Postprandial Glucose-dependent Insulinotropic Polypeptide Research Articles

Impact of dipeptidyl peptidase-4 inhibitors on glucose-dependent insulinotropic polypeptide in type 2 diabetes mellitus: a systematic review and meta-analysis.

Glucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients. Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUCGIP) using a meal or oral glucose tolerance test were included. A random-effects model was used for data pooling after incorporating heterogeneity. Overall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference [SMD]: 0.77, 95% confidence interval [CI]: 0.48-1.05, P<0.001; I2=52%) and postprandial AUCGIP (SMD: 1.33, 95% CI: 1.02-1.64, P<0.001; I2=65%). Influence analysis by excluding one dataset at a time showed consistent results. Sensitivity analyses only including studies with radioimmunoassay showed also consistent results (fasting GIP: SMD: 0.75, 95% CI: 0.51-1.00, P<0.001; I2=0%; and postprandial AUCGIP: SMD: 1.48, 95% CI: 1.18-1.78, P<0.001; I2=54%). Further subgroup analyses demonstrated that the influence of DPP4 inhibitors on fasting and postprandial GIP levels in T2DM patients was not significantly changed by study characteristics such as study design, patient mean age, baseline glycated hemoglobin (HbA1c) concentration, body mass index (BMI), background treatment, treatment duration, or method for postprandial GIP measurement (all P for subgroup effects <0.05). The use of DPP4 inhibitors effectively increases the fasting and postprandial GIP concentrations in T2DM patients. https://www.crd.york.ac.uk/prospero/, identifier CRD42022356716.

The relative importance of Endogenously Secreted incretin hormones, GLP‐1 and GIP for Postprandial Glucose Tolerance and β‐Cell Function After Roux‐en‐Y Gastric Bypass and Sleeve Gastrectomy Surgery

Bariatric surgery procedures, namely Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) is increasingly used worldwide, have been shown to be the most effective strategy to induce and maintain weight loss as well as inducing long-term remission from type 2 diabetes among people with significant obesity. The mechanism for diabetes remission remains unclear and multi-factorial, although increased secretion of endogenous glucagon-like peptide 1 (GLP-1) hormones to improve postprandial β-cell function is widely considered to be the main mechanism for diabetes remission following RYGB. However, recent studies have shown that rate of remission between the two types of bariatric surgery procedures are similar but yet, the mechanism for remission above and beyond weight loss per se following SG is less clear. Beyond GLP-1, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. A study published in Diabetes Care have therefore studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in un-operated (CON), SG-operated, and RYGB-operated people with no history of diabetes. The investigator found that, as expected, postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. Interestingly, blockage of GLP-1R reduced β-cell glucose sensitivity and increased postprandial glucose responses in both surgical groups but had no effect in CON. Blockage of GIPR however reduced β-cell glucose sensitivity and increased postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. This study showed that while GLP-1 is the most important mediator of improved beta cell function after RYGB, both GLP-1 and GIP are equally important after SG. The combine benefits of GLP-1 and GIP following SG is interesting, given the recent emergence of the dual GLP-1 and GIP agonist for the treatment of diabetes and obesity. It would be interesting also to explore the relative role of Glucagon on beta cell function following both procedures.

The Importance of Endogenously Secreted GLP-1 and GIP for Postprandial Glucose Tolerance and β-Cell Function After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy Surgery.

Enhanced secretion of glucagon-like peptide 1 (GLP-1) seems to be essential for improved postprandial β-cell function after Roux-en-Y gastric bypass (RYGB) but is less studied after sleeve gastrectomy (SG). Moreover, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. We studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in unoperated (CON), SG-operated, and RYGB-operated people with no history of diabetes. Postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. The effect of GLP-1R versus GIPR blockade differed between groups. GLP-1R blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the surgical groups but had no effect in CON. GIPR blockade reduced β-cell glucose sensitivity and increased or tended to increase postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. Our results support that GIP is the most important incretin hormone in unoperated people, whereas GLP-1 and GIP are equally important after SG, and GLP-1 is the most important incretin hormone after RYGB.

Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study.

