterified-fatty-acids, β-Hydroxybutyrate, and plasma glucagon, adrenaline, noradrenaline, IL-6, and TNF-α concentrations were measured for 180 minutes post-meal.All participants were analysed. All glycaemic, metabolic, hormonal, and cytokine responses were similar between conditions up to 60 minutes following exercise. Following the post-exercise meal, serum insulin concentrations were lower under 50% (p<0.05 resulting in 75% of patients experiencing hyperglycaemia (blood glucose ≥8.0 mmol.l-1; 50% n = 6, Full n = 3. β-Hydroxybutyrate concentrations decreased similarly, such that at 180 minutes post-meal concentrations were lower than rest under Full and 50%. IL-6 and TNF-α concentrations remained similar to fasting levels under 50% but declined under Full. Under 50% IL-6 concentrations were inversely related with serum insulin concentrations (r = -0.484, p = 0.017.Heavily reducing rapid-acting insulin dose with a carbohydrate bolus before, and a meal after intensive

  14. Insulin analogues and severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Hansen, L S; Jespersen, M J

    2012-01-01

    The effect of insulin analogues on glycaemic control is well-documented, whereas the effect on avoidance of severe hypoglycaemia remains tentative. We studied the frequency of severe hypoglycaemia in unselected patients with type 1 diabetes treated with insulin analogues, human insulin, or mixed...

  15. Large Pre- and Postexercise Rapid-Acting Insulin Reductions Preserve Glycemia and Prevent Early- but Not Late-Onset Hypoglycemia in Patients With Type 1 Diabetes

    Science.gov (United States)

    Campbell, Matthew D.; Walker, Mark; Trenell, Michael I.; Jakovljevic, Djordje G.; Stevenson, Emma J.; Bracken, Richard M.; Bain, Stephen C.; West, Daniel J.

    2013-01-01

    OBJECTIVE To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting insulin dose in type 1 diabetic patients. RESEARCH DESIGN AND METHODS After preliminary testing, 11 male patients (24 ± 2 years, HbA1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings. Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg−1 BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting insulin dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO2peak. At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg−1 BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting insulin dose. Blood glucose concentrations were measured for 3 h postmeal. Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucose monitoring system. RESULTS All glycemic responses were similar across conditions up to 60 min postexercise. After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%. Thence at 3 h, blood glucose was highest under 50% (50% [10.4 ± 1.2] vs. Full [6.2 ± 0.7] and 75% [7.6 ± 1.2 mmol ⋅ L−1], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50% (blood glucose ≤3.9; Full, n = 5; 75%, n = 2; 50%, n = 0). Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions. However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions. CONCLUSIONS A 25% pre-exercise and 50% postexercise rapid-acting insulin dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h). However, this strategy does not protect against late-onset postexercise hypoglycemia. PMID:23514728

  16. Safety and efficacy of a glucagon-like peptide-1 receptor agonist added to basal insulin therapy versus basal insulin with or without a rapid-acting insulin in patients with type 2 diabetes: results of a meta-analysis.

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    Wysham, Carol H; Lin, Jay; Kuritzky, Louis

    2017-05-01

    To consolidate the evidence from randomized controlled trials evaluating the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as add-on to basal insulin therapy in type 2 diabetes (T2D) patients. We searched the EMBASE® and NCBI PubMed (Medline) databases and relevant congress abstracts for randomized controlled trials evaluating the efficacy and safety of GLP-1 RAs as add-on to basal insulin compared with basal insulin with or without rapid-acting insulin (RAI) through 23 May 2016. The pooled data were analyzed using a random-effects meta-analysis model. A subanalysis was performed for trials investigating basal insulin plus GLP-1 RAs versus basal insulin plus RAI. Of the 2617 retrieved records, 19 randomized controlled trials enrolling 7,053 patients with T2D were included. Compared with basal insulin ± RAI, reduction in glycated hemoglobin (HbA1c) from baseline (difference in means: -0.48% [95% confidence interval (CI), -0.67 to -0.30]; p insulin plus GLP-1 RA. The subanalysis similarly showed significant results for change in HbA1c from baseline and for weight loss, as well as a significantly lower risk of symptomatic hypoglycemia in patients treated with basal insulin plus GLP-1 RA versus basal insulin plus RAI (odds ratio, 0.52 [95% CI, 0.42 to 0.64]; p insulin provided improved glycemic control, led to weight reduction and similar hypoglycemia rates versus an intensified insulin strategy; however, symptomatic hypoglycemia rates were significantly lower when compared with a basal insulin plus RAI.

  17. Insulin analogues and cancer: a note of caution

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    Joseph A.M.J.L. eJanssen

    2014-05-01

    Full Text Available Abstract In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. At present, the available data suggest that insulin analogues are safe. In line with these findings, we observed that serum of diabetic patients treated with insulin analogues, compared to that of diabetic patients treated with human insulin, did not induce an increased phosphorylation of tyrosine residues of the insulin-like growth factor-I receptor (IGF-IR. However, the classical model of the IGF-IR signaling may be insufficient to explain (all mitogenic effects of insulin analogues since also non-canonical signaling pathways of the IGF-IR may play a major role in this respect. Although phosphorylation of tyrosine residues of the IGF-IR is generally considered to be the initial activation step within the intracellular IGF-IR signaling pathway, it has been found that cells undergo a signaling switch under hyperglycemic conditions. After this switch, a completely different mechanism is utilized to activate the mitogenic (mitogen-activated protein kinase (MAPK pathways of the IGF-IR that is independent from tyrosine phosphorylation of the IGF-IR. At present it is unknown whether activation of this alternative intracellular pathway of the IGF-IR occurs during hyperglycemia in vivo and whether it is stronger in patients treated with (some insulin analogues than in patients treated with human insulin. In addition, it is unknown whether the insulin receptors (IRs also undergo a signaling switch during hyperglycemia. This should be investigated in future studies. Finally, relative overexpression of IR isoform A (IR-A in (pre cancer tissues may play a key role in the development and progression of human cancers during treatment with insulin (analogues. Further

  18. Simulation-Based Evaluation of Dose-Titration Algorithms for Rapid-Acting Insulin in Subjects with Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antihyperglycemic Medications.

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    Ma, Xiaosu; Chien, Jenny Y; Johnson, Jennal; Malone, James; Sinha, Vikram

    2017-08-01

    The purpose of this prospective, model-based simulation approach was to evaluate the impact of various rapid-acting mealtime insulin dose-titration algorithms on glycemic control (hemoglobin A1c [HbA1c]). Seven stepwise, glucose-driven insulin dose-titration algorithms were evaluated with a model-based simulation approach by using insulin lispro. Pre-meal blood glucose readings were used to adjust insulin lispro doses. Two control dosing algorithms were included for comparison: no insulin lispro (basal insulin+metformin only) or insulin lispro with fixed doses without titration. Of the seven dosing algorithms assessed, daily adjustment of insulin lispro dose, when glucose targets were met at pre-breakfast, pre-lunch, and pre-dinner, sequentially, demonstrated greater HbA1c reduction at 24 weeks, compared with the other dosing algorithms. Hypoglycemic rates were comparable among the dosing algorithms except for higher rates with the insulin lispro fixed-dose scenario (no titration), as expected. The inferior HbA1c response for the "basal plus metformin only" arm supports the additional glycemic benefit with prandial insulin lispro. Our model-based simulations support a simplified dosing algorithm that does not include carbohydrate counting, but that includes glucose targets for daily dose adjustment to maintain glycemic control with a low risk of hypoglycemia.

  19. An additional bolus of rapid-acting insulin to normalise postprandial cardiovascular risk factors following a high-carbohydrate high-fat meal in patients with type 1 diabetes: A randomised controlled trial.

    OpenAIRE

    Campbell, MD; Walker, M. (Mark); Ajjan, RA; Birch, KM; Gonzalez, JT; West, DJ

    2017-01-01

    AIM: To evaluate an additional rapid-acting insulin bolus on postprandial lipaemia, inflammation and pro-coagulation following high-carbohydrate high-fat feeding in people with type 1 diabetes. METHODS: A total of 10 males with type 1 diabetes [HbA1c 52.5 ± 5.9 mmol/mol (7.0% ± 0.5%)] underwent three conditions: (1) a low-fat (LF) meal with normal bolus insulin, (2), a high-fat (HF) meal with normal bolus insulin and (3) a high-fat meal with normal bolus insulin with an additional 30% insulin...

  20. Degludec: the new ultra-long insulin analogue.

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    Tambascia, Marcos Antonio; Eliaschewitz, Freddy Goldberg

    2015-01-01

    The development of extended-action insulin analogues was motivated by the unfavorable pharmacokinetic (PK) profile of the conventional long-acting insulin formulations, generally associated with marked inter and intra patient variability and site- and dose-dependent effect variation. The new ultra-long insulin analogue degludec (IDeg) has the same amino acid sequence as human insulin except for the removal of threonine in the position 30 of the B chain (Des-B30, "De") and the attachment, via a glutamic acid linker ("glu"), of a 16-carbon fatty diacid (hexadecanoic diacid, "dec") to lysine in the position 29 of the B chain. These modifications allow that, after changing from the pharmaceutical formulation to the subcutaneous environment, IDeg precipitates in the subcutaneous tissue, forming a depot that undergoes a highly predictable gradual dissociation. Thus, once-daily dosing of IDeg results in a low peak: trough ratio, with consequent low intra-individual variability and plasmatic concentrations less critically dependent upon the time of injections. The clinical development program of IDeg (BEGIN) was comprised of 9 therapeutic confirmatory trials of longer duration (26-52 weeks) and showed that the efficacy of IDeg is comparable to insulin glargine in type 1 (T1D) and type 2 (T2D) diabetes patients across different age, body mass index and ethnic groups. This new ultra-long insulin analogue presents as advantages flexibility in dose timing and lower risk of hypoglycemia.

  1. Insulin degludec is a new ultra-long-acting insulin analogue

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    Ivan Ivanovich Dedov

    2014-06-01

    Full Text Available Achieving optimal glycemic control is an important aspect of preventing and slowing the progression of diabetes-associated complications, and reducing the cost of their treatment. Long-acting insulin analogues, glargine and detemir, provide better metabolic control with reduced risk of hypoglycaemia as compared to NPH insulin. However, fear of hypoglycaemia and weight gain, as well as the complexity of regimen, are still the most important barriers to well-timed initiation and intensification of insulin therapy. Insulin degludec (Tresiba® is a new ultra-long-acting insulin analogue. After subcutaneous injection degludec forms repository of soluble multi-hexamers, which are gradually absorbed to the bloodstream, providing a flat, stable antihyperglycemic effect lasting more than 42 h, and low intra-individual variability as opposed to currently used basal insulin analogues, insulin glargine and insulin detemir. In the seven randomized, open label, controlled phase 3 trials lasting 26 or 52 weeks, using treat-to-target (no more non-inferiority design, insulin degludec provided glycemic control similar to that of insulin glargine with lower risk of nocturnal hypoglycaemia and good safety profile in patients with type 1 or 2 diabetes. Furthermore, trials examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes have shown that it is possible to vary the injection time without compromising glycemic control or safety of the therapy.

  2. Insulin analogues: have they changed insulin treatment and improved glycaemic control?

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2002-01-01

    To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time-action profile most studi......, the new fast-acting analogues have not achieved the expected commercial success, which emphasises the need for new strategies for basal insulin supplementation, exercise, diet and blood glucose monitoring....... in a long half-life with a residual activity of about 50% 24 h after injection. Insulin glargine is a peakless insulin and studies in both type 1 and type 2 diabetic patients indicate that glargine improves fasting blood glucose control and reduces the incidence of nocturnal hypoglycaemia. Surprisingly...

  3. Biphasic Insulin Analogues in Type 2 Diabetes: Expert Panel Recommendations

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    Sema Akalın

    2011-09-01

    Full Text Available Recently, the prevalence of type 2 diabetes has reached pandemic levels all over the world, and the problem is still growing. Type 2 diabetes is a progressive disease, in which insulin resistance and decrease in beta cell function accompany obesity. Early disorder, which ensues in clinical progression of the disease, is the defect of early phase insulin secretion. Patients have already lost approximately half of their beta cell reserve at the time of diagnosis. Aims of type 2 diabetes treatment are to eliminate hyperglycemia caused by insufficient insulin secretion and/or insulin resistance, to slow down beta cell destruction/depletion, to improve concomitant metabolic problems and to prevent complications. In treatment algorithms, insulin is evaluated as a replacement therapy at the following stage after life style changes (medical nutrition therapy, exercise and oral anti-diabetic drugs (OADs options. Since beta cell depletion is present at initial stages of the disease, it transforms insulin therapy into an earlier approach in treatment stages. Premixed insulin forms are one of the proposed treatment options in patients with hyperglycemia that is not controlled by OADs. These types of insulins are developed to meet both basal and postprandial insulin requirements of patients. Currently, premixed human insulin forms are replaced by analogue insulin forms, which can mimic the physiological secretion in more acceptable manner. Biphasic analogue insulin is one of the readily available pre-mixed analogue insulin forms, an example of this, Biphasic Insulin aspart 30 which is the one of the premixed analoge insulin forms, contains 30% insulin aspart and 70% protaminated insulin aspart. Consensus recommending the individualized approach in insulin therapy implies that physicians should have more detailed information about the use of different insulin forms. Although a global consensus report about initiation, titration and intensification and the use

  4. Safety and Efficacy of Modern Insulin Analogues

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    Hye Jin Yoo

    2013-06-01

    Full Text Available BackgroundA1chieve® was a noninterventional study evaluating the clinical safety and efficacy of biphasic insulin aspart 30, insulin detemir, and insulin aspart.MethodsKorean type 2 diabetes patients who have not been treated with the study insulin or have started it within 4 weeks before enrollment were eligible for the study. The patient selection and the choice of regimen were at the discretion of the physician. The safety and efficacy information was collected from the subjects at baseline, week 12, and week 24. The number of serious adverse drug reactions (SADRs was the primary endpoint. The changes of clinical diabetic markers at week 12 and/or at week 24 compared to baseline were the secondary endpoints.ResultsOut of 4,058 exposed patients, 3,003 completed the study. During the study period, three SADRs were reported in three patients (0.1%. No major hypoglycemic episodes were observed and the rate of minor hypoglycemic episodes marginally decreased during 24 weeks (from 2.77 to 2.42 events per patient-year. The overall quality of life score improved (from 66.7±15.9 to 72.5±13.5 while the mean body weight was slightly increased (0.6±3.0 kg. The 24-week reductions in glycated hemoglobin, fasting plasma glucose and postprandial plasma glucose were 1.6%±2.2%, 2.5±4.7 mmol/L, and 4.0±6.4 mmol/L, respectively.ConclusionThe studied regimens showed improvements in glycemic control with low incidence of SADRs, including no incidence of major hypoglycemic episodes in Korean patients with type 2 diabetes.

  5. Recombinant canine single chain insulin analogues: insulin receptor binding capacity and ability to stimulate glucose uptake.

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    Adams, Jamie P; Holder, Angela L; Catchpole, Brian

    2014-12-01

    Virtually all diabetic dogs require exogenous insulin therapy to control their hyperglycaemia. In the UK, the only licensed insulin product currently available is a purified porcine insulin preparation. Recombinant insulin is somewhat problematic in terms of its manufacture, since the gene product (preproinsulin) undergoes substantial post-translational modification in pancreatic β cells before it becomes biologically active. The aim of the present study was to develop recombinant canine single chain insulin (SCI) analogues that could be produced in a prokaryotic expression system and which would require minimal processing. Three recombinant SCI constructs were developed in a prokaryotic expression vector, by replacing the insulin C-peptide sequence with one encoding a synthetic peptide (GGGPGKR), or with one of two insulin-like growth factor (IGF)-2 C-peptide coding sequences (human: SRVSRRSR; canine: SRVTRRSSR). Recombinant proteins were expressed in the periplasmic fraction of Escherichia coli and assessed for their ability to bind to the insulin and IGF-1 receptors, and to stimulate glucose uptake in 3T3-L1 adipocytes. All three recombinant SCI analogues demonstrated preferential binding to the insulin receptor compared to the IGF-1 receptor, with increased binding compared to recombinant canine proinsulin. The recombinant SCI analogues stimulated glucose uptake in 3T3-L1 adipocytes compared to negligible uptake using recombinant canine proinsulin, with the canine insulin/cIGF-2 chimaeric SCI analogue demonstrating the greatest effect. Thus, biologically-active recombinant canine SCI analogues can be produced relatively easily in bacteria, which could potentially be used for treatment of diabetic dogs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Insulin analogues: have they changed insulin treatment and improved glycaemic control?

    DEFF Research Database (Denmark)

    Madsbad, Sten

    2002-01-01

    . This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin...... in a long half-life with a residual activity of about 50% 24 h after injection. Insulin glargine is a peakless insulin and studies in both type 1 and type 2 diabetic patients indicate that glargine improves fasting blood glucose control and reduces the incidence of nocturnal hypoglycaemia. Surprisingly...

  7. Individual stepwise intensification of insulin analogue therapy in type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Aleksandr Sergeevich Ametov

    2012-12-01

    Full Text Available Article reviews basic steps and regimens of insulin analogue therapy intensification in patients with type 2 diabetes mellitus (T2DM. Intensification of insulin therapy is commonly implemented by supplementation of basal insulin with prandial before breakfast, lunch and dinner. Updated EASD/ADA guidelines (August 2012 recommend individual stepwise intensification of T2DM insulin therapy. Application of insulin analogues simplifies diabetes training and patient self-monitoring.

  8. Insulin analogues in pregnancy and specific congenital anomalies; a literature review

    NARCIS (Netherlands)

    de Jong, Josta; Garne, Ester; Wender-Ozegowska, Ewa; Morgan, Margery; de Jong-van den Berg, Lolkje T W; Wang, Hao

    2016-01-01

    BACKGROUND: Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. METHODS: We performed a literature search for

  9. Therapeutics of Diabetes Mellitus: Focus on Insulin Analogues and Insulin Pumps

    Directory of Open Access Journals (Sweden)

    Vasiliki Valla

    2010-01-01

    Full Text Available Aim. Inadequately controlled diabetes accounts for chronic complications and increases mortality. Its therapeutic management aims in normal HbA1C, prandial and postprandial glucose levels. This review discusses diabetes management focusing on the latest insulin analogues, alternative insulin delivery systems and the artificial pancreas. Results. Intensive insulin therapy with multiple daily injections (MDI allows better imitation of the physiological rhythm of insulin secretion. Longer-acting, basal insulin analogues provide concomitant improvements in safety, efficacy and variability of glycaemic control, followed by low risks of hypoglycaemia. Continuous subcutaneous insulin infusion (CSII provides long-term glycaemic control especially in type 1 diabetic patients, while reducing hypoglycaemic episodes and glycaemic variability. Continuous subcutaneous glucose monitoring (CGM systems provide information on postprandial glucose excursions and nocturnal hypo- and/or hyperglycemias. This information enhances treatment options, provides a useful tool for self-monitoring and allows safer achievement of treatment targets. In the absence of a cure-like pancreas or islets transplants, artificial “closed-loop” systems mimicking the pancreatic activity have been also developed. Conclusions. Individualized treatment plans for insulin initiation and administration mode are critical in achieving target glycaemic levels. Progress in these fields is expected to facilitate and improve the quality of life of diabetic patients.

  10. A comparison of the pharmacodynamic profiles of jet-injected regular human insulin versus conventionally administered insulin aspart in healthy volunteers

    NARCIS (Netherlands)

    Engwerda, E.E.; Tack, C.J.; Galan, B.E. de

    2016-01-01

    AIMS: Rapid-acting insulin analogues are generally preferred over regular human insulin because of their more immediate onset of action and shorter time-action profile. However, these analogues may not always be tolerated by or universally available for people with insulin-requiring diabetes. Jet

  11. Capillary electrokinetic chromatography of insulin and related synthetic analogues.

    Science.gov (United States)

    Ortner, K; Buchberger, W; Himmelsbach, M

    2009-04-03

    With the implementation of recombinant DNA technology in the pharmaceutical industry, some synthetic insulins have been developed in order to improve the therapy of diabetes. These analogues differ only slightly in the amino acid sequence, therefore displaying a great challenge for analytical chemistry. Within the work presented in this paper, capillary zone electrophoresis (CZE), micellar electrokinetic chromatography (MEKC) with sodium dodecylsulphate (SDS) as micelle-forming agent, and microemulsion electrokinetic chromatography (MEEKC) with microemulsions consisting of SDS, n-octane and 1-butanol were investigated for the separation of human insulin and five synthetic analogues. Best results were achieved with a solvent-modified MEKC system consisting of 100mM sodium dodecyl sulphate and 15% acetonitrile in 10mM borate buffer (pH 9.2). A similar system based on perfluorooctanoic acid as micelle-forming agent in ammonium acetate (pH 9.2) was successfully employed for the hyphenation with a quadrupole/time-of-flight mass spectrometer via a sheath-flow interface. In this case, detection limits at 10mg/L could be achieved.

  12. Insulin analogues versus human insulin in type 1 diabetes: direct and indirect meta-analyses of efficacy and safety

    Directory of Open Access Journals (Sweden)

    Andréia Cristina Conegero Sanches

    2013-09-01

    Full Text Available All patients with Diabetes Mellitus (DM receive insulin therapy. In this study, we evaluated the efficacy, safety and tolerability of human insulin and insulin analogues. We performed a systematic review of the literature and a meta-analysis according to the Cochrane Collaboration methodology. In the absence of clinical studies comparing insulins, we performed a mixed treatment comparison to establish the differences between the active treatments. We included studies published from 1995 to 2010. HbA1c results, episodes of hypoglycemia and nocturnal hypoglycemia data were extracted and analyzed. Thirty-five randomized clinical trials were selected after examining the abstract and a full text review. These studies included 4,206 patients who received long-acting insulin analogues and 5,733 patients who received short-acting insulin analogues. Pooled data regarding efficacy indicated no significant differences in HbA1c values between glargine or detemir (once daily and NPH insulin. However, a twice-daily dose of detemir produced differences in HbA1c values that favored detemir (-0.14% [95% CI: -0.21 to -0.08]; p<0.0001; I²=0%. Direct and indirect comparisons are consistent and show that there were no significant differences between human insulin and insulin analogues in efficacy or safety. Our results indicate that long- and short-acting insulin analogues offer few clinical advantages over conventional human insulin.

  13. Systematic evaluation of the metabolic to mitogenic potency ratio for B10-substituted insulin analogues.

    Directory of Open Access Journals (Sweden)

    Tine Glendorf

    Full Text Available BACKGROUND: Insulin analogues comprising acidic amino acid substitutions at position B10 have previously been shown to display increased mitogenic potencies compared to human insulin and the underlying molecular mechanisms have been subject to much scrutiny and debate. However, B10 is still an attractive position for amino acid substitutions given its important role in hexamer formation. The aim of this study was to investigate the relationships between the receptor binding properties as well as the metabolic and mitogenic potencies of a series of insulin analogues with different amino acid substitutions at position B10 and to identify a B10-substituted insulin analogue without an increased mitogenic to metabolic potency ratio. METHODOLOGY/PRINCIPAL FINDINGS: A panel of ten singly-substituted B10 insulin analogues with different amino acid side chain characteristics were prepared and insulin receptor (both isoforms and IGF-I receptor binding affinities using purified receptors, insulin receptor dissociation rates using BHK cells over-expressing the human insulin receptor, metabolic potencies by lipogenesis in isolated rat adipocytes, and mitogenic potencies using two different cell types predominantly expressing either the insulin or the IGF-I receptor were systematically investigated. Only analogues B10D and B10E with significantly increased insulin and IGF-I receptor affinities as well as decreased insulin receptor dissociation rates displayed enhanced mitogenic potencies in both cell types employed. For the remaining analogues with less pronounced changes in receptor affinities and insulin receptor dissociation rates, no apparent correlation between insulin receptor occupancy time and mitogenicity was observed. CONCLUSIONS/SIGNIFICANCE: Several B10-substituted insulin analogues devoid of disproportionate increases in mitogenic compared to metabolic potencies were identified. In the present study, receptor binding affinity rather than insulin

  14. Insulin analogues versus human insulin in type 1 diabetes: direct and indirect meta-analyses of efficacy and safety

    OpenAIRE

    Andréia Cristina Conegero Sanches; Cassyano Januário Correr; Rafael Venson; Patrícia Rodrigues Gonçalves; Mariana Martins Garcia; Mário Sérgio Piantavini; Roberto Pontarolo

    2013-01-01

    All patients with Diabetes Mellitus (DM) receive insulin therapy. In this study, we evaluated the efficacy, safety and tolerability of human insulin and insulin analogues. We performed a systematic review of the literature and a meta-analysis according to the Cochrane Collaboration methodology. In the absence of clinical studies comparing insulins, we performed a mixed treatment comparison to establish the differences between the active treatments. We included studies published from 1995 to 2...

  15. Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Tarnow, L; Bay, C

    2017-01-01

    hourly during sleep. Primary endpoints were nocturnal glucose profiles and occurrence of hypoglycaemia (blood glucose ≤ 3.9 mmol/l). Results: During insulin analogue treatment, the mean nocturnal plasma glucose level was significantly higher than during treatment with human insulin (10.6 vs 8.1 mmol....... Conclusions: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens...

  16. Insulin and its analogues and their affinities for the IGF1 receptor

    NARCIS (Netherlands)

    A.J. Varewijck (Aimee); J.A.M.J.L. Janssen (Joseph)

    2012-01-01

    textabstractInsulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control. However, structural modification of the insulin molecule may result in altered binding affinities and activities to the IGF1 receptor

  17. Insulin analogues in type 1 diabetes mellitus: getting better all the time.

    Science.gov (United States)

    Mathieu, Chantal; Gillard, Pieter; Benhalima, Katrien

    2017-07-01

    The treatment of type 1 diabetes mellitus consists of external replacement of the functions of β cells in an attempt to achieve blood levels of glucose as close to the normal range as possible. This approach means that glucose sensing needs to be replaced and levels of insulin need to mimic physiological insulin-action profiles, including basal coverage and changes around meals. Training and educating patients are crucial for the achievement of good glycaemic control, but having insulin preparations with action profiles that provide stable basal insulin coverage and appropriate mealtime insulin peaks helps people with type 1 diabetes mellitus to live active lives without sacrificing tight glycaemic control. Insulin analogues enable patients to achieve this goal, as some have fast action profiles, and some have very slow action profiles, which gives people with type 1 diabetes mellitus the tools to achieve dynamic insulin-action profiles that enable tight glycaemic control with a risk of hypoglycaemia that is lower than that with human short-acting and long-acting insulins. This Review discusses the established and novel insulin analogues that are used to treat patients with type 1 diabetes mellitus and provides insights into the future development of insulin analogues.

  18. Comparison of medication adherence in diabetes mellitus patients on human versus analogue insulins.

    Science.gov (United States)

    Machado-Alba, Jorge Enrique; Medina-Morales, Diego Alejandro; Echeverri-Cataño, Luis Felipe

    2017-02-01

    Objetive: This study evaluated the results of treatment adherence scales in two cohorts of patients with diabetes mellitus treated either with human or analogue insulins. A cohort study was conducted in diabetes mellitus patients older than 18 that were being treated with human or analogue insulins. Two instruments were applied to each patient [medication possession ratio, Morisky-Green test] to evaluate treatment adherence. A total of 238 patients, were included. The majority (69.4%) of the subjects had human insulin and 30.6% had insulin analogue prescriptions. Out of the total, 163 (68.5%) cases were classified as adherent to therapy, according to the type of insulin, as follows: 69.9% for conventional and 65.3% for analogues; without differences between the groups (CI95%:0.450-1.458). The adherence to treatment was more probable in patients with elementary-secondary education (OR:2.341; CI95%:1.199-4.568) and less probable for those in the age range of 31-45 years (OR:0.427; CI95%:0.187-0.971). The results of this study show that there are no significant statistical differences in adherence when comparing human with analogue insulin therapy. Strategies to improve treatment adherence are particularly important since they improve the clinical results.

  19. Receptor-isoform-selective insulin analogues give tissue-preferential effects

    DEFF Research Database (Denmark)

    Vienberg, Sara Gry; Bouman, Stephan D; Sørensen, Heidi

    2011-01-01

    The relative expression patterns of the two IR (insulin receptor) isoforms, +/- exon 11 (IR-B/IR-A respectively), are tissue-dependent. Therefore we have developed insulin analogues with different binding affinities for the two isoforms to test whether tissue-preferential biological effects can...... be attained. In rats and mice, IR-B is the most prominent isoform in the liver (> 95%) and fat (> 90%), whereas in muscles IR-A is the dominant isoform (> 95%). As a consequence, the insulin analogue INS-A, which has a higher relative affinity for human IR-A, had a higher relative potency [compared with HI...... (human insulin)] for glycogen synthesis in rat muscle strips (26%) than for glycogen accumulation in rat hepatocytes (5%) and for lipogenesis in rat adipocytes (4%). In contrast, the INS-B analogue, which has an increased affinity for human IR-B, had higher relative potencies (compared with HI...

  20. Insulin analogues dosing and costs - comparing real-life daily doses of insulin detemir and insulin glargine in type 2 diabetes patients

    Directory of Open Access Journals (Sweden)

    Jakobsen Marie

    2012-09-01

    Full Text Available Abstract Background The uncertainties regarding dose similarities between basal long-acting insulin analogues remain. Recent real-world studies indicate dose similarities between insulin detemir and insulin glargine, but further studies are still warranted. The aim of this study was to compare real-life daily doses of insulin detemir and insulin glargine in type 2 diabetes patients when administered once daily. Methods We analysed 536 patient cases from general practice (63% and endocrinological outpatient clinics (37%. A self-administered questionnaire completed by the treating physician was used to obtain data on patient characteristics (gender, age, weight, height, latest HbA1c-value, daily doses, administration of and number of years treated with insulin detemir and insulin glargine, concomitant insulin use and use of non-insulin anti-diabetic medication. Both bivariate analyses and multivariate regression analyses were applied to examine whether there were differences in the daily doses of insulin detemir and insulin glargine. Results There was no significant difference in the mean daily doses of insulin detemir (0.414 U/kg and insulin glargine (0.416 U/kg (p = 0.4341. In multivariate regression analyses, age and BMI had a significant influence on daily insulin dose with the dose increasing 0.003 U/kg (p = 0.0375 and 0.008 U/kg (p = 0.0003 with every 1 increment in age and BMI, respectively. Conclusions Dose similarities between insulin detemir and insulin glargine were seen in type 2 diabetes patients when administered once daily. Thus, the use of insulin detemir and insulin glargine is not associated with different medical costs if the price and treating algorithm are similar.

  1. Elements of metabolic control in children with type 1 diabetes before and after introduction to insulin analogues

    Directory of Open Access Journals (Sweden)

    Baloš Ljiljana

    2011-01-01

    Full Text Available Introduction. Diabetes mellitus type 1 (T1DM in children is characterized by unstable course. A significant number of studies shows that introduction to insulin analogues treatment aims towards better control of the disease. Objective. The assessment of metabolic control in children with T1DM that were introduced to insulin analogue treatment after many years of treatment with classic (human insulin. Methods. The study included 59 patients 2-19 years old (12.9±3.8 with T1DM, transferred from treatment with human insulin to insulin analogues treatment. Data were obtained directly from patients and their parents, as well as from medical records. Results. The introduction to insulin analogues treatment, leads to a decrease in the value of glycolized haemoglobin (HbA1c after 6 months (9.27±1.68% vs 8.63±1:26%, p=0.06. Average daily dose of insulin expressed per IU/kg of classic and insulin analogue (1.04±0.38 vs 1.03±0.30; p>0.05, remained almost the same. In 39 examinees (66.1%, 6 months before the introduction to insulin analogue treatment, severe hypoglicemia was registered and 6 months after the introduction to insulin analogue treatment it appeared in only two examinees (3.4% (p<0.001. Ketoacidosis, 6 months before introduction to insulin analogues treatment, appeared in 16 examinees (27.1%, while 6 months after it was not registered (p<0.001. Conclusion. The use of insulin analogue treatment in childhood provides adequate metabolic control and substantially reduces the risk of acute complications (severe hypoglicemia, ketoacidosis.

  2. The combination of insulin and GLP-1 analogues in the treatment of type 2 diabetes

    NARCIS (Netherlands)

    van der Klauw, M. M.; Wolffenbuttel, B. H. R.

    2012-01-01

    GLP-1 analogues have been proven to be effective in the treatment of type 2 diabetes mellitus. They stimulate insulin production and secretion, and suppress glucagon secretion, depending on the blood glucose level. They also have an effect on the brain, enhancing satiety, and on the gut, where they

  3. Insulin Basics

    Science.gov (United States)

    ... Text Size: A A A Listen En Español Insulin Basics There are different types of insulin depending ... you may be experiencing a reaction. Types of Insulin Rapid-acting insulin , begins to work about 15 ...

  4. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues

    DEFF Research Database (Denmark)

    Lundby, Anders; Bolvig, Pernille; Hegelund, Anne Charlotte

    2015-01-01

    therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF......There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We......-IR. Insulin exhibited mitogenicity EC50 values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using...

  5. Glycemic control with insulin glargine plus insulin glulisine versus premixed insulin analogues in real-world practices: a cost-effectiveness study with a randomized pragmatic trial design.

    Science.gov (United States)

    Levin, Philip A; Zhang, Quanwu; Mersey, James H; Lee, Francis Y; Bromberger, Lee A; Bhushan, Madhu; Bhushan, Rajat

    2011-07-01

    Cost can be an important consideration, along with safety and efficacy, in deciding the most appropriate treatment for patients with type 2 diabetes. Both basal-bolus and premixed insulin analogue regimens are widely used in clinical practice; however, limited information is available regarding cost-effectiveness. The goal of this study was to compare glycemic control, cost-effectiveness, and quality of life effects of insulin glargine plus insulin glulisine (glargine/glulisine) versus premixed insulin analogues in real-world clinical practice. Adults with type 2 diabetes (glycosylated hemoglobin [HbA(1c)] ≥7.0%) at 3 US endocrinology centers were randomly assigned to receive either glargine/glulisine or premixed insulin analogues and continued treatment following the centers' usual practice. HbA(1c), weight, insulin dose, concomitant oral antidiabetic drug (OAD) usage, and hypoglycemia were evaluated at baseline and 3, 6, and 9 months. Medication costs, including costs for all insulin or OAD regimens, were estimated using published wholesale acquisition costs. A total of 197 patients were randomized to receive glargine/glulisine therapy (n = 106) or premixed analogue therapy (n = 91). Overall, the mean age was 56 years, the mean duration of diabetes was 13 years, with a mean HbA(1c) of 9.25% and mean BMI of 35.8 kg/m(2) at baseline. Patients randomized to receive glargine/glulisine had a greater mean HbA(1c) reduction from baseline (-2.3%) than patients receiving a premixed analogue regimen (-1.7%). Adjusted mean follow-up HbA(1c) was 6.9% versus 7.5%, respectively (difference, -0.59%; P < 0.01). The glargine/glulisine group also used a lower mean number of OADs (0.86 vs 1.14; difference, -0.28; P = 0.04) but had a higher weight (240 vs 235 lb; difference, 4.55 lb; P = 0.03) than the premixed analogue group at follow-up. There were no significant differences in daily insulin dose and rates of hypoglycemia. Overall medication costs per 1.0% reduction in HbA(1c

  6. Alternative signaling network activation through different insulin receptor family members caused by pro-mitogenic antidiabetic insulin analogues in human mammary epithelial cells.

    Science.gov (United States)

    ter Braak, Bas; Wink, Steven; Koedoot, Esmee; Pont, Chantal; Siezen, Christine; van der Laan, Jan Willem; van de Water, Bob

    2015-07-19

    Insulin analogues are designed to have improved pharmacokinetic parameters compared to regular human insulin. This provides a sustained control of blood glucose levels in diabetic patients. All novel insulin analogues are tested for their mitogenic side effects, however these assays do not take into account the molecular mode of action of different insulin analogues. Insulin analogues can bind the insulin receptor and the insulin-like growth factor 1 receptor with different affinities and consequently will activate different downstream signaling pathways. Here we used a panel of MCF7 human breast cancer cell lines that selectively express either one of the isoforms of the INSR or the IGF1R. We applied a transcriptomics approach to assess the differential transcriptional programs activated in these cells by either insulin, IGF1 or X10 treatment. Based on the differentially expressed genes between insulin versus IGF1 and X10 treatment, we retrieved a mitogenic classifier gene set. Validation by RT-qPCR confirmed the robustness of this gene set. The translational potential of these mitogenic classifier genes was examined in primary human mammary cells and in mammary gland tissue of mice in an in vivo model. The predictive power of the classifier genes was evaluated by testing all commercial insulin analogues in the in vitro model and defined X10 and glargine as the most potent mitogenic insulin analogues. We propose that these mitogenic classifier genes can be used to test the mitogenic potential of novel insulin analogues as well as other alternative molecules with an anticipated affinity for the IGF1R.

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

    Directory of Open Access Journals (Sweden)

    Heather Ulrich

    2007-07-01

    Full Text Available Heather Ulrich1,4, Benjamin Snyder1,Satish K Garg1,2,31Barbara Davis Center for Childhood Diabetes; 2Department of Medicine; 3Pediatrics; 4Department of Clinical Pharmacy, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Denver, CO, USAAbstract: Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs reduce post-prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI. Insulin glulisine (Apidra® is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs. The safety and tolerability profile of insulin glulisine is also comparable to that of insulin

  8. Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Lundby-Christensen, Louise; Tarnow, Lise; Boesgaard, Trine W

    2016-01-01

    OBJECTIVE: To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial...... g twice daily) versus placebo, aiming at an HbA1c ≤7.0% (≤53 mmol/mol). OUTCOMES: The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes...... insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p

  9. Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

    NARCIS (Netherlands)

    Bronsveld, H.K.; Braak, ter B.; Karlstad, O.; Vestergaard, P.; Starup-Linde, J.; Bazelier, M.T.; Bruin, de M.L.; Boer, de A.; Siezen, C.L.E.; Water, van de B.; van, der Laan J. W.; Schmidt, M.K.

    2015-01-01

    INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A

  10. Improved postprandial glycaemic control with insulin Aspart in type 2 diabetic patients treated with insulin

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Thorsby, P; Kjems, L

    2000-01-01

    The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 minutes before a test meal in insulin-treated type 2 diabetic patients with residual.......0 nmol/l (range, 0.3-2.5) and diabetes duration 12.5 years (range, 3.0-26.0). Twenty-two patients completed the study. A significantly improved postprandial glucose control was demonstrated with IAsp as compared to Act0, based on a significantly smaller postprandial blood glucose excursion (IAsp, 899......-meal administration of the rapid-acting insulin analogue Aspart in patients with type 2 diabetes resulted in an improved postprandial glucose control compared to Actrapid injected immediately before the meal, but showed similar control compared to Actrapid injected 30 minutes before the meal. These results indicate...

  11. Use of Insulin Analogues in Children and Adolescents: Topical Issues and Possibilities for Achieving Optimal Type 1 Diabetes Mellitus Compensation

    Directory of Open Access Journals (Sweden)

    О.A. Budreyko

    2013-02-01

    Full Text Available The review contains an analysis of the data of numerous scientific studies on the results of use of insulin analogues in comprehensive treatment of type 1 diabetes mellitus in children and adolescents. Problem of mitogenic potential of insulin preparations and ways to prevent its realization in clinical practice is discussed. Advisability of the use of insulin analogues glulisine and glargine in children and adolescents is substantiated for achievement of optimal compensation of carbohydrate metabolism due to their high efficiency and adequate level of safety, confirmed by the regulations of international consensuses (ISPAD and IDF.

  12. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

    Energy Technology Data Exchange (ETDEWEB)

    Žáková, Lenka; Kletvíková, Emília; Lepšík, Martin; Collinsová, Michaela [Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic); Watson, Christopher J.; Turkenburg, Johan P. [The University of York, Heslington, York YO10 5DD (United Kingdom); Jiráček, Jiří [Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic); Brzozowski, Andrzej M., E-mail: marek.brzozowski@york.ac.uk [The University of York, Heslington, York YO10 5DD (United Kingdom); Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic)

    2014-10-01

    [AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

  13. Effect of insulin analogues on frequency of non-severe hypoglycaemia in patients with type 1 diabetes prone to severe hypoglycaemia

    DEFF Research Database (Denmark)

    Agesen, R M; Kristensen, P L; Beck-Nielsen, H

    2016-01-01

    AIM: Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk...... two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe...... the insulin regimens during the day. The time needed to treat one patient with insulin analogues to avoid one episode (TNT1) of non-severe nocturnal hypoglycaemia was approximately 3 months. CONCLUSION: In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non...

  14. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2.

    Directory of Open Access Journals (Sweden)

    Cécile Pierre-Eugene

    Full Text Available BACKGROUND: In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R, present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids. METHODOLOGY: To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP(3 production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP(3 production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells. RESULTS: Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP(3 production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP(3 production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin. CONCLUSION: Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in

  15. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex.

    Science.gov (United States)

    Záková, Lenka; Kletvíková, Emília; Lepšík, Martin; Collinsová, Michaela; Watson, Christopher J; Turkenburg, Johan P; Jiráček, Jiří; Brzozowski, Andrzej M

    2014-10-01

    The structural characterization of the insulin-insulin receptor (IR) interaction still lacks the conformation of the crucial B21-B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

  16. Modelling the glucose-insulin-glucagon dynamics after subcutaneous administration of native glucagon and a novel glucagon analogue in dogs

    DEFF Research Database (Denmark)

    Wendt, Sabrina Lyngbye; Boye Knudsen, Carsten; Jørgensen, John Bagterp

    Zealand Pharma has invented a glucagon analogue, ZP-GA-1, with increased stability in liquid formulation for treatment of hypoglycemia. A pharmacodynamic (PD) model is needed to compare ZP-GA-1 with marketed glucagon. We aim to develop a model of the complex glucose-insulin-glucagon dynamics base...

  17. Treatment with the long-acting insulin analogues detemir or glargine during pregnancy in women with type 1 diabetes

    DEFF Research Database (Denmark)

    Callesen, Nicoline F; Mathiesen, Jonathan Michael; Ringholm, Lene

    2013-01-01

    Objective: To compare glycaemic control and pregnancy outcome in women with type 1 diabetes treated with the long-acting insulin analogues detemir or glargine. Methods: Retrospective study of singleton pregnancies from 2007 to 2011 in women with type 1 diabetes with a single living fetus at 22 we...

  18. Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

    Science.gov (United States)

    Dowlat, H A; Kuhlmann, M K; Khatami, H; Ampudia-Blasco, F J

    2016-08-01

    Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included. © 2016 John Wiley & Sons Ltd.

  19. Effects of Mealtime Insulin Aspart and Bedtime NPH Insulin on Postprandial Inflammation and Endothelial Cell Function in Patients with Type 2 Diabetes

    DEFF Research Database (Denmark)

    Bladbjerg, Else-Marie; Henriksen, Jan Erik; Akram, Sumarra

    2011-01-01

    collected at 7.40 (fasting), 9.30, 11.30, 13.30 and 15.30 and analysed for glucose, insulin, lipids, intercellular adhesion molecules (ICAM), C-reactive protein (CRP), von Willebrand factor (vWF) and fibrinogen. The postprandial glucose response differed significantly between insulin regimens......WF and fibrinogen. The rapid-acting insulin analogue aspart and the intermediate-acting insulin NPH had different effects on postprandial glucose response but similar postprandial effects on markers of inflammation and endothelial dysfunction.......  Acute hyperglycaemia exerts deleterious effects on the arterial wall. We suggested that rapid-acting insulin has a beneficial postprandial effect on endothelial dysfunction and inflammation compared with intermediate-acting insulin because of its ability to lower postprandial hyperglycaemia...

  20. The Risk of Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus Starting Insulin Therapy with Premixed Insulin Analogues Taken Twice Daily: An Observational Study in Turkish Patients

    Directory of Open Access Journals (Sweden)

    Mustafa Sait Gönen

    2013-12-01

    Full Text Available Purpose: To assess the risk of severe hypoglycemia in Turkish patients with type 2 diabetes mellitus (T2DM starting insulin therapy with premixed insulin analogues alone or in combination with oral antihyperglycemic medications. Material and Method: Data from a subset of Turkish patients who participated in a 1-year, multinational, multicenter, prospective observational study were evaluated. Insulin treatment was initiated using commonly prescribed premixed regimens: insulin lispro mix 25 (25% insulin lispro, 75% insulin lispro protamine suspension or biphasic insulin aspart 30/70 (30% insulin aspart, 70% insulin aspart protamine suspension twice daily. Results: Of the 154 patients treated, 61 (39.6% were male with a mean age of 56 years and a T2DM duration of 8.9 years. Twelve patients (7.8% experienced ≥1 episode of severe hypoglycemia, but all recovered. The severe hypoglycemic rate was 0.14 episodes/patient-year. The mean glycated hemoglobin decreased by 2.7% (10.4% to 7.8% and fasting plasma glucose by 115.9 mg/dL (265.3 mg/dL to 157.6 mg/dL (p<0.0001. Self-monitored blood glucose (2-hour post morning meal decreased by 163.3 mg/dL (327.0 mg/dL to 216.2 mg/dL; p<0.0001. Self-monitored blood glucose level was low, particularly at the 2-hour post evening meal. Body mass index increased by 1.4 kg/m2, and total daily insulin dose by 4.2 IU. Discussion: In Turkish patients with T2DM, initiation of premixed insulin analogues during routine clinical care significantly improves glycemic control during the first year of treatment, but comes with a risk for severe hypoglycemia. Improvements in physician and patient education within the Turkish population regarding hypoglycemia management may be of benefit. Turk Jem 2013; 17: 83-8

  1. Effects of mealtime insulin aspart and bedtime NPH insulin on postprandial coagulation and fibrinolysis in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Bladbjerg, Else-Marie; Henriksen, Je; Akram, S

    2012-01-01

    ), 9:30, 11:30, 13:30, and 15:30 and analysed for glucose, activated factor VII (FVIIa), D-dimer, prothrombin fragment 1+2 (F1+2), tissue plasminogen activator antigen (t-PA), and plasminogen activator inhibitor activity (PAI). Results: The postprandial glucose response differed significantly between......: The rapid-acting insulin analogue aspart and the intermediate-acting insulin NPH had similar postprandial effects on markers of coagulation activation and fibrinolysis despite different effects on postprandial glucose response.......Aims: Acute hyperglycaemia induces coagulation activation in diabetes patients. We hypothesized that rapid-acting insulin has a beneficial postprandial effect on coagulation and fibrinolysis compared with intermediate-acting insulin due to its ability to lower postprandial hyperglycaemia. Materials...

  2. Basal insulin analogues in the treatment of diabetes mellitus: What progress have we made?

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2015-01-01

    Full Text Available Over the past few decades, continuous progress has been made in the development of insulin therapy. Basal insulins were developed around 60 years ago. However, existing basal insulins were found to have limitations. An ideal basal insulin should have the following properties viz. longer duration of action, a flat time-action profile, low day-to-day glycaemic variability, and the potential for flexible dosing. Basal insulins have advanced over the years, from lectin and neutral protamine Hagedorn to the currently available insulin degludec. Currently, the focus is on developing a basal insulin that can give coverage for the entire day, with lesser variability and flexible administration. Insulin degludec has been a significant leap in that direction. In addition, U300 insulin glargine and pegylated lispro represent further developments in basal insulin pharmacotherapeutics.

  3. Insulin therapy in special conditions

    Directory of Open Access Journals (Sweden)

    León E Litwak

    2017-10-01

    Full Text Available Hyperglycemia during hospitalization is a common condition associated with poor prognosis. To date, insulin is the best strategy to treat hyperglycemia in these patients. An adequate glycemic control is associated with better clinical results. Nevertheless, glycemic goals are still controversial due to the increase of hypoglycemia and other adverse events. Diabetes mellitus is still the main cause of chronic renal failure in our country and its treatment deserves a special analysis considering that insulin pharmacokinetics is altered. Recommendations in this setting are based in expert panel opinions, focusing mainly in intermediate or long acting insulins combined with regular insulin and/or rapid acting analogues. During pregnancy, NPH and regular insulin are safe and effective. It is worth mentioning that the development of new long and rapid acting molecules yielded lower glycemic variability, better post-prandial control and less hypoglycemia. The aim of this study is to provide a review of the proper use of insulin in these special conditions.

  4. Insulin degludec, a long-acting once-daily basal analogue for type 1 and type 2 diabetes mellitus.

    Science.gov (United States)

    Berard, Lori; MacNeill, Gail

    2015-02-01

    Here, we discuss certain practical issues related to use of insulin degludec, a new long-acting basal insulin analogue. Degludec provides uniform ("peakless") action that extends over more than 24 hours and is highly consistent from dose to dose. Like the 2 previously available basal analogues (detemir and glargine), degludec is expected to simplify dose adjustment and enable patients to reach their glycemic targets with reduced risk of hypoglycemia. Phase 3 clinical trials involving type 1 and type 2 diabetes have demonstrated that degludec was noninferior to glargine in allowing patients to reach a target glycated hemoglobin (A1C) of 7%, and nocturnal hypoglycemia occurred significantly less frequently with degludec. In addition, when dosing intervals vary substantially from day to day, degludec continues to be effective and to maintain a low rate of nocturnal hypoglycemia. Degludec thus has the potential to reduce risk of nocturnal hypoglycemia, to enhance the flexibility of the dosing schedule and to improve patient and caregiver confidence in the stability of glycemic control. A dedicated injector, the FlexTouch prefilled pen, containing degludec 200 units/mL, will be recommended for most patients with type 2 diabetes. Degludec will also be available as 100 units/mL cartridges, to be used in the NovoPen 4 by patients requiring smaller basal insulin doses, including most patients with type 1 diabetes. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  5. Changes in glycemic control and quality of life in pediatric type 1 diabetics with continuous subcutaneous insulin infusion of insulin aspart following multiple daily injection therapy.

    Science.gov (United States)

    Kawamura, Tomoyuki; Urakami, Tatsuhiko; Sugihara, Shigetaka; Kim, Hey Sook; Mochizuki, Mie; Amamiya, Shin

    2008-01-01

    The efficacy of continuous subcutaneous insulin infusion (CSII) of the rapid-acting insulin analogue, insulin aspart, was evaluated in 26 patients with childhood-onset type 1 diabetes aged between 6 and 18 yr who had been on basal-bolus therapy (multiple daily injection (MDI) of regular human insulin or rapid-acting insulin and intermediate/long-acting insulin). The glycemic control in the patients was evaluated based on changes in the clinical parameters and the patient quality of life (QOL) was evaluated by using the insulin therapy-related QOL questionnaire. Twenty two patients continued CSII during the 6-mo study period. The mean HbA1c was 7.8 ± 1.8% at baseline and it decreased to 7.4 ± 0.8% at 6 mo after the start of the CSII. Overall, no decrease of the QOL post-CSII initiation was noted. The possible superiority of CSII as compared to MDI was suggested for patients who "eat out" or "have to look for an appropriate place for insulin injection." Aside from an inadequate indwelling needle placement detected after the initiation of CSII in several patients, no adverse event associated with NovoRapid(®) was seen. In conclusion, CSII of rapid-acting insulin appears to be a useful therapy for patients with childhood-onset type 1 diabetes.

  6. A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial: study rationale and design

    Directory of Open Access Journals (Sweden)

    Kristensen Peter

    2012-06-01

    Full Text Available Abstract Background Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. Methods/design The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE, multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. Discussion In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996.

