Glucagon-like Peptide-1 Responses Research Articles

A Low Dose of Pasireotide Prevents Hypoglycemia in Roux-en-Y Gastric Bypass-Operated Individuals.

Post-bariatric hypoglycemia (PBH) can be a serious complication after Roux-en-Y gastric bypass (RYGB), and treatment with somatostatin analogs has been suggested. We investigated the acute effects of three different doses of pasireotide (75 μg, 150 μg, and 300 μg) on the postprandial glucose metabolism in five RYGB-operated individuals with PBH using a mixed meal test. All three doses prevented hypoglycemia but were associated with a notable increase in postprandial hyperglycemia. Moreover, all doses greatly diminished insulin, C-peptide, and glucagon-like peptide-1 responses. Considering its strong hyperglycemic potential, we suggest that pasireotide should be administered carefully in RYGB-operated individuals with PBH, and if necessary, a 75 μg dose seems sufficient to prevent hypoglycemia.

Subjects with high fasting insulin also have higher postprandial GLP-1 and glucagon levels than controls with lower insulin

Little is known about postprandial release of serum ghrelin, glucagon, and glucagon-like peptide-1 (GLP-1) in relation with differing fasting insulin levels. We hypothesized that these hormones are affected by insulin resistance, and hence, we compared different postprandial responses of GLP-1, glucagon, and ghrelin in subjects with relatively high (RHI) or relatively low (RLI) fasting insulin levels. The trial was a randomized crossover study with 4 different meal conditions. Fourteen nonobese or obese, healthy, men and 14 women were randomly assigned to the order of supervised intake of a 750 kcal drink with the same protein contents but with 20 energy-percent (E%) or 55 E% from carbohydrates, and the remaining energy from fat. Participants were also randomized to consume the drinks as 1 large beverage or as five 150-kcal portions every 30 minutes. The 28 subjects were divided into 2 equally sized groups based on fasting insulin levels. Statistics were done with general linear mixed model. Fasting insulin levels were 3-fold higher in the group with RHI compared with the RLI group (RHI: 1004 ± 510 pg/mL, RLI: 324 ± 123 pg/mL, P < .0005). Serum GLP-1 was highest in the RHI group after both single meals and after 5 drinks and following high- and low-carbohydrate meals (both P ≤ .002), and this was the case also for glucagon levels (both P ≤ .018), whereas ghrelin levels did not differ between groups. Thus, subjects with RHI displayed both higher postprandial serum GLP-1 and glucagon than the participants with RLI, suggesting that glucagon could play a role in the advent of dysglycemia by insulin resistance.

Greater glucagon-like peptide-1 responses to oral glucose are associated with lower central and peripheral blood pressures

Background and aimCardiovascular diseases (CVDs) are globally the leading cause of death and hypertension is a significant risk factor. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with decreases in blood pressure and CVD risk. Our aim was to investigate the association between endogenous GLP-1 responses to oral glucose and peripheral and central haemodynamic measures in a population at risk of diabetes and CVD.MethodsThis cross-sectional study included 837 Danish individuals from the ADDITION-PRO cohort (52% men, median (interquartile range) age 65.5 (59.8 to 70.7) years, BMI 26.1 (23.4 to 28.5) kg/m2, without antihypertensive treatment and known diabetes). All participants received an oral glucose tolerance test with measurements of GLP-1 at 0, 30 and 120 min. Aortic stiffness was assessed by pulse wave velocity (PWV). The associations between GLP-1 response and central and brachial blood pressure (BP) and PWV were assessed in linear regression models adjusting for age and sex.ResultsA greater GLP-1 response was associated with lower central systolic and diastolic BP of − 1.17 mmHg (95% confidence interval (CI) − 2.07 to − 0.27 mmHg, P = 0.011) and − 0.74 mmHg (95% CI − 1.29 to − 0.18 mmHg, P = 0.009), respectively, as well as lower brachial systolic and diastolic BP of − 1.27 mmHg (95% CI − 2.20 to − 0.33 mmHg, P = 0.008) and − 1.00 (95% CI − 1.56 to − 0.44 mmHg, P = 0.001), respectively. PWV was not associated with GLP-1 release (P = 0.3). Individuals with the greatest quartile of GLP-1 response had clinically relevant lower BP measures compared to individuals with the lowest quartile of GLP-1 response (central systolic BP: − 4.94 (95% CI − 8.56 to − 1.31) mmHg, central diastolic BP: − 3.05 (95% CI − 5.29 to − 0.80) mmHg, brachial systolic BP: − 5.18 (95% CI − 8.94 to − 1.42) mmHg, and brachial diastolic BP: − 2.96 (95% CI − 5.26 to − 0.67) mmHg).ConclusionGreater glucose-stimulated GLP-1 responses were associated with clinically relevant lower central and peripheral blood pressures, consistent with beneficial effects on the cardiovascular system and reduced risk of CVD and mortality.Trial registration ClinicalTrials.gov Identifier: NCT00237549. Retrospectively registered 10 October 2005