OBJECTIVEInhibiting sodium–glucose cotransporters (SGLTs) improves glycemic and cardiovascular outcomes in patients with type 2 diabetes (T2D). We investigated the differential impact of selective SGLT2 inhibition and dual inhibition of SGLT1 and SGLT2 on multiple parameters.RESEARCH DESIGN AND METHODSUsing a double-blind, parallel-group design, we randomized 40 patients with T2D and hypertension to receive the dual SGLT1 and SGLT2 inhibitor sotagliflozin 400 mg or the selective SGLT2 inhibitor empagliflozin 25 mg, with preexisting antihypertensive treatment, for 8 weeks. In an in-house testing site, mixed-meal tolerance tests (MMTTs) and other laboratory and clinical evaluations were used to study metabolic, intestinal, cardiovascular, and urinary parameters over 24 h.RESULTSChanges from baseline in glycemic and blood pressure control; intestinal, urine, and metabolic parameters; and cardiovascular biomarkers were generally similar with sotagliflozin and empagliflozin. During the breakfast MMTT, sotagliflozin significantly reduced incremental area under the curve (AUC) values for postprandial glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) and significantly increased incremental AUCs for postprandial glucagon-like peptide 1 (GLP-1) relative to empagliflozin, consistent with sotagliflozin-mediated inhibition of intestinal SGLT1. These changes waned during lunch and dinner MMTTs. Both treatments significantly lowered GIP incremental AUCs relative to baseline over the 14 h MMTT interval; the most vigorous effect was seen with sotagliflozin soon after start of the first meal of the day. No serious or severe adverse events were observed.CONCLUSIONSChanges from baseline in glycemic and blood pressure control, cardiovascular biomarkers, and other parameters were comparable between sotagliflozin and empagliflozin. However, sotagliflozin but not empagliflozin inhibited intestinal SGLT1 after breakfast as shown by larger changes in postprandial glucose, insulin, GIP, and GLP-1 AUCs, particularly after breakfast. Additional study is warranted to assess the clinical relevance of transient SGLT1 inhibition and differences in incretin responses (NCT03462069).

Receptor-Mediated Bioassay Reflects Dynamic Change of Glucose-Dependent Insulinotropic Polypeptide by Dipeptidyl Peptidase 4 Inhibitor Treatment in Subjects With Type 2 Diabetes.

Objective: We recently observed a greater increase in plasma levels of bioactive glucose-dependent insulinotropic polypeptide (GIP) than glucagon-like peptide 1 (GLP-1) using the receptor-mediated bioassays in the subjects with normal glycemic tolerance (NGT) treated with dipeptidyl peptidase 4 (DPP-4) inhibitors, which may be unappreciated using conventional enzyme-linked immunosorbent assays (ELISAs) during oral glucose tolerance test. Thus, we determined incretin levels in addition to glucagon level using the bioassays in type 2 diabetes mellitus (T2DM) subjects with or without treatment of DPP-4 inhibitor, to evaluate whether these assays can accurately measure bioactivity of these peptides.Methods: We performed single meal tolerance test (MTT) by using a cookie meal (carbohydrate 75.0 g, protein 8.0 g, fat 28.5 g) in the subjects with NGT (n = 9), the subjects with T2DM treated without DPP-4 inhibitor (n = 7) and the subjects with T2DM treated with DPP-4 inhibitor (n = 10). All subjects fasted for 10–12 h before the MTT, and blood samples were collected at 0, 30, 60, and 120 min. We used the cell lines stably cotransfected with human-form GIP, GLP-1 or glucagon receptor, and a cyclic adenosine monophosphate–inducible luciferase expression construct for the bioassays. We measured active GIP, active GLP-1, and glucagon by the bioassays. To evaluate the efficacy of bioassay, we measured identical samples via ELISA kits.Results: During the single MTT study, postprandial active GIP bioassay levels of T2DM with DPP-4 inhibitor treatment were drastically higher than those of NGT and T2DM without DPP-4 inhibitor, although the DPP-4 inhibitor-treated group showed moderate increase of active GIPELISA and active GLP-1bioassay, while active GLP-1bioassay levels of T2DM subjects without DPP-4 inhibitor were comparable to those of NGT subjects. During the serial MTT, administration of DPP-4 inhibitor significantly increased active GIPbioassay levels, but not active GLP-1bioassay.Conclusions: In comparison to conventional ELISA, receptor-mediated bioassay reflects dynamic change of GIP polypeptide by DPP-4 inhibitor treatment in subjects with type 2 diabetes.