  7. Basal insulin or premix analogue therapy in type 2 diabetes patients.

    Science.gov (United States)

    Raskin, Philip R; Hollander, Priscilla A; Lewin, Andrew; Gabbay, Robert A; Bode, Bruce; Garber, Alan J

    2007-01-01

    We sought to compare the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) given twice daily with once-daily insulin glargine in patients with type 2 diabetes beginning insulin therapy and who did not use thiazolidinediones, which are contraindicated with insulin in the European Union, in a subpopulation (N=157) of the INITIATE study. At baseline, HbA(1c) was >/=8.0% on >/=1000 mg/day metformin alone or in combination with other oral antidiabetic drugs (OADs; e.g. sulphonylurea or alpha-glucosidase inhibitors). Metformin was adjusted up to 2550 mg/day and other OADs were discontinued. Starting insulin doses were subsequently adjusted weekly for 26 weeks by algorithm-directed titration. The proportion of patients achieving a HbA(1c) below 7.0% at 28 weeks was greater with BIAsp 30 than with insulin glargine (65% vs 41%, P=0.003). The mean reduction in HbA(1c) was greater for BIAsp 30 than for insulin glargine: -2.89+/-1.6% vs -2.46+/-1.6%, respectively (P=0.035). Postprandial glucose increments were lower for the BIAsp 30 group after breakfast (P=0.003) and dinner (P=0.033); post-lunch values were not significantly different. No major hypoglycemic episodes were recorded. Nocturnal hypoglycemia was reported by 25% of subjects in the BIAsp 30 group and by 10% in the insulin glargine group (P=0.021). Weight gain was 5.6+/-4.6 and 3.0+/-4.3 kg (P=0.0004) for BIAsp 30 and insulin glargine, respectively. BIAsp 30, given twice daily in combination with metformin, was more effective than insulin glargine, given once daily in combination with metformin, at controlling blood glucose in insulin-naïve patients with type 2 diabetes, but was associated with increased weight gain and minor hypoglycemic events.

  8. [Therapeutic options for a type 2 diabetic patient not well controlled with metformin plus basal insulin].

    Science.gov (United States)

    Scheen, André J; Paquot, Nicolas

    2017-08-23

    In a patient with type 2 diabetes not well controlled with a basal insulin - metformin combination, several therapeutic options may be considered: intensifying insulin therapy with different schemes (appropriate titration using a more favourable basal insulin analogue, adding one, two or three rapid-acting insulin analogues, shift to two or three premix insulin injections), adding a dipeptidyl peptidase-4 inhibitor (gliptin) or an inhibitor of sodium-glucose cotransporters type 2 (gliflozin), or combining a glucagon-like peptide-1 receptor agonist with basal insulin. The choice should be made according the individual profile and preference of the patient, in a personalized approach, taking into account the advantages and disadvantages of each therapeutic solution.

  9. Cancer risk among insulin users : comparing analogues with human insulin in the CARING five-country cohort study

    NARCIS (Netherlands)

    But, Anna; De Bruin, Marie L|info:eu-repo/dai/nl/270270906; Bazelier, Marloes T|info:eu-repo/dai/nl/341589802; Hjellvik, Vidar; Andersen, Morten; Auvinen, Anssi; Starup-Linde, Jakob; Schmidt, Marjanka K; Furu, Kari; de Vries, Frank|info:eu-repo/dai/nl/303546670; Karlstad, Øystein; Ekström, Nils; Haukka, Jari

    2017-01-01

    AIMS/HYPOTHESIS: The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. METHODS: National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway

  10. Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

    DEFF Research Database (Denmark)

    Bronsveld, Heleen K; ter Braak, Bas; Karlstad, Øystein

    2015-01-01

    , the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number......INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD...... to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5...

  11. The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats

    Directory of Open Access Journals (Sweden)

    Fernandez Rayne

    2010-08-01

    Full Text Available Abstract Background Activation of glucagon-like peptide-1 (GLP-1 receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS rats. Methods DSS rats were fed low salt (LS, 0.3% NaCl or high salt (HS, 8% NaCl diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min, or GLP-1 (25 pmol/kg/min for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day or AC3174 plus captopril. Results HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p Conclusions Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

  12. Determination of human insulin and its analogues in human blood using liquid chromatography coupled to ion mobility mass spectrometry (LC-IM-MS).

    Science.gov (United States)

    Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

    2014-01-01

    The qualitative and quantitative determination of insulin from human blood samples is an emerging topic in doping controls as well as in other related disciplines (e.g. forensics). Beside the therapeutic use, insulin represents a prohibited, performance enhancing substance in sports drug testing. In both cases accurate, sensitive, specific, and unambiguous determination of the target peptide is of the utmost importance. The challenges concerning identifying insulins in blood by liquid chromatography coupled to ion mobility mass spectrometry (LC-IM-MS) are detecting the basal concentrations of approximately 0.2 ng/mL and covering the hyperinsulinaemic clamps at > 3 ng/mL simultaneously using up to 200 μL of plasma or serum. This is achieved by immunoaffinity purification of the insulins with magnetic beads and subsequent separation by micro-scale liquid chromatography coupled to ion mobility / high resolution mass spectrometry. The method includes human insulin as well as the synthetic or animal analogues insulin aspart, glulisine, glargine, detemir, lispro, bovine, and porcine insulin. The method validation shows reliable results considering specificity, limit of detection (0.2 ng/mL except for detemir: 0.8 ng/mL), limit of quantification (0.5 ng/mL for human insulin), precision (CV  0.99), recovery, accuracy (>90%), robustness (plasma/serum), and ion suppression. For quantification of human insulin a labelled internal standard ([[(2) H10 ]-Leu(B6,B11,B15,B17) ] - human Insulin) is introduced. By means of the additional ion mobility separation of the different analogues, the chromatographic run time is shortened to 8 min without losing specificity. As proof-of-concept, the procedure was successfully applied to different blood specimens from diabetic patients receiving recombinant synthetic analogues. Copyright © 2014 John Wiley & Sons, Ltd.

  13. Basal insulin analogues in diabetic pregnancy: a literature review and baseline results of a randomised, controlled trial in type 1 diabetes

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R; Damm, Peter; Jovanovic, Lois

    2011-01-01

    and HbA1c ≤ 8.0% at randomization. At confirmation of pregnancy all subjects must have HbA1c ≤ 8.0%. Exclusion criteria include impaired hepatic function, cardiac problems, and uncontrolled hypertension. Subjects are randomized to either insulin detemir or neutral protamine hagedorn insulin, both...... of the current literature concerning basal insulin analogue use in diabetic pregnancy, and to present the design and preliminary, non-validated baseline characteristics of a currently ongoing randomized, controlled, open-label, multicentre, multinational trial comparing insulin detemir with neutral protamine...... hagedorn insulin, both with insulin aspart, in women with type 1 diabetes planning a pregnancy (n = 306) or are already pregnant (n = 164). Inclusion criteria include type 1 diabetes > 12 months' duration; screening HbA1c ≤ 9.0% (women recruited prepregnancy), or pregnant with gestational age 8-12 weeks...

  14. A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial)

    DEFF Research Database (Denmark)

    Kristensen, Peter Lommer; Pedersen-Bjergaard, Ulrik; Beck-Nielsen, Henning

    2012-01-01

    of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin...... analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial.......Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect...

  15. PK/PD modelling of glucose-insulin-glucagon dynamics in healthy dogs after a subcutaneous bolus administration of native glucagon or a novel glucagon analogue

    DEFF Research Database (Denmark)

    Wendt, Sabrina Lyngbye; Møller, Jan Kloppenborg; Boye Knudsen, Carsten

    Objective We aim to develop a simulation model of the complex glucose-insulin-glucagon dynamics based on physiology and data. Furthermore, we compare pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of marketed reconstituted glucagon with a stable liquid glucagon analogue invented by...

  16. Effect of insulin analogues on risk of severe hypoglycaemia in patients with type 1 diabetes prone to recurrent severe hypoglycaemia (HypoAna trial)

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Kristensen, Peter Lommer; Beck-Nielsen, Henning

    2014-01-01

    ) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue...... insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint...

  17. Small angle X-ray scattering-based elucidation of the self-association mechanism of human insulin analogue lys(B29)(N(e)¿-carboxyheptadecanoyl) des(B30)

    DEFF Research Database (Denmark)

    Jensen, Malene Hillerup; Wahlund, Per-Olof; Toft, Katrine Nørgaard

    2013-01-01

    Lys(B29)(N(e)¿-carboxyheptadecanoyl) des(B30) human insulin is an insulin analogue belonging to a class of analogues designed to form soluble depots in subcutis by self-association, aiming at a protracted action. On the basis of small angle X-ray scattering (SAXS) supplemented by a range of bioph......Lys(B29)(N(e)¿-carboxyheptadecanoyl) des(B30) human insulin is an insulin analogue belonging to a class of analogues designed to form soluble depots in subcutis by self-association, aiming at a protracted action. On the basis of small angle X-ray scattering (SAXS) supplemented by a range...

  18. Análogos de insulina: relevancia clínica y perspectivas futuras The clinical relevance of insulin analogues and future perspectives

    Directory of Open Access Journals (Sweden)

    Jhon Jairo BejaranoRoncancio

    2012-12-01

    Full Text Available Desde la década de los noventa han sido diseñados análogos de insulina para el manejo de pacientes diabéticos usando técnicas de ADN recombinante. Las modificaciones de la molécula original de insulina humana les confieren una rápida, ultrarrápida y prolongada acción. Entre las insulinas ultra rápidas están la Aspártica, la Lispro y la Glulisina y entre las de acción prolongada están la Glargina y la Detemir. También se encuentran mezcladas con insulina humana NPH en diferentes proporciones. Aunque existen diferentes tipos de algoritmos terapéuticos, la insulinización sigue siendo una terapia artesanal basada en la experiencia del especialista tratante. La introducción de los análogos de insulina hace más factible el empleo de bolos correctores o dosis extra de insulina para reducir las hipoglicemias puntuales en cualquier momento del día y facilitar el manejo de los carbohidratos en la dieta.Insulin analogues have been engineered through recombinant DNA techniques for managing diabetic patients since the 1990s; modifications to the original human insulin molecule have made them rapid, ultrarapid and prolonged acting. Aspart, lispro and glulisine are ultrafast insulins and glargine and detemir are longacting ones. Such insulins may be premixed in formulations combining neutral protamine Hagedorn (NPH with regular human insulin (70%/30%. Different types of therapeutic algorithms are available nowadays but insulinisation remains a crafted therapy based on the treating specialist's experience. The introduction of insulin analogues enables using correction boluses or extra doses of insulin to reduce hypoglycaemia at any time of the day and facilitates handling carbohydrates in a particular patient's diet.

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

    Directory of Open Access Journals (Sweden)

    Hui Wu

    2014-01-01

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

  20. Insulin

    Science.gov (United States)

    ... Information by Audience For Women Women's Health Topics Insulin Share Tweet Linkedin Pin it More sharing options ... medicines. You can do it. Back to Top Insulin Safety Tips Never drink insulin. Do not share ...

  1. Incorporating a Generic Model of Subcutaneous Insulin Absorption into the AIDA v4 Diabetes Simulator 3. Early Plasma Insulin Determinations

    Science.gov (United States)

    Lehmann, Eldon D.; Tarín, Cristina; Bondia, Jorge; Teufel, Edgar; Deutsch, Tibor

    2009-01-01

    Introduction AIDA is an interactive educational diabetes simulator that has been available without charge via the Internet for over 12 years. Recent articles have described the incorporation of a novel generic model of insulin absorption into AIDA as a way of enhancing its capabilities. The basic model components to be integrated have been overviewed, with the aim being to provide simulations of regimens utilizing insulin analogues, as well as insulin doses greater than 40 IU (the current upper limit within the latest release of AIDA [v4.3a]). Some preliminary calculated insulin absorption results have also recently been described. Methods This article presents the first simulated plasma insulin profiles from the integration of the generic subcutaneous insulin absorption model, and the currently implemented model in AIDA for insulin disposition. Insulin absorption has been described by the physiologically based model of Tarín and colleagues. A single compartment modeling approach has been used to specify how absorbed insulin is distributed in, and eliminated from, the human body. To enable a numerical solution of the absorption model, a spherical subcutaneous depot for the injected insulin dose has been assumed and spatially discretized into shell compartments with homogeneous concentrations, having as its center the injection site. The number of these compartments will depend on the dose and type of insulin. Insulin inflow arises as the sum of contributions to the different shells. For this report the first bench testing of plasma insulin determinations has been done. Results Simulated plasma insulin profiles are provided for currently available insulin preparations, including a rapidly acting insulin analogue (e.g., lispro/Humalog or aspart/Novolog), a short-acting (regular) insulin preparation (e.g., Actrapid), intermediate-acting insulins (both Semilente and neutral protamine Hagedorn types), and a very long-acting insulin analogue (e.g., glargine/Lantus), as

  2. Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Brock, Birgitte; Perrild, Hans

    2008-01-01

    To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin...... release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin...

  3. Initiating insulin therapy in children and adolescents with type 1 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Subhash Kumar Wangnoo

    2015-01-01

    Full Text Available The primary clinical goals to be achieved with insulin initiation are elimination of ketosis and hyperglycemia with prevention of chronic complications. Insulin therapy is the mainstay in management of type 1 diabetes, which should be aimed at achieving good glycemic control, with achievement of hemoglobin A1c (HbA1c <7.5%, pre-meal self-monitored blood glucose (SMBG of 90-130 mg/dL, bed time SMBG of 100-140 mg/dL, mean blood glucose level of 120-160 mg/dL and no ketonuria. Two classes of insulin are available for use in T1DM viz. bolus/prandial insulins (rapid-acting insulins and short-acting insulins and basal insulins (intermediate-acting insulin and long-acting insulin. Insulin glargine and glulisine can be used in children above 6 years, lispro in children above 3 years and detemir and aspart in children above 2 years. The caution for hypoglycemia should be exercised while prescribing them. Degludec is currently not approved for pediatric use. The initial insulin regimen should comprise of ≥2 daily bolus and ≥1 basal insulin injections. Insulin intensification would be required if the initial regimen fails, which can be achieved by increasing frequency of long and rapid acting insulin analogues. The American Diabetes Association guidelines recommend HbA1c targets of <8.0% for children <6 years of age, ≤7.5% for children 6 to 12 years of age, and ≤7.0% for adolescents, 12-18 years of age. However, the evidence is now in favor of a single target HbA1c of ≤7.5% for all children and adolescents <19 years of age.

  4. Type 1 Ig-E mediated allergy to human insulin, insulin analogues and beta-lactam antibiotics Hipersensibilidade imediata a insulina humana, análogos de insulina e a antibióticos beta-lactâmicos

    Directory of Open Access Journals (Sweden)

    Pedro Andrade

    2012-12-01

    Full Text Available Insulin, a crucial therapeutic agent for diabetes mellitus, has been rarely associated with hypersensitivity events. We present a 69-year-old type-2 diabetic patient with urticariform lesions on the sites of subcutaneous injection of insulin. The patient denied any known allergies, except for an unspecific cutaneous reaction after intramuscular penicillin administration in childhood. Prick tests revealed positive reactions to all tested human insulins and insulin analogues. Serum IgE levels were above normal range and RAST tests were positive for human, bovine and porcine insulins, as well as beta-lactams. Type 1 IgEmediated allergy to insulin analogues demands a prompt diagnosis and represents a significant therapeutic challenge in diabetic patients.A insulina é um agente indispensável para o controlo da diabetes mellitus. Os efeitos adversos da sua administração, em particular fenómenos de hipersensibilidade, são raros. Apresentamos um doente de 69 anos, diabético do tipo 2, com episódios recorrentes de lesões urticariformes nos locais de administração subcutânea de insulina. Negava alergias medicamentosas, à excepção de reacção não especificada na infância após penicilina intramuscular. Foram realizados testes cutâneos por puntura (prick tests com diversos tipos de insulina humana e análogos, todos com reacções positivas, associando elevação dos níveis de IgE sérica e provas RAST positivas para as insulinas humana, bovina e porcina e para os antibióticos beta-lactâmicos. A alergia a análogos de insulina exige um diagnóstico precoce, originando um desafio terapêutico importante no doente diabético.

  5. Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Lundby-Christensen, Louise; Vaag, Allan; Tarnow, Lise

    2016-01-01

    OBJECTIVE: To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial design, conducted at 8 hospitals in Denmark...... in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c≤7.0% (≤53 mmol/mol). OUTCOMES: Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious...... adverse events were other prespecified outcomes. RESULTS: Carotid IMT change did not differ between groups (biphasic -0.009 mm (95% CI -0.022 to 0.004), aspart+detemir 0.000 mm (95% CI -0.013 to 0.013), detemir -0.012 mm (95% CI -0.025 to 0.000)). HbA1c was more reduced with biphasic (-1.0% (95% CI -1...

  6. The effects of GLP-1 analogues in obese, insulin-using type 2 diabetes in relation to eating behaviour

    NARCIS (Netherlands)

    de Boer, Stefanie Amarens; Lefrandt, Joop Daniel; Petersen, Japke Frida; Boersma, Hendrikus Hessel; Mulder, Douwe Johannes; Hoogenberg, Klaas

    Background Glucagon-like peptide-1 receptor agonists (GLP-1 RA) added to insulin in type 2 diabetes patients have shown to lower body weight, improve glycaemic control and reduce total daily insulin dose in short term studies, although the individual response greatly varies. Objective To evaluate

  7. Role of premixed insulin analogues in the treatment of patients with type 2 diabetes mellitus : A narrative review

    NARCIS (Netherlands)

    Elizarova, Svetlana; Galstyan, Gagik R.; Wolffenbuttel, Bruce H. R.

    Because of the progressive nature of type 2 diabetes mellitus (T2DM), insulin therapy will eventually become necessary in most patients. Recent evidence suggests that maintaining optimal glycemic control by early insulin therapy can reduce the risk of microvascular and macrovascular complications in

  8. Total Chemical Synthesis of a Heterodimeric Interchain Bis-Lactam-Linked Peptide: Application to an Analogue of Human Insulin-Like Peptide 3

    Directory of Open Access Journals (Sweden)

    John Karas

    2013-01-01

    Full Text Available Nonreducible cystine isosteres represent important peptide design elements in that they can maintain a near-native tertiary conformation of the peptide while simultaneously extending the in vitro and in vivo half-life of the biomolecule. Examples of these cystine mimics include dicarba, diselenide, thioether, triazole, and lactam bridges. Each has unique physicochemical properties that impact upon the resulting peptide conformation. Each also requires specific conditions for its formation via chemical peptide synthesis protocols. While the preparation of peptides containing two lactam bonds within a peptide is technically possible and reported by others, to date there has been no report of the chemical synthesis of a heterodimeric peptide linked by two lactam bonds. To examine the feasibility of such an assembly, judicious use of a complementary combination of amine and acid protecting groups together with nonfragment-based, total stepwise solid phase peptide synthesis led to the successful preparation of an analogue of the model peptide, insulin-like peptide 3 (INSL3, in which both of the interchain disulfide bonds were replaced with a lactam bond. An analogue containing a single disulfide-substituted interchain lactam bond was also prepared. Both INSL3 analogues retained significant cognate RXFP2 receptor binding affinity.

  9. The effects of GLP-1 analogues in obese, insulin-using type 2 diabetes in relation to eating behaviour.

    Science.gov (United States)

    de Boer, Stefanie Amarens; Lefrandt, Joop Daniel; Petersen, Japke Frida; Boersma, Hendrikus Hessel; Mulder, Douwe Johannes; Hoogenberg, Klaas

    2016-02-01

    Glucagon-like peptide-1 receptor agonists (GLP-1 RA) added to insulin in type 2 diabetes patients have shown to lower body weight, improve glycaemic control and reduce total daily insulin dose in short term studies, although the individual response greatly varies. To evaluate GLP-1 RA treatment on body weight, glycaemic control and total daily insulin dose in obese, insulin-using type 2 diabetes patients after 2 years follow-up in a real life setting and to explore a possible relation with eating behaviour. The Martini Hospital and the University Medical Center in Groningen in the Netherlands. Eligible patients were at least 18 years of age, were on insulin therapy and obese (BMI > 30 kg/m(2)), started GLP-1 RA treatment. At baseline eating behaviour was classified according to the validated Dutch Eating Behaviour Questionnaire. A 2 years follow-up was performed. Main outcome measures Body weight, HbA1c and total daily insulin dose. 151 Patients started with exenatide or liraglutide. 120 patients completed the 2 years follow-up. From baseline to 2 years, body weight (mean ± SD) changed from 117.9 ± 22.1 to 107.9 ± 22.9 kg (P eating behaviour groups (P eating behaviour (n = 17) resulted in the smallest decline (-3.1 %) and restrained (n = 41) in the greatest (-10.3 %) in comparison with emotional (n = 37, -8.5 %) and indifferent (n = 25, -9.6 %) eating behaviours. Two year of GLP-1 RA treatment resulted in a sustained reduction of weight, HbA1c and total daily insulin dose in obese, insulin-using type 2 diabetes patients in a real life setting. Largest weight loss was achieved in patients with a predominant restraint eating pattern while a predominant external eating pattern resulted in the smallest weight reduction.

  10. Improved postprandial glycaemic control with insulin Aspart in type 2 diabetic patients treated with insulin

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Thorsby, P; Kjems, L

    2000-01-01

    beta-cell function. In a double-blind, double dummy crossover design, patients attended three study days where the following insulin injections in combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight) immediately before the meal, or insulin Actrapid (0.15 IU......The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 minutes before a test meal in insulin-treated type 2 diabetic patients with residual....../kg) immediately (Act0) or 30 minutes before (Act-30) a test meal. We studied 25 insulin-requiring type 2 diabetic patients, including 14 males and 11 females, with a mean age of 59.7 years (range, 43-71), body mass index 28.3 kg/m2 (range, 21.9-35.0), HbA1c 8.5% (range, 6.8-10.0), glucagon-stimulated C-peptide 1...

  11. Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties.

    Science.gov (United States)

    O'Harte, Finbarr P M; Parthsarathy, Vadivel; Hogg, Christopher; Flatt, Peter R

    2017-12-15

    The adipokine, apelin has many biological functions but its activity is curtailed by rapid plasma degradation. Fatty acid derived apelin analogues represent a new and exciting avenue for the treatment of obesity-diabetes. This study explores four novel fatty acid modified apelin-13 analogues, namely, (Lys 8 GluPAL)apelin-13 amide, pGlu(Lys 8 GluPAL)apelin-13 amide, Lys 8 GluPAL(Tyr 13 )apelin-13 and Lys 8 GluPAL(Val 13 )apelin-13. Fatty acid modification extended the half-life of native apelin-13 to >24 h in vitro. pGlu(Lys 8 GluPAL)apelin-13 amide was the most potent insulinotropic analogue in BRIN-BD11 cells and isolated islets with maximal stimulatory effects of up to 2.7-fold (p glucose uptake in 3T3-L1 adipocytes (2.3-fold, p glucose (39-43%, p glucose tolerance tests in diet-induced obese mice. pGlu(Lys 8 GluPAL)apelin-13 amide and (Lys 8 GluPAL)apelin-13 amide also inhibited feeding (28-40%, p < .001), whereas Lys 8 GluPAL(Val 13 )apelin-13 increased food intake (8%, p < .05) in mice. These data indicate that novel enzymatically stable analogues of apelin-13 may be suitable for future development as therapeutic agents for obesity-diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin : Results from a large population-based follow-up study

    NARCIS (Netherlands)

    R. Ruiter (Rikje); L.E. Visser (Loes); J.W.W. Coebergh (Jan Willem); M.P.P. van Herk-Sukel (Myrthe); H.R. Haak; P.H. Geelhoed-Duijvestijn; S.M.J.M. Straus (Sabine); R.M.C. Herings (Ron); B.H.Ch. Stricker (Bruno)

    2012-01-01

    textabstractAims/hypothesis Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based

  13. New ways of insulin delivery.

    Science.gov (United States)

    Heinemann, L

    2011-02-01

    The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is

  14. High-mix insulins

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2015-01-01

    Full Text Available Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use.

  15. Insulin therapy in neonatal diabetes mellitus: a review of the literature.

    Science.gov (United States)

    Rabbone, Ivana; Barbetti, Fabrizio; Gentilella, Raffaella; Mossetto, Gilberto; Bonfanti, Riccardo; Maffeis, Claudio; Iafusco, Dario; Piccinno, Elvira

    2017-07-01

    Neonatal diabetes mellitus (NDM) is a rare disorder, and guidance is limited regarding its optimal management. We reviewed insulin usage in NDM, with a focus on continuous subcutaneous insulin infusion (CSII). A PubMed search identified 40 reports of patients with NDM treated with insulin published between 1994 and 2016. Data concerning treatment of NDM are limited. CSII resolves some of the issues associated with insulin therapy in neonates. No clinical trials of CSII in NDM have been reported. Case reports suggest that CSII is a safe and effective means of treating NDM. CSII was initiated to improve glycaemic control, for practicality and convenience, and to overcome difficulties associated with the maintenance of long-term intravenous catheters. CSII can provide better glycaemic control than multiple daily injections, with few hypoglycaemic events. Continuous glucose monitoring integrated with the pump helps provide more precise control of blood glucose levels. CSII generally uses short-acting insulin or rapid-acting insulin analogues, and those that are approved for use in neonates appear to be appropriate for the treatment of NDM using an insulin pump. Information from case reports indicates that CSII is safe and effective for the management of NDM. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. INSULIN THERAPY TODAY

    Directory of Open Access Journals (Sweden)

    Saša Živić

    2002-05-01

    Full Text Available The insulin classification regarding the duration of its effect gradually be-comes outdated; it is necessary to speak first about the insulin therapy regimes. The intensified insulin therapy regarding the type of multiple daily insulin injections be-comes an indisputable standard. The progress in the "protein engineering" with the formation of a wide spectrum of insulin analogues provides for moving forward to-wards modern diabetology and the concept of strict individualization of the insulin therapy. The experience becomes a pattern in creating two existing formulas of the insulin "short" analogues, namely HUMALAG with the replacement of the proline and lysinane places with those of 28 and 29, and NOVORAPID with aspartic acid at the 28th place in the B chain. The most recent long-effect analogues are created by amino acid changes with the glycine residual at the position A21 and two ariginines added to the positions B31 and B32 - insulin "glargin" - LANTUS. The development of short and long effect analogues imposed the logical need for formulating "new" fixed insulin combination's as well. New combination's are made of two kinds of ac-tual insulin, namely, the fast-effect analogues of the aspart type or lystroinsulin and protamine-retarded preparations - neutral protamine - lystroinsulin. Three kinds of combinations are made.

  17. Basal insulin analogues in diabetic pregnancy: a literature review and baseline results of a randomised, controlled trial in type 1 diabetes

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R; Damm, Peter; Jovanovic, Lois

    2011-01-01

    hagedorn insulin, both with insulin aspart, in women with type 1 diabetes planning a pregnancy (n = 306) or are already pregnant (n = 164). Inclusion criteria include type 1 diabetes > 12 months' duration; screening HbA1c = 9.0% (women recruited prepregnancy), or pregnant with gestational age 8-12 weeks...... and HbA1c = 8.0% at randomization. At confirmation of pregnancy all subjects must have HbA1c = 8.0%. Exclusion criteria include impaired hepatic function, cardiac problems, and uncontrolled hypertension. Subjects are randomized to either insulin detemir or neutral protamine hagedorn insulin, both...

  18. Additional disulfide bonds in insulin

    DEFF Research Database (Denmark)

    Vinther, Tine N; Pettersson, Ingrid; Huus, Kasper

    2015-01-01

    The structure of insulin, a glucose homeostasis-controlling hormone, is highly conserved in all vertebrates and stabilized by three disulfide bonds. Recently, we designed a novel insulin analogue containing a fourth disulfide bond located between positions A10-B4. The N-terminus of insulin's B......-chain is flexible and can adapt multiple conformations. We examined how well disulfide bond predictions algorithms could identify disulfide bonds in this region of insulin. In order to identify stable insulin analogues with additional disulfide bonds, which could be expressed, the Cβ cut-off distance had...... in comparison to analogues with additional disulfide bonds that were more difficult to predict. In contrast, addition of the fourth disulfide bond rendered all analogues resistant to fibrillation under stress conditions and all stable analogues bound to the insulin receptor with picomolar affinities. Thus...

  19. Treatment of diabetic ketoacidosis with subcutaneous insulin lispro: a review of the current evidence from clinical studies.

    Science.gov (United States)

    Vincent, M; Nobécourt, E

    2013-09-01

    Low-dose intravenous infusions of regular insulin, usually initiated in the emergency department and continued in the intensive care unit (ICU), are the standard care for patients with diabetic ketoacidosis (DKA) to ensure rapid resolution of hyperglycaemia and ketoacidosis. Several studies have evaluated whether subcutaneous injections of the rapid-acting analogue insulin lispro may be an alternative to intravenous insulin infusion for avoiding ICU admissions of uncomplicated DKA cases. This review summarizes the current clinical evidence for the effectiveness and safety of subcutaneous insulin lispro injections in non-severe DKA patients. Relevant studies were identified by a systematic literature search through the PubMed database. To date, four small randomized studies (156 patients overall; three studies in adults and one in paediatric patients with diabetes) have directly compared subcutaneous insulin lispro injections every 1-2h vs continuous intravenous infusions of regular insulin. Patients with severe complications were excluded. In all studies, the mean time to resolution of DKA was similar in both treatment groups [range (three studies): lispro 10-14.8h; regular insulin 11-13.2h]. The mean time to resolution of hyperglycaemia, total insulin doses required, number of hospitalization days and number of hypoglycaemic episodes were similar in both treatment groups; no severe complications or DKA recurrences were reported, and one study showed a 39% cost reduction for the insulin lispro group. In patients with mild-to-moderate DKA, subcutaneous injections of insulin lispro every 1-2h offer a feasible alternative to continuous intravenous infusions of regular insulin, and should now be evaluated in larger, more appropriately powered studies. Copyright © 2013. Published by Elsevier Masson SAS.

  20. Analogue Gravity

    Directory of Open Access Journals (Sweden)

    Barceló Carlos

    2005-12-01

    Full Text Available Analogue models of (and for gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity.

  1. Analogue Gravity

    Directory of Open Access Journals (Sweden)

    Carlos Barceló

    2011-05-01

    Full Text Available Analogue gravity is a research programme which investigates analogues of general relativistic gravitational fields within other physical systems, typically but not exclusively condensed matter systems, with the aim of gaining new insights into their corresponding problems. Analogue models of (and for gravity have a long and distinguished history dating back to the earliest years of general relativity. In this review article we will discuss the history, aims, results, and future prospects for the various analogue models. We start the discussion by presenting a particularly simple example of an analogue model, before exploring the rich history and complex tapestry of models discussed in the literature. The last decade in particular has seen a remarkable and sustained development of analogue gravity ideas, leading to some hundreds of published articles, a workshop, two books, and this review article. Future prospects for the analogue gravity programme also look promising, both on the experimental front (where technology is rapidly advancing and on the theoretical front (where variants of analogue models can be used as a springboard for radical attacks on the problem of quantum gravity.

  2. Novel recombinant insulin analogue with flexible C-terminus in B chain. NMR structure of biosynthetic engineered A22G-B31K-B32R human insulin monomer in water/acetonitrile solution.

    Science.gov (United States)

    Borowicz, Piotr; Bocian, Wojciech; Sitkowski, Jerzy; Bednarek, Elżbieta; Mikiewicz-Syguła, Diana; Błażej-Sosnowska, Sylwia; Bogiel, Monika; Rusek, Dorota; Kurzynoga, Dariusz; Kozerski, Lech

    2011-11-01

    A tertiary structure of recombinant A22(G)-B31(K)-B32(R)-human insulin monomer (insulin GKR) has been characterized by (1)H, (13)C NMR at natural isotopic abundance using NOESY, TOCSY, (1)H/(13)C-GHSQC, and (1)H/(13)C-GHSQC-TOCSY spectra. Translational diffusion studies indicate the monomer structure in water/acetonitrile (65/35vol.%). CSI analysis confirms existence of secondary structure motifs present in human insulin standard (HIS). Both techniques allow to establish that in this solvent recombinant insulin GKR exists as a monomer. Starting from structures calculated by the program CYANA, two different refinement protocols used molecular dynamics simulated annealing with the program AMBER; in vacuum (AMBER_VC), and including a generalized Born solvent model (AMBER_GB). From these calculations an ensemble of 20 structures of lowest energy was chosen which represents the tertiary structure of studied insulin. Here we present novel insulin with added A22(G) amino acid which interacts with β-turn environment resulting in high flexibility of B chain C-terminus. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. THE USE OF ULTRA-LONG-ACTING INSULIN ANALOGUE DEGLUDEC IN TYPE 1 DIABETES MELLITUS IN CLINICAL PRACTICE: THE INFLUENCE ON QUALITY OF LIFE AND SATISFACTION WITH TREATMENT

    Directory of Open Access Journals (Sweden)

    M. F. Kalashnikova

    2016-01-01

    Full Text Available Background: Maintenance of stable glycemic control is an important prerequisite of effective treatment of patients with type 1 diabetes mellitus (DM. The ultra-long-acting basal insulin degludec allows for reduction of glycemic variability and for a substantial reduction in the rates of hypoglycemia with equivalent glycemic control. Evaluation of the impact of this novel insulin on diabetes-dependent quality of life and patient satisfactions with the treatment is necessary for comprehensive assessment of treatment efficacy.Aim: To study changes of glycated hemoglobin (HbA1c, rates of hypoglycemia, diabetes-dependent quality of life and treatment satisfaction in patients with type 1 DM, who have been switched to insulin degludec.Materials and methods: This open 12-week observational comparative study included 25  patients with type  1 DM (median age, 36 [20; 63] years, who were switched to insulin degludec in combination with a  ultra-short insulin analogue. The control group included 21 patients with type 1 DM (median age, 40 [23; 63] years, who continued their treatment with a long-acting insulin analogue glargine. At baseline and at week 12 after switching to insulin degludec, we assessed HbA1c level, mean insulin dose, depression score, diabetes-dependent quality of life and patient satisfaction with the treatment with the use of the Russian versions of the diabetes-specific questionnaires “Audit of Diabetes-Dependent Quality of life” (RuADDQoL, and “Diabetes Treatment Satisfaction Questionnaire” (DTSQ, respectively.Results: At 3 months, there was a significant reduction of the HbA1c levels in the main and the control groups to 7.57% (Ме 7.5 [7.1; 8.4]; р=0.03 and 8.18% (Ме 7.8% [7.4; 8.7]; р=0.04, respectively. The mean reduction of this parameter under treatment with degludec was slightly higher than under treatment with glargine (0.73 vs 0.57%, respectively, at 3 months the difference being statistically

  4. Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes

    NARCIS (Netherlands)

    Swinnen, S. G.; Dain, M.-P.; Mauricio, D.; DeVries, J. H.; Hoekstra, J. B.; Holleman, F.

    2010-01-01

    We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2

  5. Insulin resistance via modification of PGC1α function identifying a possible preventive role of vitamin D analogues in chronic inflammatory state of obesity. A double blind clinical trial study.

    Science.gov (United States)

    Mirzaei, K; Hossein-Nezhad, A; Keshavarz, S A; Eshaghi, S M; Koohdani, F; Saboor-Yaraghi, A A; Hosseini, S; Tootee, A; Djalali, M

    2014-02-01

    Obesity-induced chronic inflammation is a key component of the pathogenesis of insulin resistance. Mounting evidence has demonstrated anti-inflammatory characteristics for vitamin D. Although analogues of vitamin D3 have extensively been used in the treatment of various chronic inflammatory diseases, to our knowledge, no such research is conducted in regards with obesity. The aim of this double blind clinical trial study is to investigate whether alphacalcidol treatment in obese subjects can affect the cytokine profile and insulin resistance. Moreover, we evaluated the pathways of vitamin D receptor (VDR), PPARγ and PGC1α gene expressions which may lead to insulin resistance following treatment with either alphacalcidol or placebo. A total of 94 obese participants (BMI≥30) were recruited for the current double blind clinical trial study. Patients were divided into two intervention (N.=40) and control groups (N.=54) based on the stratified randomized method. One-Alpha® Capsules 1 microgram: alfacalcidol (1-α hydroxyvitamin D3) and placebo were given to subjects once a day for 8 weeks. Analysis of body composition was performed with use of Body Composition Analyzer. The circulating levels of TNF-α, IL-1β, IL-4, IL-6, IL-10, IL-13, IL-17, PTH, and 25-Hydroxy Vi-tamin D were measured with the use of EIA method. The PBMCs were separated from whole blood by Ficoll-hypaque technique. Total cellular RNA was extracted and the cDNA was synthesized. The real-time PCR using specific primer pairs for VDR, PGC1α, PPARγ, and β-actin was performed. The FPG, fat percent and PTH levels were decreased and the levels of HDL-cholesterol and 25-hydroxy vitamin D were significantly increased after treatment with Alfacalcidol. Regarding to cytokines levels, the levels of IL6 were significantly decreased and IL10 were significantly increased in Alfacalcidol group in comparison with the control group. The relative expressions of VDR, PGC1α, and PPARγ genes significantly

  6. Effect of insulin catheter wear-time on subcutaneous adipose tissue blood flow and insulin absorption in humans

    DEFF Research Database (Denmark)

    Clausen, Trine Schnedler; Kaastrup, Peter; Stallknecht, Bente

    2009-01-01

    BACKGROUND: Insertion of an insulin catheter for continuous subcutaneous insulin infusion into the subcutaneous adipose tissue (SAT) causes a tissue trauma that may have consequences for insulin absorption. We evaluated the importance of insulin catheter wear-time on subcutaneous adipose tissue...... blood flow (ATBF) and absorption of the rapid-acting insulin analog insulin aspart over a period of 4 days. METHODS: Teflon insulin catheters (Medtronic, Minneapolis, MN) were inserted into the abdominal SAT of 10 healthy men without diabetes (mean +/- SEM age, 23.0 +/- 1.1 years; body mass index, 22...

  7. Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes

    DEFF Research Database (Denmark)

    Rodbard, H W; Cariou, B; Zinman, B

    2013-01-01

    The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes.......The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes....

  8. 76 FR 36539 - Scientific Information Request on Insulin Delivery and Glucose Monitoring Devices for Diabetes...

    Science.gov (United States)

    2011-06-22

    ... adjusting Secondary Nephropathy insulin therapy. Hyperglycemia Neuropathy Adherence to insulin therapy... MDI, which will be defined as at least three injections of basal and rapid-acting insulin per day. 2. rt-CGM would be compared with SMBG, which will be defined as at least three fingersticks per day...

  9. Neurobiology of stress, depression, and rapid acting antidepressants: remodeling synaptic connections.

    Science.gov (United States)

    Duman, Ronald S

    2014-04-01

    Stress and depression are associated with atrophy and loss of neurons in limbic and cortical brain regions that could contribute to the symptoms of depression. Typical monoamine reuptake inhibitor antidepressants have only modest efficacy and require long-term treatment, and are only weakly effective in blocking or reversing these structural changes caused by stress. Recent findings demonstrate that ketamine, an NMDA receptor antagonist, produces rapid antidepressant actions in difficult to treat depressed patients. In addition, preclinical studies demonstrate that ketamine rapidly increases synaptic connections in the prefrontal cortex by increasing glutamate signaling and activation of pathways that control the synthesis of synaptic proteins. Moreover, ketamine rapidly reverses the synaptic deficits caused by exposure to chronic stress in rodent models. Studies of the signaling mechanisms underlying the actions of ketamine have provided novel approaches and targets for new rapid acting antidepressants with decreased side effects, as well as a better understanding of the neurobiology of stress, depression, and treatment response. © 2014 Wiley Periodicals, Inc.

  10. Insulin aspart in diabetic pregnancy

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R

    2008-01-01

    in insulin requirements during pregnancy necessitate short-acting insulins for postprandial control of hyperglycemia. The fast-acting insulin analogue insulin aspart has been tested in a large, randomized trial of pregnant women with Type 1 diabetes and offers benefits in control of postprandial......Pregnancy in women with diabetes is associated with an increased risk of obstetric complications and perinatal mortality. Maintenance of near-normal glycemia during pregnancy can bring the prevalence of fetal, neonatal and maternal complications closer to that of the nondiabetic population. Changes...... and no increase in insulin antibodies was found. Thus, the use of insulin aspart in pregnancy is regarded safe....

  11. Insulin detemir in a twice daily insulin regimen versus a three times daily insulin regimen in the treatment of type 1 diabetes in children: A pilot randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Ho Josephine

    2011-11-01

    Full Text Available Abstract Background Children with type 1 diabetes (DM1 often use three daily (TID injections with intermediate acting insulin at breakfast and bedtime, and rapid acting insulin at breakfast and dinner. Substituting the evening intermediate acting insulin with a long acting insulin analogue (LAIA at dinner in a twice daily (BID injection regimen may be as effective as a TID regimen. The objective of this pilot study was to compare HbA1c in children with DM1 using a BID regimen with a LAIA at dinner (intervention to those using a standard TID regimen (control over 6 months. Methods Randomized controlled trial with main outcome measure being HbA1c at 0, 3 and 6 months. Secondary outcomes were frequency of adverse events (hypoglycemia, diabetic ketoacidosis, weight gain and scores on the Diabetes Quality of Life Measure for Youth (DQOLY. Results 18 subjects (10 control, 8 intervention. Mean years (standard deviations for control and intervention respectively were: age at diagnosis of DM1 6.31 (2.91 vs 7.76 (3.22, duration of DM1 5.96 (4.95 vs 3.76 (3.37. No significant differences were seen in the mean HbA1c between control and intervention at 0 months [8.48(0.86 vs 8.57(1.13], 3 months [8.47(0.50 vs 7.99(0.61], or 6 months [8.42(0.63 vs 8.30(0.76]. No significant differences were found between groups for frequency of adverse events or DQOLY. Conclusions In this pilot study, incorporating LAIA in a BID regimen did not cause deterioration in HbA1c or increases in adverse events; suggesting that this may be a viable option for families where a more simplified insulin regimen would be beneficial and compliance may be improved. Trial registration ClinicalTrials.gov: NCT00522210

  12. BALANOL ANALOGUES

    DEFF Research Database (Denmark)

    1997-01-01

    The present invention relates to a solid phase methodology for the preparation of a combinatorial library of structural analogues of the natural product balanol (ophiocordin, azepinostatin), which is a protein kinase C (PKC) and protein kinase A (PKA) inhibitor. The method comprises solid-phase s...... be immobilised to the polymer support either as the monoallyl ester or as the internal anhydride. The libraries produced by the method are especially suited for high throughput screening of potential drug candidates for the treatment of mammals, especially humans....

  13. [Insulin therapy and sports].

    Science.gov (United States)

    Aigner, A

    1997-01-01

    Physical work effects a transitory enhanced affinity of insulin to its receptor in the stressed muscles and thereby a better efficiency. Therefore, in sports lasting for 30 min and more the basal and/or bolus doses of insulin have to be reduced in order to prevent hypoglycemia. An alternative supply of additional carbohydrates prior to physical work is often not practicable. Injections of insulin into areas of the body not involved in muscular work do not give sufficient warranty against hypoglycemic reactions. A new short-acting insulin-analogue (Lispro) shows a reduced effect on blood glucose levels after 3 h as compared to regular insulin. Therefore, it could be of advantage for insulin dependent diabetics doing their exercise at this time.

  14. Plerocercoid growth factor (PGF), a human growth hormone (hGH) analogue produced by the tapeworm Spirometra mansonoides, has direct insulin-like action in adipose tissue of normal rats in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Salem, M.A.M.; Phares, C.K.

    1986-03-01

    The metabolic actions of GH can be divided into acute (insulin-like) and chronic (lipolytic/anti-insulin). The insulin-like actions of GH are most readily elicited in GH-deficient animals as GH induces resistance to its own insulin-like action. Like GH, PGF stimulates growth and cross-reacts with anti-hGH antibodies. Independent experiments were conducted comparing the direct actions of PGF to insulin or hGH in vitro. Insulin-like effects were determined by the ability of PGF, insulin or hGH to stimulate (U-/sup 14/C)glucose metabolism in epidydimal fat pads from normal rats and by inhibition of epinephrine-stimulated lipolysis. Direct stimulation of lipolysis was used as anti-insulin activity. To determine if PGF competes for insulin or GH receptors, adipocytes (3 x 10/sup 5/ cells/ml) were incubated with either (/sup 125/I)insulin or (/sup 125/I)hGH +/- PGF, +/- insulin or +/- hGH. PGF stimulated glucose oxidation and /sup 14/C-incorporation into lipids. Insulin, hGH and PGF inhibited lipolysis (33%, 29% and 34%, respectively). Adipose tissue was very sensitive to the lipolytic effect of hGH but PGF was neither lipolytic nor did it confer refractoriness to its insulin-like action. PGF bound to GH but not to insulin receptors. Therefore, PGF had direct insulin-like effects but did not stimulate lipolysis in tissue from normal rats in vitro.

  15. A Comparison of the Effects of the GLP-1 Analogue Liraglutide and Insulin Glargine on Endothelial Function and Metabolic Parameters: A Randomized, Controlled Trial Sapporo Athero-Incretin Study 2 (SAIS2.

    Directory of Open Access Journals (Sweden)

    Hiroshi Nomoto

    Full Text Available GLP-1 improves hyperglycemia, and it has been reported to have favorable effects on atherosclerosis. However, it has not been fully elucidated whether GLP-1 is able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of the GLP-1 analogue, liraglutide on endothelial function and glycemic metabolism compared with insulin glargine therapy.In this multicenter, prospective randomized parallel-group comparison study, 31 diabetic outpatients (aged 60.3 ± 10.3 years with HbA1c levels of 8.6 ± 0.8% with current metformin and/or sulfonylurea treatment were enrolled and randomly assigned to receive liraglutide or glargine therapy once daily for 14 weeks. Flow mediated dilation (FMD, a comprehensive panel of hemodynamic parameters (Task Force Monitor, and serum metabolic markers were assessed before and after the treatment period.A greater reduction (worsening in %FMD was observed in the glargine group, although this change was not statistically different from the liraglutide group (liraglutide; 5.7 to 5.4%, glargine 6.7 to 5.7%. The augmentation index, C-peptide index, derivatives of reactive oxygen metabolites and BMI were significantly improved in the liraglutide group. Central systolic blood pressure and NT-proBNP also tended to be improved in the liraglutide-treated group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different.Regardless of glycemic improvement, early liraglutide therapy did not affect endothelial function but may provide favorable effects on beta-cell function and cardioprotection in type 2 diabetics without advanced atherosclerosis.UMIN Clinical Trials Registry System as trial ID UMIN000005331.

  16. Insulin Secretagogues

    Science.gov (United States)

    ... the Spikes Is mealtime insulin right for you? Insulin Secretagogues September 2017 Download PDFs English Espanol Editors ... Additional Resources Affordable Insulin Project FDA What are insulin secretagogues? Insulin secretagogues are one type of medicine ...

  17. Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice.

    Science.gov (United States)

    Alicino, Ilaria; Giglio, Mariateresa; Manca, Fabio; Bruno, Francesco; Puntillo, Filomena

    2012-01-01

    Ziconotide is a nonopioid intrathecal analgesic drug used to manage moderate to severe chronic pain. The aim of this work is to assess the safety and efficacy of intrathecal (IT) combination of ziconotide and morphine in malignant pain refractory to high doses of oral opioids. Patients with malignant pain refractory to high oral opioids doses with a mean visual analogue scale of pain intensity (VASPI) score of ≥ 70 mm were enrolled. An IT combination therapy was administered: Ziconotide was started at a dose of 2.4 μg/day, followed by increases of 1.2 μg/day at intervals of at least 7 days, and an initial IT daily dose of morphine was calculated based on its oral daily dose. Percentage change in VASPI scores from baseline was calculated at 2 days, at 7 days, and weekly until the first 28 days. The mean percentage change of VASPI score from baseline was used for efficacy assessment. Safety was monitored based on adverse events and routine laboratory values. Twenty patients were enrolled, with a mean daily VASPI score at rest of 90±7. All had a disseminated cancer with bone metastases involving the spine. The percentage changes in VASPI mean scores from baseline to 2 days, 7 days, and 28 days were 39±13% (95% confidence interval [CI]=13.61-64.49, Pziconotide and morphine allows safe and rapid control of oral opioid-refractory malignant pain. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  18. When to treat a diabetic patient using an external insulin pump. Expert consensus. Société francophone du diabète (ex ALFEDIAM) 2009.

    Science.gov (United States)

    Lassmann-Vague, V; Clavel, S; Guerci, B; Hanaire, H; Leroy, R; Loeuille, G A; Mantovani, I; Pinget, M; Renard, E; Tubiana-Rufi, N

    2010-02-01

    For years, external insulin pumps have enjoyed proven efficacy as an intensive diabetes treatment to improve glycaemic control and reduce hypoglycaemia. Since the last ALFEDIAM guidelines in 1995, however, basal-bolus treatment using a combination of long- and short-acting insulin analogues have emerged and could challenge, at a lower cost, the efficacy of pumps using rapid-acting insulin analogues, considered the 'gold standard' of insulin treatment. Nevertheless, given its theoretical and practical advantages, some patients will derive more benefit from pump treatment. These cases have been carefully evaluated in the literature by a panel of experts appointed by ALFEDIAM to determine the indications for pump treatment. In patients with type 1 diabetes, persistent elevated HbA(1c) despite multiple daily injections (MDI), and repeated hypoglycaemia and high glycaemic variability, represent the most validated indications. In patients with type 2 diabetes, pump treatment may be indicated in cases of MDI failure to achieve HbA(1c) targets. Absolute contraindications are rare, and comprise severe psychiatric disorders, rapidly progressing ischaemic or proliferative retinopathy before laser treatment and exposure to high magnetic fields. Relative contraindications are mostly related to the patient's lack of compliance or inability to cope with the treatment, and need to be evaluated individually to clearly assess the benefit/risk ratio for the given patient. However, as these conditions are progressive, there should also be annual reassessment of the appropriateness of pump treatment. Specific education on pump treatment initially and throughout the follow-up, delivered by experienced medical and paramedical teams, are the best guarantees of treatment efficacy and safety. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

  19. Insulin and Insulin Resistance

    Science.gov (United States)

    2005-01-01

    As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalisation, urbanisation and industrialisation have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits. PMID:16278749

  20. Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis?

    NARCIS (Netherlands)

    Rensing, K.L.; Houttuijn Bloemendaal, F.M.; Weijers, E.M.; Richel, D.J.; Büller, H.R.; Koolwijk, P.; van der Loos, C.M.; Twickler, T.B.; von der Thüsen, J.H.

    2010-01-01

    Negative effects on the progression of adenocarcinomas by hyperinsulinaemia and the insulin analogue glargine (A21Gly,B31Arg,B32Arg human insulin) have recently been suggested. Most actions of this insulin analogue have hitherto been explained by direct stimulation of growth potential of neoplastic

  1. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Casablanca cohort of the A1chieve study.

    Science.gov (United States)

    Farouqi, Ahmed; Chadli, Asmae

    2013-11-01

    The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Casablanca, Morocco. A total of 495 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 231), insulin detemir (n = 151), insulin aspart (n = 19), basal insulin plus insulin aspart (n = 53) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 10.2%) and insulin user (mean HbA1c: 9.4%) groups. After 24 weeks of treatment, both groups showed improvement in HbA1c (insulin naïve: -2.3%, insulin users: -1.8%). Major hypoglycaemia was observed in the insulin naïve group after 24 weeks. SADRs were reported in 1.2% of insulin naïve and 2.1% of insulin user groups. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  2. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Casablanca cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Ahmed Farouqi

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Casablanca, Morocco. Results: A total of 495 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 231, insulin detemir (n = 151, insulin aspart (n = 19, basal insulin plus insulin aspart (n = 53 and other insulin combinations (n = 41. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.2% and insulin user (mean HbA 1 c: 9.4% groups. After 24 weeks of treatment, both groups showed improvement in HbA 1 c (insulin naïve: −2.3%, insulin users: −1.8%. Major hypoglycaemia was observed in the insulin naïve group after 24 weeks. SADRs were reported in 1.2% of insulin naïve and 2.1% of insulin user groups. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  3. Analogue MIMO Detection

    Directory of Open Access Journals (Sweden)

    McNamara Darren

    2006-01-01

    Full Text Available In this contribution we propose an analogue receiver that can perform turbo detection in MIMO systems. We present the case for a receiver that is built from nonlinear analogue devices, which perform detection in a "free-flow" network (no notion of iterations. This contribution can be viewed as an extension of analogue turbo decoder concepts to include MIMO detection. These first analogue implementations report reductions of few orders of magnitude in the number of required transistors and in consumed energy, and the same order of improvement in processing speed. It is anticipated that such analogue MIMO decoder could bring about the same advantages, when compared to traditional digital implementations.