Loss of incretin effect contributes to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

To investigate the incretin axis in people with cystic fibrosis. Adults with cystic fibrosis-related diabetes, cystic fibrosis without diabetes, and controls (adults without cystic fibrosis and without diabetes) underwent an oral glucose tolerance test and then a closely matched isoglycaemic i.v. glucose infusion. On each occasion, glucose, insulin, C-peptide, total and active glucagon-like peptide-1 and gastric inhibitory polypeptide responses were recorded and incremental areas under curves were calculated for 60 and 240 min. Five adults with cystic fibrosis-related diabetes, six with cystic fibrosis without diabetes and six controls, matched for age and BMI, completed the study. Glucose during oral glucose tolerance test closely matched those during isoglycaemic i.v. glucose infusion. The calculated incretin effect was similar in the control group and the cystic fibrosis without diabetes group (28% and 29%, respectively), but was lost in the cystic fibrosis-related diabetes group (cystic fibrosis-related diabetes vs control group: -6% vs 28%; p=0.03). No hyposecretion of glucagon-like peptide-1 or gastric inhibitory polypeptide was observed; conversely, 60-min incremental area under the curve for total glucagon-like peptide-1 was significantly higher in the cystic fibrosis-related diabetes group than in the control group [1070.4 (254.7) vs 694.97 (308.1); p=0.03] CONCLUSIONS: The incretin effect was lost in cystic fibrosis-related diabetes despite adequate secretion of the incretin hormones. These data support the concept that reduced incretin hormone insulinotropic activity contributes significantly to postprandial hyperglycaemia in cystic fibrosis-related diabetes.

An impaired glucagon-like peptide-1 response is associated with prediabetes in polycystic ovary syndrome with obesity.

ObjectiveImpaired glucose homeostasis in polycystic ovary syndrome (PCOS) is associated with obesity, age, and disease phenotype. This study aimed to investigate the glucagon-like peptide-1 (GLP-1) response in patients with obesity and PCOS with normal glucose tolerance (NGT) or prediabetes.MethodsTwenty-six women with obesity and PCOS were included. Thirteen women had NGT and 13 had prediabetes. Serum glucose, insulin, and GLP-1 levels were measured during an oral glucose tolerance test. Beta-cell function and insulin resistance were determined.ResultsWomen with prediabetes had significantly lower GLP-1 levels than did those with NGT after a glucose load. GLP-1 levels <3.02 pM at 120 minutes were associated with prediabetes. Women with prediabetes had a lower oral glucose insulin sensitivity (OGIS) index and greater amount of visceral adipose tissue than did those with NGT. Plasma GLP-1 levels at 120 minutes were correlated with visceral adiposity and the OGIS index. A change in GLP-1 levels was correlated with a family history of type 2 diabetes.ConclusionThe GLP-1 response is lower in patients with obesity, PCOS, and prediabetes than in those with obesity, PCOS, and NGT. Further investigation of the GLP-1 response as a potential separate risk factor for prediabetes in PCOS is required.

Incretin Hormones: The Link between Glycemic Index and Cardiometabolic Diseases.