Enhanced GIP Secretion in Obesity Is Associated with Biochemical Alteration and miRNA Contribution to the Development of Liver Steatosis.

Nutrient excess enhances glucose-dependent insulinotropic polypeptide (GIP) secretion, which may in turn contribute to the development of liver steatosis. We hypothesized that elevated GIP levels in obesity may affect markers of liver injury through microRNAs. The study involved 128 subjects (body mass index (BMI) 25–40). Fasting and postprandial GIP, glucose, insulin, and lipids, as well as fasting alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), cytokeratin-18, fibroblast growth factor (FGF)-19, and FGF-21 were determined. TaqMan low density array was used for quantitative analysis of blood microRNAs. Fasting GIP was associated with ALT [β = 0.16 (confidence interval (CI): 0.01–0.32)], triglycerides [β = 0.21 (95% CI: 0.06–0.36], and FGF-21 [β = 0.20 (95%CI: 0.03–0.37)]; and postprandial GIP with GGT [β = 0.17 (95%CI: 0.03–0.32)]. The odds ratio for elevated fatty liver index (>73%) was 2.42 (95%CI: 1.02–5.72) for high GIP versus low GIP patients. The miRNAs profile related to a high GIP plasma level included upregulated miR-136-5p, miR-320a, miR-483-5p, miR-520d-5p, miR-520b, miR-30e-3p, and miR-571. Analysis of the interactions of these microRNAs with gene expression pathways suggests their potential contribution to the regulation of the activity of genes associated with insulin resistance, fatty acids metabolism, and adipocytokines signaling. Exaggerated fasting and postprandial secretion of GIP in obesity are associated with elevated liver damage markers as well as FGF-21 plasma levels. Differentially expressed microRNAs suggest additional, epigenetic factors contributing to the gut–liver cross-talk.

Canagliflozin Increases Postprandial Total Glucagon-Like Peptide1 Levels in the Absence of α-Glucosidase Inhibitor Therapy in Patients with Type 2 Diabetes: A Single-Arm, Non-randomized, Open-Label Study.

IntroductionTo investigate canagliflozin-induced changes in postprandial total glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels in patients with type 2 diabetes mellitus (T2DM).MethodsForty-five patients with T2DM who had inadequate glycemic control (glycated hemoglobin ≥ 6.5%) with diet and exercise alone (n = 15, drug naïve) and in combination with either a stable dose of the α-glucosidase inhibitor acarbose (n = 15) or metformin (n = 15) received canagliflozin, a sodium-glucose cotransporter 2 inhibitor, at 100 mg once daily for 12 weeks. The primary endpoint was the change from baseline to week 12 in postprandial glucose and plasma levels of total GLP-1 and GIP during a meal tolerance test (MTT).ResultsCanagliflozin significantly reduced postprandial blood glucose (mean difference − 40.2 mg/mL at 60 min) and increased postprandial total GLP-1 (mean difference 1.8 pg/mL at 60 min) during an MTT. A transient reduction in the postprandial GIP level at only 30 min (mean difference − 80.3 pg/mL) during an MTT was observed. No changes in postprandial GLP-1 or GIP levels were seen after canagliflozin treatment as an add-on to acarbose in patients with T2DM. Acarbose treatment significantly decreased postprandial total GIP levels (P < 0.05) and tended to increase postprandial total GLP-1 levels (P = 0.07) compared to the other two treatments prior to canagliflozin.ConclusionCanagliflozin 100 mg increased postprandial total GLP-1 levels in the absence of acarbose, suggesting that it may upregulate GLP-1 secretion through delayed glucose absorption in the upper intestine, as with the α-glucosidase inhibitor.Trial RegistrationUniversity Hospital Medical Information Network, UMIN000018345.FundingMitsubishi Tanabe Pharma Corporation.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-00689-w) contains supplementary material, which is available to authorized users.