  4. Options for intensification of basal insulin in type 2 diabetes: Premeal insulin or short-acting GLP-1 receptor agonists?

    Science.gov (United States)

    Darmon, P; Raccah, D

    2015-12-01

    Type 2 diabetes is an evolutive disease with a progressive defect of beta-cell insulin secretion. This characteristic points to a need for treatment that takes into account such a natural history. When oral antidiabetic drugs fail to achieve the patient's target HbA1c level, basal insulin treatment is usually initiated and titrated in association with oral drugs to manage fasting hyperglycaemia. Over a period of time, it is enough to simply achieve the HbA1c target. However, when even a good fasting blood glucose level is no longer sufficient to control overall glycaemia, then prandial treatment must be combined with the titrated basal insulin to deal with the postprandial hyperglycaemia responsible for the elevation of HbA1c. Of the different therapeutic options now available for this, rapid-acting insulins and GLP-1 receptor agonists (RAs) can be used. Rapid-acting insulins can be added either at each meal, achieving full insulin supplementation with a basal-bolus regimen, or at the main meal only as a "basal-plus" regimen. Compared with the full basal-bolus, the basal-plus strategy is associated with fewer injections, yet provides similar efficacy in terms of HbA1c improvement, but with less weight gain and lower hypoglycaemic risk. As for GLP-1 RAs, numerous studies, and especially those using short-acting GLP-1 RAs, have demonstrated more pronounced effects on postprandial hyperglycaemia, good complementary effects with basal insulin, and significant improvement of HbA1c with no weight gain and a low risk of hypoglycaemia. Similarly, direct and indirect comparisons of the use of rapid-acting insulins and GLP-1 RAs to intensify basal insulin have shown comparable efficacy in terms of HbA1c control, but with less weight gain and fewer hypoglycaemic episodes with GLP-1 RAs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Kuwait cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Alaa Daban

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Kuwait. Results: A total of 1185 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 472, insulin detemir (n = 472, insulin aspart (n = 4, basal insulin plus insulin aspart (n = 188 and other insulin combinations (n = 48. At baseline, glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.8% and insulin user (mean HbA 1 c: 9.4% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −2.4%, insulin users: −1.7%. No major hypoglycaemic episodes were observed at 24 weeks. SADR was reported in 0.1% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  6. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Agadir cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Hicham Boussouf

    2013-01-01

    Full Text Available Background: A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Agadir, Morocco. Results: A total of 201 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 98, insulin detemir (n = 54, insulin aspart (n = 8, basal insulin plus insulin aspart (n = 8 and other insulin combinations (n = 33. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.7% and insulin user (mean HbA 1 c: 9.1% groups. After 24 weeks of treatment, both groups showed improvement in HbA 1 c (insulin naïve: −2.7%, insulin users: −1.3%. No major hypoglycaemia was observed at 24 weeks. SADRs were reported in 1.5% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  7. Safety and effectiveness of rapid-acting intramuscular olanzapine for agitation associated with schizophrenia – Japan postmarketing surveillance study

    Directory of Open Access Journals (Sweden)

    Katagiri H

    2018-01-01

    Full Text Available Hideaki Katagiri,1 Masanori Taketsuna,2 Shinpei Kondo,3 Kenta Kajimoto,4 Etsuko Aoi,5 Yuka Tanji1 1Bio Medicine, 2Statistical Sciences, 3Post Marketing Study Management, 4Scientific Communications, Medicines Development Unit Japan, 5Global Patient Safety Japan, Quality and Patient Safety, Eli Lilly Japan K.K., Kobe, Japan Objective: The objective of this study was to evaluate the safety and effectiveness of rapid-acting intramuscular (IM olanzapine in the treatment of acute agitation associated with schizophrenia in real-world clinical settings in Japan.Methods: In this multicenter, postmarketing surveillance (PMS study, patients with acute agitation associated with schizophrenia were treated with IM olanzapine daily in a daily clinical setting. The observational period ranged from 1 to 7 days, including the day of initial administration. Safety was assessed by reporting treatment-emergent adverse events (TEAEs and adverse drug reactions (ADRs. The Positive and Negative Syndrome Scale – Excited Component (PANSS-EC score was used to evaluate effectiveness at baseline and at 2 hours (after each administration, 2 days, and 3 days (end of the observational period from the last administration of the IM olanzapine injection.Results: The safety analysis set included 999 patients, and the initial dose of 10 mg was administered to 955 patients. TEAEs were reported in 28 patients (36 events, the most common of which were dyslalia (5 patients, akathisia and somno­lence (4 patients each, hepatic function abnormal (3 patients, and constipation and dehydration (2 patients each. One serious adverse event of akathisia occurred during the observation period. The PANSS-EC score (mean ± standard deviation was 23.3±6.4 (n=625 at baseline, 16.9±7.0 (n=522 at 2 hours after initial injection, and 14.9±6.5 (n=650 at the last observation carried forward.Conclusion: The results of this Japanese PMS study demonstrated that IM olanzapine is safe and has a

  8. Insulin Therapy

    Science.gov (United States)

    ... Your Health Resources Drugs, Procedures & Devices Prescription Medicines Insulin Therapy Insulin Therapy Share Print When you digest food, your ... you eat into glucose (a form of sugar). Insulin allows this glucose to enter all the cells ...

  9. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Maharashtra cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Uday Phadke

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Maharashtra, India. Results: A total of 3069 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 2115, insulin detemir (n = 461, insulin aspart (n = 333, basal insulin plus insulin aspart (n = 92 and other insulin combinations (n = 61. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.8 and insulin user (mean HbA 1 c: 9.1% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −1.4%, insulin users: −1.4%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  10. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Kerala cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Sreejith N Kumar

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Kerala, India. Results: A total of 1732 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1203, insulin detemir (n = 212, insulin aspart (n = 312, basal insulin plus insulin aspart (n = 1 and other insulin combinations (n = 1. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.0% and insulin user (mean HbA 1 c: 8.3% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −2.4%, insulin users: −0.5%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  11. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Kolkata cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Anirban Majumder

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Kolkata, India. Results: A total of 576 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 417, insulin detemir (n = 70, insulin aspart (n = 55, basal insulin plus insulin aspart (n = 19 and other insulin combinations (n = 15. At baseline, glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.3% and insulin user (mean HbA 1 c: 8.6% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −1.3%, insulin users: −1.4%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  12. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Mumbai cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    P G Talwalkar

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Mumbai, India. Results: A total of 2112 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1561, insulin detemir (n = 313, insulin aspart (n = 144, basal insulin plus insulin aspart (n = 53 and other insulin combinations (n = 41. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.7% and insulin user (mean HbA 1 c: 9.2% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −1.4%, insulin users: −1.8%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  13. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Haryana cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Haryana, India. Results: A total of 345 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 236, insulin detemir (n = 66, insulin aspart (n = 28, basal insulin plus insulin aspart (n = 1 and other insulin combinations (n = 14. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.7% and insulin user (mean HbA 1 c: 10.5% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −3.9%, insulin users: −3.3%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  14. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Chennai cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    J S Kumar

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Chennai, India. Results: A total of 1334 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 983, insulin detemir (n = 205, insulin aspart (n = 42, basal insulin plus insulin aspart (n = 41 and other insulin combinations (n = 63. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.4% and insulin users (mean HbA 1 c: 9.3% groups. After 24 weeks of treatment, both groups showed improvement in HbA 1 c (insulin naïve: −2.1%, insulin users: −1.9%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  15. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Delhi cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Sudhir Tripathi

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Delhi, India. Results: A total of 2242 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1515, insulin detemir (n = 521, insulin aspart (n = 176, basal insulin plus insulin aspart (n = 11 and other insulin combinations (n = 19. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.0% and insulin user (mean HbA 1 c: 11.0% groups. After 24 weeks of treatment both the groups showed improvement in HbA 1 c (insulin naïve: −3.1%, insulin users: −3.6%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  16. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Oman cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Mustafa Al Abousi

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Oman. Results: A total of 349 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 121, insulin detemir (n = 171, insulin aspart (n = 2, basal insulin plus insulin aspart (n = 38 and other insulin combinations (n = 17. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.2% and insulin user (mean HbA 1 c: 8.8% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −2.1%, insulin users: −1.6%. SADRs including major hypoglycaemic events did not occur in the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia and no weight gain.

  17. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Gujarat cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Banshi Saboo

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Gujarat, India. Results: A total of 812 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 502, insulin detemir (n = 89, insulin aspart (n = 155, basal insulin plus insulin aspart (n = 45 and other insulin combinations (n = 21. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.9% and insulin user (mean HbA 1 c: 9.1% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −2.2%, insulin users: −2.5%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  18. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Marrakech cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    El Ansari Nawal

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Marrakech, Morocco. Results: A total of 196 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 71, insulin detemir (n = 83, insulin aspart (n = 5, basal insulin plus insulin aspart (n = 14 and other insulin combinations (n = 23. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.3% and insulin user (mean HbA 1 c: 9.3% groups. After 24 weeks of treatment, both the study groups showed improvement in HbA 1 c (insulin naïve: −2.3%, insulin users: −1.9%. SADR′s including major hypoglycaemic events did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  19. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Bangalore cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    L Srinivasa Murthy

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Bangalore, India. Results: A total of 1533 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1262, insulin detemir (n = 165, insulin aspart (n = 86, basal insulin plus insulin aspart (n = 11 and other insulin combinations (n = 2. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.2% and insulin users (mean HbA 1 c: 8.8% groups. After 24 weeks of treatment, both groups showed improvement in HbA 1 c (insulin naïve: −1.3%, insulin users: −1.5%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  20. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Punjab cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Parminder Singh

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Punjab, India. Results: A total of 655 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 587, insulin detemir (n = 28, insulin aspart (n = 24, basal insulin plus insulin aspart (n = 13 and other insulin combinations (n = 3. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.1% and insulin user (mean HbA 1 c: 9.1% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −0.8%, insulin users: −1.0%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  1. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Gujarat cohort of the A1chieve study.

    Science.gov (United States)

    Saboo, Banshi; Patel, Mayur

    2013-11-01

    The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Gujarat, India. A total of 812 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 502), insulin detemir (n = 89), insulin aspart (n = 155), basal insulin plus insulin aspart (n = 45) and other insulin combinations (n = 21). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.9%) and insulin user (mean HbA1c: 9.1%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: -2.2%, insulin users: -2.5%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  2. Insulin initiation in patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vaag, Allan; Lund, Søren

    2012-01-01

    This review addresses the apparent disconnect between international guideline recommendations, real-life clinical practice and the results of clinical trials, with regard to the initiation of insulin using basal (long-acting) or premixed insulin analogues in patients with type 2 diabetes (T2D...... and monitoring regimens. Enforced intensification of unrealistic complex treatment regimens and glycaemic targets may theoretically worsen the psychological well-being in some patients. More simple and sustainable treatment regimens and guidelines are urgently needed. As for the use of insulin in T2D......, there is limited evidence to convincingly support that initiation of insulin using basal insulin analogues is superior to initiation using premixed insulin analogues. While awaiting improved clinical efficacy and cost-effectiveness data, practical guidance from national and international diabetes organisations...

  3. Identification of Host Insulin Binding Sites on Schistosoma japonicum Insulin Receptors.

    Directory of Open Access Journals (Sweden)

    Rachel J Stephenson

    Full Text Available Schistosoma japonicum insulin receptors (SjIRs have been identified as encouraging vaccine candidates. Interrupting or blocking the binding between host insulin and the schistosome insulin receptors (IRs may result in reduced glucose uptake leading to starvation and stunting of worms with a reduction in egg output. To further understand how schistosomes are able to exploit host insulin for development and growth, and whether these parasites and their mammalian hosts compete for the same insulin source, we identified insulin binding sites on the SjIRs. Based on sequence analysis and the predicted antigenic structure of the primary sequences of the SjIRs, we designed nine and eleven peptide analogues from SjIR-1 and SjIR-2, respectively. Using the Octet RED system, we identified analogues derived from SjIR-1 (10 and SjIR-2 (20, 21 and 22 with insulin-binding sequences specific for S. japonicum. Nevertheless, the human insulin receptor (HIR may compete with the SjIRs in binding human insulin in other positions which are important for HIR binding to insulin. However, no binding occurred between insulin and parasite analogues derived from SjIR-1 (2, 7 and 8 and SjIR-2 (14, 16 and 18 at the same locations as HIR sequences which have been shown to have strong insulin binding affinities. Importantly, we found two analogues (1 and 3, derived from SjIR-1, and two analogues (13 and 15 derived from SjIR-2, were responsible for the major insulin binding affinity in S. japonicum. These peptide analogues were shown to have more than 10 times (in KD value stronger binding capacity for human insulin compared with peptides derived from the HIR in the same sequence positions. Paradoxically, analogues 1, 3, 13 and 15 do not appear to contain major antigenic determinants which resulted in poor antibody responses to native S. japonicum protein. This argues against their future development as peptide-vaccine candidates.

  4. Agonism and antagonism at the insulin receptor

    DEFF Research Database (Denmark)

    Knudsen, Louise; Hansen, Bo Falck; Jensen, Pia

    2012-01-01

    Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR) binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new...... insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs) and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs). In the case of the IR, no natural ligand or insulin analogue has been...... shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29). However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR...

  5. The GLP-1 analogue liraglutide improves first-phase insulin secretion and maximal beta-cell secretory capacity over 14 weeks of therapy in subjects with Type 2 diabetes

    DEFF Research Database (Denmark)

    Madsbad, Sten; Vilsbøll, Tina; Brock, Birgitte

    modified frequently sampled intravenous glucose tolerance test (FSIGTT), to test maximal- and first-phase insulin secretion, respectively, before and after 14 weeks’ liraglutide (0.65, 1.25 or 1.9 mg/day) or placebo treatment. Twelve healthy, untreated matched subjects were also tested. Results: Compared...... with placebo, the 1.25 and 1.9 mg/day doses of liraglutide increased maximal beta-cell secretory capacity with 6.3 pM (95% CI: 2.9–9.6) B114%, and 7.2 pM (95% CI: 3.3–11.0) B97%, respectively. These doses also increased first-phase insulin secretion relative to placebo by 11.0 pMh (95% CI: 6.6–15.4) B124...... group. Conclusion: In subjects with Type 2 diabetes, 14 weeks’ once-daily liraglutide (1.25 and 1.9 mg/day) markedly improves beta-cell function, significantly increases first-phase insulin secretion and maximal beta-cell secretory capacity....

  6. Study rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial

    DEFF Research Database (Denmark)

    Lundby Christensen, L; Almdal, T; Boesgaard, T

    2009-01-01

    unknown whether a combination of metformin and insulin analogues is superior to insulin analogues alone. Nor is it known which insulin analogue regimen is the optimal. OBJECTIVE: The primary objective of this trial is to evaluate the effect of an 18-month treatment with metformin vs. placebo...... in combination with one of three insulin analogue regimens, the primary outcome measure being carotid intima-media thickness (CIMT) in T2DM patients. DESIGN: A randomized, stratified, multicentre trial having a 2 x 3 factorial design. The metformin part is double masked and placebo controlled. The insulin...... treatment is open. The intervention period is 18 months. PATIENT POPULATION: Nine hundred and fifty patients with T2DM and HbA1c > or = 7.5% on treatment with oral hypoglycaemic agents or on insulin treatment and deemed able, by the investigator, to manage once-daily insulin therapy with a long...

  7. Acceleration of Insulin Pharmacodynamic Profile by a Novel Insulin Infusion Site Warming Device

    Science.gov (United States)

    Cengiz, Eda; Weinzimer, Stuart A.; Sherr, Jennifer L.; Tichy, Eileen; Martin, Melody; Carria, Lori; Steffen, Amy; Tamborlane, William V.

    2012-01-01

    Background and Objective Subcutaneously injected rapid-acting insulin analogs do not replicate physiologic insulin action due to delays in their onset and peak action resulting in post-prandial glucose excursions. The InsuPatch (IP) is a novel insulin infusion site warming device developed to accelerate insulin action by increasing blood flow to the area of insulin absorption. 13 adolescents with type 1 diabetes (mean age 14±4 years) were enrolled in this study to investigate the effect of the IP on the pharmacodynamics and pharmacokinetics of a 0.2u/kg bolus dose of aspart insulin using the euglycemic clamp technique. Research Design and Methods Each subject underwent two euglycemic clamp procedures on separate occasions: one with and one without IP activation in random order. Results When the insulin bolus was given with IP activation as compared to without IP activation, time to reach maximum insulin action (TGIRmax) and to reach 50% maximum action (T 50%GIRmax) were 35 and 18 minutes earlier (125±8 min vs. 90±6min, p=0.002 and 58±5min. vs. 40±3min, p=0.01, respectively), and the AUC GIR 0-90min, reflecting early glucodynamic action, was significantly greater (p=0.001). IP activation also accelerated the rise in plasma insulin levels after the bolus (p=0.03) and resulted in a higher peak (p=0.04) and greater overall increase (p=0.02) in plasma insulin levels. Conclusions Our results demonstrate that insulin infusion site warming with IP activation accelerates the time action profile of aspart insulin which may be of benefit to current open-loop and future closed-loop insulin delivery in patients with type 1 diabetes. PMID:23107353

  8. Combined treatment of somatostatin analogues with pegvisomant in acromegaly

    NARCIS (Netherlands)

    S.E. Franck (Sanne); A. Muhammad (Ammar); A-J. van der Lely (Aart-Jan); S.J.C.M.M. Neggers (Bas)

    2016-01-01

    textabstractTreatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups

  9. Special considerations with insulin therapy in older adults with diabetes mellitus.

    Science.gov (United States)

    Mooradian, Arshag D

    2011-06-01

    Aging is associated with alterations in insulin secretion and action. However, aging per se does not alter the pharmacokinetics of commercially available insulin and its analogues. Insulin therapy in older adults is complicated by psychosocial and physiological changes of aging. Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial (e.g. insulin lispro, insulin aspart or insulin glulisine) and basal insulin (e.g. insulin glargine, insulin detemir), these analogues simulate physiological insulin profiles more closely than the older conventional insulins. The availability of multiple insulin products provides new opportunities to achieve control of diabetes mellitus. The choice of initial insulin therapy can be made based on blood glucose profiles. Overall, these profiles can be divided into three general patterns that include: (i) round-the-clock hyperglycaemia; (ii) fasting hyperglycaemia with daytime euglycaemia; and (iii) daytime hyperglycaemia with normal fasting blood glucose levels. The prescription of insulin is a dynamic process, and the insulin regimen should be adjusted based on individual response. The goal of diabetes care in older adults is to enhance quality of life without subjecting individuals to complicated treatment regimens that may interfere with their independence in carrying out daily activities.

  10. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Qatar cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Mohamed Hasan Daghash

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Qatar. Results: A total of 91 patients were enrolled in the study. Two insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 88, insulin detemir (n = 2, and other insulin combinations (n = 1. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.9% and insulin users (mean HbA 1 c: 9.1% groups. After 24 weeks of treatment, all the study groups showed improvement in HbA 1 c (insulin naïve: −1.8%, insulin users: −1.3%. Major hypoglycaemia did not occur in the study patients. SADRs were reported in 1.4% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  11. Successful Pregnancy after Improving Insulin Resistance with the Glucagon-Like Peptide-1 Analogue in a Woman with Polycystic Ovary Syndrome: A Case Report and Review of the Literature.

    Science.gov (United States)

    Yang, Qianying; Wang, Fang

    2016-01-01

    The polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility. It is diagnosed by the presence of hyperandrogenemia, insulin resistance (IR), obesity and other endocrine or metabolic disorders. Exenatide (EX) is a kind of glucagon-like peptide, which is a new option for patients with diabetes mellitus. We present a patient with infertility for PCOS. She was overweight and her medical history included IR, right-sided ovarian mucinous cystadenomas, and left-sided teratoma. Although she had been treated with ovarian surgery, clomiphene citrate and gonadotropins, weight loss and metformin, which have been effective for dominant follicle development, she still failed to conceive. Then EX was initiated to intervene for 2 months. EX treatment was successful to improve IR; after that the infertile woman with PCOS became pregnant. EX improves IR and reproduction capacity in PCOS patients, reducing insulin level and ameliorating endocrine disorders, thereby improving ovarian function, promoting follicle development, and providing new avenues for the treatment of infertility with PCOS. © 2016 S. Karger AG, Basel.

  12. Hepatoselectivity and the evolution of insulin.

    Science.gov (United States)

    Herring, R; Jones, R H; Russell-Jones, D L

    2014-01-01

    In spite of major developments in insulin production, purification, pharmaceutical formulation and methods of delivery, problems remain both in the day to day management of insulin-treated diabetes and with regard to its long-term complications. The risks of hypoglycaemia and weight gain are major concerns particularly for the patient, and the persistence of microvascular and premature macrovascular complications as the main causes of morbidity and mortality in both type 1 and type 2 diabetes is a constant reminder that our therapeutic and management strategies are inadequate. One clear and striking difference between currently available insulin treatments and normal physiology is the relative difference in exposure to insulin of the liver versus peripheral tissues. Hepatoselective insulin analogues have the potential to restore the normal hepatic to peripheral gradient in insulin action. Here, we discuss the possible therapeutic potential that such analogues may have over currently available insulin preparations. These benefits could include a lower risk of hypoglycaemia, less weight gain and a potential reduction in microvascular and macrovascular complications. We explore the evolution of insulin with hepatoselectivity in mind and possible strategies to create hepatoselective insulins. © 2013 John Wiley & Sons Ltd.

  13. Short-term cost-effectiveness of insulin detemir and insulin aspart in people with type 1 diabetes who are prone to recurrent severe hypoglycemia

    DEFF Research Database (Denmark)

    Pedersen-Bjergaard, Ulrik; Kristensen, Peter Lommer; Nørgaard, Kirsten

    2016-01-01

    Objective: Based on the data of the HypoAna trial (ClinicalTrials.gov NCT00346996), a short-term cost–effectiveness analysis was conducted comparing an all insulin analogue regimen with an all human insulin regimen in people with type 1 diabetes who are prone to recurrent severe hypoglycemia......-years (QALYs) gained. Sensitivity analyses were conducted to test the robustness of the analysis. The main outcome measure was the incremental cost–effectiveness ratio (ICER). Results: The insulin analogue regimen was associated with greater total costs compared with the human insulin regimen (20,418 DKK [1972...... GBP] vs. 18,558 DKK [1793 GBP], respectively), primarily driven by the difference in insulin costs. Total costs for corrective actions for hypoglycemic events, however, were lower in the insulin analogue group (927 DKK [89 GBP]) compared with the human insulin group (1311 DKK [127 GBP]), primarily due...

  14. Clinical experience with insulin detemir type 2 diabetes mellitus, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rabat-Sale-Zemmour-Zaer Region cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Abdelmjid Chraibi

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rabat-Sale-Zemmour-Zaer region, Morocco. Results: A total of 424 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 177, insulin detemir (n = 150, insulin aspart (n = 11, basal insulin plus insulin aspart (n = 45 and other insulin combinations (n = 41. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.1% and insulin user (mean HbA 1 c: 9.4% groups. After 24 weeks of treatment, all the study groups showed improvement in HbA 1 c (insulin naïve: −2.5%, insulin users: −1.8%. Major hypoglycaemia was observed in the insulin user group after 24 weeks (0.1 events/patient-year. SADRs were reported in 0.5% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  15. Comparison of LysB28, ProB29-human insulin analog and regular human insulin in the correction of incidental hyperglycemia

    NARCIS (Netherlands)

    Holleman, F.; van den Brand, J. J.; Hoven, R. A.; van der Linden, J. M.; van der Tweel, I.; Hoekstra, J. B.; Erkelens, D. W.

    1996-01-01

    OBJECTIVE: To obtain clinically applicable data on the effects of regular human insulin and the LysB28,ProB29-human insulin analogue (lispro) on the correction of incidental hyperglycemia. RESEARCH DESIGN AND METHODS: The insulins were compared in a non-clamped randomized crossover study of 27 male

  16. Cross-reactivity of 12 recombinant insulin preparations in the Beckman Unicel DxI 800 insulin assay.

    Science.gov (United States)

    Glenn, Christine; Armston, Annie

    2010-05-01

    Insulin analogues used in the treatment of insulin-dependent diabetes may result in hypoglycaemia; however, these preparations show variable cross-reactivity in many insulin assays. In order to investigate a suspected insulin overdose, it is therefore essential to characterize the cross-reactivity of these preparations in insulin assays. The cross-reactivity of 12 commercial insulin preparations was assessed on the Beckman DxI analyser, by comparison with the insulin calibration curve corresponding to the midpoint of the dose-response curve. This was achieved by manually plotting the relative light units generated by the analyser for each preparation. All 12 insulin preparations examined showed significant cross-reactivity with the Beckman DxI insulin assay, with 11 of the insulin preparations demonstrating cross-reactivity of 83% or greater. The lowest cross-reactivity was observed with detemir with a value of 47.6%. When investigating hypoglycaemia it is important to be aware of the cross-reactivity of the recombinant insulin analogues in insulin assays. This study has established the cross-reactivity of 12 preparations in the Beckman DxI insulin assay.

  17. How insulin engages its primary binding site on the insulin receptor

    Science.gov (United States)

    Menting, John G.; Whittaker, Jonathan; Margetts, Mai B.; Whittaker, Linda J.; Kong, Geoffrey K.-W.; Smith, Brian J.; Watson, Christopher J.; Žáková, Lenka; Kletvíková, Emília; Jiráček, Jiří; Chan, Shu Jin; Steiner, Donald F.; Dodson, Guy G.; Brzozowski, Andrzej M.; Weiss, Michael A.; Ward, Colin W.; Lawrence, Michael C.

    2013-01-01

    Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival1,2. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer’s disease3; aberrant signalling occurs in diverse cancers, exacerbated by crosstalk with the homologous type 1 insulin-like growth factor receptor (IGF1R)4. Despite more than three decades of investigation, the three-dimensional structure of the insulin–insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The αCT segment displaces the B-chain C-terminal β-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone–receptor recognition is novel within the broader family of receptor tyrosine kinases5. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone–insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues. PMID:23302862

  18. Influence of Unweighting on Insulin Signal Transduction in Muscle

    Science.gov (United States)

    Tischler, Marc E.

    2002-01-01

    Unweighting of the juvenile soleus muscle is characterized by an increased binding capacity for insulin relative to muscle mass due to sparing of the receptors during atrophy. Although carbohydrate metabolism and protein degradation in the unweighted muscle develop increased sensitivity to insulin in vivo, protein synthesis in vivo and system A amino acid transport in vitro do not appear to develop such an enhanced response. The long-term goal is to identify the precise nature of this apparent resistance in the insulin signal transduction pathway and to consider how reduced weight-bearing may elicit this effect, by evaluating specific components of the insulin signalling pathway. Because the insulin-signalling pathway has components in common with the signal transduction pathway for insulin-like growth factor (IGF-1) and potentially other growth factors, the study could have important implications in the role of weight-bearing function on muscle growth and development. Since the insulin signalling pathway diverges following activation of insulin receptor tyrosine kinase, the immediate specific aims will be to study the receptor tyrosine kinase (IRTK) and those branches, which lead to phosphorylation of insulin receptor substrate-1 (IRS-1) and of Shc protein. To achieve these broader objectives, we will test in situ, by intramuscular injection, the responses of glucose transport, system A amino acid transport and protein synthesis to insulin analogues for which the receptor has either a weaker or much stronger binding affinity compared to insulin. Studies will include: (1) estimation of the ED(sub 50) for each analogue for these three processes; (2) the effect of duration (one to four days) of unweighting on the response of each process to all analogues tested; (3) the effect of unweighting and the analogues on IRTK activity; and (4) the comparative effects of unweighting and analogue binding on the tyrosine phosphorylation of IRTK, IRS-1, and Shc protein.

  19. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rajasthan cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Akhil Joshi

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rajasthan, India. Results: A total of 477 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 340, insulin detemir (n = 90, insulin aspart (n = 37, basal insulin plus insulin aspart (n = 7 and other insulin combinations (n = 2. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.3% and insulin user (mean HbA 1 c: 8.4% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −0.9%, insulin users: −1.2%. Major hypoglycaemic events decreased from 0.5 events/patient-year to 0.0 events/patient-year in insulin naïve group while no change from baseline (1.3 events/patients-year was observed for insulin users. SADRs were not reported in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  20. Insulin detemir in the treatment of type 1 and type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Jean-Christophe Philips

    2006-09-01

    Full Text Available Jean-Christophe Philips, André ScheenDivision of Diabetes, Nutrition & Metabolic Disorders, Department of Medicine, CHU Sart-Tilman, University of Liège, Liège, Belgium Abstract: Insulin detemir is a soluble long-acting human insulin analogue at neutral pH with a unique mechanism of action. Following subcutaneous injection, insulin detemir binds to albumin via fatty acid chain, thereby providing slow absorption and a prolonged metabolic effect. Insulin detemir has a less variable pharmacokinetic profile than insulin suspension isophane or insulin ultralente. The use of insulin detemir can reduce the risk of hypoglycemia (especially nocturnal hypoglycemia in type 1 and type 2 diabetic patients. However, overall glycemic control, as assessed by glycated hemoglobin, is only marginally and not significantly improved compared with usual insulin therapy. The weight gain commonly associated with insulin therapy is rather limited when insulin detemir is used. In our experience, this new insulin analogue is preferably administrated at bedtime but can be proposed twice a day (in the morning and either before the dinner or at bedtime. Detemir is a promising option for basal insulin therapy in type 1 or type 2 diabetic patients.Keywords: diabetes mellitus, insulin detemir, hypoglycemia, insulin analogue, insulin therapy

  1. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Eastern Saudi Arabia cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Faisal Hashim

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Eastern Saudi Arabia. Results: A total of 1040 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 489, insulin detemir (n = 360, insulin aspart (n = 37, basal insulin plus insulin aspart (n = 96 and other insulin combinations (n = 57. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.0% and insulin user (mean HbA 1 c: 9.2% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −2.7%, insulin users: −1.7%. No major hypoglycaemic episodes were observed at 24 weeks. SADR was reported in 0.6% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  2. ACTINOMYCIN D ANALOGUES

    DEFF Research Database (Denmark)

    1997-01-01

    The present invention relates to new compounds being structurally and functionally similar to Actinomycin D and to combinatorial libraries of such compounds. The Actinomycin D analogues according to the present invention comprise two linear or cyclic peptide moieties constituted by $g...

  3. Cobalamin analogues in humans

    DEFF Research Database (Denmark)

    Hardlei, Tore Forsingdal; Obeid, Rima; Herrmann, Wolfgang

    2013-01-01

    BACKGROUND: Haptocorrin (HC) carries cobalamin analogues (CorA), but whether CorA are produced in the body is unknown. All cobalamins (Cbl) to the foetus are delivered by the Cbl-specific protein transcobalamin (TC), and therefore analysis of cord serum for CorA may help to clarify the origin of ......A in the human body are derived from Cbl....

  4. Natural Analogue Synthesis Report

    Energy Technology Data Exchange (ETDEWEB)

    A. M. Simmons

    2002-05-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport

  5. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Andhra Pradesh cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Mohammed Abubaker

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Andhra Pradesh, India. Results: A total of 3077 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 2452, insulin detemir (n = 308, insulin aspart (n = 226, basal insulin plus insulin aspart (n = 21 and other insulin combinations (n = 68. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.9% and insulin user (mean HbA 1 c: 9.2% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −1.2%, insulin users: −1.1%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  6. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the North India cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Surender Kumar

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from North India. Results: A total of 4912 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 3619, insulin detemir (n = 880, insulin aspart (n = 331, basal insulin plus insulin aspart (n = 37 and other insulin combinations (n = 44. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.8% and insulin user (mean HbA 1 c: 9.8% groups. After 24 weeks of treatment, both the study groups showed improvement in HbA 1 c (insulin naïve: −2.7%, insulin users: −2.6%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  7. Impact of improving postprandial glycemic control with intensifying insulin therapy in type 2 diabetes.

    Science.gov (United States)

    Yacoub, Tamer

    2017-11-01

    Worldwide, many people with type 2 diabetes are not at recommended glycemic targets and remain at increased risk of microvascular and macrovascular complications. Reaching recommended glycemic targets requires normalizing both fasting and postprandial glucose (PPG). For some patients, this will require addition of a prandial insulin delivered by injection to control PPG excursions. Evidence from epidemiological studies suggests an association between postprandial hyperglycemia and cardiovascular disease, and thus, expert guidelines recommend that treatment for elevated PPG not be delayed. Indeed, studies have demonstrated that PPG makes the greatest contribution to HbA1c in patients who are approaching, but have not yet reached HbA1c insulin is critical in suppressing hepatic glucose output (and therefore PPG levels) after a meal. Rapid-acting insulin analogs, with their faster onset and shorter duration of action, offer advantages over regular human insulin. Unfortunately, even with improved pharmacokinetic/pharmacodynamic characteristics, rapid-acting insulin analogs are still unable to fully reproduce the rapid release of insulin into the portal circulation and suppression of hepatic glucose output that occurs in the individual without diabetes after starting a meal. The next generation of rapid-acting insulin analogs will have an even more favorable pharmacokinetic profile that should allow patients to further improve glycemic control. Continuous subcutaneous insulin infusion (CSII) represents another option for intensifying therapy and improving postprandial control in some patients, and studies have shown that the benefits are sustainable long-term. However, it is currently unclear which patients stand to benefit the most from the extra expense and complexity of a CSII regimen, and further studies are needed.

  8. Dronedarone: an amiodarone analogue.

    Science.gov (United States)

    Doggrell, Sheila A; Hancox, Jules C

    2004-04-01

    Of the antiarrhythmic drugs in current use, amiodarone is one of the most effective and is associated with a comparatively low risk of drug-induced pro-arrhythmia, probably due to its multiple pharmacological actions on cardiac ion channels and receptors. However, amiodarone is associated with significant extra-cardiac side effects and this has driven development of amiodarone analogues. These analogues include short acting analogues (e.g., AT-2001) with similar acute effects to amiodarone, the thyroid receptor antagonist KB-130015 and dronedarone. Dronedarone, (SR-33589; Sanofi-Synthelabo), is a non-iodinated amiodarone derivative that inhibits Na +, K + and Ca 2+ currents. It is a potent inhibitor of the acetylcholine-activated K + current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K + currents and inhibits L-type calcium current. Dronedarone is an antagonist at alpha- and beta-adrenoceptors and unlike amiodarone, has little effect at thyroid receptors. Dronedarone is more potent than amiodarone in inhibiting arrhythmias and death in animal models of ischaemia- and reperfusion-induced arrhythmias. In the Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE) clinical trial, dronedarone 800 mg/day appeared to be effective and safe for the prevention of atrial fibrillation relapses after cardioversion. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) trial was stopped due to a potential increased risk of death in the dronedarone group. Trials of dronedarone in the maintenance of sinus rhythm in patients with atrial fibrillation and a safety and tolerability study in patients with an implantable cardioverter defibrillator are ongoing. Further experimental and clinical studies are required before we have a definitive answer to whether dronedarone has advantages over amiodarone and

  9. Quantum analogue computing.

    Science.gov (United States)

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  10. Gastric inhibitory polypeptide analogues

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2002-01-01

    Gastric inhibitory polypeptide (GIP, also called glucose-dependent insulinotropic polypeptide) and glucagon-like peptide-1 (GLP-1) are peptide hormones from the gut that enhance nutrient-stimulated insulin secretion (the 'incretin' effect). Judging from experiments in mice with targeted deletions...

  11. Comparison of Insulin Lispro Protamine Suspension with NPH Insulin in Pregnant Women with Type 2 and Gestational Diabetes Mellitus: Maternal and Perinatal Outcomes

    Directory of Open Access Journals (Sweden)

    Antonietta Colatrella

    2013-01-01

    Full Text Available Insulin therapy is still the gold standard in diabetic pregnancy. Insulin lispro protamine suspension is an available basal insulin analogue. Aim. To study pregnancy outcomes of women with type 2 and gestational diabetes mellitus when insulin lispro protamine suspension or human NPH insulin was added to medical nutrition therapy and/or short-acting insulin. Methods. In this retrospective study, for maternal outcome we recorded time and mode of delivery, hypertension, glycaemic control (fasting blood glucose and HbA1c, hypoglycemias, weight increase, and insulin need. For neonatal outcome birth weight and weight class, congenital malformations was recorded and main neonatal complications. Two-tail Student's t-test and chi-square test were performed when applicable; significant P<0.05. Results. Eighty-nine pregnant women (25 with type 2 diabetes and 64 with gestational diabetes mellitus; 53 under insulin lispro protamine suspension and 36 under human NPH insulin were recruited. Maternal and neonatal outcomes were quite similar between the two therapeutic approaches; however, insulin need was higher in NPH. At the end of pregnancy, eight women with gestational diabetes continued to use only basal insulin analogue. Conclusions. Pregnancy outcome in type 2 and gestational diabetes mellitus with insulin lispro protamine suspension was similar to that with NPH insulin, except for a lower insulin requirement.

  12. The Requirement of L-Type Voltage-Dependent Calcium Channel (L-VDCC) in the Rapid-Acting Antidepressant-Like Effects of Scopolamine in Mice.

    Science.gov (United States)

    Yu, Hanjie; Li, Mengmeng; Shen, Xinbei; Lv, Dan; Sun, Xin; Wang, Jinting; Gu, Xinmei; Hu, Jingning; Wang, Chuang

    2018-02-01

    Previous studies have shown that a low dose of scopolamine produces rapid-acting antidepressant-like actions in rodents. Understanding the mechanisms underlying this effect and the dose-dependent variations of drug responses remains an important task. L-type voltage-dependent calcium channels were found to mediate rapid-acting antidepressant effects of certain medications (e.g., ketamine). Therefore, it is of great interest to determine the involvement of L-type voltage-dependent calcium channels in the action of scopolamine. Herein, we investigated the mechanisms underlying behavioral responses to various doses of scopolamine in mice to clarify the involvement of L-type voltage-dependent calcium channels in its modes of action. Open field test, novel object recognition test, and forced swimming test were performed on mice administered varied doses of scopolamine (0.025, 0.05, 0.1, 1, and 3 mg/kg, i.p.) alone or combined with L-type voltage-dependent calcium channel blocker verapamil (5 mg/kg, i.p.). Then, the changes in brain-derived neurotrophic factor and neuropeptide VGF (nonacronymic) levels in the hippocampus and prefrontal cortex of these mice were analyzed. Low doses of scopolamine (0.025 and 0.05 mg/kg) produced significant antidepressant-like effects in the forced swimming test, while higher doses (1 and 3 mg/kg) resulted in significant memory deficits and depressive-like behaviors. Moreover, the behavioral changes in responses to various doses may be related to the upregulation (0.025 and 0.05 mg/kg) and downregulation (1 and 3 mg/kg) of brain-derived neurotrophic factor and VGF in the hippocampus and prefrontal cortex in mice. We further found that the rapid-acting antidepressant-like effects and the upregulation on brain-derived neurotrophic factor and VGF produced by a low dose of scopolamine (0.025 mg/kg) were completely blocked by verapamil. These results indicate that L-type voltage-dependent calcium channels are likely involved in the behavioral

  13. Improved Postprandial Glucose Control Using the InsuPad Device in Insulin-Treated Type 2 Diabetes

    Science.gov (United States)

    Raz, Itamar; Bitton, Gabriel; Feldman, Dmitry; Alon, Tal; Pfutzner, Andreas; Tamborlane, William V.

    2015-01-01

    Background: Delays in the time-action profiles of premeal boluses of rapid-acting insulin analogs contribute to early postmeal hyperglycemia in patients with diabetes. We tested whether applying local heat to skin around the injection site to increase the rate of insulin absorption reduces postprandial hyperglycemia in patients with type 2 diabetes. Methods: Fourteen patients with type 2 diabetes (4 females; age 61.6 ± 8.4 years, HbA1c 8.42 ± 1.13%; BMI 29.10 ± 5.61 kg/m2) on intensified insulin therapy underwent 5-hour meal tolerance tests (MTTs) with a standardized liquid meal after an overnight fast on 2 study days. Subjects injected 0.2 U/kg of insulin aspart or lispro subcutaneously into the abdominal skin on both days with and without the use of the InsuPad device. Results: Following the premeal bolus injection of rapid-acting insulin analog, infusion site warming led to a rise in plasma insulin levels to peak concentrations that were significantly earlier than without skin warming (mean ± SD 52 ± 26.7 vs 80 ± 51.3 minutes, P insulin levels during the first hour after injection (mean ± SD 63.5 ± 32.7 IU vs 48.0 ± 25.0 uU.min/ml, P = .019). As a result, the area under the curve of the postprandial glucose excursion during the first 2 hours (the primary study outcome) and the entire 5 hours after the meal were significantly reduced (P = .007 and P = .03, respectively) with skin warming around the injection site. Discussion and Conclusions: Use of the InsuPad to increase the rate of insulin absorption provides an effective means to achieve better control of postmeal glucose excursions in type 2 diabetic patients receiving premeal injections of rapid-acting insulin analogs. PMID:25883166

  14. Insulin Test

    Science.gov (United States)

    ... involves changes in diet and lifestyle. The American Diabetes Association recommends losing excess weight, getting regular amounts of moderate intensity physical activity, and increasing dietary fiber to lower blood insulin levels and increase the ...

  15. Insulin Test

    Science.gov (United States)

    ... to come strictly from animal sources (cow and pig pancreas cells). Most insulin used today is synthetic, ... developing type 2 diabetes , hypertension , hyperlipidemia , and/or heart disease several years down the road. Abdominal obesity, ...

  16. Influence of the dynamics of body weight on the risk factors of cardiovascular disease in patients with type 2 diabetes during the first year of insulin treatment

    Directory of Open Access Journals (Sweden)

    T S Dzhavakhishvili

    2013-03-01

    Full Text Available The aim of the present study was to investigate whether insulin treatment-induced weight gain had an adverse impact on cardiovascular risk factors in insulin-treated type 2 diabetic patients during the first year after initiating insulin therapy when insulin analogues or human insulins are used. A total of 157 patients with newly insulinized type 2 diabetes were included in the study. The patients were divided in two groups. First group consisted of subjects (mean age 57 [45; 73], duration of diabetes of 10 years [4; 16] who had received long-acting basal (glargine, detemir, premixed (biphasic insulin aspart 30, Humalog Mix 25 or short-acting (aspart, lispro insulin analogues. Patients from second group (mean age 59 [46; 75], duration of diabetes of 10 years [5; 15] were treated with intermediate-acting basal (Protophane, Humulin NPH insulin, premixed (biphasic human insulin 30, Humulin M3 and regular (Actrapid, Humulin R human insulins. Our study has shown that insulin-induced weight gain may not adversely affect cardiovascular risk factors, particularly, lipid profile, in insulin-treated type 2 diabetic patients during the first year after initiating insulin therapy. Use of insulin analogues for treatment of type 2 diabetes patients results in better glycaemic control, significant declines in blood lipid concentrations, less increase in waist circumference compared with human insulins during the first year after initiating insulin therapy.

  17. Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia

    DEFF Research Database (Denmark)

    Jensen, Vivi Flou Hjorth; Mølck, Anne-Marie; Heydenreich, Annette

    2016-01-01

    New insulin analogues with a longer duration of action and a flatter pharmacodynamic profile are developed to improve convenience and safety for diabetic patients. During the nonclinical development of such analogues, safety studies must be conducted in nondiabetic rats, which consequently...... are rendered chronically hypoglycemic. A rat comparator model using human insulin would be valuable, as it would enable differentiation between effects related to either persistent insulin-induced hypoglycemia (IIH) or a new analogue per se. Such a model could alleviate the need for an in...... nerve and skeletal myofiber degeneration within the same animals. This suggests that the model can serve as a nonclinical comparator model during development of long-acting insulin analogues....

  18. Anti-insulin antibody test

    Science.gov (United States)

    Insulin antibodies - serum; Insulin Ab test; Insulin resistance - insulin antibodies; Diabetes - insulin antibodies ... You appear to have an allergic response to insulin Insulin no longer seems to control your diabetes

  19. CARING (CAncer Risk and INsulin analoGues)

    DEFF Research Database (Denmark)

    Starup-Linde, Jakob; Karlstad, Oystein; Eriksen, Stine Aistrup

    2013-01-01

    BACKGROUND: Patients suffering from diabetes mellitus (DM) may experience an increased risk of cancer; however, it is not certain whether this effect is due to diabetes per se. OBJECTIVE: To examine the association between DM and cancers by a systematic review and meta-analysis according to the P...

  20. Análogos de insulina Insulin analogues

    OpenAIRE

    Manuel E. Licea Puig

    2006-01-01

    Se han realizado considerables esfuerzos para desarrollar la insulina, ideal en el tratamiento de la diabetes mellitus (DM). La tecnología recombinante del ácido desoxiribonucleico (ADN) ha permitido el desarrollo de la insulina humana; sin embargo, esta no ha resuelto totalmente los problemas relacionados con la inmunogenicidad, entre otros problemas. Por tanto, las nuevas tecnologías son aplicadas para crear los análogos de insulina. Este trabajo se propone como objetivos revisar aspectos f...

  1. Mammary Analogue Secretory Carcinoma.

    Science.gov (United States)

    Stevens, Todd M; Parekh, Vishwas

    2016-09-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor that shares the same histologic appearance and ETV6 gene (12p13) rearrangement as secretory carcinoma of the breast. Prior to its recognition, MASC cases were commonly labeled acinic cell carcinoma and adenocarcinoma, not otherwise specified. Despite distinctive histologic features, MASC may be difficult to distinguish from other salivary gland tumors, in particular zymogen-poor acinic cell carcinoma and low-grade salivary duct carcinoma. Although characteristic morphologic and immunohistochemical features form the basis of a diagnosis of MASC, the presence of an ETV6-NTRK3 gene fusion is confirmatory. Given its recent recognition the true prognostic import of MASC is not yet clearly defined.

  2. A Short Term Analogue Memory

    DEFF Research Database (Denmark)

    Shah, Peter Jivan

    1992-01-01

    A short term analogue memory is described. It is based on a well-known sample-hold topology in which leakage currents have been minimized partly by circuit design and partly by layout techniques. Measurements on a test chip implemented in a standard 2.4 micron analogue CMOS process show a droop...

  3. Diabetes and Insulin

    Science.gov (United States)

    ... in the abdomen just behind the stomach, produces insulin. Insulin is a hormone that takes glucose from the ... occurs when the pancreas does not produce enough insulin or when the body doesn’t use insulin ...

  4. Insulin Resistance and Prediabetes

    Science.gov (United States)

    ... After Your Baby is Born Monogenic Diabetes Prediabetes & Insulin Resistance What is insulin? Insulin is a hormone made in the pancreas, ... body absorb glucose and use it for energy. Insulin's Role in Blood Glucose Control When blood glucose ...

  5. Amphetamine-Like Analogues in Diabetes: Speeding towards Ketogenesis

    Directory of Open Access Journals (Sweden)

    Natalia M. Branis

    2015-01-01

    Full Text Available Obesity is common in patients with type 1 and type 2 diabetes. Amphetamine-like analogues comprise the most popular class of weight loss medications. We present a case of a 34-year-old African American female with a history of type 1 diabetes, dyslipidemia, and obesity who developed diabetic ketoacidosis (DKA after starting Diethylpropion for the purpose of weight loss. Shortly after starting Diethylpropion, she developed nausea, vomiting, and periumbilical pain. Blood work revealed glucose of 718 mg/dL, pH 7.32 (7.35–7.45, bicarbonate 16 mmol/L (22–29 mmol/L, and anion gap 19 mmol/L (8–16 mmol/L. Urine analysis demonstrated large amount of ketones. She was hospitalized and successfully treated for DKA. Diethylpropion was discontinued. Amphetamine-like analogues administration leads to norepinephrine release from the lateral hypothalamus which results in the appetite suppression. Peripheral norepinephrine concentration rises as well. Norepinephrine stimulates adipocyte lipolysis and thereby increases nonesterified fatty acids (NEFA availability. It promotes β-oxidation of NEFA to ketone bodies while decreasing metabolic clearance rate of ketones. In the setting of acute insulin deficiency these effects are augmented. Females are more sensitive to norepinephrine effects compared to males. In conclusion, amphetamine-like analogues lead to a release of norepinephrine which can result in a clinically significant ketosis, especially in the setting of insulin deficiency.

  6. Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Abu Dhabi cohort of the A 1 chieve study

    Directory of Open Access Journals (Sweden)

    Oula Alhabian

    2013-01-01

    Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Abu Dhabi. Results: A total of 383 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 134, insulin detemir (n = 152, insulin aspart (n = 13, basal insulin plus insulin aspart (n = 42 and other insulin combinations (n = 41. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 9.4% and insulin user (mean HbA 1 c: 9.1% groups. After 24 weeks of treatment, both groups showed improvement in HbA 1 c (insulin naïve: −2.1%, insulin users: −1.8%. SADRs did not occur in any of the study patients. Major hypoglycaemic events remained same as that of baseline (0.1 events/patient-year for insulin naïve group whereas major hypoglycaemia reduced from 0.1 events/patient-year to 0.0 events/patient-year in insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

  7. Faster in and faster out: accelerating insulin absorption and action by insulin infusion site warming.

    Science.gov (United States)

    Cengiz, Eda; Weinzimer, Stuart A; Sherr, Jennifer L; Tichy, Eileen M; Carria, Lori; Cappiello, Darryll; Steffen, Amy; Tamborlane, William V

    2014-01-01

    This study was undertaken to investigate the effect of an insulin infusion site warming device, the InsuPatch(40)(™) (IP(40)) (InsuLine Medical Ltd., Petach-Tikvah, Israel), on insulin aspart pharmacodynamics (PD) and pharmacokinetics (PK) in adolescents with type 1 diabetes. Seventeen subjects with type 1 diabetes (age, 15±1 years; hemoglobin A1c, 7.5±0.2% [58±2.2 mmol/mol]) underwent two euglycemic clamps performed on separate mornings with and without IP(40) activation with warming temperature at 40°C. On both days, the basal infusion was suspended, and glucose levels were maintained between 90 and 100 mg/dL by a variable rate dextrose infusion for up to 5 h after a 0.2 U/kg bolus of insulin aspart. Time to peak insulin action and time to half-maximal action occurred earlier with a greater early glucodynamic effect (area under the curve [AUC] for glucose infusion rate from 0 to 30 min) with IP(40) than without the IP(40), whereas the AUC for the time-action profile and the peak action did not differ with and without infusion site warming. PK parameters were in agreement with PD parameters, namely, a significantly earlier time to reach the maximum increment in insulin concentrations and greater early bioavailability (AUC for the change in insulin concentration from 0 to 30 min) with the IP(40). The tail of the plasma insulin response curve was also shortened with infusion site warming, with the time to reach baseline insulin concentration occurring significantly earlier (P=0.04). Our data demonstrate that skin warming around the infusion site to 40°C with the IP(40) is an effective means to accelerate absorption and action of rapid-acting insulin. These improvements in time-action responses have the potential to enhance the performance of open- and closed-loop insulin delivery systems.

  8. Insulin Resistance

    DEFF Research Database (Denmark)

    Jensen, Benjamin Anderschou Holbech

    Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities...

  9. Insulin-Insulin-like Growth Factors Hybrids as Molecular Probes of Hormone:Receptor Binding Specificity.

    Science.gov (United States)

    Křížková, Květoslava; Chrudinová, Martina; Povalová, Anna; Selicharová, Irena; Collinsová, Michaela; Vaněk, Václav; Brzozowski, Andrzej M; Jiráček, Jiří; Žáková, Lenka

    2016-05-31

    Insulin, insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively), and their receptors (IR and IGF-1R) are the key elements of a complex hormonal system that is essential for the development and functioning of humans. The C and D domains of IGFs (absent in insulin) likely play important roles in the differential binding of IGF-1 and -2 to IGF-1R and to the isoforms of IR (IR-A and IR-B) and specific activation of these receptors. Here, we attempted to probe the impact of IGF-1 and IGF-2 D domains (DI and DII, respectively) and the IGF-2 C domain (CII) on the receptor specificity of these hormones. For this, we made two types of insulin hybrid analogues: (i) with the C-terminus of the insulin A chain extended by the amino acids from the DI and DII domains and (ii) with the C-terminus of the insulin B chain extended by some amino acids derived from the CII domain. The receptor binding affinities of these analogues and their receptor autophosphorylation potentials were characterized. Our results indicate that the DI domain has a more negative impact than the DII domain does on binding to IR, and that the DI domain Pro-Leu-Lys residues are important factors for a different IR-A versus IR-B binding affinity of IGF-1. We also showed that the additions of amino acids that partially "mimic" the CII domain, to the C-terminus of the insulin B chain, change the binding and autophosphorylation specificity of insulin in favor of the "metabolic" IR-B isoform. This opens new venues for rational enhancement of insulin IR-B specificity by modifications beyond the C-terminus of its B chain.

