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Impaired early-phase suppression of glucagon secretion after glucose load is associated with insulin requirement during pregnancy in gestational diabetes.
Horie, I, Haraguchi, A, Ito, A, Nozaki, A, Natsuda, S, Akazawa, S, Mori, Y, Ando, T, Higashijima, A, Hasegawa, Y, et al
Journal of diabetes investigation. 2020;(1):232-240
Abstract
AIMS/INTRODUCTION The role of glucagon abnormality has recently been reported in type 2 diabetes; however, its role in gestational diabetes mellitus (GDM) is still unknown. The glucose intolerance in GDM is heterogeneous, and not all patients require insulin treatment during pregnancy. Here, we investigated whether glucagon abnormality is associated with the requirement for insulin treatment during pregnancy. MATERIALS AND METHODS A total of 49 pregnant women diagnosed with GDM were enrolled. They underwent a 75-g oral glucose tolerance test during mid-gestation, and we measured their plasma glucagon levels (by a new sandwich enzyme-linked immunosorbent assay) at fasting (0 min), and at 30, 60 and 120 min after glucose load in addition to the levels of plasma glucose and serum insulin. All participants underwent another oral glucose tolerance test at postpartum. RESULTS Of the 49 patients, 15 required insulin treatment (Insulin group) and 34 were treated with diet therapy alone until delivery (Diet group). The early-phase glucagon secretion after glucose load, as determined by the changes in glucagon from the baseline to 30 min, was paradoxically augmented during mid-gestation in the Insulin group, but not in the Diet group. The impaired glucagon suppression during mid-gestation in the Insulin group was not associated with insulin secretory/sensitivity indexes studied, and was ameliorated postpartum, although the plasma glucose levels remained higher in the Insulin group versus the Diet group. CONCLUSIONS Impaired early-phase suppression of glucagon could be associated with the requirement for insulin treatment during pregnancy in patients with GDM.
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Postprandial Aminogenic Insulin and Glucagon Secretion Can Stimulate Glucose Flux in Humans.
Ang, T, Bruce, CR, Kowalski, GM
Diabetes. 2019;(5):939-946
Abstract
Insulin and glucagon exert opposing actions on glucose metabolism, and their secretion is classically viewed as being inversely regulated. This is, however, context specific as protein ingestion concomitantly stimulates euglycemic insulin and glucagon secretion. It remains enigmatic how euglycemia is preserved under these conditions. Accordingly, we examined the systems-level mechanisms governing such endocrine control of glucose homeostasis. Eight healthy participants completed a water (control) and multidose whey protein ingestion trial designed to augment the protein-induced endocrine response. Glucose kinetics were measured using stable isotope tracer methodology. Protein ingestion induced marked hyperaminoacidemia, hyperinsulinemia (approximately sixfold basal), and unprecedented hyperglucagonemia (approximately eightfold basal) while suppressing free fatty acids. Both glucose disposal (Rd) and endogenous glucose production (EGP) increased by ∼25%, thereby maintaining euglycemia. This demonstrates 1) that protein ingestion can stimulate glucose Rd and EGP, 2) that postprandial inhibition of adipose lipolysis does not suppress EGP, and 3) that physiological hyperglucagonemia can override the hepatic actions of insulin, rendering the liver unresponsive to insulin-mediated EGP suppression. Finally, we argue that glucagon is a bona fide postprandial hormone that evolved to concurrently and synergistically work with insulin to regulate glucose, amino acid, and nitrogen metabolism. These findings may have implications for glucagon receptor antagonist or agonist-based therapies.
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Hormonal and Metabolic Responses to a Single Bout of Resistance Exercise in Prader-Willi Syndrome
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Rubin, DA, Clark, SJ, Haqq, AM, Castner, DM, Ng, J, Judelson, DA
Hormone research in paediatrics. 2017;(3):153-161
Abstract
BACKGROUND Prader-Willi syndrome (PWS) is characterized by excessive adiposity. Excess adiposity negatively affects hormonal and metabolic responses to aerobic exercise. This study determined whether PWS and/or adiposity affected hormonal and metabolic responses to resistance exercise. METHODS Eleven children with PWS (11.4 ± 3.1 years, 43.9 ± 7.5% body fat), 12 lean children (9.3 ± 1.4 years, 18.3 ± 4.9% body fat), and 13 obese children (9.6 ± 1.3 years, 40.3 ± 5.2% body fat) participated. The children stepped onto an elevated platform while wearing a weighted vest for 6 sets of 10 repetitions per leg (sets separated by 1 min of rest). For the children with PWS, the platform height was 23.0 cm and vest load was computed as (20% of stature × 50% of lean body mass)/23.0 cm. For the controls, the platform height was 20% of the stature and vest load 50% of the lean body mass. Blood samples were obtained before, immediately after, and during recovery from exercise (+15, +30, and +60 min). RESULTS All groups had similar catecholamine, insulin, and glucagon responses. The groups showed no major differences in glucose and lactate levels. The PWS children demonstrated earlier increases in fatty acids during recovery and higher glycerol and ketone levels than the controls. CONCLUSION The PWS children demonstrated largely intact hormonal, glycolytic, and lipolytic responses to lower-body resistance exercise. In PWS, elevated ketone levels suggest an incomplete fat oxidation.
