Glucose-dependent Insulinotropic Polypeptide Responses Research Articles

A-068 Development of GIP ELISAs: The Next Level of DiabetesManagement

Abstract Background To develop sensitive and specific ELISAs for the quantitative measurement of total and intact GIP in human plasma, and other biological fluids. Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone consisting of 42 amino acids (1-42aa). This undergoes processing by a dipeptidyl peptidase-4 (DPP-4) and produces GIP (3-42aa) and GIP (3-30aa) fragments. The processed forms have higher affinity and very efficiently inhibits GIP receptor (GIPR) activity with no intrinsic activity. It has also been observed that the GIP response is dependent not only on meal size but also on meal composition. GIP has been found to have physiological and pharmacological relevance in the development of obesity and the pathogenesis of cardiovascular disease besides its involvement in type 2 diabetic pathophysiology. GIP acts in the entero-insular axis as an anabolic hormone that increases insulin levels, which in return increases glycogen and fatty acid synthesis and inhibits the breakdown of fat. GIP also has extra-pancreatic functions as well as roles in the stomach to reduce acid secretion by the parietal cells. On the bone, GIP has a dual effect as it causes the proliferation of osteoblasts as well as inhibits osteoclastic bone resorption. The widespread expression of GIP-R in the brain suggests that GIP might play an essential function in neuro-signaling mechanisms. Methods Highly specific and reproducible total GIP (AL-1013) and Intact GIP (AL-1022) ELISAs have been developed using specific monoclonal antibodies to help estimate the total and intact GIP concentrations in plasma in the respective immunoassays. Results Total and intact GIP ELISAs have been validated using well-characterized sample set and the peptide preparations. The total GIP ELISA detects 1-42aa, 3-42aa, 1-30aa, and 3-30aa in the sample. The intact GIP assay detects GIP (1-42aa) and the most abundant 3-42aa fragment equally in the human plasma. The intact GIP assay does not detect truncated C-terminal fragments(1-30aa). These assays did not cross-react to GRPP, Glucagon, Oxyntomodulin, GLP-1, and GLP-2. Method comparison between intact and total GIP assays using 388 samples yielded a slope of 0.8154 (r=0.958, p < 0.0001). Both the assays are highly reproducible with the total coefficient of variation less than 10%. GIP concentrations were measured in both assays in lean and obese subjects on fat-rich diet at 30-minute intervals. Average concentrations in intact GIP assay at 0 minutes (baseline) in lean and obese subjects (n=10) were 115.6 and 88.5 pg/mL, respectively. Average concentrations in total GIP assay at 0 minutes (baseline) in lean and obese subjects (n=10) were 151.5 and 125.9 pg/mL, respectively. Both total and intact GIP had steep increase in concentrations up to 90 minutes and then flattened up to 180 minutes. The GIP results have been also compared to the mean plasma concentrations of Glucagon, GLP-1, C-Peptide between lean and obese subjects on fat-rich meal. Conclusions Highly sensitive and specific total and intact GIP ELISAs have been developed to reliably quantify these important endocrine and local regulators in physiological and pathophysiological studies for metabolic disorders.

The effects of postprandial exercise and meal glycemic index on plasma glucose and glucoregulatory hormone responses after Roux-en-Y gastric bypass.