This review aimed to describe the potential mechanisms by which incretin hormones could mediate the relationship between glycemic index and cardiometabolic diseases. A body of evidence from many studies suggests that low glycemic index (GI) diets reduces the risk for type 2 diabetes and coronary heart disease. In fact, despite the extensive literature on this topic, the mechanisms underlying unfavorable effects of high GI foods on health remain not well defined. The postprandial and hormonal milieu could play a key role in the relationship between GI and cardiovascular risk. Incretin hormones, glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important regulators of postprandial homeostasis by amplifying insulin secretory responses. Response of GIP and GLP-1 to GI have been studied more in depth, also by several studies on isomaltulose, which have been taken as an ideal model to investigate the kinetics of incretin secretion in response to foods’ GI. In addition, extrapancreatic effects of these incretin hormones were also recently observed. Emerging from this have been exciting effects on several targets, such as body weight regulation, lipid metabolism, white adipose tissue, cardiovascular system, kidney, and liver, which may importantly affect the health status.

Effect of Laparoscopic Sleeve Gastrectomy on Static and Dynamic Measures of Glucose Homeostasis and Incretin Hormone Response 4-Years Post-Operatively

IntroductionThere is limited literature available on the long-term effect of bariatric surgery especially laparoscopic sleeve gastrectomy (LSG) on the incretin hormone response.AimOur primary aim was to investigate changes in glucose metabolism and incretin hormone responses in participants with impaired glucose regulation approximately 4 years after LSG. The secondary aim was to examine the long-term incretin hormone changes of biliopancreatic diversion (BPD).MethodA non-randomised prospective study comprising of 10 participants undergoing LSG and 6 participants undergoing BPD. Serial measurements of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were performed during an oral glucose tolerance test pre-operatively and 1 month, 6 months and at approximately 4–7 years post-operatively. Area under the curve (AUC) was examined at 60 and 120 min.ResultsIn the LSG group, a significant reduction in 2-h plasma glucose (2 h PG), HbA1c and HOMA-IR was observed at 4 years. Compared with pre-operative levels, significant increases in post-glucose GLP-1 secretion were observed at 1 and 6 months, but not maintained at 4 years. A linear increase was seen in post-glucose GIP response at 1 month and 6 months and 4 years. Within the BPD group, a reduction in HbA1c along with an increase GLP-1 response was observed at 7 years.ConclusionAn increase in GLP-1 response was not preserved at 4 years, but a significant increase in GIP response was observed along with improved glycaemic control following LSG.

Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients.

SummaryGeneration of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introduced transcription factors, critical for β-cell development and function, in differentiating human induced pluripotent stem cells (PSCs) and assessed the impact on the functionality of derived β-cell (psBC) progeny. A perifusion system revealed stepwise transduction of the PDX1, NEUROG3, and MAFA triad (PNM) enabled in vitro generation of psBCs with glucose and GLP-1 responsiveness within 3 weeks. PNM transduction upregulated genes associated with glucose sensing, insulin secretion, and β-cell maturation. In recipient diabetic mice, PNM-transduced psBCs showed glucose-responsive insulin secretion as early as 1 week post transplantation. Thus, enhanced pre-emptive β-cell specification of PSCs by PNM drives generation of glucose- and incretin-responsive psBCs in vitro, offering a competent tissue-primed biotherapy.

Effect of milk protein composition and amount of β-casein on growth performance, gut hormones, and inflammatory cytokines in an in vivo piglet model

The objective of this work was to better understand the effect of differences in milk protein composition, and specifically, a change in β-casein to total casein in a milk-based matrix, on growth performance and metabolic and inflammatory responses using a piglet model. Three formulas were optimized for piglets, with similar metabolizable energy, total protein content, and other essential nutrients. Only the protein type and ratio varied between the treatments: the protein fraction of the control diet contained only whey proteins, whereas 2 other matrices contained a whey protein to casein ratio of 60:40, and differed in the amount of β-casein (12.5 and 17.1% of total protein). Piglets fed formula containing whey proteins and caseins, regardless of the concentration of β-casein, showed a significantly higher average daily gain, average daily feed intake, and feed efficiency compared with piglets consuming the formula with only whey protein. Consumption of the formula containing only whey protein showed higher levels of plasma glucagon-like peptide-1 and ghrelin compared with the consumption of formula containing casein and whey protein. A positive correlation was observed between postprandial time and glucagon-like peptide-1 response. The intestinal pro-inflammatory cytokine tumor necrosis factor α increased significantly in piglets fed the whey protein/casein diet compared with those fed whey protein formula. All formula-fed piglets showed a lower level of IL-6 cytokine compared with the ad libitum sow-fed piglets, regardless of composition. No significant differences in the anti-inflammatory IL-10 concentration were observed between treatment groups. Milk protein composition contributed to the regulation of piglets' metabolic and physiological responses, with whey protein/casein formula promoting growth performance and a different immune regulatory balance compared with a formula containing only whey protein. Results indicated no differences between treatments containing different levels of β-casein.