  10. Chemoenzymatic preparation of germacrene analogues.

    Science.gov (United States)

    Cascón, Oscar; Touchet, Sabrina; Miller, David J; Gonzalez, Veronica; Faraldos, Juan A; Allemann, Rudolf K

    2012-10-09

    A small library of novel germacrenes was generated using a combination of two plant enzymes, germacrene A synthase, and D synthase and modified farnesyl diphosphate (FDP) analogues. This chemoenzymatic approach allows the preparation of potentially valuable volatiles for biological studies.

  11. Insulin treatment and breast cancer risk; A systematic review of in vitro, animal and epidemiological evidence

    NARCIS (Netherlands)

    Bronsveld, Heleen K.|info:eu-repo/dai/nl/371740819; Ter Braak, Bas; Karlstad, Øystein; Vestergaard, Peter; Starup-Linde, Jakob; Bazelier, Marloes T.|info:eu-repo/dai/nl/341589802; de Bruin, Marieke|info:eu-repo/dai/nl/270270906; De Boer, Anthonius|info:eu-repo/dai/nl/075097346; Siezen, Christine L.E.; Van De Water, Bob; Van Der Laan, Jan Willem; Schmidt, Marjanka K.

    2015-01-01

    Background: In 2009, the concern has been raised that insulin analogues, especially insulin glargine, might increase risk of (breast) cancer. Many in vitro and epidemiological and some animal studies have been performed, but there is still no clarity on this issue. Objectives: The aim of this study

  12. Insulin Detemir in the Treatment of Type 1 and Type 2 Diabetes

    Science.gov (United States)

    Philips, Jean-Christophe; Scheen, André

    2006-01-01

    Insulin detemir is a soluble long-acting human insulin analogue at neutral pH with a unique mechanism of action. Following subcutaneous injection, insulin detemir binds to albumin via fatty acid chain, thereby providing slow absorption and a prolonged metabolic effect. Insulin detemir has a less variable pharmacokinetic profile than insulin suspension isophane or insulin ultralente. The use of insulin detemir can reduce the risk of hypoglycemia (especially nocturnal hypoglycemia) in type 1 and type 2 diabetic patients. However, overall glycemic control, as assessed by glycated hemoglobin, is only marginally and not significantly improved compared with usual insulin therapy. The weight gain commonly associated with insulin therapy is rather limited when insulin detemir is used. In our experience, this new insulin analogue is preferably administrated at bedtime but can be proposed twice a day (in the morning and either before the dinner or at bedtime). Detemir is a promising option for basal insulin therapy in type 1 or type 2 diabetic patients. PMID:17326333

  13. Challenges constraining access to insulin in the private-sector market of Delhi, India

    Science.gov (United States)

    Kaplan, Warren A

    2016-01-01

    Objective India's majority of patients—including those living with diabetes—seek healthcare in the private sector through out-of-pocket (OOP) payments. We studied access to insulin in the private-sector market of Delhi state, India. Methods A modified World Health Organization/Health Action International (WHO/HAI) standard survey to assess insulin availability and prices, and qualitative interviews with insulin retailers (pharmacists) and wholesalers to understand insulin market dynamics. Results In 40 pharmacy outlets analysed, mean availability of the human and analogue insulins on the 2013 Delhi essential medicine list was 44.4% and 13.1%, respectively. 82% of pharmacies had domestically manufactured human insulin phials, primarily was made in India under licence to overseas pharmaceutical companies. Analogue insulin was only in cartridge and pen forms that were 4.42 and 5.81 times, respectively, the price of human insulin phials. Domestically manufactured human phial and cartridge insulin (produced for foreign and Indian companies) was less expensive than their imported counterparts. The lowest paid unskilled government worker in Delhi would work about 1.5 and 8.6 days, respectively, to be able to pay OOP for a monthly supply of human phial and analogue cartridge insulin. Interviews suggest that the Delhi insulin market is dominated by a few multinational companies that import and/or license in-country production. Several factors influence insulin uptake by patients, including doctor's prescribing preference. Wholesalers have negative perceptions about domestic insulin manufacturing. Conclusions The Delhi insulin market is an oligopoly with limited market competition. Increasing competition from Indian companies is going to require some additional policies, not presently in place. As more Indian companies produce biosimilars, brand substitution policies are needed to be able to benefit from market competition. PMID:28588966

  14. Expression of glycogen synthase and phosphofructokinase in muscle from type 1 (insulin-dependent) diabetic patients before and after intensive insulin treatment

    DEFF Research Database (Denmark)

    Vestergaard, H; Andersen, P H; Lund, S

    1994-01-01

    glycogen storage and glycolysis: glycogen synthase and phosphofructokinase, respectively. In nine diabetic patients biopsies of quadriceps muscle were taken before and 24-h after intensified insulin therapy and compared to findings in eight control subjects. Subcutaneous injections of rapid acting insulin...... diabetic patients showed a normal total glycogen synthase activity but a 48% decrease (p = 0.006) in glycogen synthase fractional velocity (0.1 mmol/l glucose 6-phosphate) (FV0.1) and a 45% increase (p = 0.01) in the half-maximal activation constant of glycogen synthase (A0.5). The activity...... of phosphofructokinase and the specific mRNA and immunoreactive protein levels of both glycogen synthase and phosphofructokinase were similar in the two groups. The 2.8-fold increase in serum insulin levels and the halving of the plasma glucose level for at least 15 h were associated with a normalization of glycogen...

  15. Insulin Resistance

    DEFF Research Database (Denmark)

    Jensen, Benjamin Anderschou Holbech

    Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities...... with IR independent of weight gain. In conclusion, the data presented in the current thesis, supported by a thorough review of available literature, advocate that 1) Inflammation is a triggering event fueling IR; 2) Commensal microbes can, when mistreated, aggravate IR and glucose intolerance; and 3) Diet...

  16. Closed-loop insulin delivery for treatment of type 1 diabetes

    Directory of Open Access Journals (Sweden)

    Elleri Daniela

    2011-11-01

    Full Text Available Abstract Type 1 diabetes is one of the most common endocrine problems in childhood and adolescence, and remains a serious chronic disorder with increased morbidity and mortality, and reduced quality of life. Technological innovations positively affect the management of type 1 diabetes. Closed-loop insulin delivery (artificial pancreas is a recent medical innovation, aiming to reduce the risk of hypoglycemia while achieving tight control of glucose. Characterized by real-time glucose-responsive insulin administration, closed-loop systems combine glucose-sensing and insulin-delivery components. In the most viable and researched configuration, a disposable sensor measures interstitial glucose levels, which are fed into a control algorithm controlling delivery of a rapid-acting insulin analog into the subcutaneous tissue by an insulin pump. Research progress builds on an increasing use of insulin pumps and availability of glucose monitors. We review the current status of insulin delivery, focusing on clinical evaluations of closed-loop systems. Future goals are outlined, and benefits and limitations of closed-loop therapy contrasted. The clinical utility of these systems is constrained by inaccuracies in glucose sensing, inter- and intra-patient variability, and delays due to absorption of insulin from the subcutaneous tissue, all of which are being gradually addressed.

  17. Clinical utility of insulin and insulin analogs

    Science.gov (United States)

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  18. Inflammation and Insulin Resistance

    OpenAIRE

    de Luca, Carl; Olefsky, Jerrold M.

    2007-01-01

    Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and the Metabolic syndrome. In this review, we focus on the interconnection between obesity, inflammation and insulin resistance. Pro-inflammatory cytokines can cause insulin resistance in adipose tissue, skeletal muscle and liver by inhibiting insulin signal transduction. The sources of cytokines in insulin resistant states are the insulin target tissue themselves, primarily fat and liver, but t...

  19. Predictive tools for designing new insulins and treatment regimens

    DEFF Research Database (Denmark)

    Klim, Søren

    on ordinary differential equations. The absence of such a program motivated the development of new a tool with PK/PD features, SDEs and mixed effects. Part II presents a software package which was developed in order to be able to handle SDEs with mixed effects. The package was implemented in R which allowed...... that describes an implemented software program able to handle stochastic differential equations (SDEs) with mixed effects. The thesis is supplemented with scientific papers published during the PhD. Developing an insulin analogue from candidate molecule to a clinical drug consists of a development programme...... on human insulin trials which was then evaluated using insulin Aspart (IAsp). The integrated model was estimated in two separate sub models due to computational complexity. Insulin model challenges were faced at the estimation step regarding separability of insulin input pathways (exogenous...

  20. Introduction to electronic analogue computers

    CERN Document Server

    Wass, C A A

    1965-01-01

    Introduction to Electronic Analogue Computers, Second Revised Edition is based on the ideas and experience of a group of workers at the Royal Aircraft Establishment, Farnborough, Hants. This edition is almost entirely the work of Mr. K. C. Garner, of the College of Aeronautics, Cranfield. As various advances have been made in the technology involving electronic analogue computers, this book presents discussions on the said progress, including some acquaintance with the capabilities of electronic circuits and equipment. This text also provides a mathematical background including simple differen

  1. Menstrual regulation with prostaglandin analogues.

    Science.gov (United States)

    Hagenfeldt, K; Bygdeman, M

    1981-01-01

    The development of generally applicable, simple non-surgical methods for menstrual regulation has been desired for a long time. Such an approach to fertility control depends on the availability of a suitable therapeutic agent that should be effective, reliable, simple to administer and free from disturbing side effects. The classical prostaglandins have shown the capability but are unsuitable mainly due to high incidence of side effects. Most of these drawbacks seem to be overcome when prostaglandin analogues are used; however, vaginal administration caused appreciable pain in 10-30% of women, and so severely limits self-administration of these analogues.

  2. Analogue Methods in Palaeoecology: Using the analogue Package

    Directory of Open Access Journals (Sweden)

    Gavin L. Simpson

    2007-08-01

    Full Text Available Palaeoecology is an important branch of ecology that uses the subfossil remains of organisms preserved in lake, ocean and bog sediments to inform on changes in ecosystems and the environment through time. The analogue package contains functions to perform modern analogue technique (MAT transfer functions, which can be used to predict past changes in the environment, such as climate or lake-water pH from species data. A related technique is that of analogue matching, which is concerned with identifying modern sites that are floristically and faunistically similar to fossil samples. These techniques, and others, are increasingly being used to inform public policy on environmental pollution and conservation practices. These methods and other functionality in analogue are illustrated using the Surface Waters Acidification Project diatom:pH training set and diatom counts on samples of a sediment core from the Round Loch of Glenhead, Galloway, Scotland. The paper is aimed at palaeoecologists who are familiar with the techniques described but not with R.

  3. Novel acetylcholine and carbamoylcholine analogues

    DEFF Research Database (Denmark)

    Hansen, Camilla Petrycer; Jensen, Anders Asbjørn; Christensen, Jeppe K.

    2008-01-01

    A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha 4beta 2 nAChR and pronounced selectivity for this ...

  4. Chemopreventive properties of curcumin analogues ...

    African Journals Online (AJOL)

    Purpose: To examine the chemopreventive activity of curcumin analogues, hexagamavunone-0 (HGV-. 0) and gamavutone-0 (GVT-0), compared to curcumin in a colorectal cancer model in Wistar rats. Methods: Rats (n = 25) were assigned to one of five groups (n = 5 in each group). Colorectal cancer was induced in the ...

  5. Efficacy of switching from premixed insulin to insulin glargine regimen in Type 2 diabetes mellitus patients with different islet functions.

    Science.gov (United States)

    Wang, Yong-Bo; Wang, Shuang; Bai, Ran; Du, Jian-Ling; Xing, Qian; Ba, Ying; Yang, Yu; Zhang, Xue-Yan; Shi, Chun-Hong; Yao, Jun-Jie

    2014-08-01

    The present study evaluated the efficacy of switching from premixed insulin or an insulin analogue to insulin glargine plus oral antidiabetic drugs (OADs) in patients with type 2 diabetes mellitus (T2DM). The feasibility and suitability of the regimen to the patients was examined based on islet function. Patients with T2DM (n=30) treated with stable doses of premixed insulin or an insulin analogue for eight weeks were divided into two groups according to islet function. Group A had a 2 h of C peptide (2hCP)/fasting C peptide (FCP) ratio ≤3, whereas group B had a 2hCP/FCP ratio >3. Eight weeks following the switch to insulin glargine plus OADs, a significant decrease in fasting blood glucose (FBG), 2 h postprandial blood glucose (2hPBG) and glycosylated‑haemoglobin (HbA1c) were observed in the two groups, with effective rates of 75, 42.9 and 39.3%, respectively. A distinct reduction in the insulin dose was particularly evident in group B. There was a marked decrease in FBG in group A, more so than that observed in group B. By contrast, the decrease in HbA1c was more evident in group B following the switch. A larger number of patients in group B had HbA1c≤7.0%, compared with group A. No difference in the incidence of hypoglycaemia and change of body weight were observed. Following the switch to insulin glargine plus OADs, patients with T2DM demonstrated improved blood glucose control and reduced insulin dosage. The results revealed that this switch in regimen is more suitable for patients with T2DM with 2hCP/FCP>3 and that administration of insulin glargine plus OADs is more efficacious for patients with T2DM with increased FBG levels.

  6. Agonism and antagonism at the insulin receptor.

    Directory of Open Access Journals (Sweden)

    Louise Knudsen

    Full Text Available Insulin can trigger metabolic as well as mitogenic effects, the latter being pharmaceutically undesirable. An understanding of the structure/function relationships between insulin receptor (IR binding and mitogenic/metabolic signalling would greatly facilitate the preclinical development of new insulin analogues. The occurrence of ligand agonism and antagonism is well described for G protein-coupled receptors (GPCRs and other receptors but in general, with the exception of antibodies, not for receptor tyrosine kinases (RTKs. In the case of the IR, no natural ligand or insulin analogue has been shown to exhibit antagonistic properties, with the exception of a crosslinked insulin dimer (B29-B'29. However, synthetic monomeric or dimeric peptides targeting sites 1 or 2 of the IR were shown to be either agonists or antagonists. We found here that the S961 peptide, previously described to be an IR antagonist, exhibited partial agonistic effects in the 1-10 nM range, showing altogether a bell-shaped dose-response curve. Intriguingly, the agonistic effects of S961 were seen only on mitogenic endpoints ((3H-thymidine incorporation, and not on metabolic endpoints ((14C-glucose incorporation in adipocytes and muscle cells. The agonistic effects of S961 were observed in 3 independent cell lines, with complete concordance between mitogenicity ((3H-thymidine incorporation and phosphorylation of the IR and Akt. Together with the B29-B'29 crosslinked dimer, S961 is a rare example of a mixed agonist/antagonist for the human IR. A plausible mechanistic explanation based on the bivalent crosslinking model of IR activation is proposed.

  7. [Adverse reactions to insulin].

    Science.gov (United States)

    Liñana, J J; Montoro, F J; Hernández, M D; Basomba, A

    1997-07-01

    The prevalence of allergic reactions to insuline has decreased during the last few years. Probably this is due to the use of the newly-developed recombinant human insuline. At present, adverse reactions to insuline occur in 5-10% of patients on therapy with insuline. Adverse reactions may be local (more frequent) or systemic (rare). Insuline resistance consists in a different type of immunological reaction. Diagnosis of allergy to insuline is based on clinical history and cutaneous and serological tests. Treatment depends upon the severity of the reaction. When insuline is indispensable despite a previous allergic reaction, a desensitization protocol may be implemented.

  8. Impact of the Type of Continuous Insulin Administration on Metabolism in a Diabetic Rat Model

    Directory of Open Access Journals (Sweden)

    A. Schaschkow

    2016-01-01

    Full Text Available Exogenous insulin is the only treatment available for type 1 diabetic patients and is mostly administered by subcutaneous (SC injection in a basal and bolus scheme using insulin pens (injection or pumps (preimplanted SC catheter. Some divergence exists between these two modes of administration, since pumps provide better glycaemic control compared to injections in humans. The aim of this study was to compare the impacts of two modes of insulin administration (single injections of long-acting insulin or pump delivery of rapid-acting insulin at the same dosage (4 IU/200 g/day on rat metabolism and tissues. The rat weight and blood glucose levels were measured periodically after treatment. Immunostaining for signs of oxidative stress and for macrophages was performed on the liver and omental tissues. The continuous insulin delivery by pumps restored normoglycaemia, which induced the reduction of both reactive oxygen species and macrophage infiltration into the liver and omentum. Injections controlled the glucose levels for only a short period of time and therefore tissue stress and inflammation were elevated. In conclusion, the insulin administration mode has a crucial impact on rat metabolic parameters, which has to be taken into account when studies are designed.

  9. Insulin causes insulin-receptor internalization in human erythrocyte ghosts.

    OpenAIRE

    Kelleher, R S; Murray, E F; Peterson, S W

    1987-01-01

    The effect of incubation with insulin on insulin-receptor internalization by erythrocyte ghosts was investigated. The number of surface insulin receptors decreased by 30-40% after incubation of ghosts with insulin. Total insulin-receptor binding to solubilized ghosts was the same in insulin-incubated and control ghosts, whereas insulin binding to an internal vesicular fraction was substantially increased in insulin-incubated ghosts. Our findings suggest that erythrocyte-ghost insulin receptor...

  10. Insulin and the Brain

    Directory of Open Access Journals (Sweden)

    Grosu Cristina

    2017-12-01

    Full Text Available The brain represents an important site for the action of insulin. Besides the traditionally known importance in glucoregulation, insulin has significant neurotrophic properties and influences the brain activity: insulin influences eating behavior, regulates the storage of energy and several aspects concerning memory and knowledge. Insulin resistance and hyperinsulinism could be associated with brain aging, vascular and metabolic pathologies. Elucidating the pathways and metabolism of brain insulin could have a major impact on future targeted therapies.

  11. Ten-year experience of insulin treatment in gestational diabetes.

    Science.gov (United States)

    Berne, C; Wibell, L; Lindmark, G

    1985-01-01

    Between 1975-1984, 119 women with gestational diabetes (GDM) were treated with insulin in Uppsala, representing a mean yearly incidence of 4.5/1,000 pregnancies. Women with GDM were older and more obese than the general pregnant population. Insulin treatment was instituted during a 5-7 day stay in hospital. The mean total daily dose of insulin prepartum, when fasting blood glucose had been normalized, was 53 (SD +/- 25) units (34 +/- 15 units of rapid-acting and 20 +/- 11 units of medium-acting insulin), divided into two doses daily. Mean duration of treatment was 6.4 weeks. The perinatal mortality was 0.8%, compared with 7.4% in previous pregnancies in the same women. The perinatal morbidity was generally mild and included hypoglycaemia (10.9%), hyperbilirubinaemia requiring treatment (2.5%), shoulder dystocia (2.5%) and one case of mild respiratory distress syndrome. The rate of macrosomia was reduced in the present pregnancies compared with previous ones in the women with GDM, but not abolished completely, probably because of too short a duration of improved metabolic control. Spontaneous delivery was favoured and the rate of Caesarean section was 13.5%. Thus, treatment with high doses of insulin in an unselected group of women with GDM is feasible. Normal perinatal mortality, reduced macrosomia, and no gross perinatal morbidity was found in the infants. Though the extent to which insulin treatment per se contributed to the favourable outcome is difficult to assess, it is suggested that the case for a high level of ambition for metabolic normalization in GDM should be a subject of further study.

  12. [New insulin types in type 1 diabetes mellitus].

    Science.gov (United States)

    Mesa, Jordi

    2015-07-20

    Since its discovery almost a century ago, insulin remains the mainstay of treatment of patients with type 1 diabetes mellitus. Although progress in the synthesis of new formulations has been remarkable, the physiological profile of insulin is still different from that observed with preparations available nowadays. In the last decade, the introduction into clinical practice of insulin analogues has allowed significantly improvement in glycemic control and has facilitated the spread of basal/bolus patterns, the most physiological ones until now. Despite the benefits of basal analogues, glycemia often varies considerably when used as a single daily injection and this is why new molecules have been further investigated. Improvement has been achieved especially in terms of duration and rate of hypoglycemia, the main limiting factor of intensive therapy. This article reviews the available data concerning the new basal insulin analogues, degludec, pegylated lispro and glargine U300, and new formulations currently under development. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  13. Alteration in insulin action

    DEFF Research Database (Denmark)

    Tanti, J F; Gual, P; Grémeaux, T

    2004-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases...

  14. IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity.

    Science.gov (United States)

    Burgdorf, Jeffrey; Colechio, Elizabeth M; Ghoreishi-Haack, Nayereh; Gross, Amanda L; Rex, Christopher S; Zhang, Xiao-Lei; Stanton, Patric K; Kroes, Roger A; Moskal, Joseph R

    2017-06-01

    Posttraumatic stress disorder is an anxiety disorder characterized by deficits in the extinction of aversive memories. Insulin-like growth factor 1 (IGF1) is the only growth factor that has shown anxiolytic and antidepressant properties in human clinical trials. In animal studies, insulin-like growth factor binding protein 2 (IGFBP2) shows both IGF1-dependent and IGF1-independent pharmacological effects, and IGFBP2 expression is upregulated by rough-and-tumble play that induces resilience to stress. IGFBP2 was evaluated in Porsolt, contextual fear conditioning, and chronic unpredictable stress models of posttraumatic stress disorder. The dependence of IGFBP2 effects on IGF1- and AMPA-receptor activation was tested using selective receptor antagonists. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex 24 hours after in vivo dosing. IGFBP2 was 100 times more potent than IGF1 in the Porsolt test. Unlike IGF1, effects of IGFBP2 were not blocked by the IGF1-receptor antagonist JB1, or by the AMPA-receptor antagonist 2,3-Dioxo-6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) in the Porsolt test. IGFBP2 (1 µg/kg) and IGF1 (100 µg/kg i.v.) each facilitated contextual fear extinction and consolidation. Using a chronic unpredictable stress paradigm, IGFBP2 reversed stress-induced effects in the Porsolt, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays. IGFBP2 also increased mature dendritic spine densities in the medial prefrontal cortex and hippocampus 24 hours postdosing. These data suggest that IGFBP2 has therapeutic-like effects in multiple rat models of posttraumatic stress disorder via a novel IGF1 receptor-independent mechanism. These data also suggest that the long-lasting effects of IGFBP2 may be due to facilitation of structural plasticity at the dendritic spine level. IGFBP2 and mimetics may have therapeutic potential for the treatment of posttraumatic stress disorder.

  15. IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity

    Science.gov (United States)

    Colechio, Elizabeth M.; Ghoreishi-Haack, Nayereh; Gross, Amanda L.; Rex, Christopher S.; Zhang, Xiao-lei; Stanton, Patric K.; Kroes, Roger A.; Moskal, Joseph R.

    2017-01-01

    Abstract Background: Posttraumatic stress disorder is an anxiety disorder characterized by deficits in the extinction of aversive memories. Insulin-like growth factor 1 (IGF1) is the only growth factor that has shown anxiolytic and antidepressant properties in human clinical trials. In animal studies, insulin-like growth factor binding protein 2 (IGFBP2) shows both IGF1-dependent and IGF1-independent pharmacological effects, and IGFBP2 expression is upregulated by rough-and-tumble play that induces resilience to stress. Methods: IGFBP2 was evaluated in Porsolt, contextual fear conditioning, and chronic unpredictable stress models of posttraumatic stress disorder. The dependence of IGFBP2 effects on IGF1- and AMPA-receptor activation was tested using selective receptor antagonists. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex 24 hours after in vivo dosing. Results: IGFBP2 was 100 times more potent than IGF1 in the Porsolt test. Unlike IGF1, effects of IGFBP2 were not blocked by the IGF1-receptor antagonist JB1, or by the AMPA-receptor antagonist 2,3-Dioxo-6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) in the Porsolt test. IGFBP2 (1 µg/kg) and IGF1 (100 µg/kg i.v.) each facilitated contextual fear extinction and consolidation. Using a chronic unpredictable stress paradigm, IGFBP2 reversed stress-induced effects in the Porsolt, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays. IGFBP2 also increased mature dendritic spine densities in the medial prefrontal cortex and hippocampus 24 hours postdosing. Conclusions: These data suggest that IGFBP2 has therapeutic-like effects in multiple rat models of posttraumatic stress disorder via a novel IGF1 receptor-independent mechanism. These data also suggest that the long-lasting effects of IGFBP2 may be due to facilitation of structural plasticity at the dendritic spine level. IGFBP2 and mimetics may have therapeutic

  16. Insulin therapy and quality of life. A review

    DEFF Research Database (Denmark)

    Pouwer, Francois; Hermanns, Norbert

    2009-01-01

    Three central goals in the treatment of diabetes mellitus are (1) the avoidance of hyperglycaemia to prevent the development or progression of diabetes complications over time, (2) the avoidance of hypoglycaemia and (3) the maintenance or achievement of good quality of life. Insulin is the most......-acting insulin analogues or biphasic mixtures; (3) multiple daily injections versus pump therapy. Having multiple complications of diabetes is clearly associated with decreased QoL. Results from large studies such as the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes...... powerful agent that can be used to control blood glucose levels. This article reviews the studies that have investigated the effects of different types of insulin and insulin delivery techniques on quality of life of patients with type 1 or type 2 diabetes. First, the concept of 'quality of life' (Qo...

  17. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial

    DEFF Research Database (Denmark)

    Bretzel, R.G.; Nuber, U.; Landgraf, W.

    2008-01-01

    .54 (4.48) kg. The improvement of treatment satisfaction was greater for insulin glargine than for insulin lispro (mean difference 3.13; 95% CI 2.04-4.22). INTERPRETATION: A therapeutic regimen involving the addition of either basal or prandial insulin analogue is equally effective in lowering......BACKGROUND: As type 2 diabetes mellitus progresses, oral hypoglycaemic agents often fail to maintain blood glucose control and insulin is needed. We investigated whether the addition of once-daily insulin glargine is non-inferior to three-times daily prandial insulin lispro in overall glycaemic...... hypoglycaemic agents were randomly assigned to either insulin glargine taken once daily at the same time every day or to insulin lispro administered three times per day. The primary objective was to compare the change in haemoglobin A(1c) from baseline to endpoint (week 44) between the two regimens...

  18. Suicide by Insulin?

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_165701.html Suicide by Insulin? Self-harm and suicidal behavior may ... higher rates of depression, the researchers explained. And suicide or suicide attempts using insulin or other diabetes ...

  19. Insulin C-peptide

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003701.htm Insulin C-peptide test To use the sharing features ... a product that is created when the hormone insulin is produced and released into the body. The ...

  20. Insulin pump (image)

    Science.gov (United States)

    The catheter at the end of the insulin pump is inserted through a needle into the abdominal ... with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin ...

  1. Classifying insulin regimens

    DEFF Research Database (Denmark)

    Neu, A; Lange, K; Barrett, T

    2015-01-01

    defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen....

  2. Synthesis of tenuazonic acid analogues.

    Science.gov (United States)

    Soliman, F S

    1977-10-01

    The synthesis of two 1.5-diaryltetramic acids, aryl analogues of tenuazonic acid, is described. The reactivity of position 4 of these tetramic acids towards primary and secondary amines, and o-methylation led to the synthesis of 4-substituted-delta3-pyrroline-2-one. Further, reactivity of position 3 has been indicated by the formation of 3-arylidenepyrrolidine-2.4-diones and by diazo-coupling. The structures assigned to the new compounds are substantiated by IR and NMR data.

  3. Insulin sensitivity and albuminuria

    DEFF Research Database (Denmark)

    Pilz, Stefan; Rutters, Femke; Nijpels, Giel

    2014-01-01

    OBJECTIVE: Accumulating evidence suggests an association between insulin sensitivity and albuminuria, which, even in the normal range, is a risk factor for cardiovascular diseases. We evaluated whether insulin sensitivity is associated with albuminuria in healthy subjects. RESEARCH DESIGN...... albuminuria. This finding suggests that reduced insulin sensitivity either is simply related to or might causally contribute to the initial pathogenesis of albuminuria....

  4. Glycosphingolipids and insulin resistance

    NARCIS (Netherlands)

    Langeveld, Mirjam; Aerts, Johannes M. F. G.

    2009-01-01

    Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple

  5. Antidiabetic Activity of Benzopyrone Analogues in Nicotinamide-Streptozotocin Induced Type 2 Diabetes in Rats

    Directory of Open Access Journals (Sweden)

    Yogendra Nayak

    2014-01-01

    Full Text Available Benzopyrones are proven antidiabetic drug candidate in diabetic drug discovery. In this view novel synthetic benzopyrone analogues were selected for testing in experimental diabetes. Type 2 diabetes (T2D was induced in Wistar rats by streptozotocin (60 mg/kg, i.p. followed by nicotinamide (120 mg/kg i.p.. Rats having fasting blood glucose (FBG >200 mg/dL, 7 days after T2D-induction, are selected for the study. Test compounds and standard treatment were continued for 15 days. FBG, oral glucose tolerance test (OGTT, and insulin tolerance test (ITT were determined on 21st day after induction of T2D. Plasma lipids and serum insulin were estimated. Homeostatic model assessment (HOMA-IR was then calculated from serum insulin. Rats were sacrificed and pancreas was isolated for histopathological observations. Oxidative stress markers were estimated in liver homogenate. Quercetin, a natural product with benzopyrone ring, showed significant hypoglycemic activity comparable to glibenclamide. Treatment with test compounds lowered the FBG and insulin resistance was significant alleviated as determined by OGTT, HOMA-IR, and ITT. There was significant normalisation of liver antioxidant enzymes compared to diabetic rats indicating that all the synthesised benzopyrone analogues are beneficial in reducing oxidative stress and are on par with the standard quercetin and glibenclamide in experimental T2D.

  6. The Valles natural analogue project

    Energy Technology Data Exchange (ETDEWEB)

    Stockman, H.; Krumhansl, J.; Ho, C. [Sandia National Labs., Albuquerque, NM (United States); McConnell, V. [Alaska Univ., Fairbanks, AK (United States). Geophysical Inst.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  7. Heteroatom-Containing Porphyrin Analogues.

    Science.gov (United States)

    Chatterjee, Tamal; Shetti, Vijayendra S; Sharma, Ritambhara; Ravikanth, Mangalampalli

    2017-02-22

    The heteroatom-containing porphyrin analogues or core-modified porphyrins that resulted from the replacement of one or two pyrrole rings with other five-membered heterocycles such as furan, thiophene, selenophene, tellurophene, indene, phosphole, and silole are highly promising macrocycles and exhibit quite different physicochemical properties compared to regular azaporphyrins. The properties of heteroporphyrins depend on the nature and number of different heterocycle(s) present in place of pyrrole ring(s). The heteroporphyrins provide unique and unprecedented coordination environments for metals. Unlike regular porphyrins, the monoheteroporphyrins are known to stabilize metals in unusual oxidation states such as Cu and Ni in +1 oxidation states. The diheteroporphyrins, which are neutral macrocycles without ionizable protons, also showed interesting coordination chemistry. Thus, significant progress has been made in last few decades on core-modified porphyrins in terms of their synthesis, their use in building multiporphyrin arrays for light-harvesting applications, their use as ligands to form interesting metal complexes, and also their use for several other studies. The synthetic methods available in the literature allow one to prepare mono- and diheteroporphyrins and their functionalized derivatives, which were used extensively to prepare several covalent and noncovalent heteroporphyrin-based multiporphyrin arrays. The methods are also developed to synthesize different hetero analogues of porphyrin derivatives such as heterocorroles, heterochlorins, heterocarbaporphyrinoids, heteroatom-substituted confused porphyrins, and so on. This Review summarizes the key developments that have occurred in heteroporphyrin chemistry over the last four decades.

  8. Isolation of a crystalline A14-(N-methylpyridinium) derivative of bovine insulin.

    Science.gov (United States)

    Drewes, S E; Robinson, H M; Gliemann, J

    1979-07-01

    Reaction of insulin with 2-chloro- or 2-iodo-N-methylpyridinium iodide affords, amongst others, an insulin analogue modified at tha A14-tyrosine residue. Degradative procedures which pinpoint the exact position of modification are described. Highest yields of the derivative are obtained using the 2-iodo-N-methylpyridinium iodide as reagent. In the mouse convulsion assay this derivative retains 72% of its activity.

  9. Comparison of a Multiple Daily Insulin Injection Regimen (Glargine or Detemir Once Daily Plus Prandial Insulin Aspart and Continuous Subcutaneous Insulin Infusion (Aspart in Short-Term Intensive Insulin Therapy for Poorly Controlled Type 2 Diabetes Patients

    Directory of Open Access Journals (Sweden)

    Wen-shan Lv

    2013-01-01

    Full Text Available Aims. To examine the potential differences between multiple daily injection (MDI regimens based on new long-acting insulin analogues (glargine or detemir plus prandial insulin aspart and continuous subcutaneous insulin aspart infusion (CSII in patients with poorly controlled type 2 diabetes. Methods. Patients (n=119 with poorly controlled type 2 diabetes of a duration exceeding five years were randomly assigned into three groups: Group A treated with CSII using insulin aspart; Group B treated with glargine-based MDI and Group C treated with detemir-based MDI. Results. Good glycemic control was achieved by patients in Group A in a significantly shorter duration than patients in Groups B and C. Total daily insulin, basal insulin dose and dose per kg body weight in Group A were significantly less than those in Groups B and C. Daily blood glucose fluctuation in Group A was significantly less than that in Groups B and C. There were no differences between Groups B and C. Conclusions. Aspart-based CSII may achieve good blood glucose control with less insulin doses over a shorter period compared with glargine or detemir-based MDI. No differences between glargine- and detemir-based MDI were detected in poorly controlled subjects with type 2 diabetes.

  10. Penetratin-Mediated Transepithelial Insulin Permeation: Importance of Cationic Residues and pH for Complexation and Permeation

    DEFF Research Database (Denmark)

    Kristensen, Mie; Franzyk, Henrik; Klausen, M. T.

    2015-01-01

    permeation. Besides penetratin, three analogues were studied. The carrier peptide-insulin complexes were characterized in terms of size and morphology at pH 5, 6.5, and 7.4 by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. At pH 7.4 mainly very large complexes were...... increased insulin permeation as compared to that of the parent penetratin. In general, pre-complexation with penetratin and its analogues at pH 5 gave rise to increased insulin permeation as compared to that observed at pH 7.4; this finding was further supported by a preliminary in vivo study using......Penetratin is a widely used carrier peptide showing promising potential for mucosal delivery of therapeutic proteins. In the present study, the importance of specific penetratin residues and pH was investigated with respect to complexation with insulin and subsequent transepithelial insulin...

  11. Active postoperative acromegaly: sustained remission after discontinuation of somatostatin analogues

    Directory of Open Access Journals (Sweden)

    Cristina Alvarez-Escola

    2016-11-01

    Full Text Available In patients with active acromegaly after pituitary surgery, somatostatin analogues are effective in controlling the disease and can even be curative in some cases. After treatment discontinuation, the likelihood of disease recurrence is high. However, a small subset of patients remains symptom-free after discontinuation, with normalized growth hormone (GH and insulin-like growth factor (IGF1 levels. The characteristics of patients most likely to achieve sustained remission after treatment discontinuation are not well understood, although limited evidence suggests that sustained remission is more likely in patients with lower GH and IGF1 levels before treatment withdrawal, in those who respond well to low-dose treatment, in those without evidence of adenoma on an MRI scan and/or in patients who receive long-term treatment. In this report, we describe the case of a 56-year-old female patient treated with lanreotide Autogel for 11 years. Treatment was successfully discontinued, and the patient is currently disease-free on all relevant parameters (clinical, biochemical and tumour status. The successful outcome in this case adds to the small body of literature suggesting that some well-selected patients who receive long-term treatment with somatostatin analogues may achieve sustained remission.

  12. Metformin and insulin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific /sup 125/I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific /sup 125/I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded.

  13. [Insulin resistance in children].

    Science.gov (United States)

    Witek, Joanna; Witek, Przemysław; Pańkowska, Ewa

    2011-01-01

    Insulin resistance is characterized by decreased tissue sensitivity to insulin. The hallmark of insulin resistance is decreased tissue glucose uptake despite normal or elevated insulin concentration. There has been an upward trend in the incidence of insulin resistance in developed countries, although in pediatric population it is difficult to assess. Both genetic and environmental factors play an important role in the etiology of insulin resistance, namely increased diet caloricity and decreased physical activity. Gradually, this leads to adipose tissue build-up. The role of visceral adipose tissue is of particular importance, mainly due to its significant endocrine activity, leading to adverse metabolic effects. The most important consequences of insulin resistance in children include increased incidence of type 2 diabetes, atherogenic dyslipidemia and arterial hypertension, which lead to increased cardiovascular risk. Children with insulin resistance can develop nonalcoholic steatohepatitis and sleep apnea syndrome. In case of female pediatric patients a higher incidence of polycystic ovary syndrome (PCOS) is observed. Furthermore, the authors reviewed opinions on risk factors for insulin resistance, as well as direct and indirect insulin resistance assessment methods. The article presents the principles of primary and secondary prevention of insulin resistance in children, with particular allowance for dietary recommendations and recommendations to increase physical activity, and, in selected cases, current guidelines on pharmacological treatment.

  14. The role of insulin detemir in overweight type 2 diabetes management

    Directory of Open Access Journals (Sweden)

    Yared N Demssie

    2009-06-01

    Full Text Available Yared N Demssie1, Naveed Younis2, Handrean Soran31Department of Diabetes and Endocrinology, Salford Royal Foundation NHS Trust, Salford, UK; 2Department of Medicine, University Hospital South Manchester Foundation NHS Trust, Wythenshawe, Manchester, UK; 3University Department of Medicine, Central Manchester and Manchester Children’s NHS Foundation Trust, Manchester, UKAbstract: The recent evidence-based shift towards an algorithm of early initiation and aggressive titration of insulin therapy in the management of type 2 diabetes requires the use of an effective insulin formulation that is both safe and acceptable to patients and physicians alike. The advent of the long-acting insulin analogues, insulin detemir and glargine, in the last decade has revolutionized insulin therapy in type 2 diabetes. Their unique pharmacokinetic and pharmacodynamic properties have offered tangible advantage over the conventional intermediate and long-acting insulin preparations in terms of improving glucose control as well as reducing risk of hypoglycemia and weight gain. This review focuses on the pharmacodynamic properties of the long-acting insulin analogue detemir, the outcome of studies on its relative efficacy and safety as well as its proposed place in the management of type 2 diabetes.Keywords: insulin detemir, type 2 diabetes, overweight

  15. Synthetic Advances in Insulin-like Peptides Enable Novel Bioactivity.

    Science.gov (United States)

    Liu, Fa; Li, Pengyun; Gelfanov, Vasily; Mayer, John; DiMarchi, Richard

    2017-08-15

    Insulin is a miraculous hormone that has served a seminal role in the treatment of insulin-dependent diabetes for nearly a century. Insulin resides within in a superfamily of structurally related peptides that are distinguished by three invariant disulfide bonds that anchor the three-dimensional conformation of the hormone. The additional family members include the insulin-like growth factors (IGF) and the relaxin-related set of peptides that includes the so-called insulin-like peptides. Advances in peptide chemistry and rDNA-based synthesis have enabled the preparation of multiple insulin analogues. The translation of these methods from insulin to related peptides has presented unique challenges that pertain to differing biophysical properties and unique amino acid compositions. This Account presents a historical context for the advances in the chemical synthesis of insulin and the related peptides, with division into two general categories where disulfide bond formation is facilitated by native conformational folding or alternatively orthogonal chemical reactivity. The inherent differences in biophysical properties of insulin-like peptides, and in particular within synthetic intermediates, have constituted a central limitation to achieving high yield synthesis of properly folded peptides. Various synthetic approaches have been advanced in the past decade to successfully address this challenge. The use of chemical ligation and metastable amide bond surrogates are two of the more important synthetic advances in the preparation of high quality synthetic precursors to high potency peptides. The discovery and application of biomimetic connecting peptides simplifies proper disulfide formation and the subsequent traceless removal by chemical methods dramatically simplifies the total synthesis of virtually any two-chain insulin-like peptide. We report the application of these higher synthetic yield methodologies to the preparation of insulin-like peptides in support of

  16. CO2 Capture with Enzyme Synthetic Analogue

    Energy Technology Data Exchange (ETDEWEB)

    Cordatos, Harry

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  17. A Review of the Clinical Efficacy and Safety of Insulin Degludec and Glargine 300 U/mL in the Treatment of Diabetes Mellitus.

    Science.gov (United States)

    Woo, Vincent C

    2017-08-01

    The treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) using insulin is not ideal at this time. Despite advances made with basal insulin analogues, many individuals achieve less than optimal glycemic control or are at risk for hypoglycemia. Currently available basal insulin analogues do not deliver steady, peakless, continuous insulin for >24 hours and are associated with adverse events, including hypoglycemia. The objective of this paper was to review the clinical efficacy and safety of upcoming long-acting insulin analogues such as insulin degludec and insulin glargine 300 U/mL (Gla-300). A comprehensive literature search of PubMed and Google Scholar was conducted from 1966 to 2015. The search included randomized controlled trials that specifically assessed the efficacy and safety of insulin degludec and Gla-300 in patients with T1DM and T2DM. The efficacy of insulin degludec and Gla-300 in achieving glycemic control has been reported in clinical trials in adults with T1DM and T2DM. Not only did a large number of patients succeed in meeting glycosylated hemoglobin targets, but they also experienced reductions in hypoglycemic events. These 2 therapies are associated with a reduced risk of nocturnal hypoglycemia and are generally well tolerated. The long-acting insulin analogues insulin degludec and Gla-300 are promising therapies in the treatment of T1DM and T2DM. Their improved insulin delivery for >24 hours offers glycemic control with a good safety profile. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  18. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

  19. Diabetes, insulin and exercise

    DEFF Research Database (Denmark)

    Richter, Erik; Galbo, H

    1986-01-01

    The metabolic and hormonal adaptations to single exercise sessions and to exercise training in normal man and in patients with insulin-dependent as well as non-insulin-dependent diabetes mellitus are reviewed. In insulin-dependent (type I) diabetes good metabolic control is best obtained...... of the patient's reaction to exercise is desirable, which necessitates frequent self-monitoring of plasma glucose. It may often be necessary to diminish the insulin dose before exercise, and/or to ingest additional carbohydrate during or after exercise. In non-insulin-dependent (type II) diabetes, exercise...... by a regular pattern of life which will lead to a fairly constant demand for insulin from day to day. Exercise is by nature a perturbation that makes treatment of diabetes difficult: Muscle contractions per se tend to decrease the plasma glucose concentration whereas the exercise-induced response of the so...

  20. Flexibility in insulin prescription

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2016-01-01

    Full Text Available This communication explores the concept of flexibility, a propos insulin preparations and insulin regimes used in the management of type 2 diabetes. The flexibility of an insulin regime or preparation is defined as their ability to be injected at variable times, with variable injection-meal time gaps, in a dose frequency and quantum determined by shared decision making, with a minimal requirement of glucose monitoring and health professional consultation, with no compromise on safety, efficiency and tolerability. The relative flexibility of various basal, prandial and dual action insulins, as well as intensive regimes, is compared. The biopsychosocial model of health is used to assess the utility of different insulins while encouraging a philosophy of flexible insulin usage.

  1. Factors that influence basal insulin requirement in type 2 diabetes.

    Science.gov (United States)

    Papa, Giuseppe; Baratta, Roberto; Calì, Vincenzo; Degano, Claudia; Iurato, Maria Pierangela; Licciardello, Carmelo; Maiorana, Raffaella; Finocchiaro, Concetta

    2012-10-01

    In clinical practice, basal insulin dosage (BID) for the treatment for type 2 diabetes given as slow-acting analogues or NPH insulin varies widely when adjusted for body weight (UI/kg). In this study, we investigated the interrelationship between BID and anthropometric, laboratory and clinical parameters. A total of 681 type 2 diabetic patients, treated with bedtime insulin in association with other antidiabetic drugs (preprandial insulin and/or oral agents), were studied. Anthropometric, clinical and biochemical parameters, as well as micro- and macrovascular complications, were evaluated. Non-alcoholic fatty liver disease (NAFLD) was assessed by liver ultrasound. BID was titrated to achieve a fasting blood glucose target of ≤6.7 mmol/L (120 mg/dL). In the multivariate analysis, BID was significantly associated with waist circumference (p = 0.04) and the insulin treatment duration (p = 0.004) as the type of insulin treatment ("basal-bolus" regimen vs. basal insulin only, p < 0.0001), the use of lipid-lowering drugs (p = 0.0003) and insulin sensitizers (p = 0.005). Several glycometabolic parameters were strongly associated with BID (HbA1c p = 0.01, FPG p < 0.0001, HDL p = 0.02, triglycerides p = 0.03). Moreover, the presence of severe NAFLD resulted in a higher BID (p = 0.03). We concluded that when starting and titrating the basal insulin in type 2 diabetes, certain anthropometric, laboratory and clinical factors can be useful to find optimal BID more quickly and appropriately.

  2. History of insulin

    Directory of Open Access Journals (Sweden)

    Celeste C. Quianzon

    2012-07-01

    Full Text Available The advancement of diabetes treatment has gone from crude extracts of insulin and accidental discovery of sulfa-like drugs in antibiotics to the development of drugs based on improved understanding of the pathophysiology of diabetes mellitus. This article will review the history of the discovery and development of insulin. A companion focusing on non-insulin diabetes agents will follow in the next issue of JCHIMP.

  3. Insulin resistance and atherosclerosis

    OpenAIRE

    Semenkovich, Clay F.

    2006-01-01

    Considerable evidence supports the association between insulin resistance and vascular disease, and this has led to wide acceptance of the clustering of hyperlipidemia, glucose intolerance, hypertension, and obesity as a clinical entity, the metabolic syndrome. While insulin resistance, by promoting dyslipidemia and other metabolic abnormalities, is part of the proatherogenic milieu, it is possible that insulin resistance itself in the vascular wall does not promote atherosclerosis. Recent fi...

  4. Insulin, cognition, and dementia

    Science.gov (United States)

    Cholerton, Brenna; Baker, Laura D.; Craft, Suzanne

    2015-01-01

    Cognitive disorders of aging represent a serious threat to the social and economic welfare of current society. It is now widely recognized that pathology related to such conditions, particularly Alzheimer’s disease, likely begins years or decades prior to the onset of clinical dementia symptoms. This revelation has led researchers to consider candidate mechanisms precipitating the cascade of neuropathological events that eventually lead to clinical Alzheimer’s disease. Insulin, a hormone with potent effects in the brain, has recently received a great deal of attention for its potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favorable effects of insulin, is related to multiple chronic conditions known to impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer’s disease and other cognitive disorders will continue to rise exponentially. Fortunately, these chronic insulin-related conditions are amenable to pharmacological intervention. As a result, novel therapeutic strategies that focus on increasing insulin sensitivity in the brain may be an important target for protecting or treating cognitive decline. The following review will highlight our current understanding of the role of insulin in brain, potential mechanisms underlying the link between insulin resistance and dementia, and current experimental therapeutic strategies aimed at improving cognitive function via modifying the brain’s insulin sensitivity. PMID:24070815

  5. Using ultra-rapid insulin analogs in children and adolescents with type 1 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    О.V. Bolshova

    2017-11-01

    Full Text Available Background. The purpose of the study was a retrospective comparative analysis of using insulin analogues of the prolonged and ultra-short action and human genetically engineered insulins of middle and short action in children and adolescents with type 1 diabetes mellitus (DM. Materials and methods. The influence of ultra-rapid insulin analog in comparison with human rapid-action insulin on the course of type 1 DM in 100 children and adolescents was studied. It was applied as basal-bolus regimen of insulin therapy. Analysis of parameters which reflect criteria of insulin therapy effectiveness, positive effect of ultra-rapid insulin analog on the course of DM has been performed. Results. Application of ultra-rapid insulin analog before each meal improved parameters of pre- and postprandial glycemia, decreased the range of fluctuations of blood sugar during the day, reduced and maintained HbA1c level without augmentation of frequency and intensity of hypoglycaemia, and also decreased the level of noctural hypoglycaemia. Conclusions. The ultra-rapid insulin analog is the drug of choice for the effective use in insulin pumps.

  6. Insulin and the polycystic ovary syndrome.

    Science.gov (United States)

    Macut, Djuro; Bjekić-Macut, Jelica; Rahelić, Dario; Doknić, Mirjana

    2017-08-01

    Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy among women during reproductive age. PCOS is characterised by hyperandrogenaemia, hyperinsulinaemia, and deranged adipokines secretion from the adipose tissue. In addition to the reduced insulin sensitivity, PCOS women exhibit β-cell dysfunction as well. Low birth weight and foetal exposure to androgens may contribute to the development of the PCOS phenotype during life. Further metabolic complications lead to dyslipidaemia, worsening obesity and glucose tolerance, high prevalence of metabolic syndrome, and greater susceptibility to diabetes. PCOS women show age-related existence of hypertension, and subtle endothelial and vascular changes. Adverse reproductive outcomes include anovulatory infertility, and unrecognised potentiation of the hormone-dependent endometrial cancer. The main therapeutic approach is lifestyle modification. Metformin is the primary insulin-sensitising drug to be used as an adjuvant therapy to lifestyle modification in patients with insulin resistance and impaired glucose tolerance, as well as in those referred to infertility treatment. Thiazolidinediones should be reserved for women intolerant of or refractory to metformin, while glucagon-like peptide 1 analogues has a potential therapeutic use in obese PCOS women. Randomised clinical trials and repetitive studies on different PCOS phenotypes for the preventive actions and therapeutic options are still lacking, though. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Antimicrobial Activity of Resveratrol Analogues

    Directory of Open Access Journals (Sweden)

    Malik Chalal

    2014-06-01

    Full Text Available Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew. Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold. The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups and antimicrobial activity.

  8. Humanin: a novel central regulator of peripheral insulin action.

    Directory of Open Access Journals (Sweden)

    Radhika H Muzumdar

    2009-07-01

    Full Text Available Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM and Alzheimer's disease (AD. A novel mitochondria-associated peptide, Humanin (HN, has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin resistance and AD, we investigated if HN influences insulin sensitivity.Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action. Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity. The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling; effects that were negated by co-inhibition of hypothalamic STAT-3. Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN. Inhibition of hypothalamic STAT-3 completely negated the effects of IV HN analog on liver, suggesting that the hepatic actions of HN are centrally mediated. This is consistent with the lack of a direct effect of HN on primary hepatocytes. Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats. Based upon the link of HN with two age-related diseases, we examined if there were age associated changes in HN levels. Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents, and circulating levels of HN were decreased with age in humans and mice.We conclude that the decline in HN with age could play a role in the pathogenesis of age-related diseases including AD and T2DM. HN represents a novel link between T2DM and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM.

  9. Design and rationale of a large, international, prospective cohort study to evaluate the occurrence of malformations and perinatal/neonatal death using insulin detemir in pregnant women with diabetes in comparison with other long-acting insulins

    OpenAIRE

    Mathiesen, Elisabeth R; Andersen, Henning; Sofia I I Kring; Damm, Peter

    2017-01-01

    Background There are a lack of data regarding the effect of basal insulin analogues on rates of events like congenital malformation and perinatal mortality in diabetic pregnancy. Methods The present study is a prospective, non-interventional, multicentre cohort study conducted in seven countries, designed to assess the safety of insulin detemir during pregnancy, and to monitor the health status of resulting infants (exposed in utero) up to 1?year of age. The study population includes women wi...