Postprandial hypoglycemia is a complication of Roux-en-Y gastric bypass (RYGB), but the effects of postprandial exercise and meal glycemic index (GI) on postprandial glucose and glucoregulatory hormone responses are unknown. Ten RYGB-operated and 10 age and weight-matched unoperated women completed four test days in random order ingesting mixed meals with high GI (HGI, GI = 93) or low GI (LGI, GI = 54), but matched on energy and macronutrient content. Ten minutes after meal completion, participants rested or cycled for 30 min at 70% of maximum oxygen uptake (V̇o2max). Blood was collected for 4 h. Postprandial exercise did not lower plasma nadir glucose in RYGB after HGI (HGI/rest 3.7 ± 0.5 vs. HGI/Ex 4.1 ± 0.4 mmol/L, P = 0.070). Replacing HGI with LGI meals raised glucose nadir in RYGB (LGI/rest 4.1 ± 0.5 mmol/L, P = 0.034) and reduced glucose excursions (Δpeak-nadir) but less so in RYGB (-14% [95% CI: -27; -1]) compared with controls (-33% [-51; -14]). Insulin responses mirrored glucose concentrations. Glucagon-like peptide 1 (GLP-1) responses were greater in RYGB versus controls, and higher with HGI versus LGI. Glucose-dependent insulinotropic polypeptide (GIP) responses were greater after HGI versus LGI in both groups. Postexercise glucagon responses were lower in RYGB than controls, and noradrenaline responses tended to be lower in RYGB, whereas adrenaline responses were similar between groups. In conclusion, moderate intensity cycling shortly after meal intake did not increase the risk of postprandial hypoglycemia after RYGB. The low GI meal increased nadir glucose and reduced glucose excursions compared with the high GI meal. RYGB participants had lower postexercise glucagon responses compared with controls.NEW & NOTEWORTHY We investigate the effect of moderate exercise after a high or a low glycemic index meal on nadir glucose and glucoregulatory hormones in gastric bypass-operated individuals and in matched unoperated controls. Cycling shortly after meal intake did not increase the risk of hypoglycemia in operated individuals. The low glycemic index meal increased glucose nadir and reduced excursions compared with the high glycemic index meal. Operated individuals had lower postexercise glucagon responses compared with controls.

Dietary Vitamin A Affects the Function of Incretin-Producing Enteroendocrine Cells in Male Mice Fed a High-Fat Diet

BackgroundRetinol-binding protein 2 (RBP2) is an intracellular carrier for vitamin A in the absorptive enterocytes. Mice lacking RBP2 (Rbp2−/−) display an unexpected phenotype of obesity, glucose intolerance, and elevated glucose-dependent insulinotropic polypeptide (GIP) levels. GIP and glucagon-like peptide 1 (GLP-1) are incretin hormones secreted by enteroendocrine cells (EECs). We recently demonstrated the presence of RBP2 and other retinoid-related proteins in EECs. ObjectivesGiven RBP2’s role in intracellular retinoid trafficking, we aimed to evaluate whether dietary vitamin A affects incretin-secreting cell function and gene expression. MethodsMale Rbp2−/− mice and sex- and age-matched controls (n = 6–9) were fed a high-fat diet (HFD) for 18 wk containing normal (VAN, 4000 IU/kg of diet) or low (VAL, 25% of normal) vitamin A concentrations. Body weight was recorded biweekly. Plasma GIP and GLP-1 levels were obtained fasting and 30 min after an oral fat gavage at week 16. Glucose tolerance tests were also performed. Mice were killed at week 18, and blood and tissue samples were obtained. ResultsRbp2−/− mice displayed greater weight gain on the VAN compared with the VAL diet from week 7 of the intervention (P ≤ 0.01). Stimulated GIP levels were elevated in Rbp2−/− mice compared with their controls fed the VAN diet (P = 0.02), whereas their GIP response was lower when fed the VAL diet (P = 0.03). Although no differences in GLP-1 levels were observed in the VAN diet group, a lower GLP-1 response was seen in Rbp2−/− mice fed the VAL diet (P = 0.02). Changes in incretin gene expression and that of other genes associated with EEC lineage and function were consistent with these observations. Circulating and hepatic retinoid levels revealed no systemic vitamin A deficiency across dietary groups. ConclusionsOur data support a role for RBP2 and dietary vitamin A in incretin secretion and gene expression in mice fed a HFD.

The entero-endocrine response following a mixed-meal tolerance test with a non-nutritive pre-load in participants with pre-diabetes and type 2 diabetes: A crossover randomized controlled trial proof of concept study.