The study of metabolic improvement by nutritional intervention controlling endogenous GIP (Mini Egg study): a randomized, cross-over study

BackgroundGiven the major role of glucose-dependent insulinotropic polypeptide (GIP) in the regulation of adiposity, this study examined the effects induced by a diet based on the Japanese tradition (SMART WASHOKU) on the visceral fat area (VFA) and GIP secretions.MethodsOverweight/obese men (n = 21; mean age, 41.0 ± 9.0 years; mean BMI, 25.2 ± 2.0 kg/m2) without diabetes were placed on either a SMART WASHOKU or control meal for 2 weeks, in a randomized, cross-over setup with a four-week washout period.ResultsFor the meal tolerance test, blood samples were collected at 0, 30, 60, 120, 180, and 240 min post-meal, followed by measuring blood glucose, insulin, GIP, and glucagon-like peptide-1 (GLP-1) levels. Relative to a control meal, SMART WASHOKU meal yielded significantly lower plasma postprandial GIP concentrations (AUC: 700.0 ± 208.0 vs. 1117.0 ± 351.4 pmol/L・4 h, P < 0.05); however, between meals, there was no significant difference in the levels of GLP-1, peptide YY, and ghrelin. Compared to the control meal, SMART WASHOKU intervention significantly reduced VFA and the levels of LDL-cholesterol, triglyceride, and HbA1c after the chronic meal intervention.ConclusionsIn conclusion, a SMART WASHOKU meal may decrease VFA and improve metabolic parameters in overweight/obese men, possibly via suppressing GIP secretion.

Low-carbohydrate diet by staple change attenuates postprandial GIP and CPR levels in type 2 diabetes patients

AimsThe aim of this study is to investigate the effects of a low-carbohydrate staple food (i.e., low-carbohydrate bread) on glucose and lipid metabolism and pancreatic and enteroendocrine hormone secretion in comparison with meals containing normal-carbohydrate bread, without consideration of the carbohydrate content of the side dishes. MethodsT2DM patients (n = 41) were provided meals containing low-carbohydrate bread (LB) together with side dishes or normal-carbohydrate bread (NB) together with side dishes every other day as a breakfast. Blood glucose levels were evaluated by using a continuous glucose monitoring system; blood samples were collected before and 1 and 2 h after the breakfast. ResultsPostprandial blood glucose levels, plasma insulin, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma triglyceride were significantly lower and plasma glucagon levels were significantly higher in LB compared with those in NB. Plasma glucagon-like peptide-1 (GLP-1) levels did not differ in the LB and NB groups. ConclusionsThese results indicate that changing only the carbohydrate content of the staple food has benefits on glucose and lipid metabolism in T2DM patients concomitant with the decrease of insulin and GIP secretion, which ameliorate body weight gain and insulin resistance.

773-P: The Study of Metabolic Improvement by Nutritional Intervention Controlling Endogenous GIP (Mini Egg Study): A Randomized, Double-Blinded, Crossover Study

Objective: Given the major role of glucose-dependent insulinotropic polypeptide (GIP) in the regulation of adiposity, this study examined the effects induced by a diet based on the Japanese tradition (SMART WASHOKU) on the visceral fat area (VFA) and GIP secretions. Research Design and Methods: Overweight/obese men (n=21; mean age: 41 ± 9 y; mean BMI: 25.2 ± 2.0 kg/m2) without diabetes were placed on either a SMART WASHOKU (protein/fat=1.0, fiber/carb ratio≥0.063, and omega-3 PUFA/fat ratio ≥0.054) or isocaloric control meal for two weeks, in a randomized, double-blind, cross-over setup with a four-week washout period. For the meal tolerance test, blood samples were collected at 0, 30, 60, 120, 180, and 240 minutes post-meal, followed by measuring blood glucose, insulin, GIP, and glucagon-like peptide-1 (GLP-1) levels. Results: Relative to a control meal, SMART WASHOKU meal yielded significantly lower plasma postprandial GIP concentrations (AUC: 700.0 ± 208.0 vs. 1117.0 ± 351.4, P &amp;lt; 0.05); however, between meals, there was no significant difference in the levels of GLP-1, PYY, and ghrelin. Relative to control meal, a SMART WASHOKU intervention produced a modest but significant reduction of VFA in our participants (-3.4 ± 12.3 vs. -13.0 ± 9.3 cm2, P &amp;lt; 0.05). Compared with the control meal, SMART WASHOKU meal did not modify the concentrations of AST, ALT, GGT, and hs-CRP; however, we did observe a significantly reduced in the levels of LDL-cholesterol, triglyceride, and HbA1c. Conclusions: Based on our findings, we conclude that in overweight/obese men, a SMART WASHOKU meal would be helpful in decreasing VFA and improving metabolic parameters, possibly via suppressing GIP secretion. Disclosure N. Sakane: Board Member; Spouse/Partner; Kao Corporation. H. Takase: Employee; Self; Kao Corporation. J. Suzuki: Employee; Self; Kao Corporation. C. Suzukamo: Employee; Self; Kao Corporation. S. Nirengi: None. A. Suganuma: None. N. Osaki: Employee; Self; Kao Corporation. Funding Kao Corporation; Japan Society for the Promotion of Science (18K01988); Strategic Innovation Project of Japan (14533567); Bio-oriented Technology Research Advancement Institution, NARO

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.