  10. Cost comparison of insulin glargine with insulin detemir in a basal-bolus regime with mealtime insulin aspart in type 2 diabetes in Germany

    Directory of Open Access Journals (Sweden)

    Dippel, Franz-Werner

    2010-01-01

    Full Text Available Objective: To compare the treatment costs of insulin glargine (IG; Lantus® to detemir (ID; Levemir®, both combined with bolus insulin aspart (NovoRapid® in type 2 diabetes (T2D in Germany. Methods: Cost comparison was based on data of a 1-year randomised controlled trial [1]. IG was administered once daily and ID once (57% of patients or twice daily (43% according to treatment response. At the end of the trial, mean daily basal insulin doses were 0.59 U/kg (IG and 0.82 U/kg (ID. Aspart doses were 0.32 U/kg (IG and 0.36 U/kg (ID. Costs were calculated from the German statutory health insurance (SHI perspective using official 2008 prices. Sensitivity analyses were performed to test robustness of the results. Results: Annual basal and bolus insulin costs per patient were € 1,473 (IG and € 1,940 (ID. The cost of lancets and blood glucose test strips were € 1,125 (IG and € 1,286 (ID. Annual costs for needles were € 393 (IG and € 449 (ID. The total annual cost per patient of administering IG was € 2,991 compared with € 3,675 for ID, translating into a 19% annual cost difference of € 684/patient. Base case results were robust to varying assumptions for insulin dose, insulin price, change in weight and proportion of ID once daily administrations. Conclusion: IG and ID basal-bolus regimes have comparative safety and efficacy, based on the Hollander study, IG however may represent a significantly more cost saving option for T2D patients in Germany requiring basal-bolus insulin analogue therapy with potential annual cost savings of € 684/patient compared to ID.

  11. Differential effects of insulin injections and insulin infusions on levels ...

    African Journals Online (AJOL)

    Studies have shown that while injections of insulin cause an increase in fat mass, infusions of insulin increase fat mass. The aim of this paper was to test the hypothesis that if an increase in glycogen is an indicator of an impending increase in adipose mass, then insulin infusions should not increase glycogen, while insulin ...

  12. Insulin in diabetes prevention.

    Science.gov (United States)

    Ramiya, V K; Maclaren, N K

    1997-01-01

    Insulin-dependent diabetes (IDD) is a chronic immune-endocrine disease in which there is a progressive destruction of insulin-secreting pancreatic beta cells, caused primarily by autoreactive T cells. Many islet cell proteins including insulin, glutamic acid decarboxylase, and tyrosine phosphatase antigens (IA-2) are targeted by the autoimmune responses in IDD patients. Since its discovery 75 years ago, insulin has been the major player in the clinical management of hyperglycaemia in these patients. The morbidity and mortality associated with IDD derives mainly from the complications of the disease. However, routine insulin injections seldom achieve a consistent, near-normal glucose level, where multiple daily doses of the hormone involve considerable restrictions to a normal lifestyle. In terms of economics, the management of diabetes is expensive, and in the USA diabetes alone accounts for one seventh of the healthcare budget. These clinical, lifestyle and economic issues emphasize the need to investigate alternative preventative measures in IDD treatment. Recent reports suggest a pivotal role for insulin in various aspects of the immune system. In this study, insulin and B-chain were used to modulate autoimmune responses in non-obese diabetic mice, findings which have therapeutic implications in man.

  13. Between Analogue and Digital Diagrams

    Directory of Open Access Journals (Sweden)

    Zoltan Bun

    2012-10-01

    Full Text Available This essay is about the interstitial. About how the diagram, as a method of design, has lead fromthe analogue deconstruction of the eighties to the digital processes of the turn of the millennium.Specifically, the main topic of the text is the interpretation and the critique of folding (as a diagramin the beginning of the nineties. It is necessary then to unfold its relationship with immediatelypreceding and following architectural trends, that is to say we have to look both backwards andforwards by about a decade. The question is the context of folding, the exchange of the analogueworld for the digital. To understand the process it is easier to investigate from the fields of artand culture, rather than from the intentionally perplicated1 thoughts of Gilles Deleuze. Both fieldsare relevant here because they can similarly be used as the yardstick against which the era itselfit measured. The cultural scene of the eighties and nineties, including performing arts, movies,literature and philosophy, is a wide milieu of architecture. Architecture responds parallel to itsera; it reacts to it, and changes with it and within it. Architecture is a medium, it has always beena medium, yet the relations are transformed. That’s not to say that technical progress, for exampleusing CAD-software and CNC-s, has led to the digital thinking of certain movements ofarchitecture, (it is at most an indirect tool. But the ‘up-to-dateness’ of the discipline, however,a kind of non-servile reading of an ‘applied culture’ or ‘used philosophy’2 could be the key.(We might recall here, parenthetically, the fortunes of the artistic in contemporary mass society.The proliferation of museums, the magnification of the figure of the artist, the existence of amassive consumption of printed and televised artistic images, the widespread appetite for informationabout the arts, all reflect, of course, an increasingly leisured society, but also relateprecisely to the fact

  14. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    PRAKASH

    studies in β cell-specific IR knockout mice, which develop peripheral insulin resistance and diabetes, most probably due to the changes in the pattern of insulin secretion (Kulkarni et al 1999). FFA also affects downstream insulin signalling molecules. It inhibits insulin activation of IRS-1-associated PI3K activity in muscle.

  15. Convergent syntheses of LeX analogues

    Directory of Open Access Journals (Sweden)

    An Wang

    2010-02-01

    Full Text Available The synthesis of three Lex derivatives from one common protected trisaccharide is reported. These analogues will be used respectively for competitive binding experiments, conjugation to carrier proteins and immobilization on gold. An N-acetylglucosamine monosaccharide acceptor was first glycosylated at O-4 with a galactosyl imidate. This coupling was performed at 40 °C under excess of BF3·OEt2 activation and proceeded best if the acceptor carried a 6-chlorohexyl rather than a 6-azidohexyl aglycon. The 6-chlorohexyl disaccharide was then converted to an acceptor and submitted to fucosylation yielding the corresponding protected 6-chlorohexyl Lex trisaccharide. This protected trisaccharide was used as a precursor to the 6-azidohexyl, 6-acetylthiohexyl and 6-benzylthiohexyl trisaccharide analogues which were obtained in excellent yields (70–95%. In turn, we describe the deprotection of these intermediates in one single step using dissolving metal conditions. Under these conditions, the 6-chlorohexyl and 6-azidohexyl intermediates led respectively to the n-hexyl and 6-aminohexyl trisaccharide targets. Unexpectedly, the 6-acetylthiohexyl analogue underwent desulfurization and gave the n-hexyl glycoside product, whereas the 6-benzylthiohexyl analogue gave the desired disulfide trisaccharide dimer. This study constitutes a particularly efficient and convergent preparation of these three Lex analogues.

  16. AMPK and insulin action

    DEFF Research Database (Denmark)

    Frøsig, Christian; Jensen, Thomas Elbenhardt; Jeppesen, Jacob

    2013-01-01

    The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact...... role of AMPK is not well understood. Here we hypothesized that mice lacking a2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (~4 month) or old (~18 month) wild type and muscle specific a2AMPK...... kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis...

  17. Insulin Detemir Causes Lesser Weight Gain in Comparison to Insulin Glargine: Role on Hypothalamic NPY and Galanin

    Directory of Open Access Journals (Sweden)

    Mohammad Ishraq Zafar

    2014-01-01

    Full Text Available Objective. Compared with other insulin analogues, insulin detemir induces less weight gain. This study investigated whether this effect was achieved by influencing the hypothalamic appetite regulators neuropeptide Y (NPY and galanin (GAL. Methods. Type  2 diabetic rat models were established with a high-fat diet and intraperitoneal injection of STZ. All rats were divided into NC, DM, DM+DE and DM+GLA groups. Glycemic levels of all study groups were checked at study onset and after 4 weeks of insulin treatment. Food intake and body weight were monitored during treatment. After 4 weeks, the hypothalamus of rats was examined for NPY and GAL mRNA and protein expression. Results. After 4 weeks of treatment, compared with the DM+GLA group, the DM+DE group exhibited less food intake (P<0.05 and less weight gain (P<0.05, but showed similar glycemic control. The expression of hypothalamic NPY and GAL at both mRNA and protein level were significantly lower (P<0.05 in the DM+DE group. Conclusion. Insulin detemir decreased food intake in type 2 diabetic rats, which led to reduced weight gain when compared to insulin glargine treatment. This effect is likely due to downregulation of hypothalamic NPY and GAL.

  18. Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

    Science.gov (United States)

    Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

    2011-01-01

    The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

  19. Insulin and the Lung

    DEFF Research Database (Denmark)

    Singh, Suchita; Prakash, Y S; Linneberg, Allan

    2013-01-01

    Obesity, metabolic syndrome, and asthma are all rapidly increasing globally. Substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked. Since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage...... and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin...

  20. Insulin and Glucagon

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Holland, William; Gromada, Jesper

    2017-01-01

    In August 2016, several leaders in glucagon biology gathered for the European Association for the Study of Diabetes Hagedorn Workshop in Oxford, England. A key point of discussion focused on the need for basal insulin to allow for the therapeutic benefit of glucagon blockade in the treatment...... of the discussion as a consensus was reached. Agents that antagonize glucagon may be of great benefit for the treatment of diabetes; however, sufficient levels of basal insulin are required for their therapeutic efficacy....

  1. Antibody-Mediated Insulin Resistance: When Insulin and Insulin Receptor Act as Autoantigens in Humans.

    Science.gov (United States)

    Liminet, Christelle; Vouillarmet, Julien; Chikh, Karim; Disse, Emmanuel

    2016-10-01

    We report the case of a patient with diabetes presenting a severe insulin-resistance syndrome due to the production of insulin autoantibodies by a lymphocytic lymphoma. We describe the various mechanisms leading to the production of insulin autoantibodies and insulin receptor autoantibodies and review the therapeutic possibilities. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  2. Insulin Resistance: Causes And Metabolic Implications | Igharo ...

    African Journals Online (AJOL)

    Insulin is an anabolic hormone that plays key roles in glucose metabolism. Insulin resistance is a decreased biological response to normal concentration of circulating insulin. In insulin resistance, normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin ...

  3. Synthesis and anticancer evaluation of spermatinamine analogues.

    Science.gov (United States)

    Moosa, Basem A; Sagar, Sunil; Li, Song; Esau, Luke; Kaur, Mandeep; Khashab, Niveen M

    2016-03-15

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcysteine carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines, that is, cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5-10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Synthesis and anticancer evaluation of spermatinamine analogues

    KAUST Repository

    Moosa, Basem

    2016-02-04

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcystiene carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines i.e. cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5 - 10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines.

  5. Treating Diabetes Mellitus: Pharmacophore Based Designing of Potential Drugs from Gymnema sylvestre against Insulin Receptor Protein

    Directory of Open Access Journals (Sweden)

    Mohammad Uzzal Hossain

    2016-01-01

    Full Text Available Diabetes mellitus (DM is one of the most prevalent metabolic disorders which can affect the quality of life severely. Injectable insulin is currently being used to treat DM which is mainly associated with patient inconvenience. Small molecules that can act as insulin receptor (IR agonist would be better alternatives to insulin injection. Herein, ten bioactive small compounds derived from Gymnema sylvestre (G. sylvestre were chosen to determine their IR binding affinity and ADMET properties using a combined approach of molecular docking study and computational pharmacokinetic elucidation. Designing structural analogues were also performed for the compounds associated with toxicity and less IR affinity. Among the ten parent compounds, six were found to have significant pharmacokinetic properties with considerable binding affinity towards IR while four compounds were associated with toxicity and less IR affinity. Among the forty structural analogues, four compounds demonstrated considerably increased binding affinity towards IR and less toxicity compared with parent compounds. Finally, molecular interaction analysis revealed that six parent compounds and four analogues interact with the active site amino acids of IR. So this study would be a way to identify new therapeutics and alternatives to insulin for diabetic patients.

  6. The development of novel ninhydrin analogues.

    Science.gov (United States)

    Hansen, Darren B; Joullie, Madeleine M

    2005-05-01

    Following its discovery by Siegfried Ruhemann in 1910, ninhydrin rapidly became a practical analytical tool. In 1954 it was found to be an important reagent to develop fingerprints on porous surfaces. Since its use in forensic chemistry, many efforts have focused on improving the reagent. Many of the shortcomings of ninhydrin have been met by the synthesis of a variety of ninhydrin analogues. This tutorial review provides a short introduction to ninhydrin and highlights the different synthetic approaches used in the development of analogues for the detection of latent fingerprints.

  7. Discrete analogues in harmonic analysis: Spherical averages

    OpenAIRE

    Magyar, A; Stein, E. M.; Wainger, S.

    2004-01-01

    In this paper we prove an analogue in the discrete setting of \\Bbb Z^d, of the spherical maximal theorem for \\Bbb R^d. The methods used are two-fold: the application of certain "sampling" techniques, and ideas arising in the study of the number of representations of an integer as a sum of d squares in particular, the "circle method". The results we obtained are by necessity limited to d \\ge 5, and moreover the range of p for the L^p estimates differs from its analogue in \\Bbb R^d.

  8. Molecular biocoding of insulin

    Directory of Open Access Journals (Sweden)

    Lutvo Kuric

    2010-07-01

    Full Text Available Lutvo KuricNovi Travnik, Kalinska, Bosnia and Herzegovina Abstract: This paper discusses cyberinformation studies of the amino acid composition of insulin, in particular the identification of scientific terminology that could describe this phenomenon, ie, the study of genetic information, as well as the relationship between the genetic language of proteins and theoretical aspects of this system and cybernetics. The results of this research show that there is a matrix code for insulin. It also shows that the coding system within the amino acid language gives detailed information, not only on the amino acid “record”, but also on its structure, configuration, and various shapes. The issue of the existence of an insulin code and coding of the individual structural elements of this protein are discussed. Answers to the following questions are sought. Does the matrix mechanism for biosynthesis of this protein function within the law of the general theory of information systems, and what is the significance of this for understanding the genetic language of insulin? What is the essence of existence and functioning of this language? Is the genetic information characterized only by biochemical principles or it is also characterized by cyberinformation principles? The potential effects of physical and chemical, as well as cybernetic and information principles, on the biochemical basis of insulin are also investigated. This paper discusses new methods for developing genetic technologies, in particular more advanced digital technology based on programming, cybernetics, and informational laws and systems, and how this new technology could be useful in medicine, bioinformatics, genetics, biochemistry, and other natural sciences.Keywords: human insulin, insulin model, biocode, genetic code, amino acids

  9. Effects of GLP-1 and 2,5-Anhydro-D-Mannitol on Insulin Secretion and Plasma Glucose in Mice

    NARCIS (Netherlands)

    Ahrén, B.; Lindskog, S.; Dijk, G. van; Scheurink, A.J.W.; Steffens, A.B.

    1995-01-01

    The truncated glucagon-like peptide-1 (GLP-1((7.36))amide or GLP-1) stimulates insulin secretion, enhances glucose elimination and is of potential interest in diabetes treatment. We studied the hypoglycemic action of GLP-1 in normal mice when given alone or together with the fructose analogue,

  10. Analogue alternative the electronic analogue computer in Britain and the USA, 1930-1975

    CERN Document Server

    Small, James S

    2013-01-01

    We are in the midst of a digital revolution - until recently, the majority of appliances used in everyday life have been developed with analogue technology. Now, either at home or out and about, we are surrounded by digital technology such as digital 'film', audio systems, computers and telephones. From the late 1940s until the 1970s, analogue technology was a genuine alternative to digital, and the two competing technologies ran parallel with each other. During this period, a community of engineers, scientists, academics and businessmen continued to develop and promote the analogue computer.

  11. Prediction of Excessive Weight Gain in Insulin Treated Patients with Type 2 Diabetes

    DEFF Research Database (Denmark)

    Cichosz, Simon Lebech; Lundby-Christensen, Louise; Johansen, Mette D

    2017-01-01

    AIMS: Weight gain is an ongoing challenge when initiating insulin therapy in patients with Type 2 diabetes mellitus. However, if prediction of insulin associated weight gain was possible on an individualized level, targeted initiatives could be implemented to reduce weight gain. The objective...... of this study was to identify predictors of weight gain in insulin treated patients with Type 2 diabetes mellitus. METHODS: A total of 412 individuals with Type 2 diabetes mellitus were, in addition to metformin or placebo, randomized into 18-month treatment groups with three different insulin analogue...... treatment regimens. Participants with excessive weight gain were defined as the group with weight gain in the 4(th) quartile. We developed a pattern classification method to predict individuals prone to excessive weight gain. RESULTS: The median weight gain among all patients (n = 412) was 2.4 (95...

  12. Analogues of Euler and Poisson summation formulae

    Indian Academy of Sciences (India)

    Home; Journals; Proceedings – Mathematical Sciences; Volume 113; Issue 3. Analogues of Euler and Poisson Summation Formulae. Vivek V Rane. Volume 113 Issue 3 ... Keywords. Abel's summation formula; Euler summation formula; Euler–Maclaurin summation formula; Poisson's summation formula; Fourier series.

  13. as an inorganic analogue of carboxylate group

    Indian Academy of Sciences (India)

    is a tridentate ONS donor) as an inorganic analogue of carboxylate group: A journey to a new domain of coordination chemistry. SATYABRATA SAMANTAa, SUBODH KANTI DUTTAa,b and. MUKTIMOY CHAUDHURYa,*. aDepartment of Inorganic Chemistry, Indian Association for the Cultivation of Science, Kolkata 700 032.

  14. Helical chirality induction of expanded porphyrin analogues

    Indian Academy of Sciences (India)

    Helical porphyrin analogues. 1163. References. 1. (a) Jasat A and Dolphin A 1997 Chem. Rev. 97 2267;. (b) Sessler J L, Gebauer A and Weghorn S J 2000 in The porphyrin handbook, vol. 2, K M Kadish, K M Smith,. R Guilard (eds) (San Diego: Academic Press) pp55;. (c) Sessler J L and Seidel D 2003 Angew. Chem. Int.

  15. -Phenyl heteroarylamine analogues of fluazinam using the ...

    Indian Academy of Sciences (India)

    Permanent link: http://www.ias.ac.in/article/fulltext/jcsc/126/04/1107-1114. Keywords. Diarylamine compounds; 2,6-Dichloro-3,5-dinitrotoluene; intermediate derivatization method; fungicides. Abstract. Twenty-one N-phenyl heteroarylamine analogues of fluazinam 3a-3u were prepared via nucleophilic substitution reaction of ...

  16. Analoguing Creativity & Culture: A Method for Metaphors.

    Science.gov (United States)

    Thompson, Timothy N.

    Adding to the benefits of using metaphors as tools, "analoguing" (a method of analysis that focuses on metaphors for meanings in use and meanings of metaphors in use) helps avoid excessive categorization and separation by looking for unities and patterns in phenomena rather than for divisions. Six months of observation of patterns of…

  17. The World Is either Digital or Analogue

    NARCIS (Netherlands)

    Berto, F.; Tagliabue, J.

    2014-01-01

    We address an argument by Floridi (Synthese 168(1):151-178, 2009; 2011a), to the effect that digital and analogue are not features of reality, only of modes of presentation of reality. One can therefore have an informational ontology, like Floridi’s Informational Structural Realism, without

  18. Somatostatin analogues for acute bleeding oesophageal varices

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C.; Hrobjartsson, A.

    2008-01-01

    with bleeding oesophageal varices. SEARCH STRATEGY: PubMed and The Cochrane Library were searched (November 2007). Reference lists of publications, contacts with authors. SELECTION CRITERIA: All randomised trials comparing somatostatin or analogues with placebo or no treatment in patients suspected of acute...

  19. New Insulins and New Aspects in Insulin Delivery.

    Science.gov (United States)

    Woo, Vincent C

    2015-08-01

    The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  20. Improved insulin sensitivity after exercise: focus on insulin signaling

    DEFF Research Database (Denmark)

    Frøsig, Christian; Richter, Erik

    2009-01-01

    After a single bout of exercise, the ability of insulin to stimulate glucose uptake is markedly improved locally in the previously active muscles. This makes exercise a potent stimulus counteracting insulin resistance characterizing type 2 diabetes (T2D). It is believed that at least part...... of the mechanism relates to an improved ability of insulin to stimulate translocation of glucose transporters (GLUT4) to the muscle membrane after exercise. How this is accomplished is still unclear; however, an obvious possibility is that exercise interacts with the insulin signaling pathway to GLUT4...... translocation allowing for a more potent insulin response. Parallel to unraveling of the insulin signaling cascade, this has been investigated within the past 25 years. Reviewing existing studies clearly indicates that improved insulin action can occur independent of interactions with proximal insulin signaling...

  1. Insulin detemir versus insulin glargine for type 2 diabetes mellitus

    NARCIS (Netherlands)

    Swinnen, Sanne G.; Simon, Airin C. R.; Holleman, Frits; Hoekstra, Joost B.; DeVries, J. Hans

    2011-01-01

    Chronically elevated blood glucose levels are associated with significant morbidity and mortality. Many diabetes patients will eventually require insulin treatment to maintain good glycaemic control. There are still uncertainties about the optimal insulin treatment regimens for type 2 diabetes, but

  2. Development of insulin delivery systems.

    Science.gov (United States)

    Siddiqui, N I; Siddiqui, Ni; Rahman, S; Nessa, A

    2008-01-01

    Delivery system of insulin is vital for its acceptance and adherence to therapy for achieving the glycemic targets. Enormous developments have occurred in the delivery system of insulin during the last twenty years and each improvement was aimed at two common goals: patients convenience and better glycemic control. Till to date, the various insulin delivery systems are: syringes/vials, injection aids, jet injectors, transmucosal delivery, transdermal delivery, external insulin infusion pump, implantable insulin pumps, insulin pens and insulin inhalers. Syringe/vial is the oldest and conventional method, still widely used and relatively cheaper. Modern plastic syringes are disposable, light weight with microfine needle for patients convenience and comfort. Oral route could be the most acceptable and viable, if the barriers can be overcome and under extensive trial. Insulin pen device is an important milestone in the delivery system of insulin as it is convenient, discrete, painless, attractive, portable with flexible life style and improved quality of life. More than 80% of European diabetic patients are using insulin pen. Future digital pen will have better memory option, blood glucose monitoring system, insulin dose calculator etc. Insulin infusion pump is a good option for the children, busy patients with flexible lifestyle and those who want to avoid multiple daily injections. Pulmonary route of insulin delivery is a promising, effective, non-invasive and acceptable alternative method. Exubera, the world first insulin inhaler was approved by FDA in 28 January 2006. But due to certain limitations, it has been withdrawn from the market in October 2007. The main concern of inhaled insulin are: long term pulmonary safety issues, cost effectiveness and user friendly device. In future, more acceptable and cost effective insulin inhaler will be introduced. Newer avenues are under extensive trial for better future insulin delivery systems.

  3. Prospective randomized study for optimal insulin therapy in type 2 diabetic patients with secondary failure

    Directory of Open Access Journals (Sweden)

    Tojo Katsuyoshi

    2008-05-01

    Full Text Available Abstract Background The large clinical trials proved that Basal-Bolus (BB insulin therapy was effective in the prevention of diabetic complications and their progression. However, BB therapy needs multiple insulin injections per a day. In this regard, a biphasic insulin analogue needs only twice-daily injections, and is able to correct postprandial hyperglycemia. Therefore it may achieve the blood glucose control as same as that of BB therapy and prevent the diabetic complications including macroangiopathy. Methods In PROBE (Prospective, Randomized, Open, Blinded-Endpoint design, forty-two type 2 diabetic patients (male: 73.8%, median(inter quartile range age: 64.5(56.8~71.0years with secondary failure of sulfonylurea (SU were randomly assigned to BB therapy with a thrice-daily insulin aspart and once-daily basal insulin (BB group or to conventional therapy with a twice-daily biphasic insulin analogue (30 Mix group, and were followed up for 6 months to compare changes in HbA1c, daily glycemic profile, intima-media thickness (IMT of carotid artery, adiponectin levels, amounts of insulin used, and QOL between the two groups. Results After 6 months, HbA1c was significantly reduced in both groups compared to baseline (30 Mix; 9.3(8.1~11.3 → 7.4(6.9~8.7%, p Conclusion Both BB and 30 mix group produced comparable reductions in HbA1c in type 2 diabetic patients with secondary failure. There was no significant change in IMT as an indicator of early atherosclerotic changes between the two groups. The basal-bolus insulin therapy may not be necessarily needed if the type 2 diabetic patients have become secondary failure. Trial registration Current Controlled Trials number, NCT00348231

  4. A great disappearing act: the electronic analogue computer

    OpenAIRE

    Bissell, C. C.

    2004-01-01

    One historian of technology has called the analogue computer 'one of the great disappearing acts of the Twentieth Century'. This paper will look briefly at the origins, development and decline of the electronic analogue computer ..

  5. Chemical and thermal stability of insulin

    DEFF Research Database (Denmark)

    Huus, Kasper; Havelund, Svend; Olsen, Helle B

    2006-01-01

    To study the correlation between the thermal and chemical stability of insulin formulations with various insulin hexamer ligands.......To study the correlation between the thermal and chemical stability of insulin formulations with various insulin hexamer ligands....

  6. PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice

    NARCIS (Netherlands)

    Filipsson, K; Pacini, G; Scheurink, AJW; Ahren, B

    Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as

  7. Insulin Micropump with Embedded Pressure Sensors for Failure Detection and Delivery of Accurate Monitoring

    Directory of Open Access Journals (Sweden)

    Dimitry Dumont-Fillon

    2014-11-01

    Full Text Available Improved glycemic control with insulin pump therapy in patients with type 1 diabetes mellitus has shown gradual reductions in nephropathy and retinopathy. More recently, the emerging concept of the artificial pancreas, comprising an insulin pump coupled to a continuous glucose meter and a control algorithm, would become the next major breakthrough in diabetes care. The patient safety and the efficiency of the therapy are directly derived from the delivery accuracy of rapid-acting insulin. For this purpose, a specific precision-oriented design of micropump has been built. The device, made of a stack of three silicon wafers, comprises two check valves and a pumping membrane that is actuated against stop limiters by a piezo actuator. Two membranes comprising piezoresistive strain gauges have been implemented to measure the pressure in the pumping chamber and at the outlet of the pump. Their high sensitivity makes possible the monitoring of the pumping accuracy with a tolerance of ±5% for each individual stroke of 200 nL. The capability of these sensors to monitor priming, reservoir overpressure, reservoir emptying, outlet occlusion and valve leakage has also been studied.

  8. Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review

    Directory of Open Access Journals (Sweden)

    Wang F

    2012-07-01

    BIAsp 30, respectively.Keywords: basal insulin analog/analogue, degludec, degludec/aspart, IDeg, IDegAsp, NN1250, efficacy, safety, comparative study

  9. Assessment of implantable infusion pumps for continuous infusion of human insulin in rats: potential for group housing

    DEFF Research Database (Denmark)

    Jensen, Vivi Flou Hjorth; Molck, Anne-Marie; Martensson, Martin

    2017-01-01

    compound in these studies, and a comparator model of persistent exposure by HI infusion from external pumps has recently been developed to support toxicological evaluation of long-acting insulin analogues. However, this model requires single housing of the animals. Developing an insulin-infusion model...... which allows group housing would therefore greatly improve animal welfare. The aim of the present study was to investigate the suitability of implantable infusion pumps for HI infusion in group-housed rats. Group housing of rats implanted with a battery-driven pump proved to be possible. Intravenous...... infusion of HI lowered blood glucose levels persistently for two weeks, providing a comparator model for use in two-week repeated-dose toxicity studies with new long-acting insulin analogues, which allows group housing, and thereby increasing animal welfare compared with an external infusion model....

  10. Oral Insulin - Fact or Fiction?

    Indian Academy of Sciences (India)

    Insulin is a major protein hormone secreted by the p-cells of the pancreas and is important for the control of diabetes. Insulin is usually administered to diabetic patients through subcutaneous injection. This mode of therapy has certain inherent disadvantages such as local pain, itching and insulin lipodystrophy around the ...

  11. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, ...

  12. Insulin Resistance in Alzheimer's Disease

    Science.gov (United States)

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  13. Molecular mechanisms of insulin resistance

    African Journals Online (AJOL)

    basis of insulin resistance could ultimately lead to a better understanding of the causation of these conditions and the design of rational therapy to ameliorate them. Here, particular attention is devoted to the initial events that follow the binding of insulin to its receptor, including changes in insulin receptor phosphorylation.

  14. A comparison of the pharmacodynamic profiles of insulin detemir and insulin glargine: a single dose clamp study in people with type 2 diabetes.

    Science.gov (United States)

    Luzio, S D; Dunseath, G J; Atkinson, M D; Owens, D R

    2013-12-01

    The pharmacodynamic properties of a single dose of 0.5 U/kg insulin detemir and insulin glargine were compared during two 24-h isoglycaemic clamps, one week apart. The order of treatments was randomised. At approximately 0830 h, persons with T2DM received subcutaneous administration of a 0.5 U/kg dose of either insulin detemir or insulin glargine into the anterior abdominal wall. Plasma glucose was measured at 10-min intervals throughout the 24-h clamp period and isoglycaemia was maintained by variable infusion of 20% glucose. Glucose infusion rates (GIR) and plasma C-peptide were determined throughout each 24-h period. Eleven persons with type 2 diabetes (8 male) with mean (SD) age 58.5 years (8.5), BMI 30.8 kg/m² (2.8) and HbA1c 7.5% (0.6) were studied. Plasma glucose remained constant during the clamp (CV: insulin detemir 3.7%; insulin glargine 3.8%). Following injection of insulin detemir, GIR increased, reaching a mean peak of 2.29 mg/kg/min (95% CI 1.64, 2.94) at 11.6h (range 8.9 to 14.3) compared to 1.71 mg/kg/min (95% CI 1.4, 2.0) at 10.2 h (8.1 to 12.3) for insulin glargine (P=0.025 for GIR(max)). Plasma C-peptide decreased during the study period, remaining significantly lower than the fasting level at the study end after both analogues, insulin detemir (P=0.01) and insulin glargine (P=0.02). In persons with T2DM, no difference in duration of action following a single subcutaneous dose of insulin detemir and insulin glargine could be observed. Insulin detemir showed greater between subject variability and achieved a significantly higher maximum GIR than insulin glargine. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  15. Combining insulins with oral antidiabetic agents: effect on hyperglycemic control, markers of cardiovascular risk and disease

    Directory of Open Access Journals (Sweden)

    Kjeld Hermansen

    2008-06-01

    Full Text Available Kjeld Hermansen, Lene Sundahl Mortensen, Marie-Louise HermansenDepartment of Endocrinology and Metabolism C, Aarhus University Hospital, DK-8000 Aarhus, DenmarkAbstract: Patients with type 2 diabetes mellitus (T2DM have an increased risk of cardiovascular disease (CVD. Unfortunately, several potential barriers exist for CVD risk management in diabetes, including the need for significant lifestyle changes, potential problems with hypoglycemia, weight gain, injection tolerability, treatment complexity with current diabetes therapies and other, unmodifiable factors. Improving glycemic control may impact CVD risk. Treatment of T2DM usually starts with lifestyle changes such as diet and exercise. When these become insufficient, pharmacotherapy is required. Various oral antidiabetic drugs (OADs are available that reduce hyperglycemia. The first line of therapy is usually metformin, since it does not increase weight and seems to have a beneficial effect on CVD mortality and risk factors. As T2DM progresses, insulin treatment becomes necessary for the majority of patients. The last few years have seen the development of long-acting, rapid-acting, and premixed insulin analog formulations. The treat-to-target algorithms of recent studies combining OADs plus insulin analogs have demonstrated that patients can reach glycemic treatment targets with low risk of hypoglycemia, greater convenience, and – with some analogs – limited weight gain vs conventional insulins. These factors may possibly have a positive influence on CVD risk. Future studies will hopefully elucidate the benefits of this approach.Keywords: diabetes mellitus, type 2 diabetes, cardiovascular disease, hyperglycemia, insulin, oral antidiabetic drugs

  16. Insulin som trickster

    DEFF Research Database (Denmark)

    Lassen, Aske Juul

    2011-01-01

    grænser nedbrydes i en konstant penetrering af huden, når blodsukkeret måles eller insulinen indsprøjtes. Insulin analyseres som en tricksterfigur, der udøver et grænsearbejde på kroppen, leger med dens kategorier og vender forholdet mellem gift og medicin, frihed og ufrihed, kunstighed og naturlighed...

  17. Visual analogue scale correlates of musculoskeletal fatigue.

    Science.gov (United States)

    Leung, Ada W S; Chan, Chetwyn C H; Lee, Alice H S; Lam, Keith W H

    2004-08-01

    Visual analogue scale has been shown to reflect subjective feelings but rarely has it been used for musculoskeletal fatigue so in the present study VAS ratings were used to quantify musculoskeletal fatigue. A total of 20 students underwent a fatigue protocol (M age=21.3 yr., SD= 1.0). A series of randomized external loads at 0, 5, 10, 15, 25, 35, and 50% of the maximum voluntary contraction was generated by the BTE Primus and applied at the distal end of the dominant arm, which was sustained at the 90 degrees forward flexion position. After 60 sec. of force exertion for each loading, the subject marked the scale to reflect their extent of fatigue at the shoulder muscle. Analysis showed fatigue scores were significantly correlated with the percentages of maximum load applied (r =.73, p validity of using a visual analogue scale as a measure of musculoskeletal fatigue requires further study, particularly for a low load.

  18. Insulin Resistance and Hypogonadism

    Directory of Open Access Journals (Sweden)

    Shahana Shermin

    2013-05-01

    Full Text Available Backgound: The number of hypogonads is increasing day by day. It may be due to sedentary life style with increased obesity, increased tension or stressed lifestyle among all groups of populations. Visceral obesity is associated with insulin resistance, diabetes mellitus and also with hypogonadism.Objective: This study was carried out to determine the proportion of insulin resistance among male subjects with hypogonadism in different age groups along with status of erectile quality among diabetics and non diabetics.Materials and method: This cross sectional study among 161 adult male subjects aged ≥ 20 to ≤ 60 years were purposively selected from Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrine and Metabolic Disorders (BIRDEM, Dhaka, Bangladesh between May 2009 to September 2010. Glycemic status and insulin resistance (by HOMA-R were done and relevant history were documented.Results: The highest proportion (38.9% of hypogonadism was in ≥ 50 years age group whereas highest proportion (39.6% of the eugonads was in the age group of 40 to 49 years. More than half of the hypogonad subjects had weak erectile quality (54.0% which were followed by absent erectile quality in 32.7% and 13.3% subjects had normal erectile quality. Among the eugonad subjects 41.7% had normal erectile quality, 41.6% subjects had weak erectile quality and 16.7% subjects had no erectile quality. More than ninety percent of the hypogonad subjects and about 60% of the eugonad subjects had insulin resistance. The average HOMA-R was more in the subjects with hypogonadism with diabetes which was highly significant (p-value < 0.001.Conclusion: Hypogonadism is associated with insulin resistance.

  19. Synthesis of rosmarinic acid analogues in Escherichia coli.

    Science.gov (United States)

    Zhuang, Yibin; Jiang, Jingjie; Bi, Huiping; Yin, Hua; Liu, Shaowei; Liu, Tao

    2016-04-01

    To produce rosmarinic acid analogues in the recombinant Escherichia coli BLRA1, harboring a 4-coumarate: CoA ligase from Arabidopsis thaliana (At4CL) and a rosmarinic acid synthase from Coleus blumei (CbRAS). Incubation of the recombinant E. coli strain BLRA1 with exogenously supplied phenyllactic acid (PL) and analogues as acceptor substrates, and coumaric acid and analogues as donor substrates led to production of 18 compounds, including 13 unnatural RA analogues. This work demonstrates the viability of synthesizing a broad range of rosmarinic acid analogues in E. coli, and sheds new light on the substrate specificity of CbRAS.

  20. Relapsing insulin-induced lipoatrophy, cured by prolonged low-dose oral prednisone: a case report

    Directory of Open Access Journals (Sweden)

    Chantelau Ernst A

    2011-12-01

    Full Text Available Abstract Introduction Circumscript, progressing lipoatrophy at the insulin injection sites is an unexplained, however rare condition in diabetes mellitus. Case presentation We report a case of severe localised lipoatrophy developing during insulin pump-treatment (continuous subcutaneous insulin infusion with the insulin analogue lispro (Humalog® in a woman with type-1 diabetes mellitus. After 11 months of progressing lipoatrophy at two spots on the abdomen, low-dose prednisone (5-10 mg p.o. was given at breakfast for 8 months, whereby the atrophic lesions centripetally re-filled with subcutaneous fat tissue (confirmed by MRI despite ongoing use of insulin lispro. However, 4 weeks after cessation of prednisone, lipoatrophy relapsed, but resolved after another 2 months of low-dose prednisone. No further relapse was noted during 12 months of follow-up on insulin-pump therapy with Humalog®. Conclusion Consistent with an assumed inflammatory nature of the condition, low-dose oral prednisone appeared to have cured the lipoatrophic reaction in our patient. Our observation suggests a temporary intolerance of the subcutaneous fat tissue to insulin lispro (Humalog®, triggered by an unknown endogenous mechanism.

  1. Effect of experimental diabetes and insulin replacement on intestinal metabolism and excretion of 4-nitrophenol in rats.

    Science.gov (United States)

    Fischer, Emil; Almási, Attila; Bojcsev, Sztojan; Fischer, Tamás; Kovács, Noémi Piroska; Perjési, Pál

    2015-06-01

    Luminal appearance of 4-nitrophenol (PNP) metabolites (4-nitrophenol-β-glucuronide (PNP-G) and 4-nitrophenol-sulfate (PNP-S)) and activity of the related metabolic enzymes have been investigated in control and experimental diabetic rats. Experimental diabetes was induced by administration of streptozotocin (65 mg/kg i.v.). PNP (500 μmol/L) was luminally perfused in the small intestine and the metabolites were determined in the perfusion solution. Effect of insulin replacement was also investigated in the diabetic rats. It was found that experimental diabetes increased the luminal appearance of PNP-G, which could be completely compensated by rapid-acting insulin administration (1 U/kg i.v.). Activities of the enzymes involved in PNP-G production (UDP-glucuronyltransferase and β-glucuronidase) were also elevated; however, these changes were only partially compensated by insulin. Luminal appearance of PNP-S was not significantly changed by administration of streptozotocin and insulin. Activities of the enzymes of PNP-S production (sulfotransferases and arylsulfatases) did not change in the diabetic rats. The results indicate that experimental diabetes can provoke changes in intestinal drug metabolism. It increased intestinal glucuronidation of PNP but did not influence sulfate conjugation. No direct correlation was found between the changes of metabolic enzyme activities and the luminal appearance of the metabolites.

  2. Geometric Analogue of Holographic Reduced Representation

    OpenAIRE

    Aerts, Diederik; Czachor, Marek; De Moor, Bart

    2007-01-01

    Holographic reduced representations (HRR) are based on superpositions of convolution-bound $n$-tuples, but the $n$-tuples cannot be regarded as vectors since the formalism is basis dependent. This is why HRR cannot be associated with geometric structures. Replacing convolutions by geometric products one arrives at reduced representations analogous to HRR but interpretable in terms of geometry. Variable bindings occurring in both HRR and its geometric analogue mathematically correspond to two ...

  3. Analogues of Euler and Poisson summation formulae

    Indian Academy of Sciences (India)

    R. Narasimhan (Krishtel eMaging) 1461 1996 Oct 15 13:05:22

    Their results are similar to our results for. ∑ aanalogues of.

  4. The Brookhaven electron analogue, 1953--1957

    Energy Technology Data Exchange (ETDEWEB)

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  5. Electromagnetic wave analogue of electronic diode

    OpenAIRE

    Shadrivov, Ilya V.; Powell, David A.; Kivshar, Yuri S.; Fedotov, Vassili A.; Zheludev, Nikolay I.

    2010-01-01

    An electronic diode is a nonlinear semiconductor circuit component that allows conduction of electrical current in one direction only. A component with similar functionality for electromagnetic waves, an electromagnetic isolator, is based on the Faraday effect of the polarization state rotation and is also a key component of optical and microwave systems. Here we demonstrate a chiral electromagnetic diode, which is a direct analogue of an electronic diode: its functionality is underpinned by ...

  6. Analogue forecasting of New Zealand climate anomalies

    Science.gov (United States)

    Mullan, A. Brett; Thompson, Craig S.

    2006-03-01

    An analogue forecast scheme is described for multifield prediction of monthly and seasonal New Zealand climate anomalies on the basis of the methodology of Livezey and Barnston ([1988]) for US seasonal temperatures. The method is applied to predicting terciles of temperature and precipitation for six regions of New Zealand. Empirical orthogonal function analysis is used to reduce sea surface temperature and sea-level pressure predictors down to a set of five independent indices, which incorporate variations due to El Niño-Southern Oscillation, Indian Ocean sea temperatures and a wave 3 pattern in the Southern Hemisphere westerlies. A full bootstrap cross-validation procedure is carried out, along with Monte Carlo tests, to assess the skill of the method on independent data and to determine the significance of the results. Significant skill is found for seasonal temperature forecasts for the summer and winter seasons; there is less success in predicting monthly temperatures or rainfall at either timescale. Considerable care is required to constrain the climate state vector, from which analogues are defined, and to constrain the search procedure itself, in order to produce results that are stable with respect to small parameter changes in the model. For the New Zealand region, 5 to 7 is found to be the optimum number of closest analogues, and the inclusion of anti-analogues improves the predictions, at least in the seasonal case. Skill in predicting regional temperature and rainfall is shown to be related to a combination of skill in predicting sea-level pressure patterns and to how strongly these patterns project onto temperature and rainfall anomalies.

  7. Mammary Analogue Secretory Carcinoma Mimicking Salivary Adenoma

    OpenAIRE

    Williams, Lindsay; Chiosea, Simion I.

    2013-01-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor characterized by ETV6 translocation. It appears that prior studies have identified MASC by reviewing salivary gland carcinomas, such as acinic cell carcinoma and adenocarcinoma, not otherwise specified. To address the possibility of MASC mimicking benign salivary neoplasms we reviewed 12 salivary gland (cyst)adenomas diagnosed prior to the discovery of MASC. One encapsulated (cyst)adenoma of the parotid g...

  8. New developments in insulin delivery.

    Science.gov (United States)

    Khan Ghilzai, Naushad M

    2003-03-01

    A vigorous research effort has been undertaken worldwide to replace injectable insulin by a more comfortable and painless delivery method. Several routes have been explored for their suitability with respect to insulin degradation in the human body. Considerable progress has been made in achieving the common goal for a convenient and equally effective insulin delivery. This article reviews the different routes available for insulin administration and the many successful developments that have been made in recent years for improving that particular route for a much better insulin delivery.

  9. Adipokines and Hepatic Insulin Resistance

    Science.gov (United States)

    Hassan, Waseem

    2013-01-01

    Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipose tissue is now considered to be an active endocrine organ that secretes various adipokines such as adiponectin, leptin, resistin, tumour necrosis factor-α, and interleukin-6. Recent studies have shown that these factors might provide a molecular link between increased adiposity and impaired insulin sensitivity. Since hepatic insulin resistance plays the key role in the whole body insulin resistance, clarification of the regulatory processes about hepatic insulin resistance by adipokines in rodents and human would seem essential in order to understand the mechanism of type 2 diabetes and for developing novel therapeutic strategies to treat it. PMID:23762871

  10. Dendrimers as nanocarriers for nucleoside analogues.

    Science.gov (United States)

    Gorzkiewicz, Michał; Klajnert-Maculewicz, Barbara

    2017-05-01

    Dendrimers constitute a class of hyperbranched macromolecules with several potential applications due to their unique properties such as a well-defined structure, multivalency and biocompatibility. These polymers became one of the most promising drug nanocarriers, providing improved solubility of therapeutics, high loading capacity and controllable biodistribution pattern. In addition, the use of dendrimers as drug delivery devices in cancer therapies may help to overcome the resistance mechanisms by transporting activated drug molecules directly to cancer cells. In the recent years, dendrimers were intensively studied for delivery of nucleoside analogues (NAs), essential elements of antiviral therapies, as well as treatments of leukemia, lymphoma and various types of solid tumors. These agents act as antimetabolites, competing with physiological nucleosides, and interacting with intracellular enzymes and nuclear acids to induce cytotoxicity. However, efficiency of NAs-based therapies is often limited by factors like fast metabolism, disadvantageous biodistribution, low solubility and various side effects. In case of treatment of leukemia, target cells usually develop drug resistance, which reduces the activity of nucleoside analogues even further. Thus, drug carrier systems are studied to improve the efficacy and specificity of action of these compounds. In this review, we summarize available data concerning the possibility of application of dendrimers as delivery devices for nucleoside analogues and their active, triphosphate forms. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Selective Insulin Resistance in Adipocytes*

    Science.gov (United States)

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  12. Insulin resistance and chronic inflammation

    Directory of Open Access Journals (Sweden)

    Natalia Matulewicz

    2016-12-01

    Full Text Available Insulin resistance is a condition of reduced biological response to insulin. Growing evidence indicates the role of the chronic low-grade inflammatory response in the pathogenesis of insulin resistance. Adipose tissue in obesity is characterized by increased lipolysis with the excessive release of free fatty acids, and is also a source of proinflammatory cytokines. Both these factors may inhibit insulin action. Proinflammatory cytokines exert their effect by stimulating major inflammatory NFκB and JNK pathways within the cells. Inflammatory processes in other insulin responsive tissues may also play a role in inducing insulin resistance. This paper is an overview of the chronic low-grade inflammation in adipose tissue, skeletal muscle, liver and endothelial cells during the development of insulin resistance.

  13. Periodontal disease decreases insulin sensitivity and insulin signaling.

    Science.gov (United States)

    Colombo, Natalia H; Shirakashi, Daisy J; Chiba, Fernando Y; Coutinho, Maria Sara de Lima; Ervolino, Edilson; Garbin, Cléa Adas Saliba; Machado, Ubiratan Fabres; Sumida, Doris H

    2012-07-01

    The purpose of this study is to investigate whether local inflammatory events, such as periodontal disease, are able to increase tumor necrosis factor-alpha (TNF-α) plasmatic concentration and decrease insulin sensitivity and insulin signaling in non-diabetic rats. Forty-eight male Wistar rats (2 months old) were divided into two groups, with either ligature-induced periodontal disease (LPD) or control conditions (CN). Experiments were performed in both groups 28 days after ligature placement. Plasmatic concentration of glycemia and TNF-α (n = 10) were analyzed by the glucose oxidase and enzyme-linked immunosorbent assay method, respectively. Insulin sensitivity (n = 7) was measured using the insulin tolerance test. Insulin signal transduction (n = 7) was measured by pp185 tyrosine phosphorylation status in insulin-sensitive tissues using the Western blotting method. The LPD group showed decreased insulin sensitivity (P 0.05). TNF-α plasmatic concentration was higher in LPD rats compared to CN rats. In addition, a decrease in the pp185 tyrosine phosphorylation status was observed after insulin stimulus in both white adipose and skeletal muscle tissues of the LPD group compared with the CN group. LPD is able to cause alterations to both insulin signaling and insulin sensitivity, probably because of the elevation of TNF-α plasmatic concentration. Thus, the present results emphasize the importance of the prevention of local inflammatory diseases, such as periodontitis, to prevent diabetes mellitus.

  14. Synthesis and biological assay of erlotinib analogues and BSA-conjugated erlotinib analogue.

    Science.gov (United States)

    Boobalan, Ramalingam; Liu, Kuang-Kai; Chao, Jui-I; Chen, Chinpiao

    2017-04-15

    A series of erlotinib analogues that have structural modification at 6,7-alkoxyl positions is efficiently synthesized. The in vitro anti-tumor activity of synthesized compounds is studied in two non-small cell lung cancer (NSCLC) cell lines (A549 and H1975). Among the synthesized compounds, the iodo compound 6 (ETN-6) exhibits higher anti-cancer activity compared to erlotinib. An efficient method is developed for the conjugation of erlotinib analogue-4, alcohol compound, with protein, bovine serum albumin (BSA), via succinic acid linker. The in vitro anti-tumor activity of the protein attached erlotinib analogue, 8 (ETN-4-Suc-BSA), showed stronger inhibitory activity in both A549 and H1975 NSCLC cell lines. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Analogue to Digital and Digital to Analogue Converters (ADCs and DACs): A Review Update

    CERN Document Server

    Pickering, J.

    2015-06-15

    This is a review paper updated from that presented for CAS 2004. Essentially, since then, commercial components have continued to extend their performance boundaries but the basic building blocks and the techniques for choosing the best device and implementing it in a design have not changed. Analogue to digital and digital to analogue converters are crucial components in the continued drive to replace analogue circuitry with more controllable and less costly digital processing. This paper discusses the technologies available to perform in the likely measurement and control applications that arise within accelerators. It covers much of the terminology and 'specmanship' together with an application-oriented analysis of the realisable performance of the various types. Finally, some hints and warnings on system integration problems are given.

  16. Insulin and Glucagon

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Holland, William; Gromada, Jesper

    2017-01-01

    In August 2016, several leaders in glucagon biology gathered for the European Association for the Study of Diabetes Hagedorn Workshop in Oxford, England. A key point of discussion focused on the need for basal insulin to allow for the therapeutic benefit of glucagon blockade in the treatment...... of diabetes. Among the most enlightening experimental results presented were findings from studies in which glucagon receptor-deficient mice were administered streptozotocin to destroy pancreatic β cells or had undergone diphtheria toxin-induced β cell ablation. This article summarizes key features...... of the discussion as a consensus was reached. Agents that antagonize glucagon may be of great benefit for the treatment of diabetes; however, sufficient levels of basal insulin are required for their therapeutic efficacy....

  17. [Insulin-requiring diabetes].

    Science.gov (United States)

    Leutenegger, M; Gross, A; Ostermann, G; Grulet, H; Pasqual, C; Dijoux, B

    1988-01-01

    The insulinorequiring diabetes is a notion which deserves a clear definition, essentially clinical, because it covers a wide range of physiopathological situations. The progressive degradation of Diabetes type II means a progressive discrepancy of insulinosecretion and above all an increase of insulinoresistance. The noxious part of chronical hyperglycemia is at present well known. The present therapeutical prospects tend to delay or limit insulinotherapy, by trying to obtain remission of insulinorequiring and some attempt to give a combined treatment associating insulin and hypoglycemic drugs.

  18. Insulin resistance in obesity can be reliably identified from fasting plasma insulin

    NARCIS (Netherlands)

    ter Horst, K. W.; Gilijamse, P. W.; Koopman, K. E.; de Weijer, B. A.; Brands, M.; Kootte, R. S.; Romijn, J. A.; Ackermans, M. T.; Nieuwdorp, M.; Soeters, M. R.; Serlie, M. J.

    2015-01-01

    Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely

  19. The Greenland analogue project. Yearly report 2010

    Energy Technology Data Exchange (ETDEWEB)

    Harper, J.; Brinkerhoff, D.; Johnson, J. [University of Montana, Missoula (United States); Ruskeeniemi, T.; Engstroem, J.; Kukkonen, I. [Geological Survey of Finland (Finland)] [and others

    2012-04-15

    A four-year field and modelling study of the Greenland ice sheet and subsurface conditions, Greenland Analogue Project (GAP), has been initiated collaboratively by SKB, Posiva and NWMO to advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository. The study site encompasses a land terminus portion of the Greenland ice sheet, east of Kangerlussuaq, and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project begins in 2009 and is scheduled for completion in 2012. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with cold climate conditions and glacial cycles, and their impact on the long-term performance of deep geological repositories for spent nuclear fuel, will be significantly improved by studying a modern analogue. The GAP will conduct the first in situ investigations of some of the parameters and processes needed to achieve a better understanding of how an ice sheet may impact a deep repository, and will provide measurements, observations and data that may significantly improve our safety assessments and risk analyses of glaciation scenarios. This report was produced by the GAP team members and presents an overview of the activities within the GAP during the interval January 1 to December 31, 2010, as well as research results obtained during this time frame. Research for the GAP is ongoing, and additional results related to the data presented here may become available in the future and will be presented in subsequent annual reports. (orig.)