Gastric Emptying and Distal Gastrectomy Independently Enhance Postprandial Glucagon-Like Peptide-1 Release After a Mixed Meal and Improve Glycemic Control in Subjects Having Undergone Pancreaticoduodenectomy.

New-onset diabetes frequently resolves after pancreaticoduodenectomy (PD). Glucagon-like peptide-1 (GLP-1) conceivably is involved as its release is enhanced by rapid gastric emptying and distal bowel exposure to nutrients. We aimed at studying factors associated with GLP-1 release after PD. Fifteen PD subjects with distal gastrectomy (Whipple) and 15 with pylorus preservation were evaluated. A test meal containing 1 g paracetamol to measure gastric emptying was ingested. Blood for the measurement of paracetamol, glucose, insulin, and GLP-1 was drawn at baseline and 10, 20, 30, 60, 90, 120, 150, and 180 minutes thereafter. The Matsuda index of insulin sensitivity was calculated. In univariate analysis, gastric emptying correlated with GLP-1. Glucagon-like peptide-1 responses to the modes of operation did not differ. Multiple regression analysis confirmed gastric emptying and Whipple versus pylorus-preserving pancreaticoduodenectomy as independent predictors of GLP-1 release. The Matsuda index of insulin sensitivity correlated with GLP-1 concentrations and inversely with body mass index. Patients after Whipple procedure revealed lower glycated hemoglobin as compared with pylorus-preserving pancreaticoduodenectomy. Following PD, the postprandial GLP-1 release seems to be enhanced by rapid gastric emptying and to improve insulin sensitivity. Partial gastrectomy versus pylorus preservation enhanced the release of GLP-1, conceivably because of greater distal bowel exposure to undigested nutrients.

Differential effects of a 40-hour fast and bile acid supplementation on human GLP-1 and FGF19 responses.

Bile acids, glucagon-like peptide-1 (GLP-1), and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1, and FGF19. First, we investigated the postprandial response to 40-h fast. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. We performed two separate observational randomized crossover studies on healthy, lean men. In experiment 1: we tested 4-h mixed meal after an overnight fast and a 40-h fast. In experiment 2, we tested a 4-h mixed meal test with and without gDCA supplementation. Both studies measured postprandial glucose, insulin, bile acids, GLP-1, and FGF19. In experiment 1, 40 h of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA levels at specific time points. In experiment 2, administration of gDCA increased GLP-1 levels and lowered late postprandial glucose without effect on FGF19. Energy expenditure was not affected by gDCA administration. Unexpectedly, 40 h of fasting increased both GLP-1 and FGF19, where the former appeared bile acid independent and the latter bile acid dependent. Second, a single dose of gDCA increased postprandial GLP-1. Therefore, our data add complexity to the physiological regulation of the enterokines GLP-1 and FGF19 by bile acids.

1827-P: Higher Glucagon-Like Peptide-1 Response and Lower Beta-Cell Glucose Sensitivity Are Associated with Increased Glycemic Variability among Individuals with Prediabetes