This crossover randomized controlled trial (RCT) investigated differences in short-term entero-endocrine response to a mixed-meal tolerance test preceded by nutrient sensing between participants with pre-diabetes (pre-T2D) and type 2 diabetes (T2D). Additionally, differences in gut and oral microbiome composition between participants with a high and low entero-endocrine response were investigated. Ten participants with pre-T2D and ten with T2D underwent three test days with pre-loads consisting of either swallowing water (control), or rinsing with a non-nutritive sweetener solution, or swallowing the sweetener solution before a mixed-meal tolerance test. Blood glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon, glucose, insulin and peptide YY (PYY) were determined at t = -20, 0, 15, 30, 60, 120 and 240 minutes. The composition of the oral and gut microbiome at baseline were also determined. The entero-endocrine response differed by pre-loads, e.g. a lower PYY response after swallowing the non-nutritive sweetener (-3585.2pg/mL [95% CI: -6440.6; -729.8]; p = 0.01). But it also differed by T2D status, e.g. a higher glucose, glucagon and PYY response was found in participants with T2D, compared to those with pre-T2D. Evidence for associations between the oral and gut microbiome composition and the entero-endocrine response was limited. Still, the level of entero-endocrine response was associated with several oral microbiome measures. Higher oral anterior α-diversity was associated with a lower PYY response (e.g. Inverse Simpson index -1357pg/mL [95% CI -2378; -336; 1.24]), and higher oral posterior α-diversitywith a higher GIP response (e.g. Inverse Simpson index 6773pg/mL [95% CI 132; 13414]) in models adjusted for sex, age and T2D status. Non-nutritive pre-loads influence the entero-endocrine response to a mixed-meal, and this effect varies based on (pre-)T2D status. The entero-endocrine response is likely not associated with the gut microbiome, and there is limited evidence for association with the α-diversity of the oral microbiome composition. Trial register: Netherlands Trial Register NTR7212, accessible through International Clinical Trials Registry Platform: ICTRP Search Portal (who.int).

Increased Glucagon Immunoreactivity in a Rat Model of Diet-Induced Obesity following Sleeve Gastrectomy

Objective: Bariatric surgery is currently the most effective treatment for obesity, and procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy (SG) also result in rapid improvements in insulin sensitivity and glucose tolerance. In addition, these procedures cause changes in the secretion of various gut-derived hormones. The role these hormones play in the mechanism of the beneficial effects of bariatric surgery is still debated, but nonetheless, their importance provides inspiration for novel obesity-targeted pharmacotherapies. Methods: Male Sprague-Dawley rats were fed either regular chow or a cafeteria diet to induce obesity. A sub-group of the obese animals then underwent either sham surgery or SG. Results: Following a 4-week recovery period, SG rats weighed significantly less than obese or sham-operated rats. Improvements in glucose tolerance and insulin sensitivity also occurred in the SG group, but these were not always statistically significant. We measured the intracellular lipid content of liver samples and found that obese rats showed signs of non-alcoholic fatty liver disease, which were significantly ameliorated by SG. There were significantly higher glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide responses to a standard mixed meal in the SG group, as well as paradoxically higher glucagon secretion. Conclusion: These data highlight the need for more specific anti-glucagon antibodies to characterize the changes in proglucagon-derived peptide concentrations that occur following SG. Further studies are required to determine whether these peptides contribute to the therapeutic effects of SG.

Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 secretion in humans: Characteristics and regulation.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important incretin hormones. They are released from the gut after meal ingestion and potentiate glucose-stimulated insulin secretion. Their release after meal ingestion and oral glucose are well established and have been characterized previously. During recent years, knowledge of other regulatory aspects that potentially may affect GIP and GLP-1 secretion after meal ingestion have also begun to emerge. Here, the results of human studies on these novel aspects of meal- and nutrient-stimulated incretin hormone secretion are reviewed. The human literature was revisited by identifying articles in PubMed using key words GIP, GLP-1, secretion, meal, and nutrients. The results show that all macronutrients individually stimulate GIP and GLP-1 secretion. However, there was no synergistic action when given in combination. A pre-load 30 min before a meal augments the GIP and GLP-1 response. GIP and GLP-1 secretion have a diurnal variation with a higher response to an identical meal in the morning than in the afternoon. There is no difference in GIP and GLP-1 secretion whether a meal is ingested slowly or rapidly. GIP and GLP-1 secretion after dinner are the same whether or not breakfast and lunch have been ingested. The temperature of the food may be of importance for the incretin hormone response. These novel findings have increased our knowledge on the regulation of the complexity of the incretin system and are also important knowledge when designing future studies.