  20. Satellite television analogue and digital reception techniques

    CERN Document Server

    Benoit, Herve

    1999-01-01

    Satellite television is part of the lives of millions of television viewers worldwide and its influence is set to increase significantly with the launch of digital satellite television services.This comprehensive reference book, written by the author of the highly successful 'Digital Television', provides a technical overview of both analogue and digital satellite TV. Written concisely and thoroughly, it covers all aspects of satellite TV necessary to understand its operation and installation. It also covers the evolution of satellite television, and contains a detailed glossary of tec

  1. Somatostatin analogue scintigraphy in granulomatous diseases

    Energy Technology Data Exchange (ETDEWEB)

    Vanhagen, P.M. (Dept. of Internal Medicine 3, Dijkzigt Univ. Hospital, Rotterdam (Netherlands) Dept. of Immunology, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Krenning, E.P. (Dept. of Internal Medicine 3, Dijkzigt Univ. Hospital, Rotterdam (Netherlands) Dept. of Nuclear Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Reubi, J.C. (Inst. of Pathology, Bern Univ. (Switzerland)); Kwekkeboom, D.J. (Dept. of Nuclear Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Bakker, W.H. (Dept. of Nuclear Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Mulder, A.H. (Dept. of Pathology, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Laissue, I. (Inst. of Pathology, Bern Univ. (Switzerland)); Hoogstede, H.C. (Dept. of Chest Medicine, Dijkzigt Univ. Hospital, Rotterdam (Netherlands)); Lamberts, S.W.J. (Dept. of Internal Medicine 3, Dijkzigt Univ. Hospital, Rotterdam (Netherlands))

    1994-06-01

    In the present study 20 consecutive patients were investigated, 12 with sarcoidosis, one with both sarcoidosis and aspergillosis, four with tuberculosis and three with Wegener's granulomatosis. For in vivo SS-R imaging, total-body scintigraphy was performed 24 and 48 h after the administration of [sup 111]In-octreotide. Granuloma localizations could be visualized in all patients studied; additional sites were found in nine patients with sarcoidosis and in two patients with tuberculosis. In vitro autoradiography of fresh tissue biopsies, using the SS analogue [[sup 125]I-Tyr[sup 3

  2. Analogue holographic correspondence in optical metamaterials

    Science.gov (United States)

    Khveshchenko, D. V.

    2015-03-01

    We assess the prospects of using metamaterials for simulating various aspects of analogue gravity and holographic correspondence. Albeit requiring a careful engineering of the dielectric media, some hallmark features reminiscent of the hypothetical “generalized holographic conjecture” can be detected by measuring non-local optical field correlations. The possibility of such simulated behavior might also shed light on the true origin of those ostensibly holographic phenomena in the condensed-matter systems with emergent effective metrics which may not, in fact, require any reference to the string-theoretical holography.

  3. Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages

    Directory of Open Access Journals (Sweden)

    C. Guo

    Full Text Available Glucagon-like peptide 1 (GLP-1, a kind of gut hormone, is used in the treatment of type 2 diabetes (T2D. Emerging evidence indicates that GLP-1 has anti-inflammatory activity. Chronic inflammation in the adipose tissue of obese individuals is a cause of insulin resistance and T2D. We hypothesized that GLP-1 analogue therapy in patients with T2D could suppress the inflammatory response of macrophages, and therefore inhibit insulin resistance. Our results showed that GLP-1 agonist (exendin-4 not only attenuated macrophage infiltration, but also inhibited the macrophage secretion of inflammatory cytokines including TNF-β, IL-6, and IL-1β. Furthermore, we observed that lipopolysaccharide (LPS-induced macrophage conditioned media could impair insulin-stimulated glucose uptake. This effect was compensated by treatment with the conditioned media from macrophages treated with the combination of LPS and exendin-4. It was also observed that exendin-4 directly inhibited the activation of NF-κB in macrophages. In conclusion, our results indicated that GLP-1 improved inflammatory macrophage-derived insulin resistance by inhibiting NF-κB pathway and secretion of inflammatory cytokines in macrophages. Furthermore, our observations suggested that the anti-inflammatory effect of GLP-1 on macrophages can contribute to GLP-1 analogue therapy of T2D.

  4. Insulin Resistance, Hyperglycemia, and Atherosclerosis

    OpenAIRE

    Bornfeldt, Karin E.; Tabas, Ira

    2011-01-01

    Progress in preventing atherosclerotic coronary artery disease (CAD) has been stalled by the epidemic of type 2 diabetes. Further advances in this area demand a thorough understanding of how two major features of type 2 diabetes, insulin resistance and hyperglycemia, impact atherosclerosis. Insulin resistance is associated with systemic CAD risk factors, but increasing evidence suggests that defective insulin signaling in atherosclerotic lesional cells also plays an important role. The role o...

  5. Long-term efficacy of insulin glargine therapy with an educational programme in type 1 diabetes patients in clinical practice.

    Science.gov (United States)

    Schreiber, Stephan A; Russmann, Anika

    2007-12-01

    To investigate the effect of initiating insulin glargine (glargine: LANTUS), a once-daily basal insulin analogue, plus an educational programme, on glycaemic control and body weight in patients with type 1 diabetes in clinical practice. A retrospective analysis of the medical records of 65 patients (mean age: 40.7 +/- 13.3 years) with type 1 diabetes was performed. Patients had previously been treated with NPH insulin (NPH; n = 54) or NPH insulin + lente insulin (NPH + lente; n = 11) and then received glargine once daily (bedtime), plus short-acting prandial insulin, for 30 months. Before initiation of glargine, patients participated in a diabetes educational programme and then received physician consultations throughout the study. Metabolic control, body weight and severe hypoglycaemia data were analysed at 9 and 30 months. Following initiation of glargine, patients showed a decrease in HbA(1c) from 7.29 +/- 1.1% to 7.06 +/- 1.0%; p weight was observed in the overall group. No episodes of severe hypoglycaemia (blood glucose weight gain versus previous treatment with NPH insulin or insulin lente. Further studies in a larger cohort of patients would help to confirm these results.

  6. Effect of octreotide on plasma concentrations of glucose, insulin, glucagon, growth hormone, and cortisol in healthy dogs and dogs with insulinoma

    NARCIS (Netherlands)

    Robben, J.H.; Brom, W.E. van den; Mol, J.A.; Haeften, T.W. van; Rijnberk, A.

    2006-01-01

    The inhibitory effect of the somatostatin analogue octreotide on the secretion of insulin could be used in the treatment of insulinoma. However, current information on the effectiveness of octreotide in dogs is conflicting. Therefore, the endocrine effects of a single subcutaneous dose of 50 lg

  7. Insulin Resistance and Mitochondrial Dysfunction.

    Science.gov (United States)

    Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

    2017-01-01

    Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

  8. Insulin Resistance and Mitochondrial Dysfunction

    DEFF Research Database (Denmark)

    Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

    2017-01-01

    Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glu......Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin...... of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion...... present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D....

  9. U.S. Nuclear Regulatory Commission natural analogue research program

    Energy Technology Data Exchange (ETDEWEB)

    Kovach, L.A.; Ott, W.R. [Nuclear Regulatory Commission, Washington, DC (United States)

    1995-09-01

    This article describes the natural analogue research program of the U.S. Nuclear Regulatory Commission (US NRC). It contains information on the regulatory context and organizational structure of the high-level radioactive waste research program plan. It also includes information on the conditions and processes constraining selection of natural analogues, describes initiatives of the US NRC, and describes the role of analogues in the licensing process.

  10. Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina

    2007-01-01

    The incretin hormones are intestinal peptides that enhance insulin secretion following ingestion of nutrients. Liraglutide is a glucagon-like peptide-1 receptor analogue, which is obtained by derivatising glucagon-like peptide-1 with a fatty acid, providing a compound with pharmacokinetic propert...... transient nausea and diarrhoea. This article reviews the mechanisms of action and efficacy of liraglutide for the treatment of Type 2 diabetes mellitus. This agent is presently in Phase III clinical development....... properties that are suitable for once-daily dosing. Liraglutide has demonstrated lasting improvement of HbA(1c )levels, weight reduction and improved beta-cell function in patients with Type 2 diabetes mellitus. Liraglutide is well tolerated; the adverse events that are most frequently reported being...

  11. Adiponectin, Leptin, and Leptin Receptor in Obese Patients with Type 2 Diabetes Treated with Insulin Detemir

    Directory of Open Access Journals (Sweden)

    Paweł Olczyk

    2017-07-01

    Full Text Available The aim of the present study is to quantitatively assess the expression of selected regulatory molecules, such as leptin, leptin receptor, and adiponectin in the blood of obese patients with type 2 diabetes both before treatment and after six months of pharmacological therapy with the long-lasting insulin analogue, insulin detemir. A significant decrease in the analysed regulatory molecules, i.e., leptin receptor and adiponectin, was found in blood plasma of the patients with untreated type 2 diabetes. These changes were accompanied by an increase in plasma leptin concentrations. Insulin treatment resulted in the normalization of plasma leptin receptor and adiponectin concentrations. The circulating leptin level did not change following anti-diabetic therapy with insulin detemir. Gender was a significant factor modifying the circulating level of all the analysed regulatory active compounds. Bioinformatic analysis was performed using Matlab with the Signal Processing Toolbox. The conducted discriminant analysis revealed that the leptin receptor, Δw(19, and adiponectin, Δw(21, were the parameters undergoing the most significant quantitative changes during the six-month therapy with insulin detemir. The conducted examinations indicated the contribution of adipocytokines—the biologically-active mediators of systemic metabolism, such as leptin and adiponectin in the pathomechanism of disorders being the basis for obesity which leads to development of insulin resistance, which, in turn, results in the occurrence of type 2 diabetes.

  12. Long-term predictions using natural analogues

    Energy Technology Data Exchange (ETDEWEB)

    Ewing, R.C. [Univ. of New Mexico, Albuquerque, NM (United States)

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  13. Ways to Optimize Analogue Switched Circuits

    Directory of Open Access Journals (Sweden)

    J. Hospodka

    2008-12-01

    Full Text Available This paper describes how analogue switched circuits (switched-capacitor and switched-current circuits can be optimized by means of a personal computer. The optimization of this kind of circuits is not so common and their analysis is more difficult in comparison with continuously working circuits. Firstly, the nonidealities occurring in these circuits whose effect on their characteristics should be optimized are discussed. Then a few ways to analyze analogue switched circuits are shown. From all optimization algorithms applicable for this kind of optimization, two ones that seem to be the most promising are proposed. The differential evolution (one of evolutionary algorithms combined with the simplex method was found to be most appropriate from these two ones. Two types of programs are required for the optimization of these circuits: a program for implementing calculations of the used optimization algorithm and a program for the analysis of the optimized circuit. Several suitable computer programs from both of the groups together with their proper settings according to authors’ experience are proposed. At the end of the paper, an example of a switched-current circuit optimization documenting the previous description is presented.

  14. Insulin Plays a Permissive Role for the Vasoactive Effect of GIP Regulating Adipose Tissue Metabolism in Humans

    DEFF Research Database (Denmark)

    Asmar, Meena; Simonsen, Lene; Asmar, Ali

    2016-01-01

    of insulin for the vasoactive effect of GIP in adipose tissue metabolism and whether the vasodilatory effect of GIP is dependent on C-peptide. METHODS: Six lean healthy subjects were studied. The sc abdominal adipose tissue metabolism was assessed by Fick's principle during GIP infusion (1.5 pmol....../kg/min) in combination with 1) euglycemic-high insulinemic clamp (Eugluc-Hiinsu), raising plasma insulin concentrations to postprandial levels, 2) hyperglycemic-euinsulinemic clamp (Hygluc-Euinsu), and 3) hyperglycemic-hyperinsulinemic clamp, raising plasma insulin concentrations to supraphysiological levels. During...... the hyperglycemic clamps, endogenous insulin and C-peptide secretion were inhibited by infusion of the somatostatin analogue octreotide. RESULTS: During GIP infusion, Eugluc-Hiinsu, and hyperglycemic-hyperinsulinemic clamps, sc abdominal adipose tissue blood flow (ATBF) was similar and increased from 2.1 ± 0...

  15. Synthesis of Patulin and Its Cyclohexane Analogue from Furan Derivatives

    National Research Council Canada - National Science Library

    Masahiro TADA; Kazuhisa OHTSU; Kazuhiro CHIBA

    1994-01-01

      Patulin, a mycotoxin from fungi of Penicillium and Aspergillis species, and its cyclohexane analogue were synthesized concisely via oxidation of furan derivatives, followed by cyclization to give...

  16. Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

    Science.gov (United States)

    Zeng, Yi; Zhang, Le; Hu, Zhiping

    2016-01-01

    Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

  17. The evolutionary benefit of insulin resistance

    NARCIS (Netherlands)

    Soeters, Maarten R.; Soeters, Peter B.

    2012-01-01

    Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in

  18. Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

    Directory of Open Access Journals (Sweden)

    Dhindsa G

    2004-04-01

    Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

  19. Insulin therapy and dietary adjustments to normalize glycemia and prevent nocturnal hypoglycemia after evening exercise in type 1 diabetes: a randomized controlled trial.

    Science.gov (United States)

    Campbell, Matthew D; Walker, Mark; Bracken, Richard M; Turner, Daniel; Stevenson, Emma J; Gonzalez, Javier T; Shaw, James A; West, Daniel J

    2015-01-01

    Evening-time exercise is a frequent cause of severe hypoglycemia in type 1 diabetes, fear of which deters participation in regular exercise. Recommendations for normalizing glycemia around exercise consist of prandial adjustments to bolus insulin therapy and food composition, but this carries only short-lasting protection from hypoglycemia. Therefore, this study aimed to examine the impact of a combined basal-bolus insulin dose reduction and carbohydrate feeding strategy on glycemia and metabolic parameters following evening exercise in type 1 diabetes. Ten male participants (glycated hemoglobin: 52.4±2.2 mmol/mol), treated with multiple daily injections, completed two randomized study-days, whereby administration of total daily basal insulin dose was unchanged (100%), or reduced by 20% (80%). Participants attended the laboratory at ∼08:00 h for a fasted blood sample, before returning in the evening. On arrival (∼17:00 h), participants consumed a carbohydrate meal and administered a 75% reduced rapid-acting insulin dose and 60 min later performed 45 min of treadmill running. At 60 min postexercise, participants consumed a low glycemic index (LGI) meal and administered a 50% reduced rapid-acting insulin dose, before returning home. At ∼23:00 h, participants consumed a LGI bedtime snack and returned to the laboratory the following morning (∼08:00 h) for a fasted blood sample. Venous blood samples were analyzed for glucose, glucoregulatory hormones, non-esterified fatty acids, β-hydroxybutyrate, interleukin 6, and tumor necrosis factor α. Interstitial glucose was monitored for 24 h pre-exercise and postexercise. Glycemia was similar until 6 h postexercise, with no hypoglycemic episodes. Beyond 6 h glucose levels fell during 100%, and nine participants experienced nocturnal hypoglycemia. Conversely, all participants during 80% were protected from nocturnal hypoglycemia, and remained protected for 24 h postexercise. All metabolic

  20. Intradermal Insulin Delivery

    Science.gov (United States)

    Hultström, Michael; Roxhed, Niclas

    2014-01-01

    The incidence of insulinopenic diabetes mellitus is constantly increasing, and in addition, approximately a third of all hyperinsulinemic diabetic patients develop insulinopenia. Optimal glycemic control is essential to minimize the risk for diabetes-induced complications, but the majority of diabetic patients fail to achieve proper long-term glucose levels even in clinical trials, and even more so in clinical practice. Compliance with a treatment regimen is likely to be higher if the procedure is simple, painless, and discreet. Thus, insulin has been suggested for nasal, gastrointestinal, and inhalation therapy, but so far with considerable downsides in effect, side effects, or patient acceptance. The stratum corneum is the main barrier preventing convenient drug administration without the drawbacks of subcutaneous injections. Recently, devices with miniaturized needles have been developed that combine the simplicity and discretion of patch-based treatments, but with the potential of peptide and protein administration. As this review describes, initial comparisons with subcutaneous administration now suggest microneedle patches for active insulin delivery are efficient in maintaining glycemic control. Hollow microneedle technology could also prove to be efficient in systemic as well as local delivery of other macromolecular drugs, such as vaccines. PMID:24876605

  1. Slip dynamics in an analogue faultzone

    Science.gov (United States)

    Rudolf, Michael; Rosenau, Matthias; Oncken, Onno

    2017-04-01

    Elastic stress in the lithosphere releases through slip along pre-existing planes of weakness (fault zones). Slip events may occur on many spatial and temporal scales. They range from short-term localised seismic slip (earthquakes) to aseismic slip transients and long-term distributed slip in cataclastic or ductile shear zones. The interplay of seismic and aseismic fault slip is poorly understood, potentially complex and very costly to model numerically. Therefore, we designed an analogue experiment using a rate-and-state frictional material (fused glass beads), that shows unstable (seismic) and stable (aseismic) slip. This is embedded in an elastic material (ballistic gelatin) that models upper crustal elastic rebound. In the analogue model presented here, we examine the influence of multiple parameters on the slip dynamics and overall statistics of ruptures within a glass bead shear zone. We use a customised rotary shear apparatus (Schulze ring-shear tester) to monitor shear stress during shear. The apparatus allows a direct control of shear rate and normal stress. Its transparent lid enables concurrent monitoring of the frictional contact surface. Digital image correlation is used to measure on-fault deformation. Because of the rate-and-state frictional properties of glass beads (a-b = -0.0138), the used setup produces regular stick-slip events under certain normal loading and strain rate conditions. Preliminary analysis shows the following: The events feature statistics similar to natural slip systems, i.e. a magnitude distribution similar to single faults. Estimated moment magnitudes of the laboratory earthquakes range from MW = -7 to -6. A Gutenberg-Richter like decay up to a certain corner magnitude followed by a characteristic peak is observable. With decreasing loading rate the recurrence time and size of events increase exponentially with exponents similar to natural events. Rupture dynamics are characterised by a transition from two-dimensional crack

  2. Space Analogue Environments: Are the Populations Comparable?

    Science.gov (United States)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that

  3. Insulin Signaling and Heart Failure

    Science.gov (United States)

    Riehle, Christian; Abel, E. Dale

    2016-01-01

    Heart failure is associated with generalized insulin resistance. Moreover, insulin resistant states such as type 2 diabetes and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes alters the systemic and neurohumoral milieu leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead (FOXO) transcriptional signaling or glucose transport which may also impair cardiac metabolism, structure and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed. PMID:27034277

  4. The cardiovascular effects of insulin.

    Science.gov (United States)

    Younk, Lisa M; Lamos, Elizabeth M; Davis, Stephen N

    2014-07-01

    Cardiovascular disease remains one of the leading causes of morbidity and mortality in diabetes mellitus. A causal link between insulin, atherosclerosis and cardiovascular risk has been investigated at the basic science level and studied in large clinical trials. The cardiovascular actions of insulin and its role at the level of the endothelium will be reviewed. Cardiovascular outcomes in several large diabetes trials where insulin management was prominent will be summarized. The vascular actions of insulin are complex and mediated primarily via nitric oxide and endothelin-1. It appears that insulin resistance, rather than hyperinsulinemia itself, increases cardiovascular risk. In fact, hyperinsulinemia in the setting of normal beta cell function protects obese and insulin-resistant individuals from type 2 diabetes. Large clinical trials have supported that insulin management is not associated with increased adverse outcomes. A multifactorial approach targeting modifiable risk factors, including smoking cessation, blood pressure and lipid management, reduces cardiovascular risk. Therapy goals should be individualized and hypoglycemia, especially in individuals receiving insulin management, should be strictly avoided.

  5. Gravitational analogue of the Witten effect

    Energy Technology Data Exchange (ETDEWEB)

    Foda, O. (International Centre for Theoretical Physics, Trieste (Italy))

    1985-07-22

    In the presence of massive fermions, and assuming a non-vanishing theta-parameter as the only source of CP violation, the Witten effect (a shift in the electric charge of a magnetic monopole due to CP non-conservation) is shown to follow from an anomalous chiral commutator. Next, given the gravitational contribution to the chiral anomaly, the corresponding anomalous commutator for Dirac fermion currents in a gravitational background is derived. From that, we infer the equivalence of a thetaR tildeR term in the lagrangian to a shift in the mass parameter of the NUT metric, in proportion to theta. This is interpreted as the gravitational analogue of the Witten effect. Its relevance to certain Kaluza-Klein monopoles is briefly discussed.

  6. Synthesis and Characterization of Urofuranoic Acids: In Vivo Metabolism of 2-(2-Carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic Acid (CMPF) and Effects on in Vitro Insulin Secretion.

    Science.gov (United States)

    Nagy, Edith; Liu, Ying; Prentice, Kacey J; Sloop, Kyle W; Sanders, Phillip E; Batchuluun, Battsetseg; Hammond, Craig D; Wheeler, Michael B; Durham, Timothy B

    2017-03-09

    CMPF (2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid) is a metabolite that circulates at high concentrations in type 2 and gestational diabetes patients. Further, human clinical studies suggest it might have a causal role in these diseases. CMPF inhibits insulin secretion in mouse and human islets in vitro and in vivo in rodents. However, the metabolic fate of CMPF and the relationship of structure to effects on insulin secretion have not been significantly studied. The syntheses of CMPF and analogues are described. These include isotopically labeled molecules. Study of these materials in vivo has led to the first observation of a metabolite of CMPF. In addition, a wide range of CMPF analogues have been prepared and characterized in insulin secretion assays using both mouse and human islets. Several molecules that influence insulin secretion in vitro were identified. The molecules described should serve as interesting probes to further study the biology of CMPF.

  7. Black Hole Analogue in Bose–Einstein Condensation

    Indian Academy of Sciences (India)

    Abstract. We have proposed a black hole analogue in a Bose–Einstein condensation. By introducing the Painlevé co-ordinates and using K–G equations, we have obtained the critical temperature of the black hole analogue in a Bose–Einstein condensation.

  8. Dipeptide analogues containing 4-ethoxy-3-pyrrolin-2-ones

    DEFF Research Database (Denmark)

    Hosseini, Masood; Kringelum, Henriette; Murray, A.

    2006-01-01

    Pyrrolidine-2,4-diones (1) are naturally occurring analogues of amino acids. We herein present a facile synthesis of N-acylated, O-alkylated pyrrolin-2-ones (2) in high yield and excellent enantiopurity. Molecular mechanics calculations suggest that the resulting dipeptide analogues adopt a linea...

  9. An assessment of billing electricity consumers via analogue meters ...

    African Journals Online (AJOL)

    This paper assesses the perception of billing consumers via analogue meter in Kano Electricity Distribution Plc, Nigeria. Questionnaire survey was used to collect data from the consumers, frequency counts and percentages were used to analyze the generated data. The result of the study revealed that 38% of the Analogue ...

  10. MAQARIN natural analogue study: phase III

    Energy Technology Data Exchange (ETDEWEB)

    Alexander, W.R.; Mazurek, M.; Waber, H.N. [Univ. of Berne (Switzerland). Institutes of Geology, Mineralogy and Petrology, Rock-Water Interaction Group (GGWW); Arlinger, J.; Erlandson, A.C.; Hallbeck, L.; Pedersen, K. [Goeteborg Univ. (Sweden). Dept. of General and Marine Microbiology; Boehlmann, W.; Fritz, P.; Geyer, S.; Geyer, W.; Hanschman, G.; Kopinke, F.D.; Poerschmann, J. [Umweltforschungszentrum Leipzig-Halle (Germany); Chambers, A.V.; Haworth, A.; Ilett, D.; Linklater, C.M.; Tweed, C.J. [AEA Technology plc, Harwell (United Kingdom); Chenery, S.R.N.; Kemp, S.J.; Milodowski, A.E.; Pearce, J.M.; Reeder, S.; Rochelle, C.A.; Smith, B.; Wetton, P.D.; Wragg, J. [British Geological Survey, Keyworth (United Kingdom); Clark, I.D. [Univ. of Ottawa (Canada). Dept. of Geology; Hodginson, E.; Hughes, C.R. [Univ. of Manchester (United Kingdom). Dept. of Earth Sciences; Hyslop, E.K. [British Geological Survey, Edinburgh (United Kingdom); Karlsson, F. [Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden); Khoury, H.N.; Salameh, E. [Univ. of Jordan, Amman (Jordan); Lagerblad, B. [Cement Inst., Stockholm (Sweden); Longworth, G. [Univ. of Manchester (United Kingdom). Dept. of Geology; Pitty, A.F. [Private consultant, Norwich (United Kingdom); Savage, D. [QuantiSci Ltd, Melton Mowbray (United Kingdom); Smellie, J.A.T. [ed.] [Conterra AB, Uppsala (Sweden)

    1998-12-01

    This report represents the conclusion to Phase III of the Maqarin Natural Analogue Study. The main thrust was to establish the origin and chemistry of the Western Springs hyper alkaline groundwaters (Na/K enriched Ca(OH){sub 2} type) and to study their interaction with rocks of different compositions, as natural analogues to key processes that might occur at an early stage within the `alkali disturbed zone` of cementitious repositories in different host rocks. Whilst earlier studies at Maqarin were very much site-specific and process-oriented, Phase III provided a regional perspective to the geological evolution of the Maqarin region. This was made possible by greater field access which allowed a more systematic structural and geomorphological study of the area. This has resulted in a greater understanding of the age and spatial relationships concerning formation of the cement zones through spontaneous combustion of the Bituminous Marls, and the subsequent formation of high pH groundwaters at the Eastern and Western Springs locations. At the Western Springs locality, hydrochemical and hydrogeological evaluation of new and published data (plus access to unpublished data), together with detailed mineralogical and geochemical studies, helped to clarify the very earliest stage of cement leachate/host rock interaction. The data were used also to test coupled flow/transport codes developed to assess the long-term evolution of a cementitious repository. Additional objectives addressed include: a) rock matrix diffusion, b) the occurrence and chemical controls on zeolite composition, e) the occurrence and chemical controls on clay stability, and d) the role of microbes, organics and colloids in trace element transport. The Maqarin site now provides a consistent picture explaining the origin of the hyperalkaline groundwaters, and is therefore a unique location for the examination of the mechanisms and processes associated with cementitious repositories. Application of these

  11. Terrestrial analogues for lunar impact melt flows

    Science.gov (United States)

    Neish, C. D.; Hamilton, C. W.; Hughes, S. S.; Nawotniak, S. Kobs; Garry, W. B.; Skok, J. R.; Elphic, R. C.; Schaefer, E.; Carter, L. M.; Bandfield, J. L.; Osinski, G. R.; Lim, D.; Heldmann, J. L.

    2017-01-01

    Lunar impact melt deposits have unique physical properties. They have among the highest observed radar returns at S-Band (12.6 cm wavelength), implying that they are rough at the decimeter scale. However, they are also observed in high-resolution optical imagery to be quite smooth at the meter scale. These characteristics distinguish them from well-studied terrestrial analogues, such as Hawaiian pāhoehoe and ´a´ā lava flows. The morphology of impact melt deposits can be related to their emplacement conditions, so understanding the origin of these unique surface properties will help to inform us as to the circumstances under which they were formed. In this work, we seek to find a terrestrial analogue for well-preserved lunar impact melt flows by examining fresh lava flows on Earth. We compare the radar return and high-resolution topographic variations of impact melt flows to terrestrial lava flows with a range of surface textures. The lava flows examined in this work range from smooth Hawaiian pāhoehoe to transitional basaltic flows at Craters of the Moon (COTM) National Monument and Preserve in Idaho to rubbly and spiny pāhoehoe-like flows at the recent eruption at Holuhraun in Iceland. The physical properties of lunar impact melt flows appear to differ from those of all the terrestrial lava flows studied in this work. This may be due to (a) differences in post-emplacement modification processes or (b) fundamental differences in the surface texture of the melt flows due to the melts' unique emplacement and/or cooling environment. Information about the surface properties of lunar impact melt deposits will be critical for future landed missions that wish to sample these materials.

  12. MAQARIN natural analogue study: phase III

    Energy Technology Data Exchange (ETDEWEB)

    Alexander, W.R.; Mazurek, M.; Waber, H.N. [Univ. of Berne (Switzerland). Institutes of Geology, Mineralogy and Petrology, Rock-Water Interaction Group (GGWW); Arlinger, J.; Erlandson, A.C.; Hallbeck, L.; Pedersen, K. [Goeteborg University (Sweden). Dept. of General and Marine Microbiology; Boehlmann, W.; Fritz, P.; Geyer, S.; Geyer, W.; Hanschman, G.; Kopinke, F.D.; Poerschmann, J. [Umweltforschungszentrum Leipzig-Halle (Germany); Chambers, A.V.; Haworth, A.; Ilett, D.; Linklater, C.M.; Tweed, C.J. [AEA Technology plc, Harwell (United Kingdom); Chenery, S.R.N.; Kemp, S.J.; Milodowski, A.E.; Pearce, J.M.; Reeder, S.; Rochelle, C.A.; Smith, B.; Wetton, P.D.; Wragg, J. [British Geological Survey, Keyworth (United Kingdom); Clark, I.D. [Univ. of Ottawa (Canada). Dept. of Geology; Hodginson, E.; Hughes, C.R. [Univ. of Manchester (United Kingdom). Dept. of Earth Sciences; Hyslop, E.K. [British Geological Survey, Edinburgh (United Kingdom); Karlsson, F. [Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden); Khoury, H.N.; Salameh, E. [Univ. of Jordan, Amman (Jordan); Lagerblad, B. [Cement Institute, Stockholm (Sweden); Longworth, G. [Univ. of Manchester (United Kingdom). Dept. of Geology; Pitty, A.F. [Private consultant, Norwich (United Kingdom); Savage, D. [QuantiSci Ltd, Melton Mowbray (United Kingdom); Smellie, J.A.T. [ed.] [Conterra AB, Uppsala (Sweden)

    1998-12-01

    This report represents the conclusion to Phase III of the Maqarin Natural Analogue Study. The main thrust was to establish the origin and chemistry of the Western Springs hyper alkaline groundwaters (Na/K enriched Ca(OH){sub 2} type) and to study their interaction with rocks of different compositions, as natural analogues to key processes that might occur at an early stage within the `alkali disturbed zone` of cementitious repositories in different host rocks. Whilst earlier studies at Maqarin were very much site-specific and process-oriented, Phase III provided a regional perspective to the geological evolution of the Maqarin region. This was made possible by greater field access which allowed a more systematic structural and geomorphological study of the area. This has resulted in a greater understanding of the age and spatial relationships concerning formation of the cement zones through spontaneous combustion of the Bituminous Marls, and the subsequent formation of high pH groundwaters at the Eastern and Western Springs locations. At the Western Springs locality, hydrochemical and hydrogeological evaluation of new and published data (plus access to unpublished data), together with detailed mineralogical and geochemical studies, helped to clarify the very earliest stage of cement leachate/host rock interaction. The data were used also to test coupled flow/transport codes developed to assess the long-term evolution of a cementitious repository. Additional objectives addressed include: a) rock matrix diffusion, b) the occurrence and chemical controls on zeolite composition, e) the occurrence and chemical controls on clay stability, and d) the role of microbes, organics and colloids in trace element transport. The Maqarin site now provides a consistent picture explaining the origin of the hyperalkaline groundwaters, and is therefore a unique location for the examination of the mechanisms and processes associated with cementitious repositories. Application of these

  13. Natural analogues of nuclear waste glass corrosion.

    Energy Technology Data Exchange (ETDEWEB)

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  14. Basal insulin treatment intensification in patients with type 2 diabetes mellitus: A comprehensive systematic review of current options.

    Science.gov (United States)

    Raccah, D

    2017-04-01

    As type 2 diabetes mellitus progresses, most patients require treatment with basal insulin in combination with another agent to achieve recommended glycaemic targets. The purpose of this systematic review was to examine the evidence supporting the use of the available add-on treatments [rapid-acting insulin (RAI), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors] to basal insulin. MEDLINE, EMBASE and EBSCOhost were searched for English-language articles, and all those captured were original articles (case studies and narrative reviews were omitted). Data on study design, population demographics, interventions and outcomes were tabulated. The extracted outcome data included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), as well as body weight and safety data. A total of 88 publications were deemed relevant. All treatments reduced HbA1c and FPG. The most pronounced reductions in PPG, an unmet need in patients not controlled by basal insulin, were seen following administration of RAIs and short-acting GLP-1 RAs, although data for this outcome are generally lacking. Body weight benefits were observed with GLP-1 RAs and SGLT-2 inhibitors. However, as only articles in English were included, the result was a possible publication bias, while the diversity of study designs and drug combinations limited comparisons between studies. The evidence supports effectiveness of the available add-on treatments to basal insulin. However, other factors, such as potential body-weight increases, convenience/compliance and adverse events, particularly hypoglycaemia, should be considered on a patient-by-patient basis to optimalize treatment outcomes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Sharma Pawana

    2010-12-01

    Full Text Available Abstract Background Glucagon-like peptide (GLP-1 analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs. Methods MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events. Results Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily. Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists

  16. Insulin: discovery and controversy.

    Science.gov (United States)

    Rosenfeld, Louis

    2002-12-01

    During the first two decades of the 20th century, several investigators prepared extracts of pancreas that were often successful in lowering blood sugar and reducing glycosuria in test animals. However, they were unable to remove impurities, and toxic reactions prevented its use in humans with diabetes. In the spring of 1921, Frederick G. Banting, a young Ontario orthopedic surgeon, was given laboratory space by J.J.R. Macleod, the head of physiology at the University of Toronto, to investigate the function of the pancreatic islets. A student assistant, Charles Best, and an allotment of dogs were provided to test Banting's hypothesis that ligation of the pancreatic ducts before extraction of the pancreas, destroys the enzyme-secreting parts, whereas the islets of Langerhans, which were believed to produce an internal secretion regulating sugar metabolism, remained intact. He believed that earlier failures were attributable to the destructive action of trypsin. The name "insuline" had been introduced in 1909 for this hypothetic substance. Their experiments produced an extract of pancreas that reduced the hyperglycemia and glycosuria in dogs made diabetic by the removal of their pancreases. They next developed a procedure for extraction from the entire pancreas without the need for duct ligation. This extract, now made from whole beef pancreas, was successful for treating humans with diabetes. Facilitating their success was a development in clinical chemistry that allowed blood sugar to be frequently and accurately determined in small volumes of blood. Success with purification was largely the work of J.B. Collip. Yield and standardization were improved by cooperation with Eli Lilly and Company. When the Nobel Prize was awarded to Banting and Macleod for the discovery of insulin, it aggravated the contentious relationship that had developed between them during the course of the investigation. Banting was outraged that Macleod and not Best had been selected, and he

  17. Exogenous thyroxine improves glucose intolerance in insulin-resistant rats.

    Science.gov (United States)

    Vazquez-Anaya, Guillermo; Martinez, Bridget; Soñanez-Organis, José G; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M

    2017-03-01

    Both hypothyroidism and hyperthyroidism are associated with glucose intolerance, calling into question the contribution of thyroid hormones (TH) on glucose regulation. TH analogues and derivatives may be effective treatment options for glucose intolerance and insulin resistance (IR), but their potential glucoregulatory effects during conditions of impaired metabolism are not well described. To assess the effects of thyroxine (T4) on glucose intolerance in a model of insulin resistance, an oral glucose tolerance test (oGTT) was performed on three groups of rats (n = 8): (1) lean, Long Evans Tokushima Otsuka (LETO), (2) obese, Otsuka Long Evans Tokushima Fatty (OLETF) and (3) OLETF + T4 (8.0 µg/100 g BM/day × 5 weeks). T4 attenuated glucose intolerance by 15% and decreased IR index (IRI) by 34% in T4-treated OLETF compared to untreated OLETF despite a 31% decrease in muscle Glut4 mRNA expression. T4 increased the mRNA expressions of muscle monocarboxylate transporter 10 (Mct10), deiodinase type 2 (Di2), sirtuin 1 (Sirt1) and uncoupling protein 2 (Ucp2) by 1.8-, 2.2-, 2.7- and 1.4-fold, respectively, compared to OLETF. Activation of AMP-activated protein kinase (AMPK) and insulin receptor were not significantly altered suggesting that the improvements in glucose intolerance and IR were independent of enhanced insulin-mediated signaling. The results suggest that T4 treatment increased the influx of T4 in skeletal muscle and, with an increase of DI2, increased the availability of the biologically active T3 to upregulate key factors such SIRT1 and UCP2 involved in cellular metabolism and glucose homeostasis. © 2017 Society for Endocrinology.

  18. Analogues of uracil nucleosides with intrinsic fluorescence (NIF-analogues): synthesis and photophysical properties.

    Science.gov (United States)

    Segal, Meirav; Fischer, Bilha

    2012-02-28

    Uridine cannot be utilized as fluorescent probe due to its extremely low quantum yield. For improving the uracil fluorescence characteristics we extended the natural chromophore at the C5 position by coupling substituted aromatic rings directly or via an alkenyl or alkynyl linker to create fluorophores. Extension of the uracil base was achieved by treating 5-I-uridine with the appropriate boronic acid under the Suzuki coupling conditions. Analogues containing an alkynyl linker were obtained from 5-I-uridine and the suitable boronic acid in a Sonogashira coupling reaction. The uracil fluorescent analogues proposed here were designed to satisfy the following requirements: a minimal chemical modification at a position not involved in base-pairing, resulting in relatively long absorption and emission wavelengths and high quantum yield. 5-((4-Methoxy-phenyl)-trans-vinyl)-2'-deoxy-uridine, 6b, was found to be a promising fluorescent probe. Probe 6b exhibits a quantum yield that is 3000-fold larger than that of the natural chromophore (Φ 0.12), maximum emission (478 nm) which is 170 nm red shifted as compared to uridine, and a Stokes shift of 143 nm. In addition, since probe 6b adopts the anti conformation and S sugar puckering favored by B-DNA, it makes a promising nucleoside analogue to be incorporated in an oligonucleotide probe for detection of genetic material.

  19. Analogue to Digital and Digital to Analogue (AD/DA) Conversion Techniques: An Overview

    CERN Multimedia

    CERN. Geneva

    2002-01-01

    The basic ideas behind modern Analogue to Digital and Digital to Analogue (AD/DA) conversion methods will be introduced: a general view of the importance of these devices will be given, along with the digital representation of time-varying, real-world analogue signals. Some CERN applications will be outlined. The variety of conversion methods, their limitations, error sources and measurement methods will form the major part of this presentation. A review of the technological progress in this field over the last 30 years will be presented, concluding with the present 'state of the art' and a quick look at what is just around the corner. This Technical Training Seminar is in the framework of the FEED-2002 Lecture Series, and it is a prerequisite to attending to any of the FEED-2002 Terms. FEED-2002 is a two-term course that will review the techniques dealing with closed loop systems, focussing on time-invariant linear systems. (free attendance, no registration required) More information on the FEED-2002 ...

  20. 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

  1. Insulin resistance vs. hyperinsulinemia in hypertension: insulin regulation of Ca2+ transport and Ca(2+)-regulation of insulin sensitivity.

    Science.gov (United States)

    Zemel, M B

    1995-06-01

    Hypertension in obesity and insulin resistance has been attributed to insulin stimulation of sympathetic neural output and renal sodium retention. However, recent data demonstrates a significant vasodilatory effect of insulin and suggests that vascular smooth muscle resistance to this action may instead be the cause of hypertension in insulin resistance. This concept is supported by the observation that pharmacological amplification of peripheral insulin sensitivity results in reduced arterial pressure. Insulin attenuates vasoconstrictor responses to pressor agonists and accelerates vascular smooth muscle relaxation, while these effects are blunted in obesity and insulin resistance. Insulin regulation of vasoconstriction and vascular relaxation appears to be secondary to regulation of intracellular Ca2+ ([Ca2+]i), as insulin attenuates both voltage- and receptor-mediated Ca2+ influx and stimulates both the transcription and activity of Ca(2+)-ATPase in vascular smooth muscle cells. Further, these effects are also blunted in insulin resistance. Although [Ca2+]i plays a poorly understood role in insulin signalling, increases beyond an optimal range results in impaired insulin sensitivity, possibly by Ca(2+)-inhibition of insulin-induced dephosphorylation of insulin-sensitive substrates. Consistent with this concept, ectopic overexpression of the agouti gene in the viable yellow (Avy) mouse results in increased skeletal myocyte [Ca2+]i. Accordingly, increased [Ca2+]i in primary insulin target tissues appears to result in peripheral insulin resistance which then results in aberrant regulation of vascular smooth muscle [Ca2+]i and increases in arterial pressure.

  2. [Insulin edema in hepatic glycogenosis].

    Science.gov (United States)

    Mahévas, T; Gobert, D; Gatfossé, M; Mekinian, A; Fain, O

    2017-03-01

    Hepatic glycogenosis is a rare syndrome, which includes poorly controlled diabetes mellitus, hepatomegaly, delayed puberty, and growth delay. Insulin edema is sometimes associated. An 18-year-old woman presented with diffuse edema, hepatomegaly, amenorrhea, uncontrolled diabetes, and elevated transaminases and cholestasis. Hepatic ultrasonography and abdominal computed tomographic scan confirmed the hepatomegaly. The liver biopsy showed a massive glycogenosis and the diagnosis of hepatic glycogenosis was confirmed. Too large doses of insulin were responsible of diffuse edema. Diabetes equilibration and diminution of insulin intakes allow correction of this disorder. Excess of insulin can lead to excessive hepatic glycogen storage by activation of glycogenosis enzymes. Biological manifestations consist on elevated liver enzymes and hyperlactatemia. There is a link between administration of high dose of insulin and edema. Hepatic glycogenosis should be suspected when diabetes is uncontrolled and be considered as a differential diagnosis of steatosis. It may be associated and revealed by insulin edema directly related to excessive insulin intakes. Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  3. Incretins, insulin secretion and Type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, T; Holst, Jens Juul

    2004-01-01

    the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism...... of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas...... the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown...

  4. Insulin Resistance, Hyperglycemia, and Atherosclerosis

    Science.gov (United States)

    Bornfeldt, Karin E.; Tabas, Ira

    2011-01-01

    Progress in preventing atherosclerotic coronary artery disease (CAD) has been stalled by the epidemic of type 2 diabetes. Further advances in this area demand a thorough understanding of how two major features of type 2 diabetes, insulin resistance and hyperglycemia, impact atherosclerosis. Insulin resistance is associated with systemic CAD risk factors, but increasing evidence suggests that defective insulin signaling in atherosclerotic lesional cells also plays an important role. The role of hyperglycemia in CAD associated with type 2 diabetes is less clear. Understanding the mechanisms whereby type 2 diabetes exacerbates CAD offers hope for new therapeutic strategies to prevent and treat atherosclerotic vascular disease. PMID:22055501

  5. Autoantibodies to Insulin Receptor Spontaneously Develop as Anti-Idiotypes in Mice Immunized with Insulin

    Science.gov (United States)

    Shechter, Yoram; Maron, Ruth; Elias, Dana; Cohen, Irun R.

    1982-04-01

    Mice immunized with insulin developed antibodies to both insulin and the insulin receptor. The antibodies to insulin receptor displaced labeled insulin from insulin receptors and mimicked the actions of insulin in stimulating the oxidation of glucose and its incorporation into lipids, and in inhibiting lipolysis. The antibodies to insulin receptor could be blocked by or bound to the antibodies to insulin, and therefore were identified as anti-idiotypes. Thus, immunization against a hormone may activate spontaneously an idiotype-anti-idiotype network resulting in antibodies to the hormone receptor.

  6. Structural Perspectives of Insulin Receptor Isoform-Selective Insulin Analogs

    Czech Academy of Sciences Publication Activity Database

    Jiráček, Jiří; Žáková, Lenka

    2017-01-01

    Roč. 8, Jul 27 (2017), č. článku 167. ISSN 1664-2392 R&D Projects: GA ČR GA15-19018S Institutional support: RVO:61388963 Keywords : insulin receptor * insulin binding * analog * diabetes * glucose Subject RIV: CE - Biochemistry Impact factor: 3.675, year: 2016 http:// journal .frontiersin.org/article/10.3389/fendo.2017.00167/full

  7. The Greenland Analogue Project. Yearly Report 2009

    Energy Technology Data Exchange (ETDEWEB)

    2010-12-15

    A deep geological repository for spent nuclear fuel needs to be designed to keep used nuclear fuel isolated from mankind and the environment for a million years. Within this time frame glacial conditions are expected in regions that have been glaciated in the past two to ten million years. Climate induced changes such as the growth of ice sheets and permafrost will influence and alter the ground surface and subsurface environment, including its hydrology, which may impact repository safety. Glaciation impact assessments have to-date used over-simplified models and conservative assumptions, for example in the representation of ice sheet hydrology, that do not reflect the complexity of natural systems and processes. This is largely due to lack of direct observations of such processes from existing ice sheets, which if more readily available could help reduce uncertainties and provide a strong scientific basis for the treatment of glacial impacts in safety assessments. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with glacial cycles and their impact on the long-term performance of deep geological repositories for spent nuclear fuel will be significantly improved by studying a modern analogue. To advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository, the Greenland Analogue Project (GAP), a four-year field and modelling study of the Greenland ice sheet and sub-surface conditions, has been initiated collaboratively by SKB, Posiva and NWMO. The study site encompasses a land terminus portion of the Greenland ice sheet east of Kangerlussuaq and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project is planned to run from 2009 until 2012. The GAP will conduct the first in situ investigations of some of

  8. Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY.

    Science.gov (United States)

    El Hage, Krystel; Pandyarajan, Vijay; Phillips, Nelson B; Smith, Brian J; Menting, John G; Whittaker, Jonathan; Lawrence, Michael C; Meuwly, Markus; Weiss, Michael A

    2016-12-30

    Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (TyrB26) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-TyrB26]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (TyrB16, PheB24, PheB25, 3-I-TyrB26, and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-TyrB26]insulin analog (determined as an R6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-TyrB26 in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-TyrB26 engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Role of the glucose-sensing receptor in insulin secretion.

    Science.gov (United States)

    Kojima, Itaru; Medina, Johan; Nakagawa, Yuko

    2017-09-01

    Glucose is a primary stimulator of insulin secretion. It has been thought that glucose exerts its effect by a mechanism solely dependent on glucose metabolism. We show here that glucose induces rapid Ca2+ and cyclic AMP signals in β-cells. These rapid signals are independent of glucose-metabolism and are reproduced by non-metabolizable glucose analogues. These results led us to postulate that glucose activates a cell-surface receptor, namely the glucose-sensing receptor. Rapid signals induced by glucose are blocked by inhibition of a sweet taste receptor subunit T1R3 and a calcium-sensing receptor subunit CaSR. In accordance with these observations, T1R3 and CaSR form a heterodimer. In addition, a heterodimer of T1R3 and CaSR is activated by glucose. These results suggest that a heterodimer of T1R3 and CaSR is a major component of the glucose-sensing receptor. When the glucose-sensing receptor is blocked, glucose-induced insulin secretion is inhibited. Also, ATP production is significantly attenuated by the inhibition of the receptor. Conversely, stimulation of the glucose-sensing receptor by either artificial sweeteners or non-metabolizable glucose analogue increases ATP. Hence, the glucose-sensing receptor signals promote glucose metabolism. Collectively, glucose activates the cell-surface glucose-sensing receptor and promotes its own metabolism. Glucose then enters the cells and is metabolized through already activated metabolic pathways. The glucose-sensing receptor is a key molecule regulating the action of glucose in β-cells. © 2017 John Wiley & Sons Ltd.

  10. Insulin receptor signaling in cones

    National Research Council Canada - National Science Library

    Rajala, Ammaji; Dighe, Radhika; Agbaga, Martin-Paul; Anderson, Robert E; Rajala, Raju V S

    2013-01-01

    .... To date there are no studies on the insulin receptor signaling in cones; however, mRNA levels of IR signaling proteins are significantly higher in cone-dominant neural retina leucine zipper (Nrl...

  11. Taspoglutide, a novel human once-weekly analogue of glucagon-like peptide-1, improves glucose homeostasis and body weight in the Zucker diabetic fatty rat.

    Science.gov (United States)

    Sebokova, E; Bénardeau, A; Sprecher, U; Sewing, S; Tobalina, L; Migliorini, C

    2010-08-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a novel class of pharmacotherapy for type 2 diabetes. We investigated the effects of a novel, long-acting human GLP-1 analogue, taspoglutide, in the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. Blood glucose and plasma levels of insulin, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP) and triglycerides were measured during oral glucose tolerance tests (oGTT) conducted in ZDF rats treated acutely or chronically with a single long-acting dose of taspoglutide. Pioglitazone was used as a positive control in the chronic study. Postprandial glucose, body weight, glycaemic control and insulin sensitivity were assessed over 21 days in chronically treated animals. Acute treatment with taspoglutide reduced glucose excursion and increased insulin response during oGTT. In chronically treated rats, glucose excursion and levels of GIP, PYY and triglycerides during oGTT on day 21 were significantly reduced. Postprandial glucose levels were significantly lower than vehicle controls by day 15. A significant reduction in body weight gain was noticed by day 8, and continued until the end of the study when body weight was approximately 7% lower in rats treated with taspoglutide compared to vehicle. Glycaemic control (increased levels of 1,5-anhydroglucitol) and insulin sensitivity (Matsuda index) were improved by taspoglutide treatment. Taspoglutide showed typical effects of native GLP-1, with improvement in glucose tolerance, postprandial glucose, body weight, glycaemic control and insulin sensitivity.

  12. A chemoselective and continuous synthesis of m-sulfamoylbenzamide analogues

    Directory of Open Access Journals (Sweden)

    Arno Verlee

    2017-02-01

    Full Text Available For the synthesis of m-sulfamoylbenzamide analogues, small molecules which are known for their bioactivity, a chemoselective procedure has been developed starting from m-(chlorosulfonylbenzoyl chloride. Although a chemoselective process in batch was already reported, a continuous-flow process reveals an increased selectivity at higher temperatures and without catalysts. In total, 15 analogues were synthesized, using similar conditions, with yields ranging between 65 and 99%. This is the first automated and chemoselective synthesis of m-sulfamoylbenzamide analogues.

  13. Mammary analogue secretory carcinoma mimicking salivary adenoma.

    Science.gov (United States)

    Williams, Lindsay; Chiosea, Simion I

    2013-12-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumor characterized by ETV6 translocation. It appears that prior studies have identified MASC by reviewing salivary gland carcinomas, such as acinic cell carcinoma and adenocarcinoma, not otherwise specified. To address the possibility of MASC mimicking benign salivary neoplasms we reviewed 12 salivary gland (cyst)adenomas diagnosed prior to the discovery of MASC. One encapsulated (cyst)adenoma of the parotid gland demonstrated features of MASC. The diagnosis was confirmed by fluorescence in situ hybridization with an ETV6 break-apart probe. An unusual complex pattern of ETV6 rearrangement with duplication of the telomeric/distal ETV6 probe was identified. This case illustrates that MASC may mimic salivary (cyst)adenomas. To more accurately assess true clinical and morphologic spectrum of MASC, future studies may have to include review of salivary (cyst)adenomas. The differential diagnosis of MASC may have to be expanded to include cases resembling salivary (cyst)adenomas.

  14. Metabolic flexibility and insulin resistance

    OpenAIRE

    Galgani, Jose E.; Moro, Cedric; Ravussin, Eric

    2008-01-01

    Metabolic flexibility is the capacity for the organism to adapt fuel oxidation to fuel availability. The inability to modify fuel oxidation in response to changes in nutrient availability has been implicated in the accumulation of intramyocellular lipid and insulin resistance. The metabolic flexibility assessed by the ability to switch from fat to carbohydrate oxidation is usually impaired during a hyperinsulinemic clamp in insulin-resistant subjects; however, this “metabolic inflexibility” i...

  15. [Insulin secretion: mechanisms of regulation].