Postprandial levels of GLP-1, GIP and glucagon after 2 years of weight loss with a Paleolithic diet: a randomised controlled trial in healthy obese women.

ObjectiveTo investigate how weight loss by different diets impacts postprandial levels of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon.MethodsIn this single-centre, parallel group 2-year trial, 70 healthy postmenopausal obese women were randomised to the Paleolithic diet or a healthy control diet based on Nordic Nutrition Recommendations. Both diets were without calorie restriction. The primary outcome was the change in fat mass. Here, secondary analyses on GLP-1, GIP and glucagon measured during an OGTT are described.ResultsIn the Paleolithic diet group, mean weight loss compared to baseline was 11% at 6 months and 10% at 24 months. In the control diet group, mean weight loss was 6% after 6 and 24 months (P = 0.0001 and P = 0.049 for the comparison between groups at 6 and 24 months respectively). Compared to baseline, the mean incremental area under the curve (iAUC) for GLP-1 increased by 34 and 45% after 6 and 24 months in the Paleolithic diet group and increased by 59% after 24 months in the control diet group. The mean iAUC for GIP increased only in the Paleolithic diet group. The area under the curve (AUC) for glucagon increased during the first 6 months in both groups. The fasting glucagon increase correlated with the β-hydroxybutyrate increase.ConclusionsWeight loss caused an increase in postprandial GLP-1 levels and a further rise occurred during weight maintenance. Postprandial GIP levels increased only after the Paleolithic diet. Reduced postprandial glucagon suppression may be caused by a catabolic state.

Appetite and Gastrointestinal Hormone Response to a Gluten-Free Meal in Patients with Coeliac Disease.

Coeliac disease (CeD) is an immune-mediated inflammatory enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Gastrointestinal (GI) hormone response related to appetite and glucose metabolism is still under-investigated in patients with CeD. This study aimed at shedding light on the appetite sensations, glycaemia and hormone response induced by a complex meal in patients with coeliac disease. Twenty-two women with CeD, nine at the diagnosis (CeDD) and thirteen under a gluten-free diet (CeDGF), and ten healthy subjects (HS) were enrolled in a single day intervention study. All subjects consumed a test meal, recorded their appetite sensations, and blood was collected over three hours after meal consumption. The study found a lower decrease in hunger in CeDD compared to CeDGF and HS after meal intake. Data showed no difference of fullness and satiety between the groups. CeDD had lower insulin and glucose-dependent insulinotropic polypeptide (GIP) than CeDGF and HS. Both CeDD and CeDGF experienced a lower post-prandial response of glucose than HS. Data suggested that patients with CeD have an impaired glucose absorption after more than 12 months of gluten-free diet. Postprandial GIP may play a significant role in appetite cues and insulin response to a complex meal.

Effects of MEDI0382 on Pancreatic and Incretin Hormones

MEDI0382, a GLP-1/glucagon dual receptor agonist, is being developed for the treatment of T2DM. GLP-1 receptor agonists promote glucose-dependent insulin release, suppress glucagon, and increase or have minimal effect on glucose-dependent insulinotropic polypeptide (GIP); knowledge of the effect on GLP-1 is limited. We characterized fasting and postprandial hormone profiles associated with MEDI0382 therapy. In a phase 2a study (NCT02548585), 51 subjects with T2DM and BMI 27-40 kg/m2 received MEDI0382 (uptitrated to 200 µg) or placebo (PBO) daily for 41 days. Glucose, insulin, glucagon, GIP, and GLP-1 were measured at baseline (day -1) and day 41 during a liquid mixed-meal tolerance test. MEDI0382 significantly reduced fasting glucose (-49.9 vs. -19.2 mg/dL for PBO; P &amp;lt; 0.0001) and glucose AUC0-4h (-32.8 vs. -10.2% for PBO; P &amp;lt; 0.0001) in association with increased fasting insulin (2.2 mU/L vs. -3.9 mU/L for PBO; P = 0.016), but postprandial insulin AUC was unchanged. In contrast, fasting and postprandial endogenous glucagon, GIP (Figure), and active and inactive GLP-1 were suppressed, and a delay in their kinetics was observed after MEDI0382 therapy. The results suggest that MEDI0382 is insulinotropic and might also cause delayed gastric emptying. The effects of MEDI0382 on GIP have not been observed with GLP-1 receptor mono-agonists and may represent a footprint of dual GLP-1/glucagon receptor agonism in this complex hormone signaling network. Disclosure V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.