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Adding Glucagon-Stimulated GH Testing to the Diagnostic Fast Increases the Detection of GH-Sufficient Children.
Hawkes, CP, Grimberg, A, Dzata, VE, De Leon, DD
Hormone research in paediatrics. 2016;(4):265-72
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Abstract
BACKGROUND/AIMS: The evaluation of children with unexplained hypoglycemia may include a diagnostic fast. However, low growth hormone (GH) concentration during hypoglycemia is not specific to GH deficiency (GHD). The aim of this study was to determine if serial GH measurement following glucagon administration, in the setting of a diagnostic fast, would increase the number of children identified as not having GHD. METHODS We conducted a retrospective chart review of children who had serial GH measurements performed after glucagon administration at the end of a diagnostic fast. Glucagon was administered at the end of the fasting study, and GH was measured every 30 min for 210 min. RESULTS Of the 29 children in this series, only 3 (10%) had GH concentrations >7 ng/ml at the end of the fast, which increased by 16 (55%) after serial GH testing. The percentages of samples with GH concentrations >7 ng/ml were: 10% at baseline, and 25, 39, 41, 41, 33, 43, and 0% every 30 min thereafter. CONCLUSION Additional GH measurements after glucagon administration following a diagnostic fast can improve the identification of children without GHD and thereby save them unnecessary GH stimulation testing and potential GH treatment.
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Comparison of a carbohydrate-free diet vs. fasting on plasma glucose, insulin and glucagon in type 2 diabetes.
Nuttall, FQ, Almokayyad, RM, Gannon, MC
Metabolism: clinical and experimental. 2015;(2):253-62
Abstract
OBJECTIVE Hyperglycemia improves when patients with type 2 diabetes are placed on a weight-loss diet. Improvement typically occurs soon after diet implementation. This rapid response could result from low fuel supply (calories), lower carbohydrate content of the weight-loss diet, and/or weight loss per se. To differentiate these effects, glucose, insulin, C-peptide and glucagon were determined during the last 24 h of a 3-day period without food (severe calorie restriction) and a calorie-sufficient, carbohydrate-free diet. RESEARCH DESIGN Seven subjects with untreated type 2 diabetes were studied. A randomized-crossover design with a 4-week washout period between arms was used. METHODS Results from both the calorie-sufficient, carbohydrate-free diet and the 3-day fast were compared with the initial standard diet consisting of 55% carbohydrate, 15% protein and 30% fat. RESULTS The overnight fasting glucose concentration decreased from 196 (standard diet) to 160 (carbohydrate-free diet) to 127 mg/dl (fasting). The 24 h glucose and insulin area responses decreased by 35% and 48% on day 3 of the carbohydrate-free diet, and by 49% and 69% after fasting. Overnight basal insulin and glucagon remained unchanged. CONCLUSIONS Short-term fasting dramatically lowered overnight fasting and 24 h integrated glucose concentrations. Carbohydrate restriction per se could account for 71% of the reduction. Insulin could not entirely explain the glucose responses. In the absence of carbohydrate, the net insulin response was 28% of the standard diet. Glucagon did not contribute to the metabolic adaptations observed.
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Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients.
Yabe, D, Kuroe, A, Watanabe, K, Iwasaki, M, Hamasaki, A, Hamamoto, Y, Harada, N, Yamane, S, Lee, S, Murotani, K, et al
Journal of diabetes and its complications. 2015;(3):413-21
Abstract
AIMS: Hypersecretion of glucagon and reduced insulin secretion both contribute to hyperglycemia in type 2 diabetes (T2DM). However, the relative contributions of impaired glucagon and insulin secretions in glucose excursions at the various stages of T2DM development remain to be determined. METHODS The responses of glucagon and insulin as well as those of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were examined before and after ingestion of glucose or mixed meal in Japanese subjects with normal or impaired glucose tolerance (NGT and IGT) and in non-obese, untreated T2DM of short duration. RESULTS In OGTT, T2DM showed a rise in glucagon at 0-30 min, unlike NGT and IGT, along with reduced insulin. In MTT, all three groups showed a rise in glucagon at 0-30 min, with that in T2DM being highest, while T2DM showed a significant reduction in insulin. Linear regression analyses revealed that glucose area under the curve (AUC)0-120 min was associated with glucagon-AUC0-30 min and insulin-AUC0-30 min in both OGTT and MTT. Total and biologically intact GIP and GLP-1 levels were similar among the three groups. CONCLUSIONS Disordered early phase insulin and glucagon secretions but not incretin secretion are involved in hyperglycemia after ingestion of nutrients in T2DM of even a short duration.