Background: Increased glycemic variability (GV) is thought to represent abnormalities of glucose homeostasis in the progression from prediabetes to diabetes. We evaluated the association between GV, beta-cell function and glucagon-like peptide 1 (GLP-1) response among individuals with prediabetes. Methods: 61 individuals with prediabetes (age Mean±SD 56±9 years, 31 male) each wore a blinded continuous glucose monitor (Medtronic iPro2) for 72 hours. Standard deviation (SD) and coefficient of variation (CV) were calculated from CGM glucose. Participants underwent a 2-hour mixed-meal tolerance test with measurement of insulin, C-peptide, GLP-1 for modelling of beta-cell function. Results: Early and late GLP-1/glucose ratio were positively correlated with CGM sensor glucose SD (r = 0.29, p=0.02 and r= 0.28 p = 0.048 respectively). Beta-cell glucose sensitivity (βCGS) was negatively correlated with SD (r = -0.28, p = 0.03). In multivariate analyses, only βCGS and GLP-1 response were significant predictors of SD, while early phase insulin and insulin secretion rate predicted average sensor glucose but not indices of GV. Conclusions: Higher GLP-1 response and reduced βCGS are associated with greater glucose fluctuations in the prediabetic range. Disclosure E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. A. Luk: None. J. Ling: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. E. Ferrannini: None. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp &amp; Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare.

2488-PUB: The Role of GLP-1 in Metabolic Responses during Sepsis

Sepsis is characterized by a dysregulated immune response that can result in end organ damage and is the number one cause of death in the ICU. Among the hormones that are altered by sepsis, there is an increase in the gut peptide glucagon-like peptide-1 (GLP-1). Traditionally, GLP-1 is important for regulating glucose homeostasis and has previously been linked to appetite inhibition. However, its function during sepsis remains unknown. GLP-1 is coded by the preproglucagon gene (Gcg) and is expressed not only by intestinal endocrine cells but also in pancreatic α-cells. Previously, we have shown increases in plasma GLP-1 in response to LPS are contributed to by both pancreatic and intestinal sources and that either pancreatic or intestinal sources of GLP-1 are sufficient to maintain glucose responses to LPS. Because T2DM patients have an increased susceptibility to sepsis, the goal of this study was to determine if high-fat diet and impaired glucose tolerance change the metabolic or appetitive inhibition response during sepsis. To model sepsis, we administered lipopolysaccharide (LPS) to C57BL/6 mice who had been on high-fat diet (HFD) or chow for 12 weeks. We observed that compared to vehicle treatment, LPS significantly increased plasma levels of GLP-1 in both HFD and chow-fed mice, but plasma GLP-1 was significantly higher in HFD mice compared to chow-fed. HFD mice also had a greater decrease in glucose in response to LPS. Furthermore, we observed that HFD mice had increased and prolonged appetite inhibition in response to LPS. Future directions will explore tissue-specific changes in GLP-1 response, source, and effectiveness during sepsis under the conditions of high-fat diet and impaired glucose control. Disclosure E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. M. Lehrke: Consultant; Self; Boehringer Ingelheim International GmbH, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S, Zafgen, Inc.

Starch Digestion Products Activate Enteroendocrine L-cells and Their Ileal Delivery Through the Diet Contributes to Weight Management in Mice (P08-005-19)

ObjectivesOur laboratory has recently shown that slowly digestible starch (SDS) that locationally digests to the ileum activates the gut-brain axis and reduces food intake in obese animals. Glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are the main appetite-suppressing (anorexigenic) peptides of the intestinal enterendocrine L-cells that regulate postprandial insulin levels and satiety signals. We investigated the in vitro L-cell chemosensation of α-amylase starch digestion products, named maltooligosaccharides (MOS), and using SDS to deliver MOS in vivo. MethodsMouse (STC-1) and human (NCI-H716) cells were used to test chemosensation response and release of GLP-1, OXM and PYY after MOS treatment. Differential gene expression and comparable global protein profiling of STC-1 cell treated with MOS was tested using RNA sequencing and LC-MS/MS analysis. Alginate-entrapped SDS microspheres that digest distally into the ileum were used to examine the role of SDS in the intervention and prevention of obesity in C57BL/6 J obese and lean mice, respectively. Body weight, food intake and body composition were monitored periodically. ResultsMOS exhibited significantly higher stimulatory effect on GLP-1 and OXM secretion in mouse and human L-cells, respectively, compared to glucose. Multi-omics analysis showed that MOS induced exocytosis of GLP-1- and OXM-containing vesicles and did not induce positive regulation of the proglucagon gene suggesting that secretion, but not synthesis, of the proglucagon gene products was enhanced by MOS. In vivo Results showed that 20% SDS in low-fat diets significantly improved weight loss and food intake reduction in obese mice. Similarly, 15% SDS in high-fat diets showed significant reduction in body fat %, increase in lean body mass, and considerable reduction in weight gain rate and food intake in lean mice fed on high-fat diets. ConclusionsWe propose several insights into L-cell sensation of dietary starch-degraded MOS delivered by the consumption of slowly digestible starch. MOS exhibit unique influences on L-cell sensitivity and gut hormone productivity. The intricate role of dietary carbohydrates on gut physiological response, related to satiety and food intake could be a new approach for design of foods for obesity prevention. Funding SourcesWhistler Center for Carbohydrate Research, Purdue University. Supporting Tables, Images and/or Graphs▪▪