Regular low-calorie sweetener consumption is associated with increased secretion of glucose-dependent insulinotropic polypeptide.

Low-calorie sweeteners (LCSs) are widely used for weight control despite limited evidence of their effectiveness and studies linking LCS consumption with incident obesity. We tested the hypothesis that regular LCS consumption is associated with higher postprandial glucose-dependent insulinotropic polypeptide (GIP) secretion, which has been linked to obesity. We used data from participants in the Baltimore Longitudinal Study of Aging who had completed a diet diary, had at least one visit during which they underwent an oral glucose tolerance test (OGTT), and had no diabetes. Of 232 participants, 166 contributed 1, 39 contributed 2, and 27 contributed 3 visits, and 96 (41%) reported using LCS. Plasma OGTT samples were analysed for glucose, insulin and GIP. Fasting glucose, insulin and GIP levels were no different between LCS users and non-users. The association of LCS use with 2-hour OGTT responses after adjustment for covariates was non-significant for glucose (P = .98) and insulin (P = .18), but significant for greater increase in GIP in LCS users (P = .037). Regular consumption of LCSs was associated with greater increases in GIP secretion after food intake, which may potentially lead to weight gain through the lipogenic properties of GIP.

Apple and blackcurrant polyphenol-rich drinks decrease postprandial glucose, insulin and incretin response to a high-carbohydrate meal in healthy men and women

Postprandial glycemic responses to meals are inhibited by polyphenol-rich plant foods. Combinations of polyphenols may be particularly effective through complementary mechanisms. A randomized, controlled, double-blinded cross-over trial was conducted in healthy volunteers to test the hypothesis that apple and blackcurrant polyphenol-rich drinks would reduce postprandial blood glucose concentrations. Secondary outcomes included insulin and glucose-dependent insulinotropic polypeptide (GIP) secretion. Twenty men (mean age 26 y, SD 8) and 5 postmenopausal women (mean age 57 y, SD 3) consumed a placebo drink (CON) and 2 polyphenol-rich drinks containing fruit extracts: either 1200 mg apple polyphenols (AE), or 600 mg apple polyphenols+600 mg blackcurrant anthocyanins (AE+BE), in random order with a starch and sucrose meal. Incremental areas under the curve (iAUC) for plasma glucose concentrations were lower following AE+BE over 0–30 and 0–120 min compared with CON; mean differences (95% CI) −32 mmol/L·min (−41, −22, P<.0005) and −52 mmol/L min (−94, −9, P<.05), respectively. AE significantly reduced iAUC 0–30 min (mean difference −26 mmol/L min, −35, −18, P<.0005) compared with CON, but the difference over 120 min was not significant. Postprandial insulin, C-peptide and GIP concentrations were significantly reduced relative to CON. A dose response inhibition of glucose transport was demonstrated in Caco-2 cells, including total and GLUT-mediated transport, and SGLT1-mediated glucose transport was strongly inhibited at all doses in Xenopus oocytes, following 10 min incubation with 0.125–4 mg apple polyphenols/ml. In conclusion, ingestion of apple and blackcurrant polyphenols decreased postprandial glycemia, which may be partly related to inhibition of intestinal glucose transport.

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.

The equine glucose-dependent insulinotropic polypeptide receptor: A potential therapeutic target for insulin dysregulation.