    Science.gov (United States)

    Radosavljević, Tatjana; Todorović, Vera; Sikić, Branka

    2004-01-01

    REGULATION OF INSULIN SECRETION: Beta cells are unique endocrine cells. They respond positively, in terms of insulin secretion, not only to changes in the extracellular glucose concentration, but also to activators of the phospholipase C (cholecystokinin or acetylcholine), and to activators of adenylate cyclase (glucagon, glucagon-like peptide-1, or gastric inhibitory polypeptide). Major messengers which mediate glucose action for insulin release are Ca2+, adenosine triphosphate (ATP) and diacylglycerol (DAG). MAJOR PATHWAYS OF INSULIN RELEASE STIMULATION: There are four major pathways involved in stimulation of insulin release. The first pathway is KATP channel-dependent pathway in which increased blood glucose concentrations and increased b-cell metabolism result in a change in intracellular ATP/ADP ratio. This is a contributory factor in closure of ATP-dependent K+ channels, depolarization of b-cell membrane, in increased voltage-dependent L-type Ca2+ channel activity. Increased Ca2+ influx results in increased intracellular Ca2+ and stimulated insulin release. KATP channel-independent pathway augments Ca(2+) -stimulated insulin secretion of KATP channel-dependent pathway. Major potentiation of release results from hormonal and peptidergic activation of receptors linked to adenylyl cyclase. Adenylyl cyclase activity is stimulated by hormones such as vasoactive intestinal peptide (VIP), glucagon-like peptide-1 (GLP-1), and so on. These hormones, acting via G protein, stimulate adenylyl cyclase, thus causing a rise in cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA). Increased activity of PKA results in potentiation of insulin secretion.

  16. Insulin Resistance, Obesity and Lipotoxicity.

    Science.gov (United States)

    Yazıcı, Dilek; Sezer, Havva

    2017-01-01

    Lipotoxicity , originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. Lipotoxicity has roles in insulin resistance and pancreatic beta cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling, have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.

  17. Trustworthiness and Influence: A Reexamination in an Extended Counseling Analogue.

    Science.gov (United States)

    Rothmeier, Rosemarie C.; Dixon, David N.

    1980-01-01

    The study demonstrated that: (1) interviewer trustworthiness can be manipulated in an analogue interview setting; and (2) interviewer trustworthiness is related to interpersonal influence in the interview setting. Findings follow a pattern of outcomes predicted by cognitive dissonance theory. (Author)

  18. Solistatinol, a novel phenolic compactin analogue from Penicillium solitum

    DEFF Research Database (Denmark)

    Larsen, Thomas Ostenfeld; Lange, Lene; Schnorr, Kirk

    2007-01-01

    Solistatinol, a novel phenolic compactin analogue, has been isolated from Penicillium solitum using a UV-guided strategy. The structure and relative stereochemistry were determined by NMR spectroscopy and mass spectrometry. The absolute stereochemistry was determined by chemical degradation...

  19. Minimal transient modes for faults detection in analogue VLSI circuits

    OpenAIRE

    KADIM H.J.

    2003-01-01

    The method introduced here uses an investigation of the dominant natural mode to identify possible abnormalities in analogue circuits due to faults and parameter variations, and determining the reliability of circuits when operating in the presence of faults.

  20. Analogue and Mixed-Signal Integrated Circuits for Space Applications

    CERN Document Server

    2014-01-01

    The purpose of AMICSA 2014 (organised in collaboration of ESA and CERN) is to provide an international forum for the presentation and discussion of recent advances in analogue and mixed-signal VLSI design techniques and technologies for space applications.

  1. Nuances of insulin therapy in the treatment of the diabetic ketoacidosis

    Directory of Open Access Journals (Sweden)

    Z.P. Nizhynska-Astapenko

    2017-08-01

    Full Text Available Background. The well-defined program of the insulin therapy is a guarantee of efficient treatment of a patient with the diabetic ketoacidosis. The approaches to the treatment varied depending on the gained experience, however, the experts’ opinions about the dose and methods of the insulin therapy are still ambiguous. The evaluation of the insulin therapy efficacy via continuous infusion by means of a syringe pump with the initial dose 0.1 unit/kg/h under the control of the glycemia without the usage of a bolus insulin dose IV and the determination of the necessary daily insulin dose on the first day of the diabetic ketoacidosis treatment. The purpose of the study — the evaluation of the insulin therapy efficacy for the diabetic ketoacidosis with syringe pump by means of the continuous infusion with the initial dose 0.1 unit/kg/h under the control of the glycemia as the principal component of the pathogenetic treatment and the determination of the necessary daily insulin dose on the first day of the diabetic ketoacidosis treatment in parallel with the rehydration start by means of physiological solution. Materials and methods. 55 patients with diabetic ketoacidosis aged from 9 to 65 years were examined. The average age of the patients was 31.58 ± 17.18 years. The specific weight of the female patients was 56 %, and male patients — 44 %. 80 % of patients had the type 1 diabetes mellitus. The determination of the glucose level was carried out in the capillary blood by means of the automatic glucose analyzer. For all the patients the glycemia was controlled in an hour after the injection of 0.1 unit/kg/h of insulin and then the dose was corrected in case of necessity with the control of the glucose level. For the treatment the fast-acting insulin was used and analogues of ultra fast-acting insulins, their total dose was calculated during the first day of treatment. Results. The glycemia level during the hospitalization fluctuated

  2. Design and rationale of a large, international, prospective cohort study to evaluate the occurrence of malformations and perinatal/neonatal death using insulin detemir in pregnant women with diabetes in comparison with other long-acting insulins

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R.; Andersen, Henning; Kring, Sofia I.I.

    2017-01-01

    in the context of routine practice. The primary endpoint is the proportion of pregnancies in women treated with insulin detemir, compared with other basal insulin regimens, which do not result in any of the following events: major congenital malformations, perinatal death or neonatal death. A sample size of 3075......Background: There are a lack of data regarding the effect of basal insulin analogues on rates of events like congenital malformation and perinatal mortality in diabetic pregnancy. Methods: The present study is a prospective, non-interventional, multicentre cohort study conducted in seven countries...... pregnancies was calculated to provide an 80% power to detect a difference of 3.5% between groups in the primary endpoint at a 5% level. Discussion: The study will also examine other important maternal endpoints (e.g., incidences of severe hypoglycaemia and pre-eclampsia) and perinatal outcomes...

  3. Design and rationale of a large, international, prospective cohort study to evaluate the occurrence of malformations and perinatal/neonatal death using insulin detemir in pregnant women with diabetes in comparison with other long-acting insulins

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R; Andersen, Henning; Kring, Sofia I I

    2017-01-01

    in the context of routine practice. The primary endpoint is the proportion of pregnancies in women treated with insulin detemir, compared with other basal insulin regimens, which do not result in any of the following events: major congenital malformations, perinatal death or neonatal death. A sample size of 3075......BACKGROUND: There are a lack of data regarding the effect of basal insulin analogues on rates of events like congenital malformation and perinatal mortality in diabetic pregnancy. METHODS: The present study is a prospective, non-interventional, multicentre cohort study conducted in seven countries...... pregnancies was calculated to provide an 80% power to detect a difference of 3.5% between groups in the primary endpoint at a 5% level. DISCUSSION: The study will also examine other important maternal endpoints (e.g., incidences of severe hypoglycaemia and pre-eclampsia) and perinatal outcomes...

  4. Pioglitazone acutely reduces energy metabolism and insulin secretion in rats

    National Research Council Canada - National Science Library

    Lamontagne, Julien; Jalbert-Arsenault, Elise; Pepin, Emilie; Peyot, Marie-Line; Ruderman, Neil B; Nolan, Christopher J; Joly, Erik; Madiraju, S R Murthy; Poitout, Vincent; Prentki, Marc

    2013-01-01

    Our objective was to determine if the insulin-sensitizing drug pioglitazone acutely reduces insulin secretion and causes metabolic deceleration in vivo independently of change in insulin sensitivity...

  5. 3-alkyl fentanyl analogues: Structure-activity-relationship study

    OpenAIRE

    Vučković, Sonja; Savić-Vujović, Katarina; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Stojanović, Radan; Prostran, Milica

    2012-01-01

    Introduction. Fentanyl belongs to 4-anilidopiperidine class of synthetic opioid analgesics. It is characterized by high potency, rapid onset and short duration of action. A large number of fentanyl analogues have been synthesized so far, both to establish the structure-activity-relationship (SAR) and to find novel, clinically useful analgesic drugs. Objective. In this study, newly synthesized 3-alkyl fentanyl analogues were examined for analgesic activity and compared with fentanyl. Methods. ...

  6. Analogue transformation acoustics and the compression of spacetime

    OpenAIRE

    García Meca, Carlos; Carloni, Sante; Barceló, Carlos; Jannes, Gil Georges Paul; Sánchez-Dehesa Moreno-Cid, José; Martínez Abietar, Alejandro José

    2014-01-01

    A recently developed technique known as analogue transformation acoustics has allowed the extension of the transformational paradigm to general spacetime transformations under which the acoustic equations are not form invariant. In this paper, we review the fundamentals of analogue transformation acoustics and show how this technique can be applied to build a device that increases the density of events within a given spacetime region by simultaneously compressing space and t...

  7. Analogue Signal Processing: Collected Papers 1994-95

    DEFF Research Database (Denmark)

    1996-01-01

    This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of Electronics Institute, Technical University of Denmark, in 1994 and 1995.......This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of Electronics Institute, Technical University of Denmark, in 1994 and 1995....

  8. Analogue Signal Processing: Collected Papers 1996-97

    DEFF Research Database (Denmark)

    1997-01-01

    This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of the Department of Information Technology, Technical University of Denmark, in 1996 and 1997.......This document is a collection of the papers presented at international conferences and in international journals by the analogue signal processing group of the Department of Information Technology, Technical University of Denmark, in 1996 and 1997....

  9. Synthesis of tritium labelled phosphonate analogues of sphinganine-1-phosphate

    Energy Technology Data Exchange (ETDEWEB)

    Schick, Andreas; Schwarzmann, Guenter; Kolter, Thomas; Sandhoff, Konrad [Universitaet Bonn, Inst. fuer Organische Chemie und Biochemie, Bonn (Germany)

    1997-05-01

    Tritiated phosphonate analogues 9 and 10 are prepared as analogues of sphinganine-1-phosphate 4. The key step in this synthesis is the catalytic tritiation of the triple bond in reduction of the protected diethyl-3-(S)-tert.-butoxycarbonylamino -4-hydroxy-5-tridecinyl-1-phosphonate by means of sodium boro[{sup 3}H]hydride as tritium source. These compounds are synthesized to study their metabolic stability and to evaluate their biological properties. (author).

  10. Somatostatin analogues suppress the inflammatory reaction in vivo.

    OpenAIRE

    Karalis, K; Mastorakos, G.; Chrousos, G. P.; Tolis, G

    1994-01-01

    Somatostatin (Sms) and its agonist analogues inhibit the secretory activities of endocrine and neural cells. Recent studies have suggested that Sms has significant immunomodulatory properties. In this study, we examine the effects of two Sms octapeptide analogues on the inflammatory reaction in vivo. BIM 23014 (Somatulin) and Sandostatin were administered to male Sprague-Dawley rats subject to carrageenin-induced aseptic inflammation, at doses of 2-10 micrograms/rat, given either systemically...

  11. Molecular Biodynamers: Dynamic Covalent Analogues of Biopolymers.

    Science.gov (United States)

    Liu, Yun; Lehn, Jean-Marie; Hirsch, Anna K H

    2017-02-21

    Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition, molecular

  12. Cytopathologic features of mammary analogue secretory carcinoma.

    Science.gov (United States)

    Bishop, Justin A; Yonescu, Raluca; Batista, Denise A S; Westra, William H; Ali, Syed Z

    2013-05-01

    Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is defined by ETV6-NTRK3 gene fusion. To the best of the authors' knowledge, only rare case reports of the cytopathologic features of MASC have been published to date. A wide variety of archival salivary gland tumors were tested for ETV6 translocation by break-apart fluorescent in situ hybridization. Positive cases with preoperative fine-needle aspiration (FNA) specimens or intraoperative touch preparations were retrieved from the archives of The Johns Hopkins Hospital. All smears were reviewed and the cytologic characteristics were described. Five cases of MASC with cytopathologic material (4 FNA specimens and 1 touch preparation) were identified. The cases occurred in 3 men and 2 women ranging in age from 21 years to 78 years (mean, 52 years). On the cytologic smears, the MASCs were variably cellular and exhibited 2 different architectural patterns: 1) intact tissue fragments with isomorphic cells arranged in a sheet-like or papillary configuration; and 2) dispersed and dissociated cells with a mostly "histiocyte-like" appearance with large cells containing abundant vacuolated cytoplasm. No matrix tissue or stromal spindled cells were present. The cells did not display acinic differentiation in the form of cytoplasmic zymogen granules. In each case, the preoperative FNA correctly identified a neoplasm, and the most frequent diagnostic considerations were acinic cell carcinoma, mucoepidermoid carcinoma, and pleomorphic adenoma. MASC is a newly described salivary gland tumor that should be considered in the differential diagnosis of low-grade salivary gland neoplasms. Its cytologic features overlap considerably with those of other tumors, especially acinic cell carcinoma and mucoepidermoid carcinoma. Copyright © 2013 American Cancer Society.

  13. Bioavailability and variability of biphasic insulin mixtures

    DEFF Research Database (Denmark)

    Søeborg, Tue; Rasmussen, Christian Hove; Mosekilde, Erik

    2012-01-01

    Absorption of subcutaneously administered insulin is associated with considerable variability. Some of this variability was quantitatively explained for both soluble insulin and insulin suspensions in a recent contribution to this journal (Søeborg et al., 2009). In the present article......, the absorption kinetics for mixtures of insulins is described. This requires that the bioavailability of the different insulins is considered. A short review of insulin bioavailability and a description of the subcutaneous depot thus precede the presentation of possible mechanisms associated with subcutaneous...... insulin degradation. Soluble insulins are assumed to be degraded enzymatically in the subcutaneous tissue. Suspended insulin crystals form condensed heaps that are assumed to be degraded from their surface by invading macrophages. It is demonstrated how the shape of the heaps affects the absorption...

  14. Design and rationale of a large, international, prospective cohort study to evaluate the occurrence of malformations and perinatal/neonatal death using insulin detemir in pregnant women with diabetes in comparison with other long-acting insulins.

    Science.gov (United States)

    Mathiesen, Elisabeth R; Andersen, Henning; Kring, Sofia I I; Damm, Peter

    2017-01-18

    There are a lack of data regarding the effect of basal insulin analogues on rates of events like congenital malformation and perinatal mortality in diabetic pregnancy. The present study is a prospective, non-interventional, multicentre cohort study conducted in seven countries, designed to assess the safety of insulin detemir during pregnancy, and to monitor the health status of resulting infants (exposed in utero) up to 1 year of age. The study population includes women with type 1 or type 2 diabetes, who are pregnant and being treated with insulin. Data will be collected in the context of routine practice. The primary endpoint is the proportion of pregnancies in women treated with insulin detemir, compared with other basal insulin regimens, which do not result in any of the following events: major congenital malformations, perinatal death or neonatal death. A sample size of 3075 pregnancies was calculated to provide an 80% power to detect a difference of 3.5% between groups in the primary endpoint at a 5% level. The study will also examine other important maternal endpoints (e.g., incidences of severe hypoglycaemia and pre-eclampsia) and perinatal outcomes such as overweight neonates, as well as infant outcomes at 1 year of age. It has a fixed recruitment period from 2013 to 2018, enrolling all eligible patients, and is expected to inform future prescribing with basal insulins in diabetic pregnancy. ClinicalTrials.gov: NCT01892319 (date registered: 27.06.2013).

  15. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    Science.gov (United States)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International

  16. Cladribine Analogues via O6-(Benzotriazolyl Derivatives of Guanine Nucleosides

    Directory of Open Access Journals (Sweden)

    Sakilam Satishkumar

    2015-10-01

    Full Text Available Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious, clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest in the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxytris(dimethylaminophosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities, and the data are presented herein. Against hairy cell leukemia (HCL, T-cell lymphoma (TCL and chronic lymphocytic leukemia (CLL, cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribose analogue of cladribine showed activity, but was the least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, cladribine and its ribose analogue were most active.

  17. Structure-activity studies of antitumor agent irofulven (hydroxymethylacylfulvene) and analogues.

    Science.gov (United States)

    McMorris, T C; Yu, J; Lira, R; Dawe, R; MacDonald, J R; Waters, S J; Estes, L A; Kelner, M J

    2001-09-07

    Many analogues of the antitumor agent irofulven have been readily prepared by replacing the allylic hydroxyl with a variety of nucleophiles. Analogues of acylfulvene (the precursor to irofulven) were also prepared by Michael reaction with acrolein. The toxicity of the analogues was determined, as well as preclinical antitumor activity. Several analogues exhibited good activity in mouse xenografts. Structural requirements for activity are discussed.

  18. INFLUENCE OF BETA-BLOCKERS ON INSULIN RESISTANCE IN PATIEN TS WITH DIABETES MELLITUS TYPE 2

    Directory of Open Access Journals (Sweden)

    Nataša Đinđić

    2011-12-01

    Full Text Available The insulin resistance is present when the concentration of insulin is normal and biological response is decreased. The most frequent metabolic change that was detected during anti-hypertension therapy is a change in the insulin resistance. Beta-blockers are generally accompanied by the deterioration of metabolic control in patients with diabetes. It is considered that using certain beta-blockers in hypertension therapy in patients with diabetes mellitus type 2 (DM type 2 can significantly influence the insulin resistance. Taking into consideration the latest knowledge on pharmaco-dynamics of insulin analogues and beta -blockers, by observing the parameters of glycoregulation, it would be of great interest and practical significance to determine the following influence of beta - blockers and their selectivity on the insulin resistance in patients with DM type 2 and hypertension. The research was conducted at the Endocrinology Clinic of the Clinical Centre Niš, and it included 60 patients with diagnosed diabetes mellitus type 2. After collecting anamnesis data, clinical and laboratory research performance, all patients were divided into two therapy groups: first group, 30 patients that were administered the therapy based on insulin glargine and second group, 30 patients that were administered the therapy based on insulin glargine and blocker divided into two therapy subgroups: 15 patients that were administered the therapy based on insulin glargine and carvedilol and 15 patients that were administered the therapy based on insulin glargine and metoprolol. Higher values of glycaemia and glycolised haemoglobin were found in patients receiving therapy based on beta–blocker (p<0.05. Therapy group treated with metoprolol had higher average values of glycaemia and HbA1C, compared to the group treated with carvedilol. The obtained difference was not statistically significant. Is confirmed that the group of patients to which beta–blockers had been

  19. Oral insulin--a perspective.

    Science.gov (United States)

    Raj, N K Kavitha; Sharma, Chandra P

    2003-01-01

    Diabetes mellitus is generally controlled quite well with the administration of oral medications or by the use of insulin injections. The current practice is the use of one or more doses, intermediate or long acting insulin per day. Oral insulin is a promising yet experimental method providing tight glycemic control for patients with diabetes. A biologically adhesive delivery systems offer important advantage over conventional drug delivery systems. The engineered polymer microspheres made of erodable polymer display strong adhesive interactions with gastrointestinal mucus and cellular lining can traverse both the mucosal epithelium and the follicle associated epithelium covering the lymphoid tissue of Peyer's patches. Alginate, a natural polymer recovered from seaweed is being developed as a nanoparticle for the delivery of insulin without being destroyed in the stomach. Alginate is in fact finding application in biotechnology industry as thickening agent, a gelling agent and a colloid stabilizer. Alginate has in addition, several other properties that have enabled it to be used as a matrix for entrapment and for the delivery of a variety of proteins such as insulin and cells. These properties include: a relatively inert aqueous environment within the matrix; a mild room temperature encapsulation process free of organic solvents; a high gel porosity which allows for high diffusion rates of macromolecules; the ability to control this porosity with simple coating procedures and dissolution and biodegradation of the system under normal physiological conditions.

  20. Cancer risk among insulin users

    DEFF Research Database (Denmark)

    But, Anna; De Bruin, Marie L.; Bazelier, Marloes T.

    2017-01-01

    AIMS/HYPOTHESIS: The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. METHODS: National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005......-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression...... models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (≤0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6 and >6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. RESULTS: A total of 21,390 cancer cases occurred during a mean...

  1. Insulin Analogs Applied with Continuous Subcutaneous Insulin Infusion (Pump in the Treatment of Diabetes

    Directory of Open Access Journals (Sweden)

    Ercan Tuncel

    2015-03-01

    Full Text Available Diabetes mellitus (DM is an important health problem that should be treated efficiently because of its high prevalence and high morbidity and mortality due to its complications. In patients with DM, the application of a treatment which provides physiologic insulin secretion as such in healthy individuals is directly related with the prevention of diabetes complications. Insulin analogs, which were developed in recent years and shown to have pharmacokinetic and pharmacodynamic superiority to human insulin, have made it possible to obtain natural insulin pattern in the body. In addition to development of insulin analogs, introduction of insulin application method of “continuous subcutaneous insulin infusion” (insulin pump has led a new era in the treatment of DM. In this review, treatment of type 1 and 2 DM patients with insulin analogs, particularly insulin aspart, applied with insulin pump was discussed in the light of the current literature.

  2. The effects of humanin and its analogues on male germ cell apoptosis induced by chemotherapeutic drugs.

    Science.gov (United States)

    Jia, Yue; Ohanyan, Aikoui; Lue, Yan-He; Swerdloff, Ronald S; Liu, Peter Y; Cohen, Pinchas; Wang, Christina

    2015-04-01

    Human (HN) prevents stress-induced apoptosis in many cells/tissues. In this study we showed that HN ameliorated chemotherapy [cyclophosphamide (CP) and Doxorubicin (DOX)]-induced male germ cell apoptosis both ex vivo in seminiferous tubule cultures and in vivo in the testis. HN acts by several putative mechanisms via binding to: an IL-12 like trimeric membrane receptor; BAX; or insulin-like growth factor binding protein-3 (IGFBP-3, a proapoptotic factor). To understand the mechanisms of HN on male germ cell apoptosis, we studied five HN analogues including: HNG (HN-S14G, a potent agonist), HNG-F6A (no binding to IGFBP-3), HN-S7A (no self-dimerization), HN-C8P (no binding to BAX), and HN-L12A (a HN antagonist) on CP-induced male germ cell apoptosis in mice. CP-induced germ cell apoptosis was inhibited by HN, HNG, HNG-F6A, HN-S7A, and HN-C8P (less effective); but not by HN-L12A. HN-L12A, but not HN-S7A or HN-C8P, blocked the protective effect of HN against CP-induced male germ cell apoptosis. HN, HN-S7A, and HN-C8P restored CP-suppressed STAT3 phosphorylation. These results suggest that HN: (1) decreases DOX (ex vivo) and CP (in vivo) induced male germ cell apoptosis; (2) action is mediated by the membrane receptor/STAT3 with minor contribution by BAX-binding pathway; (3) self-dimerization or binding to IGFBP-3 may not be involved in HN's effect in testis. HN is an important molecule in the regulation of germ cell homeostasis after injury and agonistic analogues may be developed for treating male infertility or protection against chemotherapy side effects.

  3. Novas opções na terapia insulínica New options in insulin therapy

    Directory of Open Access Journals (Sweden)

    Helena Schmid

    2007-11-01

    de Diabetes consensus documents. SUMMARY OF THE FINDINGS: Information is presented on new analogs of insulin and, for purposes of comparison, the other insulin modalities currently available are also reviewed, focusing on insulin therapies which attempt to approximate basal-bolus treatment strategies to physiology. With the objective of obtaining improved metabolic control, more and more children are being put on multiple daily injection regimes or using continuous subcutaneous insulin infusion. It is difficult to achieve optimum glycemic control in children due to the increased risk of hypoglycemia resulting from the great variability in dietary intake habits and in physical activity levels. With diabetes type 1, if rapid-acting analogs are given subcutaneously in bolus, they generally reduce hypoglycemia episodes and postprandial glycemia levels, compared with regular human insulin, while basal analogs tend to reduce particularly the number of episodes of nocturnal hypoglycemia. CONCLUSIONS: Although the benefits to individual metabolic and clinical outcomes appear modest, the majority of studies demonstrate benefits when insulin analogs are used in the treatment of diabetes type 1 or 2.

  4. Iron isotopes in an Archean ocean analogue

    Science.gov (United States)

    Busigny, Vincent; Planavsky, Noah J.; Jézéquel, Didier; Crowe, Sean; Louvat, Pascale; Moureau, Julien; Viollier, Eric; Lyons, Timothy W.

    2014-05-01

    Iron isotopes have been extensively used to trace the history of microbial metabolisms and the redox evolution of the oceans. Archean sedimentary rocks display greater variability in iron isotope ratios and more markedly negative values than those deposited in the Proterozoic and Phanerozoic. This increased variability has been linked to changes in either water column iron cycling or the extent of benthic microbial iron reduction through time. We tested these contrasting scenarios through a detailed study of anoxic and ferruginous Lac Pavin (France), which can serve as a modern analogue of the Archean ocean. A depth-profile in the water column of Lac Pavin shows a remarkable increase in dissolved Fe concentration (0.1-1200 μM) and δ56Fe values (-2.14‰ to +0.31‰) across the oxic-anoxic boundary to the lake bottom. The largest Fe isotope variability is found at the redox boundary and is related to partial oxidation of dissolved ferrous iron, leaving the residual Fe enriched in light isotopes. The analysis of four sediment cores collected along a lateral profile (one in the oxic layer, one at the redox boundary, one in the anoxic zone, and one at the bottom of the lake) indicates that bulk sediments, porewaters, and reactive Fe mostly have δ56Fe values near 0.0 ± 0.2‰, similar to detrital iron. In contrast, pyrite δ56Fe values in sub-chemocline cores (60, 65, and 92 m) are highly variable and show significant deviations from the detrital iron isotope composition (δ56Fepyrite between -1.51‰ and +0.09‰; average -0.93‰). Importantly, the pyrite δ56Fe values mirror the δ56Fe of dissolved iron at the redox boundary—where near quantitative sulfate and sulfide drawdown occurs—suggesting limited iron isotope fractionation during iron sulfide formation. This finding has important implications for the Archean environment. Specifically, this work suggests that in a ferruginous system, most of the Fe isotope variability observed in sedimentary pyrites can

  5. A novel benzonitrile analogue inhibits rhinovirus replication.

    Science.gov (United States)

    Lacroix, Céline; Querol-Audí, Jordi; Roche, Manon; Franco, David; Froeyen, Mathy; Guerra, Pablo; Terme, Thierry; Vanelle, Patrice; Verdaguer, Núria; Neyts, Johan; Leyssen, Pieter

    2014-10-01

    To study the characteristics and the mode of action of the anti-rhinovirus compound 4-[1-hydroxy-2-(4,5-dimethoxy-2-nitrophenyl)ethyl]benzonitrile (LPCRW_0005). The antiviral activity of LPCRW_0005 was evaluated in a cytopathic effect reduction assay against a panel of human rhinovirus (HRV) strains. To unravel its precise molecular mechanism of action, a time-of-drug-addition study, resistance selection and thermostability assays were performed. The crystal structure of the HRV14/LPCRW_0005 complex was elucidated as well. LPCRW_0005 proved to be a selective inhibitor of the replication of HRV14 (EC(50) of 2 ± 1 μM). Time-of-drug-addition studies revealed that LPCRW_0005 interferes with the earliest stages of virus replication. Phenotypic drug-resistant virus variants were obtained (≥30-fold decrease in susceptibility to the inhibitory effect of LPCRW_0005), which carried either an A150T or A150V amino acid substitution in the VP1 capsid protein. The link between the mutant genotype and drug-resistant phenotype was confirmed by reverse genetics. Cross-resistance studies and thermostability assays revealed that LPCRW_0005 has a similar mechanism of action to the capsid binder pleconaril. Elucidation of the crystal structure of the HRV14/LPCRW_0005 complex revealed the existence of multiple hydrophobic and polar interactions between the VP1 pocket and LPCRW_0005. LPCRW_0005 is a novel inhibitor of HRV14 replication that acts as a capsid binder. The compound has a chemical structure that is markedly smaller than that of other capsid binders. Structural studies show that LPCRW_0005, in contrast to pleconaril, leaves the toe end of the pocket in VP1 empty. This suggests that extended analogues of LPCRW_0005 that fill the full cavity could be more potent inhibitors of rhinovirus replication. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e

  6. Terrestrial research in Mars analogue environments

    Science.gov (United States)

    Osipov, G.

    Fatty acids (FA) content was measured by GC-MS SIM technique in Sulfide ores of present day (Mid-Atlantic Ridge and others) and ancient (Ural Paleocene, Russia) black smokers; Early Proterozoic kerites of Volyn; Siberian, Canadian and Antarctic permafrosts and also in rocks of East-European platform Achaean crystalline basement. Analysis was shown presence those and only those fatty acids which are specific to microorganisms. FA with 12 up 19 of carbon atoms are thought to be a bacterial biomass sign. 3-Hydroxy fatty acids also found in samples and are strong specific markers of gram-negative bacteria. Cultivation yield living bacteria in some cases. The East-European platform Achaean crystalline basement rocks opened by Vorotilov Deep Well (VDW) drilled through Puchezh-Katunski impact structure were studied within depths 2575 - 2805 m. 34 microbial lipid markers were detected by GC-MS and 22 species were identified. Bacteria of g. Bacillus reached 6,8 % in subsurface communities. However, members of gg. Clostridium (37,1 - 33,2 %) and Rhodococcus (27,6 - 33,7 %) were absolute dominants within studied depth interval. Some lipid patterns of kerite samples could be assessed to definite genera or, in special cases, to species of contemporary microorganisms. For instance, 2-hydroxylauric acid is specific to Pseudomonas putida group or Acinetobacter spp., and hydroxymyristic together with hydroxypalmitic are specific to P.cepacea and cyanobacteria. 3-hydroxystearic acid was known as component of Acetobacter diazothrophycus and Gloebacter violaceous cyanobacterium. 10-hydroxystearic acid associated with Nocardia spp., which oxidizes oleic acid in organic substrates. 10-methylhexadecanoic (10Me16) acid together with 10Me14, 10Me15 and 10Me17 analogues are markers of actinomycetes. Significant part of Black Smokers organic matter is probably biogenic. Fatty acid features strongly assigns it to bacterial, microeucariotic and planta cells. Par example 3-hydroxy acids are

  7. Meal-induced platelet activation in diabetes mellitus type 1 or type 2 is related to postprandial insulin rather than glucose levels.

    Science.gov (United States)

    Spectre, Galia; Stålesen, Ragnhild; Östenson, Claes-Göran; Hjemdahl, Paul

    2016-05-01

    Postprandial platelet activation was related to postprandial insulin rather than glucose levels in a previous meal insulin study in type 2 diabetes mellitus (T2DM). We therefore compared postprandial platelet activation in type 1 (T1DM) patients without insulin secretion and T2DM patients with high postprandial insulin levels. Patients with T1DM (n=11) and T2DM (n=12) were studied before and 90min after a standardized meal without premeal insulin. Five T1DM patients volunteered for a restudy with their regular premeal insulin. Platelet activation was assessed by flow cytometry, with and without the thromboxane analogue U46619 or ADP, and by whole blood aggregometry (Multiplate®). Effects of insulin (100μU/mL) in vitro were also studied. Before the meal, glucose, insulin and platelet activation markers other than platelet-leukocyte aggregates (PLAs) were similar in T1DM and T2DM; PLAs were higher in T1DM. Postprandial glucose levels increased more markedly in T1DM (to 22.1±1.4 vs. 11.2±0.6mmol/L) while insulin levels increased only in T2DM (from 24.4±4.4 to 68.8±12.3μU/mL). Platelet P-selectin expression, fibrinogen binding and PLA formation stimulated by U46619 were markedly enhanced (approximately doubled) and whole blood aggregation stimulated by U46619 was increased (ppostprandial platelet activation when postprandial insulin levels increased. In vitro insulin mildly activated platelets in both groups. Postprandial platelet activation via the thromboxane pathway is related to postprandial hyperinsulinemia and not to postprandial hyperglycaemia in patients with diabetes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Insulin poisoning with suicidal intent

    Directory of Open Access Journals (Sweden)

    Abhay Gundgurthi

    2012-01-01

    Full Text Available We report a 27-year-old paramedical lady with no known comorbidities, who presented with rapid-onset coma with hypoglycemia (plasma glucose at admission was 35 mg/dL. Clinical alertness suspected and confirmed the diagnosis of exogenous insulin administration probably with suicidal intent. During the course of her ICU stay, she developed bradycardia and hypotension which required ionotropic support. She remained in coma for 90 hours. A total of 470 g of dextrose was infused until she regained consciousness. No other complications of insulin overdose were observed during her stay in the hospital. Recovery was complete without any residual neurological deficits. Insulin administration should be kept in differential diagnosis when any case presents with coma and hypoglycemia, especially in paramedical personnel.

  9. Obesity, inflammation, and insulin resistance

    Directory of Open Access Journals (Sweden)

    Luana Mota Martins

    2014-12-01

    Full Text Available White adipose tissue (WAT is considered an endocrine organ. When present in excess, WAT can influence metabolism via biologically active molecules. Following unregulated production of such molecules, adipose tissue dysfunction results, contributing to complications associated with obesity. Previous studies have implicated pro- and anti-inflammatory substances in the regulation of inflammatory response and in the development of insulin resistance. In obese individuals, pro-inflammatory molecules produced by adipose tissue contribute to the development of insulin resistance and increased risk of cardiovascular disease. On the other hand, the molecules with anti-inflammatory action, that have been associated with the improvement of insulin sensitivity, have your decreased production. Imbalance of these substances contributes significantly to metabolic disorders found in obese individuals. The current review aims to provide updated information regarding the activity of biomolecules produced by WAT.

  10. Toward Complete Sequence Flexibility of Nucleic Acid Base Analogue FRET.

    Science.gov (United States)

    Wranne, Moa S; Füchtbauer, Anders Foller; Dumat, Blaise; Bood, Mattias; El-Sagheer, Afaf H; Brown, Tom; Gradén, Henrik; Grøtli, Morten; Wilhelmsson, L Marcus

    2017-07-12

    Förster resonance energy transfer (FRET) using fluorescent base analogues is a powerful means of obtaining high-resolution nucleic acid structure and dynamics information that favorably complements techniques such as NMR and X-ray crystallography. Here, we expand the base-base FRET repertoire with an adenine analogue FRET-pair. Phosphoramidite-protected quadracyclic 2'-deoxyadenosine analogues qAN1 (donor) and qAnitro (acceptor) were synthesized and incorporated into DNA by a generic, reliable, and high-yielding route, and both constitute excellent adenine analogues. The donor, qAN1, has quantum yields reaching 21% and 11% in single- and double-strands, respectively. To the best of our knowledge, this results in the highest average brightness of an adenine analogue inside DNA. Its potent emissive features overlap well with the absorption of qAnitro and thus enable accurate FRET-measurements over more than one turn of B-DNA. As we have shown previously for our cytosine analogue FRET-pair, FRET between qAN1 and qAnitro positioned at different base separations inside DNA results in efficiencies that are highly dependent on both distance and orientation. This facilitates significantly enhanced resolution in FRET structure determinations, demonstrated here in a study of conformational changes of DNA upon binding of the minor groove binder netropsin. Finally, we note that the donor and acceptor of our cytosine FRET-pair, tC(O) and tCnitro, can be conveniently combined with the acceptor and donor of our current adenine pair, respectively. Consequently, our base analogues can now measure base-base FRET between 3 of the 10 possible base combinations and, through base-complementarity, between all sequence positions in a duplex.

  11. Incorporation of tryptophan analogues into the lantibiotic nisin.

    Science.gov (United States)

    Zhou, Liang; Shao, Jinfeng; Li, Qian; van Heel, Auke J; de Vries, Marcel P; Broos, Jaap; Kuipers, Oscar P

    2016-05-01

    Lantibiotics are posttranslationally modified peptides with efficient inhibitory activity against various Gram-positive bacteria. In addition to the original modifications, incorporation of non-canonical amino acids can render new properties and functions to lantibiotics. Nisin is the most studied lantibiotic and contains no tryptophan residues. In this study, a system was constructed to incorporate tryptophan analogues into nisin, which included the modification machinery (NisBTC) and the overexpression of tryptophanyl-tRNA synthetase (TrpRS). Tryptophan and three different tryptophan analogues (5-fluoroTrp (5FW), 5-hydroxyTrp (5HW) and 5-methylTrp (5MeW)) were successfully incorporated at four different positions of nisin (I1W, I4W, M17W and V32W). The incorporation efficiency of tryptophan analogues into mutants I1W, M17W and V32W was over 97 %, while the mutant I4W showed relatively low incorporation efficiency (69-93 %). The variants with 5FW showed relatively higher production yield, while 5MeW-containing variants showed the lowest yield. The dehydration efficiency of serines or threonines was affected by the tryptophan mutants of I4W and V32W. The affinity of the peptides for the cation-ion exchange and reverse phase chromatography columns was significantly reduced when 5HW was incorporated. The antimicrobial activity of IIW and its 5FW analogue both decreased two times compared to that of nisin, while that of its 5HW analogue decreased four times. The 5FW analogue of I4W also showed two times decreased activity than nisin. However, the mutant M17W and its 5HW analogue both showed 32 times reduced activity relative to that of nisin.

  12. Insulin requirements in type 1 diabetic pregnancy

    DEFF Research Database (Denmark)

    Callesen, Nicoline; Ringholm, Lene; Stage, Edna

    2012-01-01

    To evaluate the insulin requirements in women with type 1 diabetes during twin pregnancy compared with singleton pregnancy.......To evaluate the insulin requirements in women with type 1 diabetes during twin pregnancy compared with singleton pregnancy....

  13. Intensive Insulin Therapy: Tight Blood Sugar Control

    Science.gov (United States)

    Intensive insulin therapy: Tight blood sugar control Intensive insulin therapy can help prevent long-term diabetes complications. Consider the benefits — and understand the commitment. By Mayo Clinic ...

  14. Beta cell dysfunction and insulin resistance

    Directory of Open Access Journals (Sweden)

    Marlon E Cerf

    2013-03-01

    Full Text Available Beta cell dysfunction and insulin resistance are inherently complex with their interrelation for triggering the pathogenesis of diabetes also somewhat undefined. Both pathogenic states induce hyperglycemia and therefore increase insulin demand. Beta cell dysfunction results from inadequate glucose sensing to stimulate insulin secretion therefore elevated glucose concentrations prevail. Persistently elevated glucose concentrations above the physiological range result in the manifestation of hyperglycemia. With systemic insulin resistance, insulin signaling within glucose recipient tissues is defective therefore hyperglycemia perseveres. Beta cell dysfunction supersedes insulin resistance in inducing diabetes. Both pathological states influence each other and presumably synergistically exacerbate diabetes. Preserving beta cell function and insulin signaling in beta cells and insulin signaling in the glucose recipient tissues will maintain glucose homeostasis.

  15. Patients with psoriasis are insulin resistant

    DEFF Research Database (Denmark)

    Gyldenløve, Mette; Storgaard, Heidi; Holst, Jens Juul

    2015-01-01

    BACKGROUND: Patients with psoriasis have increased risk of type 2 diabetes. The pathophysiology is largely unknown, but it is hypothesized that systemic inflammation causes insulin resistance. Insulin sensitivity has only been sparsely investigated in patients with psoriasis, and previous studies...

  16. Redox regulation of insulin degradation by insulin-degrading enzyme.

    Directory of Open Access Journals (Sweden)

    Crystal M Cordes

    Full Text Available Insulin-degrading enzyme (IDE is a thiol sensitive peptidase that degrades insulin and amyloid β, and has been linked to type 2 diabetes mellitus and Alzheimer's disease. We examined the thiol sensitivity of IDE using S-nitrosoglutathione, reduced glutathione, and oxidized glutathione to distinguish the effects of nitric oxide from that of the redox state. The in vitro activity of IDE was studied using either partially purified cytosolic enzyme from male Sprague-Dawley rats, or purified rat recombinant enzyme. We confirm that nitric oxide inhibits the degrading activity of IDE, and that it affects proteasome activity through this interaction with IDE, but does not affect the proteasome directly. Oxidized glutathione inhibits IDE through glutathionylation, which was reversible by dithiothreitol but not by ascorbic acid. Reduced glutathione had no effect on IDE, but reacted with partially degraded insulin to disrupt its disulfide bonds and accelerate its breakdown to trichloroacetic acid soluble fragments. Our results demonstrate the sensitivity of insulin degradation by IDE to the redox environment and suggest another mechanism by which the cell's oxidation state may contribute to the development of, and the link between, type 2 diabetes and Alzheimer's disease.

  17. Treatment Approach to Patients With Severe Insulin Resistance

    Science.gov (United States)

    Church, Timothy J.

    2016-01-01

    In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin. PMID:27092020

  18. Allergy to soft cannula of insulin pump in diabetic patient

    OpenAIRE

    Chen, Yu-Min; Huang, Hui

    2017-01-01

    Insulin pump is a relatively good choice for diabetic patients who require multiple daily injections with wide fluctuations of blood glucose. Patients using insulin pump therapy and still having uncontrolled blood glucose levels for various factors: insulin pump not working properly, insulin instability, insulin autoantibody, insulin allergy, etc. We described a 46-year-old woman with type 2 diabetes and progressive hyperglycemia after switching multiple daily insulin injections to insulin pu...

  19. Comparison of metformin and insulin versus insulin alone for type 2 diabetes

    DEFF Research Database (Denmark)

    Hemmingsen, Bianca; Christensen, Louise Lundby; Wetterslev, Jørn

    2012-01-01

    To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes.......To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes....

  20. Intranasal insulin: from nose to brain.

    Science.gov (United States)

    Henkin, R I

    2010-06-01

    Intranasal insulin has proven useful to control hyperglycemia in diabetics but its mechanism of action has not been well defined. We attempted to understand several aspects of human insulin metabolism by measurement of and interaction of insulin and its associated moieties in nasal mucus, saliva and blood plasma under various physiological and pathological conditions. Insulin, insulin receptors, insulin-like growth factor 1 (IGF1) and insulin-like growth receptor 3 (IGFR3) were measured in nasal mucus, saliva and blood plasma in normal subjects, in thin and obese subjects and in diabetics under fasting and fed conditions. There are complex relationships among each of these moieties in each biological fluid. Insulin and its associated moieties are present in both nasal mucus and saliva. These moieties in nasal mucus and saliva report on physiological and pathological changes in glucose metabolism as do these moieties in plasma. Indeed, insulin and its associated moieties in nasal mucus may offer specific data on how insulin enters the brain and thereby play essential roles in control of insulin metabolism. These data support the concept that insulin is synthesized not only in parotid glands but also in nasal serous glands. They also support the concept that insulin enters the brain following intranasal administration either 1) by direct entry through the cribriform plate, along the olfactory nerves and into brain parenchyma, 2) by entry through specific receptors in blood-brain barrier and thereby into the brain or 3) some combination of 1) and 2). Conversely, data also show that insulin introduced directly into the brain is secreted out of brain into the peripheral circulation. Data in this study demonstrate for the first time that insulin and its associated moieties are present not only in saliva but also in nasal mucus. How these complex relationships among nasal mucus, saliva and plasma occur are unclear but results demonstrate these relationships play separate

  1. A preliminary feasibility study on natural analogue in Korea

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chun Soo; Bae, Dae Seok; Kim, Kyung Su; Koh, Yong Kwon; Park, Byung Yun

    2000-03-01

    Preliminary study on the assessment of natural analogue study in Korea for the deep geological disposal of high-level radioactive waste was carried out. The project on natural analogue study in other countries are introduced. The uranium-bearing deposit in Okcheon belt are summarized, which reported to be uranium-bearing minerals in order to assess to feasibility for natural analogue study in Korea. Among the uranium-bearing deposits, the Deokpyeong area, reported to be the highest reservoir and grade, are selected as the study site, and the elementary investigation, including survey of radioactivity and geochemistry are carried out. According to the investigation of surface environment, the radioactivity and uranium content in the surface water and shallow groundwater does not show any anormal values. However, the radioactivity is expected to be increased in depth and the groundwater reacted with uranium-bearing graphite formation shows high unanium content, indicating the potential possibility for natural analogue study in Korea. In future, if more detail study are performed, the assessment of natural analogue study in Korea are expected.

  2. Vitamine D analogue-based therapies for psoriasis.

    Science.gov (United States)

    O'Neill, J L; Feldman, S R

    2010-05-01

    Topical vitamin D3 analogues are a mainstay of treatment in mild to moderate plaque psoriasis. Vitamin D3 analogues exert their effect in psoriasis via binding nuclear vitamin D3 receptors on genes involved in cellular proliferation, differentiation and inflammation. Currently available synthetic vitamin D3 analogues include calcipotriol, maxacalcitol, tacalcitol and calcitriol. These agents are only minimally systemically absorbed and therefore have few systemic side effects. Local irritation is the most frequently noted side effect and can be managed by combining vitamin D3 analogues with other topical or systemic therapies, such as topical corticosteroids or narrow-band UVB phototherapy. The use of a vitamin D agent helps improve the efficacy of topical corticosteroids for psoriasis and helps minimize the potential for adverse events associated with topical corticosteroid treatment. Care should be taken when combining with other topical therapies due to potential inactivation of either agent. Topical vitamin D3 analogues can be a cost-effective addition to a psoriasis treatment regimen, especially when compliance is encouraged by the tolerability of these agents and more costly systemic agents are avoided. Copyright (c) 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

  3. Somatostatin analogues suppress the inflammatory reaction in vivo.

    Science.gov (United States)

    Karalis, K; Mastorakos, G; Chrousos, G P; Tolis, G

    1994-01-01

    Somatostatin (Sms) and its agonist analogues inhibit the secretory activities of endocrine and neural cells. Recent studies have suggested that Sms has significant immunomodulatory properties. In this study, we examine the effects of two Sms octapeptide analogues on the inflammatory reaction in vivo. BIM 23014 (Somatulin) and Sandostatin were administered to male Sprague-Dawley rats subject to carrageenin-induced aseptic inflammation, at doses of 2-10 micrograms/rat, given either systemically or locally. Animals were killed 7 h after the induction of the inflammation, and the inflammatory exudates were aspirated and quantitated in terms of volume and leukocyte concentration. Sms analogues, administered via either route, significantly reduced the volume and the leukocyte concentration of the exudate in a time- and dose-dependent fashion. In corroboration of these, immunohistochemical evaluation of the levels of local inflammatory mediators, such as immunoreactive (Ir) TNF-alpha, Irsubstance P, and Ircorticotropin-releasing hormone, was inhibited significantly by Sms analogue treatment. These findings suggest that Sms analogues have significant antiinflammatory effects in vivo, associated with suppression of proinflammatory cytokines and neuropeptides. Furthermore, these data suggest that Sms agonists may be useful in the control of inflammatory reaction. Images PMID:7514191

  4. Use and Effectiveness of Continuous Subcutaneous Insulin Infusion (CSII) and Multiple Daily Insulin Injection Therapy (MIT) in Children, Adolescents and Young Adults with Type 1 Diabetes Mellitus.

    Science.gov (United States)

    Schiel, R; Burgard, D; Perenthaler, T; Stein, G; Kramer, G; Steveling, A

    2016-02-01

    Today continuous subcutaneous insulin infusion (CSII) is frequently used in children and adolescents with type 1 diabetes mellitus. The present cross-sectional trial aimed to document current practice, quality of diabetes control and incidence of acute complications in different age-groups under CSII vs. multiple daily insulin injection therapy (MIT). Moreover the survey analyzed socio-demographic backgrounds of the patients. A total of 901 patients (age 11.5±4.0, diabetes duration 4.0±3.6 years) was entered in the database. Clinical data, laboratory parameters and, using a standardized questionnaire, socio-demographic data were assessed. For age-related analyses patients were allocated to 4 groups: pre-school children (diabetes duration, they used more frequently insulin analogues, performed more frequently blood-glucose self-tests and had a lower insulin dosage per kilogram body weight. In respect of HbA1c, the mean amplitude of blood-glucose excursions, but also of lipids, creatinine, microalbuminuria and blood pressure, there were no differences in neither age-group between patients with CSII and MIT. In patients with CSII and MIT, there was a tendency (plevel. Pre-adolescents, adolescents and young adults with CSII have also better diabetes-related knowledge. Moreover, in all age-groups, the parents of patients with CSII had mostly a lower unemployment rate and higher educational levels. The present analyses demonstrate that in all age-groups CSII provides convenient and flexible insulin delivery during routine treatment of type 1 diabetes. There is reasonable quality of diabetes control accompanied by a low incidence of hypoglycaemia and ketoacidosis. However, under CSII and MIT there is an increase of HbA1c towards adolescence. It must also highlighted that CSII seems to be expansive and that CSII is more frequently used in patients with better educational levels and deriving from higher social classes. © Georg Thieme Verlag KG Stuttgart · New York.

  5. The future of basal insulin supplementation

    NARCIS (Netherlands)

    Simon, Airin C. R.; DeVries, J. Hans

    2011-01-01

    This review presents an overview of the candidates for an improved basal insulin in the pharmaceutical pipeline. The first new basal insulin to enter the market is most likely insulin degludec (IDeg), currently reporting in phase 3 of development, from Novo Nordisk (Bagsvaerd, Denmark). IDeg has a

  6. Factoren die de insuline gevoeligheid beinvloeden

    OpenAIRE

    Numan, Witte

    1980-01-01

    Volgens de gegevens uit de literatuur die in hoofdstuk 1 worden besproken, is glucose de belangrijkste prikkel voor de insuline afgifte. Na orale toediening van glucose worden hogere insuline spiegels gevonden dan na het toedienen van glucose intraverneus. Het gastric inhibitory polypeptide is van de darmhormonen, het hormaan dat de belangrijkste rol lijkt te spelen bij deze versterkte insuline afgifte. ... Zie: Samenvatting

  7. Lipohypertrophy – a complication of insulin injections

    African Journals Online (AJOL)

    Lipohypertrophy and lipoatrophy of injection sites was a major problem with the old impure insulins.1 The problem improved somewhat with the advent of the monocomponent bovine and porcine insulins and the current pure human insulins, such that lipoatrophy in particular is now very rare.1,2 However it now manifests ...

  8. 21 CFR 522.1160 - Insulin.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Insulin. 522.1160 Section 522.1160 Food and Drugs..., AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1160 Insulin. (a) Specifications—(1) Each milliliter (mL) of porcine insulin zinc suspension contains 40 international units (IU...

  9. Insulin sensitivity : modulation by the brain

    NARCIS (Netherlands)

    Coomans, Claudia Pascalle

    2012-01-01

    The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated

  10. HOW TO START AND OPTIMISE INSULIN THERAPY

    African Journals Online (AJOL)

    intimidating, as understanding how and when to use insulin is vital to diabetes management and ... for the insulin resistance. In the United ..... No change. 3.3 - 4.3. - 2. <3.3. - 4. *Average over 3 days. Mooradian AD et al. Ann Intern Med 2006;145:125-. 134. Table v. Titration schedule premix insulin therapy. Fasting glucose ...

  11. Intranasal insulin therapy: the clinical realities

    DEFF Research Database (Denmark)

    Hilsted, J; Madsbad, Sten; Hvidberg, A

    1995-01-01

    randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more...

  12. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

    Science.gov (United States)

    Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

    2017-12-01

    Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. [Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy].

    Science.gov (United States)

    Pesić, Milica; Zivić, Sasa; Radenković, Sasa; Velojić, Milena; Dimić, Dragan; Antić, Slobodan

    2007-04-01

    Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin) for basal insulin supply in patients with type 1 diabetes. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IT) were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15); 2. NPH insulin twice daily (n = 15); 3. insulin glargine once daily (n = 18). Meal time insulin aspart was continued in all groups. Fasting blood glucose (FBG) was lower in the glargine group (7.30+/-0.98 mmol/1) than in the twice daily NPH group (7.47+/-1.06 mmol/1), but without significant difference. FBG was significantly higher in the once daily NPH group (8.44+/-0.85 mmol/l; p < 0.05). HbAlc after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72+/-0.86% to 6.87+/-0.50%), as well as in the twice daily NPH group (from 7.80+/-0.83% to 7.01+/-0.63%). Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56+/-2.09) than in both NPH groups (9.0+/-1.65 in twice daily NPH group and 8.13+/-1.30 in other NPH group) (episodes/patients-month, p < 0.05). Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbAlc and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

  14. Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy

    Directory of Open Access Journals (Sweden)

    Pešić Milica

    2007-01-01

    Full Text Available Background/Aim. Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin for basal insulin supply in patients with type 1 diabetes. Methods. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IIT were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15; 2. NPH insulin twice daily (n = 15; 3. insulin glargine once daily (n = 18. Meal time insulin aspart was continued in all groups. Results. Fasting blood glucose (FBG was lower in the glargine group (7.30±0.98 mmol/l than in the twice daily NPH group (7.47±1.06 mmol/l, but without significant difference. FBG was significantly higher in the once daily NPH group (8.44±0.85 mmol/l; p < 0.05. HbA1c after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72±0.86% to 6.87±0.50%, as well as in the twice daily NPH group (from 7.80±0.83% to 7.01±0.63%. Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56±2.09 than in both NPH groups (9.0±1.65 in twice daily NPH group and 8.13±1.30 in other NPH group (episodes/patients-month, p < 0.05. Conclusion. Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbA1c and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

  15. Nutritional Modulation of Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Martin O. Weickert

    2012-01-01

    Full Text Available Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM. Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts.