1145-P: Acarbose-Induced Glucagon-Like Peptide-1 Secretion Contributes to the Glucose-Lowering Effect of Acarbose

The glucose-lowering alpha-glucosidase inhibitor acarbose, is believed to act by delaying digestion and absorption of dietary carbohydrates. It has been shown that acarbose increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes (T2D). In a double-blinded, placebo-controlled, randomized, cross-over study, 15 participants with metformin-treated T2D (age 57-85 years, BMI 23.6-34.6 kg/m2, HbA1c 40-74 mmol/mol (5.8-8.9%)) were subjected to two 14-day treatment periods with acarbose (uptitrated to 100 mg TID) and placebo treatment, respectively, with an interposed 6-week wash-out period. At the end of each treatment period, we performed two randomized 4-hour mixed meal tests (including acetaminophen for evaluation of gastric emptying) with concomitant infusion of exendin(9-39)NH2 (1000 pmol/kg/min for 20 min followed by 450 pmol/kg/min for 240 min) and saline, respectively. Acarbose treatment lowered fasting plasma glucose (P&amp;lt;0.0001) and postprandial plasma glucose excursions (P&amp;lt;0.0001) compared to placebo. Furthermore, acarbose almost doubled the postprandial GLP-1 response (P=0.0032), reduced postprandial glucose-dependent insulinotropic polypeptide (P&amp;lt;0.0001) and delayed gastric emptying (P=0.0395). No absolute difference was seen in exendin(9-39)NH2-induced postprandial plasma glucose changes between treatment periods (P=0.54), but relative to postprandial glucose tolerance during exendin(9-39)NH2 infusions, the change (i.e., contribution of GLP-1) was significantly higher during acarbose (56±26%) compared to placebo treatment (37±15%) (P=0.042). We conclude that acarbose treatment robustly stimulates GLP-1 secretion in patients with T2D and that acarbose-induced GLP-1 secretion contributes to the glucose-lowering effect of acarbose. Disclosure N.B. Dalsgaard: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Hansen: None. N.L. Hansen: None. S. Stensen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.

Fructose Consumption Contributes to Hyperinsulinemia in Adolescents With Obesity Through a GLP-1-Mediated Mechanism.

The consumption of high-fructose beverages is associated with a higher risk for obesity and diabetes. Fructose can stimulate glucagon-like peptide 1 (GLP-1) secretion in lean adults, in the absence of any anorexic effect. We hypothesized that the ingestion of glucose and fructose may differentially stimulate GLP-1 and insulin response in lean adolescents and adolescents with obesity. We studied 14 lean adolescents [four females; 15.9 ± 1.6 years of age; body mass index (BMI), 21.8 ± 2.2 kg/m2] and 23 adolescents with obesity (five females; 15.1 ± 1.6 years of age; BMI, 34.5 ± 4.6 kg/m2). Participants underwent a baseline oral glucose tolerance test to determine their glucose tolerance and estimate insulin sensitivity and β-cell function [oral disposition index (oDIcpep)]. Eligible subjects received, in a double-blind, crossover design, 75 g of glucose or fructose. Plasma was obtained every 10 minutes for 60 minutes for the measures of glucose, insulin, and GLP-1 (radioimmunoassay) and glucose-dependent insulinotropic polypeptide (GIP; ELISA). Incremental glucose and hormone levels were compared between lean individuals and those with obesity by a linear mixed model. The relationship between GLP-1 increment and oDIcpep was evaluated by regression analysis. Following the fructose challenge, plasma glucose excursions were similar in both groups, yet the adolescents with obesity exhibited a greater insulin (P < 0.001) and GLP-1 (P < 0.001) increase than did their lean peers. Changes in GIP were similar in both groups. After glucose ingestion, the GLP-1 response (P < 0.001) was higher in the lean group. The GLP-1 increment during 60 minutes from fructose drink was correlated with a lower oDIcpep (r2 = 0.22, P = 0.009). Fructose, but not glucose, ingestion elicits a higher GLP-1 and insulin response in adolescents with obesity than in lean adolescents. Fructose consumption may contribute to the hyperinsulinemic phenotype of adolescent obesity through a GLP-1-mediated mechanism.