Metabolic disease is a significant problem that causes a range of species-specific comorbidities. Recently, a better understanding of glucose-dependent insulinotropic polypeptide (GIP) biology has led to the suggestion that inhibiting its action may attenuate obesity in several species. In horses, antagonism of GIP may also reduce hyperinsulinemia, which leads to insulin-associated laminitis, a painful comorbidity unique to this species. However, little is known about GIP in horses. The aims of this study were to examine the tissue distribution of equine GIP receptors (eGIPR), to determine whether eGIPR can be blocked using a GIP antagonist not tested previously in horses, and to establish whether there is any association between GIP concentrations and body mass in this species. Archived tissues from healthy horses were used to establish that eGIPR gene expression was strong in pancreas, heart, liver, kidney, and duodenum and absent in gluteal muscle. Pancreatic islets were isolated from fresh horse pancreas using collagenase digestion and layering through a density gradient. Islet viability was confirmed microscopically and by demonstrating that insulin production was stimulated by glucose in a concentration-dependent manner. Insulin release was also shown to be concentration-dependent with GIP up to 0.1µM, and the response to GIP was decreased ( = 0.037) by the antagonist (Pro3)GIP. As for the relationship between body mass and GIP in vivo postprandial GIP concentrations in archived plasma samples were positively correlated with body condition and cresty neck scores ( < 0.05). Thus, the eGIPR is a potential therapeutic target for insulin dysregulation and obesity in horses.

Dietary steamed wheat bran increases postprandial fat oxidation in association with a reduced blood glucose-dependent insulinotropic polypeptide response in mice

ABSTRACTObesity is a global epidemic associated with a higher risk of cardiovascular disease and metabolic disorders, such as type 2 diabetes. Previous studies demonstrated that chronic feeding of steamed wheat bran (WB) decreases obesity. To clarify the underlying mechanism and the responsible component for the anti-obesity effects of steamed WB, we investigated the effects of dietary steamed WB and arabinoxylan on postprandial energy metabolism and blood variables. Overnight-fasted male C57BL/6J mice were fed an isocaloric diet with or without steamed WB (30%). Energy metabolism was evaluated using an indirect calorimeter, and plasma glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) levels were measured for 120 min after feeding. We similarly investigated the effect of arabinoxylan, a major component of steamed WB. Mice fed the WB diet had higher postprandial fat oxidation and a lower blood GIP response compared with mice fed the control diet. Mice fed the arabinoxylan diet exhibited a dose-dependent postprandial blood GIP response; increasing the arabinoxylan content in the diet led to a lower postprandial blood GIP response. The arabinoxylan-fed mice also had higher fat oxidation and energy expenditure compared with the control mice. In conclusion, the findings of the present study revealed that dietary steamed WB increases fat oxidation in mice. Increased fat oxidation may have a significant role in the anti-obesity effects of steamed WB. The postprandial effects of steamed WB are due to arabinoxylan, a major component of WB. The reduction of the postprandial blood GIP response may be responsible for the increase in postprandial fat utilization after feeding on a diet containing steamed WB and arabinoxylan.

Effect of Acarbose, Sitagliptin and combination therapy on blood glucose, insulin, and incretin hormone concentrations in experimentally induced postprandial hyperglycemia of healthy cats

Acarbose (AC) and Sitagliptin (STGP) are oral hypoglycemic agents currently used either alone or in conjunction with human diabetic (Type 2) patients. AC has been used with diabetic cats, but not STGP thus far. Therefore, the objective of this study was to determine the potential use of AC or STGP alone and in combination for diabetic cats, by observing their effect on short-term post-prandial serum glucose, insulin, and incretin hormone (active glucagon-like peptide-1 (GLP-1) and total glucose dependent insulinotropic polypeptide (GIP)) concentrations in five healthy cats, following ingestion of a meal with maltose.All treatments tended (p<0.10; 5–7.5% reduction) to reduce postprandial glucose area under the curve (AUC), with an accompanying significant reduction (p<0.05, 35–45%) in postprandial insulin AUC as compared to no treatment. Meanwhile, a significant increase (p<0.05) in postprandial active GLP-1 AUC was observed with STGP (100% higher) and combined treatment (130% greater), as compared to either AC or no treatment. Lastly, a significant reduction (p<0.05) in postprandial total GIP AUC was observed with STGP (21% reduction) and combined treatment (7% reduction) as compared to control. Overall, AC, STGP, or combined treatment can significantly induce positive post-prandial changes to insulin and incretin hormone levels of healthy cats. Increasing active GLP-1 and reducing postprandial hyperglycemia appear to be the principal mechanisms of combined treatment. Considering the different, but complementary mechanisms of action by which AC and STGP induce lower glucose and insulin levels, combination therapy with both these agents offers great potential for treating diabetic cats in the future.