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Prior exercise does not alter the incretin response to a subsequent meal in obese women.
Nyhoff, LM, Heden, TD, Leidy, HJ, Winn, NC, Park, YM, Thyfault, JP, Kanaley, JA
Peptides. 2015;:94-9
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Abstract
Prior research has shown an increase in GLP-1 concentrations during exercise but this exercise bout was conducted postprandially. The purpose of this study was to examine the incretin response to a meal following an exercise bout of different intensities in obese subjects. Eleven women (BMI>37.3±7.0kg/m(2); Age 24.3±4.6year) participated in 3 counter- balanced study days, where a standardized meal was preceded by: (1) No exercise (NoEx), (2) ModEx (55% VO2max), and (3) IntEx (4min (80% VO2max)/3min (50% VO2max). Frequent blood samples were analyzed for glucose, lactate, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and C-peptide concentrations throughout 280min of testing. Glucose concentrations were not different between conditions during exercise or meals. There were no differences between conditions in insulin levels during exercise and recovery, but postprandial insulin incremental area under the curve was lower in ModEx vs. NoEx (p<0.01). GIP and GLP-1 levels were not different between conditions during exercise, but during exercise recovery, GLP-1 concentrations were higher in ModEx vs. NoEx (p=0.03). The meal increased the incretin responses (p<0.01) but this response was not affected by prior exercise. Glucagon concentrations increased with exercise (p<0.05) and continued to be elevated during recovery, with the greatest increase with IntEx compared with NoEx (p<0.05). No differences between conditions were detected for hepatic insulin extraction, insulin secretion, or insulin sensitivity. Exercise prior to an evening meal has no impact on the incretin response to the subsequent meal, yet insulin concentrations were lower during the meals that followed exercise. Exercise intensity had no impact on this response.
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Evaluation of long-term treatment effect in a type 1 diabetes intervention trial: differences after stimulation with glucagon or a mixed meal.
Pozzilli, P, Raz, I, Peled, D, Elias, D, Avron, A, Tamir, M, Eren, R, Dagan, S, Cohen, IR
Diabetes care. 2014;(5):1384-91
Abstract
OBJECTIVE Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes. RESEARCH DESIGN AND METHODS A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson's correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (AUC). RESULTS The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74-0.9). However, the correlations between the AUC were much weaker (r = 0.39-0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4-11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose. CONCLUSIONS Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.
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Regulation of glucagon secretion in normal and diabetic human islets by γ-hydroxybutyrate and glycine.
Li, C, Liu, C, Nissim, I, Chen, J, Chen, P, Doliba, N, Zhang, T, Nissim, I, Daikhin, Y, Stokes, D, et al
The Journal of biological chemistry. 2013;(6):3938-51
Abstract
Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace the responses of amino acids and other potential neurotransmitters to stimulation with [U-(13)C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose: one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets, we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling α-cell secretory responses to metabolic fuels.
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Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study.
DeFronzo, RA, Okerson, T, Viswanathan, P, Guan, X, Holcombe, JH, MacConell, L
Current medical research and opinion. 2008;(10):2943-52
Abstract
BACKGROUND This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients. METHODS This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33 +/- 5 kg/m(2); HbA(1c): 8.5 +/- 1.2%; 2-h PPG: 245 +/- 65 mg/dL. Patients received exenatide (5 microg BID for 1 week, then 10 microg BID for 1 week) or sitagliptin (100 mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581). RESULTS After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133 +/- 6 mg/dL versus 208 +/- 6 mg/dL, p < 0.0001 (evaluable, N = 61). Switching from exenatide to sitagliptin increased 2-h PPG by +73 +/- 11 mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by -76 +/- 10 mg/dL. Postprandial glucose parameters (AUC, C(ave), C(max)) were lower with exenatide than sitagliptin (p < 0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (-15 +/- 4 mg/dL vs. -19 +/- 4 mg/dL, p = 0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50 +/- 0.26, p = 0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88 +/- 0.03, p = 0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90 +/- 0.04, p = 0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56 +/- 0.05, p < 0.0001). Exenatide reduced total caloric intake compared to sitagliptin (-134 +/- 97 kcal vs. +130 +/- 97 kcal, p = 0.0227, N = 25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature. CONCLUSIONS Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.