The inhibitory heterotrimeric G protein, Gz, regulates alpha‐cell active glucagon‐like peptide 1 (GLP‐1) levels

Biologically‐active glucagon‐like peptide 1 (GLP‐1) is a product of the proglucagon gene and amplifies glucose stimulated insulin secretion and promotes beta‐cell survival via stimulation of cAMP production. Neighboring alpha cells produce and secrete active GLP‐1 to influence beta‐cell function. Although alpha‐cell GLP‐1 production and secretion is poorly understood, cyclic AMP (cAMP) signaling promotes GLP‐1 released from gut L‐cells. Furthermore, cAMP signaling, through activation of cyclic AMP‐responsive transcription factors, may influence expression of the prohormone convertase enzymes specific for GLP‐1. Therefore, it is possible cAMP positively regulates both GLP‐1 production and secretion. Cyclic AMP levels are augmented by stimulatory heterotrimeric G proteins (Gs) and blocked by inhibitory heterotrimeric G proteins (Gi). A unique Gi family member, Gz, is expressed in both alpha and beta cells. Mice lacking the catalytic alpha subunit of Gz (Gαz), are protected from hyperglycemia in several diabetes model systems due to increased beta‐cell function and beta‐cell replication. At least part of this phenotype is beta‐cell autonomous. We hypothesized part of the protective phenotype may be due to loss of Gαz in the alpha‐cell and increased GLP‐1 production and/or secretion. To determine alpha‐cell levels of active GLP‐1, we used immunofluorescence to co‐localize active GLP‐1 to glucagon positive alpha cells in pancreas sections from wild‐type and Gαz‐null mice in different models of diabetes mellitus. Pancreas sections lacking Gαz displayed a dramatic increase in the percentage of cells that are both active GLP‐1 positive and glucagon positive compared to wild‐type counterparts. To determine if beta‐cell Gαz regulates alpha‐cell active GLP‐1 levels, we imaged pancreas sections from beta‐cell specific Gz‐null mice. Because published evidence has shown that alpha‐cell active GLP‐1 levels are elevated in pre‐diabetic and diabetic conditions, we determined if beta cell Gαz expression altered this compensatory increase in active GLP‐1 production. Whether increased active GLP‐1 levels correlated with increased active GLP‐1 secretion over time was determined by high‐sensitivity ELISA of islet incubation medium. Future experiments will focus whether the Gaz‐null mutation affects the production and/or secretion of active GLP‐1 in response to the glucolipotoxic conditions of severe insulin resistance and type 2 diabetes. Our results identify Gαz as a potential new therapeutic target to promote beta‐cell function and replication and underscore the role of intra‐islet cell‐cell communication in beta‐cell biology.Support or Funding InformationVA Merit Review Award: I01 BX003700‐01A1, VA BLR&amp;DR01: R01 DK102598, NIH/NIDDK Type 2 Diabetes/Fatty Acid Diet projects (started by 2016) American Diabetes Association Innovative Basic Science Award: 1‐14‐BS‐115 Type 1 Diabetes projects or projects using Gaz‐floxed miceJDRF J&amp;J Industry Partnership Award: 17‐2011‐608This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Novel Pharmacological Treatment of Post-prandial Hyperinsulinemic Hypoglycemia

Background: Post Roux-en-Y gastric bypass (RYGB) hyperinsulinemia hypoglycemia (HH) is presumably related to enhanced glucagon-like peptide-1 (GLP-1) response with partial pancreatectomy as recommended treatment. A new approach successfully uses short-acting GLP-1 mimetics, challenging assumptions about post-RYGB HH etiology and standard treatment.