  16. Cancer risk among insulin users

    DEFF Research Database (Denmark)

    But, Anna; De Bruin, Marie L; Bazelier, Marloes T

    2017-01-01

    AIMS/HYPOTHESIS: The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. METHODS: National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2...

  17. Continue subcutane insuline-infusie

    NARCIS (Netherlands)

    Ballegooie, Evert van

    1984-01-01

    In dit proefschrift worden de resultaten beschreven van een onderzoek naar: (1) de rol van bloedsuikerstrips en insuline-infusiepompjes bij de behandeling van diabetes mellitus; (2) de invloed van een verbetering van de diabetesregulatie op het verloop van de nefro-, neuro- en retinopathie en (3) de

  18. Mitochondrial efficiency and insulin resistance

    Directory of Open Access Journals (Sweden)

    Raffaella eCrescenzo

    2015-01-01

    Full Text Available Insulin resistance, ‘a relative impairment in the ability of insulin to exert its effects on glucose,protein and lipid metabolism in target tissues’, has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type 2 diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle.

  19. Microbial Modulation of Insulin Sensitivity

    NARCIS (Netherlands)

    Khan, Muhammad Tanweer; Nieuwdorp, Max; Bäckhed, Fredrik

    2014-01-01

    The gut microbiota has emerged as an integral factor that impacts host metabolism and has been suggested to play a vital role in metabolic diseases such as obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. In humans, cross-sectional studies have identified microbiota profiles

  20. Pathophysiological mechanisms of insulin resistance

    NARCIS (Netherlands)

    Brands, M.

    2013-01-01

    In this thesis we studied pathophysiological mechanisms of insulin resistance in different conditions in humans, i.e. in obesity, during lipid infusions, after hypercaloric feeding, and glucocorticoid treatment. We focused on 3 important hypotheses that are suggested to be implicated in the

  1. Insulin resistance in obesity can be reliably identified from fasting plasma insulin.

    Science.gov (United States)

    ter Horst, K W; Gilijamse, P W; Koopman, K E; de Weijer, B A; Brands, M; Kootte, R S; Romijn, J A; Ackermans, M T; Nieuwdorp, M; Soeters, M R; Serlie, M J

    2015-12-01

    Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely measured variables. We assembled data from non-obese (n=112) and obese (n=100) men who underwent two-step EHCs using [6,6-(2)H2]glucose as tracer (insulin infusion dose 20 and 60 mU m(-2) min(-1), respectively). Reference ranges for hepatic and peripheral insulin sensitivity were calculated from healthy non-obese men. Based on these reference values, obese men with preserved insulin sensitivity or insulin resistance were identified. Cutoff points for insulin-mediated suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disappearance rate (Rd) were 46.5% and 37.3 μmol kg(-)(1) min(-)(1), respectively. Most obese men (78%) had EGP suppression within the reference range, whereas only 12% of obese men had Rd within the reference range. Obese men with Rd insulin-sensitive obese men in age, body mass index (BMI), body composition, fasting glucose or cholesterol, but did have higher fasting insulin (110±49 vs 63±29 pmol l(-1), Pinsulin resistance (HOMA-IR) (4.5±2.2 vs 2.7±1.4, P=0.004). Insulin-resistant obese men could be identified with good sensitivity (80%) and specificity (75%) from fasting insulin >74 pmol l(-1). Most obese men have hepatic insulin sensitivity within the range of non-obese controls, but below-normal peripheral insulin sensitivity, that is, insulin resistance. Fasting insulin (>74 pmol l(-1) with current insulin immunoassay) may be used for identification of insulin-resistant (or metabolically unhealthy) obese men in research and clinical settings.

  2. New rubrolide analogues as inhibitors of photosynthesis light reactions.

    Science.gov (United States)

    Varejão, Jodieh O S; Barbosa, Luiz C A; Ramos, Gabriela Álvarez; Varejão, Eduardo V V; King-Díaz, Beatriz; Lotina-Hennsen, Blas

    2015-04-01

    Natural products called rubrolides have been investigated as a model for the development of new herbicides that act on the photosynthesis apparatus. This study comprises a comprehensive analysis of the photosynthesis inhibitory ability of 27 new structurally diverse rubrolide analogues. In general, the results revealed that the compounds exhibited efficient inhibition of the photosynthetic process, but in some cases low water solubility may be a limiting factor. To elucidate their mode of action, the effects of the compounds on PSII and PSI, as well as their partial reaction on chloroplasts and the chlorophyll a fluorescence transients were measured. Our results showed that some of the most active rubrolide analogues act as a Hill reaction inhibitors at the QB level by interacting with the D1 protein at the reducing side of PSII. All of the active analogues follow Tice's rule of 5, which indicates that these compounds present physicochemical properties suitable for herbicides. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Gold Nanoparticles Decorated with Mannose-6-phosphate Analogues

    Directory of Open Access Journals (Sweden)

    Stéphanie Combemale

    2014-01-01

    Full Text Available Herein, the preparation of neoglycoconjugates bearing mannose-6-phosphate analogues is described by: (a synthesis of a cyclic sulfate precursor to access the carbohydrate head-group by nucleophilic displacement with an appropriate nucleophile; (b introduction of spacers on the mannose-6-phosphate analogues via Huisgen’s cycloaddition, the Julia reaction, or the thiol-ene reaction under ultrasound activation. With the resulting compounds in hand, gold nanoparticles could be functionalized with various carbohydrate derivatives (glycoconjugates and then tested for angiogenic activity. It was observed that the length and flexibility of the spacer separating the sugar analogue from the nanoparticle have little influence on the biological response. One particular nanoparticle system substantially inhibits blood vessel growth in contrast to activation by the corresponding monomeric glycoconjugate, thereby demonstrating the importance of multivalency in angiogenic activity.

  4. Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

    Directory of Open Access Journals (Sweden)

    Yongseok Kwon

    2015-02-01

    Full Text Available A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1.

  5. Unintended Insulin Pump Delivery in Hyperbaric Conditions.

    Science.gov (United States)

    Bertuzzi, Federico; Pintaudi, Basilio; Bonomo, Matteo; Garuti, Fabio

    2017-04-01

    Unintended pump insulin delivery was reported to occur as a consequence of decreased atmospheric pressure, probably mediated by air bubble formation and the expansion of existing bubbles. This observation has been used to explain some hypoglycemic episodes occurring in patients on insulin pump treatment in between 1 and 1 h 45 min after the flight takeoff. New models of insulin pumps have been introduced in the market, most of them are waterproof certified. It is not clear if in these new pumps the influence of atmospheric pressure changes on the insulin delivery is still present. Moreover, there are no evidences related to the insulin pump operations in hyperbaric conditions, like as during diving activities. Our aim is therefore to verify the eventual variation of insulin pump delivery determined by atmospheric pressure changes in hyperbaric conditions. Three new models of insulin pumps were tested in hyperbaric conditions at a flow rate of 2 U/h. Atmospheric pressure variation affected pump insulin release. An increase in the atmospheric pressure from 1 to 1.3 atmosphere (ATA) induced a decrease of pump basal insulin release (about -0.2 U/10 min); conversely, when the atmospheric pressure returned from 1.3 to 1 ATA, an unintended insulin delivery was observed (about +0.3 U/10 min). This phenomenon appeared to be independent of the insulin pump rate and dependent on the presence of air bubbles within the insulin tube setting and cartridge. Unintended insulin delivery driven by atmospheric pressure changes in hyperbaric conditions occurred in the new insulin pumps available. Patients should pay attention to possible variation of insulin rate during the flight or during diving activities.

  6. Toxicogenomic and bioinformatics platforms to identify key molecular mechanisms of a curcumin-analogue DM-1 toxicity in melanoma cells.

    Science.gov (United States)

    Oliveira, Érica Aparecida de; Lima, Diogenes Saulo de; Cardozo, Lucas Esteves; Souza, Garcia Ferreira de; de Souza, Nayane; Alves-Fernandes, Debora Kristina; Faião-Flores, Fernanda; Quincoces, José Agustín Pablo; Barros, Silvia Berlanga de Moraes; Nakaya, Helder I; Monteiro, Gisele; Maria-Engler, Silvya Stuchi

    2017-11-01

    Melanoma is a highly invasive and metastatic cancer with high mortality rates and chemoresistance. Around 50% of melanomas are driven by activating mutations in BRAF that has led to the development of potent anti-BRAF inhibitors. However resistance to anti-BRAF therapy usually develops within a few months and consequently there is a need to identify alternative therapies that will bypass BRAF inhibitor resistance. The curcumin analogue DM-1 (sodium 4-[5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) has substantial anti-tumor activity in melanoma, but its mechanism of action remains unclear. Here we use a synthetic lethal genetic screen in Saccharomyces cerevisiae to identify 211 genes implicated in sensitivity to DM-1 toxicity. From these 211 genes, 74 had close human orthologues implicated in oxidative phosphorylation, insulin signaling and iron and RNA metabolism. Further analysis identified 7 target genes (ADK, ATP6V0B, PEMT, TOP1, ZFP36, ZFP36L1, ZFP36L2) with differential expression during melanoma progression implicated in regulation of tumor progression, cell differentiation, and epithelial-mesenchymal transition. Of these TOP1 and ADK were regulated by DM-1 in treatment-naïve and vemurafenib-resistant melanoma cells respectively. These data reveal that the anticancer effect of curcumin analogues is likely to be mediated via multiple targets and identify several genes that represent candidates for combinatorial targeting in melanoma. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Insulin aggregation tracked by its intrinsic TRES

    Science.gov (United States)

    Chung, Li Hung C.; Birch, David J. S.; Vyshemirsky, Vladislav; Ryadnov, Maxim G.; Rolinski, Olaf J.

    2017-12-01

    Time-resolved emission spectra (TRES) have been used to detect conformational changes of intrinsic tyrosines within bovine insulin at a physiological pH. The approach offers the ability to detect the initial stages of insulin aggregation at the molecular level. The data analysis has revealed the existence of at least three fluorescent species undergoing dielectric relaxation and significant spectral changes due to insulin aggregation. The results indicate the suitability of the intrinsic TRES approach for insulin studies and for monitoring its stability during storage and aggregation in insulin delivery devices.

  8. Analogue Kerr-like geometries in a MHD inflow

    CERN Document Server

    Noda, Sousuke; Takahashi, Masaaki

    2016-01-01

    We present a model of the analogue black hole in magnetohydrodynamic (MHD) flow. For a two dimensional axisymmetric stationary trans-magnetosonic inflow with a sink, using the dispersion relation of the MHD waves, we introduce the effective geometries for magnetoacoustic waves propagating in the MHD flow. Investigating the properties of the effective potentials for magnetoacoustic rays, we find that the effective geometries can be classified into five types which include analogue spacetimes of the Kerr black hole, ultra spinning stars with ergoregions and spinning stars without ergoregions. We address the effects of the magnetic pressure and the magnetic tension on each magnetoacoustic geometries.

  9. Carbohydrate Analogue Microarrays for Identification of Lectin-Selective Ligands.

    Science.gov (United States)

    Hyun, Ji Young; Park, Cheol Wan; Liu, Yanna; Kwon, Daeun; Park, Seong-Hyun; Park, Sungjin; Pai, Jaeyoung; Shin, Injae

    2017-06-19

    Fifty-five mono- and disaccharide analogues were prepared and used for the construction of microarrays to uncover lectin-selective ligands. The microarray study showed that two disaccharide analogues, 28' and 44', selectively bind to Solanum tuberosum lectin (STL) and wheat germ agglutinin (WGA), respectively. Cell studies indicated that 28' and 44' selectively block the binding of STL and WGA to mammalian cells, unlike the natural ligand LacNAc, which suppresses binding of both STL and WGA to cells. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Medical applications of analogue and digital telephone data links.

    Science.gov (United States)

    Hill, D W; Mable, S E; Payne, J P

    1976-07-20

    The increasing use of digital computer techniques for the analysis of signals such as the EEG, ECG, plethysmograms and cardiac output curves has led to the use of multichannel analogue frequency modulation telephone data links in the forward direction from the patient to the computer and digital links in the return direction. Single-channel analogue links are also being used for the surveillance of cardiac pacemaker patients and the television Viewphone offers the possibility of a visual contact between two centers. Examples will be given of the use of these various forms of telephone link.

  11. Desert spring mounds: a potential analogue to Martian arid environments?

    Science.gov (United States)

    Franchi, F.; Frisia, S.

    2017-09-01

    Spring carbonates have been often considered as putative analogues of Martian arid environments. On Earth these are believed to form by the interaction of highly saline water and microbial communities, which favor the formation of authigenic micrite. Here we present new data from spring mounds in the western Makgadikgadi Pan (Botswana) and the Great Artesian Basin (South Australia). In both areas, upwelling of ground water give rise to mounds and layered deposits which are close morphological analogues of landforms documented on Mars. The authigenic carbonates and evaporites associated with the spring mounds retain evidence of microbial microfabric founded elsewhere, pointing to the potential existence of similar microbial in the extreme Martian conditions.

  12. Synthesis of an Orthogonal Topological Analogue of Helicene

    DEFF Research Database (Denmark)

    Wixe, Torbjörn; Wallentin, Carl‐Johan; Johnson, Magnus T.

    2013-01-01

    The synthesis of an orthogonal topological pentamer analogue of helicene is presented. This analogue forms a tubular structure with its aromatic systems directed parallel to the axis of propagation, which creates a cavity with the potential to function as a host molecule. The synthetic strategy...... reported, based on a series of repeating Friedländer condensations that utilize pyrido[3,2‐d]pyrimidine moieties as protected amino aldehydes, allows for the facile access of higher generations of helical, tubular structures. As a result of the synthetic strategy, only a helical isomer of the pentamer...

  13. Rotating black hole solutions in relativistic analogue gravity

    Science.gov (United States)

    Giacomelli, Luca; Liberati, Stefano

    2017-09-01

    Simulation and experimental realization of acoustic black holes in analogue gravity systems have lead to a novel understanding of relevant phenomena such as Hawking radiation or superradiance. We explore here the possibility of using relativistic systems for simulating rotating black hole solutions and possibly get an acoustic analogue of a Kerr black hole. In doing so, we demonstrate a precise relation between nonrelativistic and relativistic solutions and provide a new class of vortex solutions for relativistic systems. Such solutions might be used in the future as a test bed in numerical simulations as well as concrete experiments.

  14. Naturally occurring crystalline phases: analogues for radioactive waste forms

    Energy Technology Data Exchange (ETDEWEB)

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  15. Biological evaluation of two anomeric glucose analogues iodinated in position 6

    Energy Technology Data Exchange (ETDEWEB)

    Koumanov, Francoise; Henry, Christelle; Ghezzi, Catherine; Mathieu, Jean-Paul; Morin, Christophe; Vidal, Michel; Leiris, Joeel de; Comet, Michel; Fagret, Daniel

    1997-08-01

    Two anomeric analogues of glucose labelled with 123 iodine in position 6, proposed as tracers of glucose transport in vivo, have been synthesized: {alpha}- and {beta}-methyl-6-deoxy-6-iodo-D-glucopyranoside ({alpha}MDIG and {beta}MDIG). The aim of this study was to determine whether these molecules interact with the glucose transporter and whether they could be used as tracers of glucose transport in vivo. The biodistribution of {alpha}MDIG and {beta}MDIG was studied in the mouse in vivo. To determine if these two anomers enter the cell via the glucose transporter, their uptake was measured in isolated perfused rat hearts, in human erythrocytes in suspension, and in cardiomyocytes of neonatal rat in culture. Both {alpha}MDIG and {beta}MDIG had similar repartitions in the mouse: myocardial uptake averaged 7% of the injected dose/g of organ at 2 min postinjection and {alpha}MDIG competed with D-glucose to enter the cells. Insulin produced a 123% increase of its uptake in isolated perfused rat hearts and a 100% increase in cardiomyocytes of neonatal rat in culture. {alpha}MDIG uptake was lowered in the presence of glucose transport inhibitors in each experimental model. An interaction between {beta}MDIG and glucose transporters was observed only in human erythrocytes in suspension. Only {alpha}MDIG interacts with the glucose transporter, and thus could be used to estimate glucose transport in vivo.

  16. Therapeutic uses of somatostatin and its analogues: Current view and potential applications.

    Science.gov (United States)

    Rai, Uma; Thrimawithana, Thilini R; Valery, Celine; Young, Simon A

    2015-08-01

    Somatostatin is an endogeneous cyclic tetradecapeptide hormone that exerts multiple biological activities via five ubiquitously distributed receptor subtypes. Classified as a broad inhibitory neuropeptide, somatostatin has anti-secretory, anti-proliferative and anti-angiogenic effects. The clinical use of native somatostatin is limited by a very short half-life (1 to 3min) and the broad spectrum of biological responses. Thus stable, receptor-selective agonists have been developed. The majority of these somatostatin therapeutic agonists bind strongly to two of the five receptor subtypes, although recently an agonist of wider affinity has been introduced. Somatostatin agonists are established in the treatment of acromegaly with recently approved indications in the therapy of neuroendocrine tumours. Potential therapeutic uses for somatostatin analogues include diabetic complications like retinopathy, nephropathy and obesity, due to inhibition of IGF-1, VEGF together with insulin secretion and effects upon the renin-angiotensin-aldosterone system. Wider uses in anti-neoplastic therapy may also be considered and recent studies have further revealed anti-inflammatory and anti-nociceptive effects. This review provides a comprehensive, current view of the biological functions of somatostatin and potential therapeutic uses, informed by the wide range of pharmacological advances reported since the last published review in 2004 by P. Dasgupta. The pharmacology of somatostatin receptors is explained, the current uses of somatostatin agonists are discussed, and the potential future of therapeutic applications is explored. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Insulin and the insulin-like growth factors I and II are mitogenic to cultured rat sciatic nerve segments and stimulate [3H]thymidine incorporation through their respective receptors

    DEFF Research Database (Denmark)

    Svenningsen, Åsa Fex; Kanje, M

    1996-01-01

    The factors that control proliferation of Schwann cells during peripheral nerve regeneration are not yet known. In this study we investigated the effects of insulin, insulin-like growth factor I and II (IGF-I and IGF-II), IGF-I analogues, and factors that interfere with their respective receptors......, on [3H]thymidine incorporation into cultured nerve segments from the rat sciatic nerve. Segments cultured in nM (0.1-1.7 nM) concentrations of insulin, truncated IGF-I (tIGF-I), long R3IGF-I, or IGF-II exhibited an increase in [3H]thymidine incorporation compared with control segments. IGF-II was most...... potent. JB1, an IGF-I antagonist, counteracted the effects of tIGF-I and insulin. The results suggest that non-neuronal cells in the nerve segment, probably Schwann cells, possess distinct receptors for insulin, IGF-I, and IGF-II and that these receptors may be involved in the control of Schwann cell...

  18. Mechanisms of insulin resistance in obesity.

    Science.gov (United States)

    Ye, Jianping

    2013-03-01

    Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy.

  19. Plasma insulin disturbances in primary hyperparathyroidism

    Science.gov (United States)

    Kim, Hakjoong; Kalkhoff, Ronald K.; Costrini, Nicholas V.; Cerletty, James M.; Jacobson, Mitchell

    1971-01-01

    Plasma insulin dynamics were evaluated in 10 patients with primary hyperparathyroidism before and after parathyroidectomy and correction of hypercalcemia. Before surgery fasting plasma insulin concentrations and insulin responses to administered glucose, tolbutamide, and glucagon were significantly greater than postoperative values. Hyperinsulinemia was not associated with altered glucose curves during glucose or glucagon tolerance tests, but a relatively greater insulin response to tolbutamide resulted in an increased hypoglycemic effect following its administration. The glucose-lowering action of intravenous insulin was slightly impaired before treatment. Intramuscular injections of parathormone to six normal men for 8 days induced mild hypercalcemia and hypophosphatemia and reproduced augmented plasma insulin responses to oral glucose and intravenous tolbutamide. 4-hr intravenous infusions of calcium to another group of six normal men raised serum calcium concentrations above 11 mg/100 ml. This did not alter glucose or insulin curves during oral glucose tolerance but markedly accentuated insulin responses to tolbutamide and potentiated its hypoglycemic effect. When highly purified parathormone was incubated with isolated pancreatic islets of male rats, glucose-stimulated insulin secretion was unaffected. These findings suggest that chronic hypercalcemia of hyperparathyroidism sustains a form of endogenous insulin resistance that necessitates augmented insulin secretion to maintain plasma glucose homeostasis. This state is insufficient to oppose tolbutamide-induced hypoglycemia because of an additional direct, selective enhancement of hypercalcemia on pancreatic beta cell responsiveness to the sulfonylurea. The possible direct role of parathormone in these events has not been established. PMID:5129311

  20. Selective Insulin Resistance in the Kidney

    Science.gov (United States)

    Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

    2016-01-01

    Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

  1. Mechanisms of insulin resistance in obesity

    Science.gov (United States)

    Ye, Jianping

    2014-01-01

    Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy. PMID:23471659

  2. Transdermal delivery of insulin via microneedles.

    Science.gov (United States)

    Narayan, Roger J

    2014-09-01

    Treatment of insulin-dependent diabetes mellitus, also known as Type 1 diabetes mellitus, requires delivery of exogenous insulin via injection or pump. An alternative to syringe-based subcutaneous delivery of insulin involves use of microneedles. These delivery of insulin. Benefits associated with microneedle-based delivery of insulin include minimal training for use, painless insertion, as well as the potential to combine microneedles with sensors and drug delivery devices to create an autonomous artificial pancreas. In this review, the efforts of academic and industrial researchers over the past decade to examine the functionality of microneedles for delivery of insulin, including insulin-containing nanomaterials, via in vitro, ex vivo, and in vivo studies are considered.

  3. Pathogenesis of Insulin Resistance in Skeletal Muscle

    Directory of Open Access Journals (Sweden)

    Muhammad A. Abdul-Ghani

    2010-01-01

    Full Text Available Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.

  4. Serum leptin levels in acromegaly--a significant role for adipose tissue and fasting insulin/glucose ratio.

    Science.gov (United States)

    Bolanowski, Marek; Milewicz, Andrzej; Bidzińska, Bozena; Jedrzejuk, Diana; Daroszewski, Jacek; Mikulski, Emil

    2002-10-01

    Leptin plays an important role in controlling satiety and maintaining energy balance. Acromegaly is characterized by decreased fat, which increases after the disease is cured. Our objective was to investigate serum leptin in acromegaly in terms of disease activity, body fat content, insulin and glucose levels, and selected anthropometric variables. We examined 40 patients with acromegaly and 20 sex- and age-matched controls for the levels of serum GH, IGF-I, leptin, glucose, and insulin, and for body composition by DEXA, BMI and WHR. In 10 cases the acute effect on serum leptin of a somatostatin analogue, lanreotide, was studied. We observed lower leptin in patients with active acromegaly than in cured patients and controls. Body fat was higher in cured than active patients. In the patients, we found significant correlations (p<0.05) between leptin and percent body fat (r=0.77), leptin and body fat mass (r=0.74), leptin and fasting insulin (r=0.62), leptin and fasting insulin/glucose ratio (r=0.97), leptin and BMI (r=0.44), leptin and height (r=-0.47). In the controls there was a significant correlation (p<0.05) only between leptin and WHR (r=-0.45). A paradoxical decrease of the leptin level after lanreotide was observed in 7 out of 10 patients with active acromegaly. Changes in leptin release in acromegaly are related to differences in body fat content and mass, and in insulin resistance. Leptin in acromegaly is not influenced directly by GH or IGF-I secretion. The acute effect of medical treatment of acromegaly by a somatostatin analogue on leptin levels differs from the effect of a radical cure following pituitary adenoma surgery.

  5. [The use of human insulin in 3 patients with diabetes mellitus and insulin resistance].

    Science.gov (United States)

    Khristov, V; Manov, A

    1989-01-01

    Human insulin was applied to three insulin resistant diabetic patients with moderate insulin needs of 1.9 U/kg body mass/24 hours. The mean level of the insulin antibodies was 61%. In all three patients biostator control was carried out before beginning the treatment with human insulin. After an 8 month treatment a satisfactory compensation of diabetes was achieved with an average insulin dose of 1.02 U/kg body mass, a considerable lowering of the mean blood sugar level and a reduction of the glycosilated hemoglobin examined in two of the patients. At the end of the 8 month period the level of the insulin antibodies was considerably lowered in all three patients. The advantage of human insulin as an alternative for the treatment of immunologic insulin resistance is pointed out.

  6. [Effect of arotinolol on insulin secretion and insulin clearance rate in patients with Graves' disease].

    Science.gov (United States)

    Ohguni, S; Notsu, K; Tanaka, J; Sato, T; Kato, Y

    1993-08-20

    Glucose-induced insulin secretion, 24-h urinary C-peptide (CPR) and euglycemic clamp were examined in five patients with hyperthyroid Graves' disease before and 2 weeks after treatment with arotinolol (20 mg/day, p.o.). Plasma glucose and insulin responses to oral administration of 75 g glucose were not changed by arotinolol treatment. 24-h urinary CPR and basal posthepatic insulin delivery rate (BPIDR) as an indicator of insulin secretion were significantly suppressed by arotinolol. Glucose infusion rate (GIR) as an indicator of insulin sensitivity and glucose clearance rate (GCR) were not influenced by arotinolol therapy. Insulin clearance rate (ICR) was significantly suppressed by arotinolol. These findings suggest that arotinolol inhibits insulin secretion by decreasing ICR but does not attenuate insulin release induced by glucose in hyperthyroid patients, and that insulin sensitivity and GCR are not affected by arotinolol.

  7. Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

    Directory of Open Access Journals (Sweden)

    Nicole M. Templeman

    2017-07-01

    Full Text Available The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1 signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2+/− mice to Ins2+/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2+/− mice. Halving Ins2 lowered circulating insulin by 25%–34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.

  8. Insulin and Insulin-like Growth Factor II Differentially Regulate Endocytic Sorting and Stability of Insulin Receptor Isoform A*

    Science.gov (United States)

    Morcavallo, Alaide; Genua, Marco; Palummo, Angela; Kletvikova, Emilia; Jiracek, Jiri; Brzozowski, Andrzej M.; Iozzo, Renato V.; Belfiore, Antonino; Morrione, Andrea

    2012-01-01

    The insulin receptor isoform A (IR-A) binds both insulin and insulin-like growth factor (IGF)-II, although the affinity for IGF-II is 3–10-fold lower than insulin depending on a cell and tissue context. Notably, in mouse embryonic fibroblasts lacking the IGF-IR and expressing solely the IR-A (R−/IR-A), IGF-II is a more potent mitogen than insulin. As receptor endocytosis and degradation provide spatial and temporal regulation of signaling events, we hypothesized that insulin and IGF-II could affect IR-A biological responses by differentially regulating IR-A trafficking. Using R−/IR-A cells, we discovered that insulin evoked significant IR-A internalization, a process modestly affected by IGF-II. However, the differential internalization was not due to IR-A ubiquitination. Notably, prolonged stimulation of R−/IR-A cells with insulin, but not with IGF-II, targeted the receptor to a degradative pathway. Similarly, the docking protein insulin receptor substrate 1 (IRS-1) was down-regulated after prolonged insulin but not IGF-II exposure. Similar results were also obtained in experiments using [NMeTyrB26]-insulin, an insulin analog with IR-A binding affinity similar to IGF-II. Finally, we discovered that IR-A was internalized through clathrin-dependent and -independent pathways, which differentially regulated the activation of downstream effectors. Collectively, our results suggest that a lower affinity of IGF-II for the IR-A promotes lower IR-A phosphorylation and activation of early downstream effectors vis à vis insulin but may protect IR-A and IRS-1 from down-regulation thereby evoking sustained and robust mitogenic stimuli. PMID:22318726

  9. Real-world therapeutic benefits of patients on insulin glargine versus NPH insulin.

    Science.gov (United States)

    Fiesselmann, Albrecht; Wiesner, Tobias; Fleischmann, Holger; Bramlage, Peter

    2016-10-01

    The addition of a single injection of insulin to the oral drugs (basal supported oral therapy; BOT) has been shown to greatly reduce blood glucose levels. The intermediate-acting NPH insulin (NPH) and the long-acting insulin glargine (Lantus(®)) have been compared for use in BOT in numerous clinical trials; however, their efficacy and safety in a real-life setting have not been described. TIP (therapeutic benefits of patients on insulin glargine vs. NPH insulin being poorly controlled on prior short-time basal-insulin supported therapy with NPH insulin or insulin glargine) is a non-interventional, multicentre, observational study over 24 weeks. A total of 2629 patients were enrolled and 1931 were fully evaluable (1614 insulin glargine, 303 NPH insulin). Propensity scoring (PSM) was used to match 570 patients into 2 similar cohorts of 285 patients. In the PSM cohort, a slightly greater reduction in FBG and HbA1c levels was seen in the insulin glargine group compared to the NPH group. A weight loss, which was slightly more pronounced in insulin glargine patients despite receiving a lower insulin dose relative to the NPH group, was seen in both the groups. Additionally, hypoglycaemia, including nocturnal and severe events, was more prevalent in the patients receiving BOT with NPH. The occurrence of new micro- or macro-vascular complications and adverse events was low for both groups. A large proportion of patients changed from NPH therapy to insulin glargine therapy during the study, which was mainly attributable to insufficient glucose modulation. Improvements in quality of life and treatment satisfaction were found for both types of insulin. This observational study provides evidence from a real-life setting that BOT with insulin glargine provides slightly greater reductions in weight, FBG and HbA1c levels, with a lower risk of hypoglycaemia than patients receiving NPH. This conclusion indicates that insulin glargine may be preferable to NPH insulin for BOT.

  10. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

    Directory of Open Access Journals (Sweden)

    Maarten Walmagh

    2015-06-01

    Full Text Available Trehalose (α-d-glucopyranosyl α-d-glucopyranoside is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals, medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-d-glucopyranosyl α-d-galactopyranoside or galactotrehalose (α-d-galactopyranosyl α-d-galactopyranoside, offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis.

  11. Iron Sulfur Proteins and their Synthetic Analogues: Structure ...

    Indian Academy of Sciences (India)

    ... Public Lectures · Lecture Workshops · Refresher Courses · Symposia. Home; Journals; Resonance – Journal of Science Education; Volume 3; Issue 6. Iron Sulfur Proteins and their Synthetic Analogues: Structure, Reactivity and Redox Properties. B N Anand. General Article Volume 3 Issue 6 June 1998 pp 52-61 ...

  12. The -Fractional Analogue for Gronwall-Type Inequality

    Directory of Open Access Journals (Sweden)

    Thabet Abdeljawad

    2013-01-01

    Full Text Available We utilize -fractional Caputo initial value problems of order to derive a -analogue for Gronwall-type inequality. Some particular cases are derived where -Mittag-Leffler functions and -exponential type functions are used. An example is given to illustrate the validity of the derived inequality.

  13. Evaluation of the antibacterial spectrum of drosocin analogues

    NARCIS (Netherlands)

    Bikker, F.J.; Kaman-van Zanten, W.E.; Vries-van de Ruit, A.M.B.C. de; Voskamp-Visser, I.; Hooft, P.A.V. van; Mars-Groenendijk, R.H.; Visser, P.C. de; Noort, D.

    2006-01-01

    Drosocin is a 19-mer, cationic antimicrobial peptide from Drosophila melanogaster. The aim of the study was to examine the antibacterial spectrum of unglycosylated drosocin analogues. Furthermore, the amino acid sequence of DnaK, drosocin's intracellular target, from susceptible species was aligned

  14. Impact of new synthesized analogues of dehydroacetic acid on ...

    African Journals Online (AJOL)

    Previous work indicated that some of the new synthesized analogues of dehydroacetic acid (DHA) were inhibitory to the growth of mycotoxin producing moulds and accumulation of aflatoxin B1 (AFB1) and ochratoxin A (OTA). The objective of this study was to determine the specific new synthesized chemical compounds ...

  15. Cytotoxicity of natural ginseng glycosides and semisynthetic analogues

    NARCIS (Netherlands)

    Atopkina, LN; Malinovskaya, GV; Elyakov, GB; Uvarova, NI; Woerdenbag, HJ; Koulman, A; Potier, P

    The cytotoxicity of natural glycosides from Ginseng, semisynthetic analogues and related triterpenes of the dammarane series, isolated from the leaves of the Far-East species of the genus Betula was studied in order to elucidate structure-activity relationships. Some of the compounds studied were

  16. Synthesis and biological evaluation of novel gramicidin s analogues

    NARCIS (Netherlands)

    Tuin, A.W.; Palachanis, D.K.; Buizert, A.; Grotenbreg, G.M.; Spalburg, E.; Neeling, A.J. de; Mars-Groenendijk, R.H.; Noort, D.; Marel, G.A. van der; Overkleeft, H.S.; Overhand, M.

    2009-01-01

    The synthesis of three new analogues of the cyclic cationic antimicrobial peptide Gramicidin S is described. These derivatives contain a modified turn region in which the DPhe-Pro motif has been replaced by a constrained furanoid sugar amino acid or a flexible linear aminoethoxy acetic acid moiety.

  17. On $q$-analogues of multiple zeta values

    OpenAIRE

    Singer, Johannes

    2015-01-01

    We study a $q$-analogue of multiple zeta values that was proposed by Zudilin and is closely related to that of Schlesinger. We explore the double $q$-shuffle structure and provide an Euler decomposition formula. Furthermore we compare our results with the classical multiple zeta values and the $q$-models of Ohno-Okuda-Zudilin and Bradley.

  18. Charged analogue of Vlasenko–Pronin superdense star with ...

    Indian Academy of Sciences (India)

    Home; Journals; Pramana – Journal of Physics; Volume 86; Issue 4. Charged analogue of Vlasenko–Pronin superdense ... 31, 1017 (2000), some particular values of the cosmological term are taken to obtain well-behaved solutionsof the Einstein–Maxwell field equations. All the results given by Maurya and Gupta can be ...

  19. Total synthesis and biological evaluation of neodysiherbaine A and analogues.

    Science.gov (United States)

    Shoji, Muneo; Akiyama, Nobuyuki; Tsubone, Koichi; Lash, L Leanne; Sanders, James M; Swanson, Geoffrey T; Sakai, Ryuichi; Shimamoto, Keiko; Oikawa, Masato; Sasaki, Makoto

    2006-07-07

    Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.

  20. Mammary analogue secretory carcinoma: A rare salivary gland tumour

    African Journals Online (AJOL)

    Salivary gland malignancy is rare, with a global annual incidence of. 3 per 100 000 people.[1,2] A rare salivary gland tumour, mammary analogue secretory carcinoma (MASC), has only recently been described.[3] The few reports and studies concerning MASC have been published in several pathology journals. We report ...

  1. Synthesis of 4” manipulated Lewis X trisaccharide analogues

    Directory of Open Access Journals (Sweden)

    Christopher J. Moore

    2012-07-01

    Full Text Available Three analogues of the Lex trisaccharide antigen (β-D-Galp(1→4[α-L-Fucp(1→3]-D-GlcNAcp in which the galactosyl residue is modified at O-4 as a methyloxy, deoxychloro or deoxyfluoro, were synthesized. We first report the preparation of the modified 4-OMe, 4-Cl and 4-F trichloroacetimidate galactosyl donors and then report their use in the glycosylation of an N-acetylglucosamine glycosyl acceptor. Thus, we observed that the reactivity of these donors towards the BF3·OEt2-promoted glycosylation at O-4 of the N-acetylglucosamine glycosyl acceptors followed the ranking 4-F > 4-OAc ≈ 4-OMe > 4-Cl. The resulting disaccharides were deprotected at O-3 of the glucosamine residue and fucosylated, giving access to the desired protected Lex analogues. One-step global deprotection (Na/NH3 of the protected 4”-methoxy analogue, and two-step deprotections (removal of a p-methoxybenzyl with DDQ, then Zemplén deacylation of the 4”-deoxychloro and 4”-deoxyfluoro protected Lex analogues gave the desired compounds in good yields.

  2. Design and synthesis of epicocconone analogues with improved fluorescence properties.

    Science.gov (United States)

    Peixoto, Philippe A; Boulangé, Agathe; Ball, Malcolm; Naudin, Bertrand; Alle, Thibault; Cosette, Pascal; Karuso, Peter; Franck, Xavier

    2014-10-29

    Epicocconone is a natural latent fluorophore that is widely used in biotechnology because of its large Stokes shift and lack of fluorescence in its unconjugated state. However, the low photostability and quantum yields of epicocconone have limited its wider use, and in the absence of a total synthesis, this limitation has been a long-standing problem. Here we report a general strategy for the synthesis of epicocconone analogues that relies on a 2-iodoxybenzoic acid-mediated dearomatization and on the replacement of the triene tail of the natural product by an aromatic ring. This design element is general and the synthesis is straightforward, providing ready access to libraries of polyfunctional fluorophores with long Stokes shifts based on the epicocconone core. Our structural modifications resulted in analogues with increased photostability and quantum yields compared with the natural product. Staining proteomic gels with these new analogues showed significant lowering of the detection limit and a 30% increase in the number of low-abundance proteins detected. These epiccoconone analogues will substantially improve the discovery rate of biomarker needles in the proteomic haystack.

  3. Evaluative comparison of palm wine analogue and oil palm wine ...

    African Journals Online (AJOL)

    Various analyses and sensory evaluation of palm wine analogue and oil palm wine have been carried out. Important parameters such as physicochemical properties, nutritive values, phytochemical screening and microbiological analysis of the two brands of wines were assessed. The results show that the wines have ...

  4. Insulin Resistance and Skin Diseases

    Directory of Open Access Journals (Sweden)

    Maddalena Napolitano

    2015-01-01

    Full Text Available In medical practice, almost every clinician may encounter patients with skin disease. However, it is not always easy for physicians of all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations. Are they confined to the skin, representing a pure dermatologic event? Or are they also markers of internal conditions relating to the patient’s overall health? In this review, we will discuss the principal cutaneous conditions which have been linked to metabolic alterations. Particularly, since insulin has an important role in homeostasis and physiology of the skin, we will focus on the relationships between insulin resistance (IR and skin diseases, analyzing strongly IR-associated conditions such as acanthosis nigricans, acne, and psoriasis, without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa, androgenetic alopecia, and hirsutism.

  5. Insulin dysfunction and Tau pathology

    Directory of Open Access Journals (Sweden)

    Noura eEl Khoury

    2014-02-01

    Full Text Available The neuropathological hallmarks of Alzheimer's disease (AD include senile plaques of β-amyloid (Aβ peptides (a cleavage product of the Amyloid Precursor Protein, or APP and neurofibrillary tangles (NFT of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF. NFT pathology is important since it correlates with the degree of cognitive impairment in AD.Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99% is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease.Insulin dysfunction, manifested by diabetes mellitus (DM might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM and type 2 diabetes (T2DM are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment.Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting on Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

  6. Insulin alters the permeability of sheep pleura.

    Science.gov (United States)

    Kouritas, V K; Hatzoglou, C; Ioannou, M; Gourgoulianis, K I; Molyvdas, P A

    2010-05-01

    Insulin promotes ion transportation across epithelia, mainly kidneys, leading to water and electrolyte abnormalities, possibly causing 'insulin oedema syndrome', which rarely presents as pleural effusion. Direct stimulation of sheep pleura by insulin and the possible electrophysiology mechanisms involved were investigated. Sheep visceral and parietal pleural specimens were mounted between Ussing chambers. Insulin solutions (10 (-9) to 10 (-5) M), L-NAME, Nitroprussid sodium, amiloride and ouabain were used. Trans-mesothelial Resistance was determined. Immunohistochemistry for presence of Insulin Receptors was performed. Insulin increased Trans-mesothelial Resistance within 1st minute when added mesothelially of visceral (p=0.008) and parietal pleura (p=0.046) for concentrations higher than 10 (-7) M. L-NAME or Nitroprussid sodium didn't but amiloride and ouabain inhibited insulin's effect. Immunohistochemistry revealed the presence of Insulin Receptors. Insulin changes the permeability of sheep pleura by altering its electrophysiology and may interfere in pleural effusion formation. Involvement of Insulin Receptors may be suggested.

  7. Convolutamydine A and synthetic analogues have antinociceptive properties in mice.

    Science.gov (United States)

    Figueiredo, Gabriela S M; Zardo, Renata S; Silva, Bárbara V; Violante, Flávio A; Pinto, Angelo C; Fernandes, Patricia D

    2013-01-01

    Convolutamydine A, an oxindole that originated from a marine bryozoan, has several biological effects. In this study, we aimed to investigate the antinociceptive effects of convolutamydine A and two new synthetic analogues. Convolutamydine A and the two analogues were given orally to assess their ability to induce antinociceptive effects. Formalin-induced licking response, acetic acid-induced contortions, and hot plate models were used to characterize the effects of convolutamydine A and its analogues. Convolutamydine A (4,6-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole), compound 1 (3-(2-oxopropyl)-3-hydroxy-2-oxindole), and compound 2 (5-bromo-3-(2-oxopropyl)-3-hydroxy-2-oxindole) caused peripheral antinociceptive and anti-inflammatory effects in the acetic acid-induced contortions and the formalin-induced licking models. Supraspinal effects were also observed in the hot plate model and were similar to those obtained with morphine. The peripheral effects were not mediated by the cholinergic or opioid systems. The antinociceptive effects of convolutamydine A seem to be mediated by all three systems (cholinergic, opioid, and nitric oxide systems), and the mechanism of action of compounds 1 and 2 involved cholinergic and nitric oxide-mediated mechanisms. Convolutamydine A and its analogues (compounds 1 and 2) showed good antinociceptive ability after systemic administration in acute pain models. The antinociceptive action mediated by cholinergic, opioid, and nitric oxide systems could explain why convolutamydine A, compound 1, and compound 2 retained their antinociceptive effects. The doses used were similar to the doses of morphine and were much lower than that of acetylsalicylic acid, the classical analgesic and anti-inflammatory drug. In conclusion, convolutamydine A and the two analogues demonstrated antinociceptive effects comparable to morphine's effects. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Fentanyl and its analogues in clinical and forensic toxicology.

    Science.gov (United States)

    Skulska, Agnieszka; Kała, Maria; Parczewski, Andrzej

    2005-01-01

    Fentanyl and its analogues are commonly named synthetic opiates. Some compounds from fentanyl group (e.g. fentanyl, alfentanil, sufentanil, remifentanil) are used as anaesthetic and analgesic of high potency and short duration of action. Effects of acting fentanyls are indistinguishable from those produced by nasal inhalation of street heroin. In view of this, fentanyls are very "attractive" for the narcotic market. In least years an increase in number of reports about illegal production and non-medical use of fentanyl and its analogues have appeared. Numerous fentanyl analogues are sold under one name synthetic heroine or China white. Fentanyl and its analogues also can be used as gas warfare agents. One of fentanyl-related compound was used during action of easing hostages from Dubrovka theatre. Because of respiratory depression, which was caused by used compound, died over 100 hostages. Because of high potency fentanyl-related compounds are used in very low doses. So fentanyls appear in biological material in very low concentrations, not higher than several nanograms per millilitre or per gram. The drugs in these concentrations cannot be detected by means of routinely used screening procedures. Therefore direct methods for determination of this group of compounds are needed. Screening method for determination of fentanyl and its analogues was elaborated and validated. Liquid chromatography-mass spectrometry (LC/MS) technique was applied. The method is characterised by the limit of quantification (LOQ) and the limit of detection (LOD) ranged from 0.6 to 2 ng/ml and from 0.2 to 0.6 ng/ml, respectively for four above-mentioned compounds. The method was used for determination of fentanyl in three forensic cases. The blood, bile and blood from lung samples were taken during autopsy of persons who died shortly after surgical procedure in which fentanyl was used as an adjunct to general anaesthesia.

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

    OpenAIRE

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

    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 in...

  10. Insecticidal action of synthetic girgensohnine analogues and essential oils on Rhodnius prolixus (Hemiptera: Reduviidae

    Directory of Open Access Journals (Sweden)

    Juliana Cuadros

    2017-03-01

    Conclusion: Synthetic girgensohnine analogues, and C. flexuosus and C. sinensis essential oils showed insecticidal activity in R. prolixus. Analogue 3 showed the greatest insecticidal activity among all molecules and oils evaluated under our laboratory conditions.

  11. Quality of casein based Mozzarella cheese analogue as affected by stabilizer blends

    National Research Council Canada - National Science Library

    Jana, A H; Patel, H G; Suneeta, Pinto; Prajapati, J P

    2010-01-01

    ...% in the formulation was assessed in the manufacture of Mozzarella cheese analogue. The stabilizer blends did not significantly influence the composition, texture profile, organoleptic, baking qualities and pizza-related characteristics of cheese analogues...

  12. The impact of watching educational video clips on analogue patients' physiological arousal and information recall

    NARCIS (Netherlands)

    Bruinessen, I.R. van; Ende, I.T. van den; Visser, L.N.; Dulmen, S. van

    2016-01-01

    OBJECTIVE: Investigating the influence of watching three educational patient-provider interactions on analogue patients' emotional arousal and information recall. METHODS: In 75 analogue patients the emotional arousal was measured with physiological responses (electrodermal activity and heart rate)

  13. The impact of watching educational video clips on analogue patients' physiological arousal and information recall

    NARCIS (Netherlands)

    van Bruinessen, I. R.; van den Ende, I. T. A.; Visser, L. N. C.; van Dulmen, S.

    2016-01-01

    Investigating the influence of watching three educational patient-provider interactions on analogue patients' emotional arousal and information recall. In 75 analogue patients the emotional arousal was measured with physiological responses (electrodermal activity and heart rate) and self-reported

  14. The impact of watching educational video clips on analogue patients' physiological arousal and information recall.

    NARCIS (Netherlands)

    Bruinessen, I.R. van; Ende, I.T.A. van den; Visser, I.N.C.; Dulmen, S. van

    2016-01-01

    Objective: Investigating the influence of watching three educational patient–provider interactions on analogue patients’ emotional arousal and information recall. Methods: In 75 analogue patients the emotional arousal was measured with physiological responses (electrodermal activity and heart rate)

  15. Delivering needle-free insulin using AERx iDMS (insulin diabetes management system) technology.

    Science.gov (United States)

    Wollmer, Per; Pieber, Thomas R; Gall, Mari-Anne; Brunton, Stephen

    2007-06-01

    Inhaled insulin has recently emerged as an alternative to subcutaneous insulin administration. One inhaled insulin device, AERx (a registered trademark of Aradigm Corp., Hayward, CA, or its affiliates in the United States and other countries) insulin diabetes management system (iDMS) (Novo Nordisk A/S, Bagsvaerd, Denmark), uses a unique liquid human insulin strip to deliver an aerosol of insulin to the lungs. AERx iDMS enables 1-unit increment dosing, and the device ensures that the insulin dose is released at the optimal point of inhalation for delivery to the lungs. Compared with subcutaneous human insulin, the pharmacokinetic and pharmacodynamic profile of inhaled insulin with AERx iDMS is similar, but with a more rapid onset of action. Data from these pharmacokinetic studies have also demonstrated that inhaled insulin dosing with AERx iDMS is as consistent and reproducible as subcutaneous human insulin. In individuals with diabetes, prandial inhaled insulin with AERx iDMS is as effective and well tolerated as subcutaneous prandial human insulin or insulin aspart in terms of glycemic control and overall hypoglycemia. No major safety concerns have been raised with respect to pulmonary function tests. Other clinical studies using AERx iDMS in special populations, such as smokers, people with asthma, or people suffering from upper respiratory tract infections, have provided important information regarding the use of inhaled insulin in these circumstances. Overall, pulmonary insulin delivery with the AERx iDMS device appears to be a promising safe and efficacious alternative to subcutaneous insulin injections.

  16. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.

    Science.gov (United States)

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-09-01

    Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague-Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by

  17. Assessment of structurally diverse philanthotoxin analogues for inhibitory activity on ionotropic glutamate receptor subtypes

    DEFF Research Database (Denmark)

    Frølund, Sidsel; Bella, Angelo; Kristensen, Anders Skov

    2010-01-01

    moiety was extended with an amino acid tail, six compounds contained an N-acylated cyclohexylalanine, and four analogues were based on a novel diamino acid design with systematically changed spacer length between N-cyclohexylcarbonyl and N-phenylacetyl substituents. The analogues were studied using two......M. For the diamino acid-based analogues, the optimal spacer length between two N-acyl groups was determined, resulting in an analogue with an IC(50) value of 106 nM....

  18. Analogue Electrical Circuit for Simulation of the Duffing-Holmes Equation

    DEFF Research Database (Denmark)

    Tamaseviciute, E.; Tamasevicius, A.; Mykolaitis, G.

    2008-01-01

    An extremely simple second order analogue electrical circuit for simulating the two-well Duffing-Holmes mathematical oscillator is described. Numerical results and analogue electrical simulations are illustrated with the snapshots of chaotic waveforms, phase portraits (Lissajous figures) and stro......An extremely simple second order analogue electrical circuit for simulating the two-well Duffing-Holmes mathematical oscillator is described. Numerical results and analogue electrical simulations are illustrated with the snapshots of chaotic waveforms, phase portraits (Lissajous figures...

  19. Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

    DEFF Research Database (Denmark)

    Højlund, Kurt; Wojtaszewski, Jørgen F.P.; Birk, J.

    2006-01-01

    AIMS/HYPOTHESIS: Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable...... in vivo insulin signalling in muscle in these carriers of a mutant INSR, probably by increasing insulin action on the non-mutated insulin receptors......., and therefore the cellular mechanisms underlying insulin resistance in Arg1174Gln carriers remain to be clarified. SUBJECTS, MATERIALS AND METHODS: We studied glucose metabolism and insulin signalling in skeletal muscle from six Arg1174Gln carriers and matched control subjects during a euglycaemic...

  20. Original paper: Efficacy and safety analysis of insulin degludec/insulin aspart compared with biphasic insulin aspart 30: A phase 3, multicentre, international, open-label, randomised, treat-to-target trial in patients with type 2 diabetes fasting during Ramadan.

    Science.gov (United States)

    Hassanein, Mohamed; Echtay, Akram Salim; Malek, Rachid; Omar, Mahomed; Shaikh, Shehla Sajid; Ekelund, Magnus; Kaplan, Kadriye; Kamaruddin, Nor Azmi

    2017-11-26

    To compare the efficacy and safety of insulin degludec/insulin aspart (IDegAsp) and biphasic insulin aspart 30 (BIAsp 30) before, during and after Ramadan in patients with type 2 diabetes mellitus (T2DM) who fasted during Ramadan. In this multinational, randomised, treat-to-target trial, patients with T2DM who intended to fast and were on basal, pre- or self-mixed insulin ± oral antidiabetic drugs for ≥90 days were randomised (1:1) to IDegAsp twice daily (BID) or BIAsp 30 BID. Treatment period included pre-Ramadan treatment initiation (with insulin titration for 8-20 weeks), Ramadan (4 weeks) and post-Ramadan (4 weeks). Insulin doses were reduced by 30-50% for the pre-dawn meal (suhur) on the first day of Ramadan, and readjusted to the pre-Ramadan levels at the end of Ramadan. Hypoglycaemia was analysed as overall (severe or plasma glucose Ramadan, despite achieving significantly lower pre-iftar (meal at sunset) self-measured plasma glucose (estimated treatment difference: -0.54 mmol/L [-1.02; -0.07]95% CI, p = .0247; post hoc) with similar overall glycaemic efficacy, IDegAsp showed significantly lower overall and nocturnal hypoglycaemia rates versus BIAsp 30. IDegAsp is a suitable therapeutic agent for patients who need insulin for sustained glucose control before, during and after Ramadan fasting, with a significantly lower risk of hypoglycaemia, versus BIAsp 30, an existing premixed insulin analogue. Copyright © 2017. Published by Elsevier B.V.