The Pattern of Fasting and Post 75 G Glucose Loading of Glucagon-Like Peptide 1 Levels in Obese and Non-Obese Subjects.

BACKGROUND:Prevalence of obesity increased sharply recently; it was associated with an increased prevalence of several cardiometabolic diseases. Reduced glucagon-like peptide 1 (GLP-1) secretion is observed among obese subjects in many studies, and it may mediate the failure of insulin secretion response to food intake.AIM:To evaluate the pattern of fasting and post 75 g glucose loading of GLP-1 levels in obese and non-obese subjects.METHODS:An experimental study on the pattern of GLP-1 levels in fasting state and response in post 75 g glucose loading in obese and non-obese subjects, was conducted. Sixteen obese and 16 non-obese subjects were enrolled in the study, with age- and sex-matching in both groups. GLP-1 levels were measured at fasting state (0), 15, 30, 60, and 120 minutes post-glucose loading.RESULTS:The GLP-1 response to glucose loading were similar in obese and non-obese subjects, which increased from fasting state to post glucose loading and reaching the peak levels in 15 minutes, then declined until the end of observation. There was tendency that GLP-1 levels in fasting state and post glucose loading were lower in obese subjects compared to in non-obese subjects (in fasting state, 5.67 vs. 6.16 ng/mL, P = 0.338; in 15 minutes, 6.20 vs. 6.94 ng/mL, P = 0.239; in 30 minutes 6.20 vs. 6.90 ng/mL, P = 0.264; in 60 minutes, 5.77 vs. 6.12 ng/mL, P = 0.242), but the difference were not statistically significant, except in 120 minutes (5.24 vs. 6.67 ng/mL, P = 0.049; in obese and non-obese subjects, respectively). Similar finding was also seen in the pattern of response (delta) of GLP-1 from time-to-time observation among obese and non-obese subjects (0-15 minutes [0.52 vs. 0.8 ng/mL, P = 0.350], 0-30 minutes [0.53 vs. 0.74, P = 0.550], 0-60 minutes [0.11 vs. 0.31 ng/mL, P = 0.546], in 0-120 minute [-0.42 vs. 0.31, P = 0.006]).CONCLUSIONS:The patterns of GLP-1 levels post glucose loading were similar in obese and non-obese subjects which increased from fasting state to post glucose loading, reaching the peak levels in 15 minutes and then declined until the end of observation, except in non-obese subjects where the GLP-1 levels were increased at 120 minutes. There was a tendency of GLP-1 levels in fasting state and post-glucose loading to be lower in obese subjects compared within non-obese subjects.

Incretin dysfunction and hyperglycemia in cystic fibrosis: Role of acyl-ghrelin

BackgroundInsulin secretion is insufficient in cystic fibrosis (CF), even before diabetes is present, though the mechanisms involved remain unclear. Acyl-ghrelin (AG) can diminish insulin secretion and is elevated in humans with CF. MethodsWe tested the hypothesis that elevated AG contributes to reduced insulin secretion and hyperglycemia in CF ferrets. ResultsFasting AG was elevated in CF versus non-CF ferrets. Similar to its effects in other species, AG administration in non-CF ferrets acutely reduced insulin, increased growth hormone, and induced hyperglycemia. During oral glucose tolerance testing, non-CF ferrets had responsive insulin, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels and maintained normal glucose levels, whereas CF ferrets had insufficient responses and became hyperglycemic. Interestingly in wild-type ferrets, the acyl-ghrelin receptor antagonist [D-Lys3]-GHRP-6 impaired glucose tolerance, and abolished insulin, GLP-1, and GIP responses during glucose tolerance testing. By contrast, in CF ferrets [D-Lys3]-GHRP-6 improved glucose tolerance, enhanced the insulin-to-glucose ratio, but did not impact the already low GLP-1 and GIP levels. ConclusionsThese results suggest a mechanism by which elevated AG contributes to CF hyperglycemia through inhibition of insulin secretion, an effect magnified by low GLP-1 and GIP. Interventions that lower ghrelin, ghrelin action, and/or raise GLP-1 or GIP might improve glycemia in CF.