Acute feeding with almonds compared to a carbohydrate-based snack improves appetite-regulating hormones with no effect on self-reported appetite sensations: a randomised controlled trial

PurposeEarly satiety has been identified as one of the mechanisms that may explain the beneficial effects of nuts for reducing obesity. This study compared postprandial changes in appetite-regulating hormones and self-reported appetite ratings after consuming almonds (AL, 15% of energy requirement) or an isocaloric carbohydrate-rich snack bar (SB).MethodsThis is a sub-analysis of baseline assessments of a larger parallel-arm randomised controlled trial in overweight and obese (Body Mass Index 27.5–34.9 kg/m2) adults (25–65 years). After an overnight fast, 140 participants consumed a randomly allocated snack (AL [n = 68] or SB [n = 72]). Appetite-regulating hormones and self-reported appetite sensations, measured using visual analogue scales, were assessed immediately before snack food consumption, and at 30, 60, 90 and 120 min following snack consumption. A sub-set of participants (AL, n = 49; SB, n = 48) then consumed a meal challenge buffet ad libitum to assess subsequent energy intake. An additional appetite rating assessment was administered post buffet at 150 min.ResultsPostprandial C-peptide area under the curve (AUC) response was 47% smaller with AL compared to SB (p < 0.001). Glucose-dependent insulinotropic polypeptide, glucagon and pancreatic polypeptide AUC responses were larger with AL compared to SB (18%, p = 0.005; 39% p < 0.001; 45% p < 0.001 respectively). Cholecystokinin, ghrelin, glucagon-like peptide-1, leptin and polypeptide YY AUCs were not different between groups. Self-reported appetite ratings and energy intake following the buffet did not differ between groups.ConclusionMore favourable appetite-regulating hormone responses to AL did not translate into better self-reported appetite or reduced short-term energy consumption. Future studies should investigate implications for longer term appetite regulation.ANZCTR Reference NumberACTRN12618001861246 2018.

Comparison of Hormonal Response to a Mixed-Meal Challenge in Hypoglycemia After Sleeve Gastrectomy vs Gastric Bypass.

Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB. We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups. Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB. Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

A Pilot Study to Assess Glucose, Insulin, and Incretin Responses Following Novel High Resistant Starch Rice Ingestion in Healthy Men.

IntroductionA newly developed resistant starch (RS) rice line with double mutation of starch synthase IIIa and branching enzyme IIb (ss3a/be2b) exhibits a tenfold greater percentage RS value than the wild-type rice line. Currently, the effects of cooked rice with such high RS content on secretion and action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are unclear. Therefore, we conducted a pilot study to assess postprandial responses of GLP-1 and GIP along with glucose and insulin and also gastric emptying after ingestion of the high-RS cooked rice with ss3a/be2b in healthy subjects.MethodsIn a non-randomized crossover design, five healthy men ingested two test foods, control (low-RS) and high-RS cooked rice, with at least 1-week washout period between testing days. Plasma glucose, serum insulin, plasma total GLP-1, plasma total GIP, and also gastric emptying rate were measured after ingestion of each test food, and the incremental area under the curves (iAUC) was calculated for each biochemical parameter using the values from 0 to 180 min after ingestion.ResultsThe high-RS cooked rice ingestion tended to reduce iAUC-glucose (p = 0.06) and significantly reduced iAUC-insulin (p < 0.01) and iAUC-GLP-1 (p < 0.05) but not iAUC-GIP (p = 0.21) relative to control cooked rice ingestion. In addition, the high-RS cooked rice ingestion did not affect gastric emptying.ConclusionsThe present results indicate that the suppressive effects of the high-RS cooked rice ingestion on postprandial responses of glucose and insulin may be provided through attenuation in GLP-1 secretion along with its low digestibility into glucose. We suggest that the high-RS rice with ss3a/be2b may serve as a better carbohydrate source and also as a novel functional food for dietary interventions to improve postprandial hyperglycemia and hyperinsulinemia without both enhancing GLP-1 secretion and affecting gastric emptying in patients with diabetes.

Efficacy of L-Arabinose in Lowering Glycemic and Insulinemic Responses: The Modifying Effect of Starch and Fat.

L-arabinose is a bio-active compound derived from the side-streams of plant food processing. L-arabinose lowers glycemic and insulinemic responses when added to simple water-based sugary liquids. However, the effect in more complex foods, including fat and starch, is inconsistent. This study assessed the effect of fat or starch in a sugary drink on the efficacy of L-arabinose. Twenty-three healthy volunteers (12 female/11 male; aged 24 ± 3 years; BMI 23 ± 3 kg/m2) participated in a randomised cross-over trial with six drinks: control: 50 g sucrose in water; fat: control + 22 g oil; starch: control + 50 g starch; and all three with and without the addition of 5 g L-arabinose. The addition of L-arabinose to the control drink lowered glucose and insulin peaks by 15% and 52%; for the fat drink by 8% and 45%; and for the starch drink by 7% and 29%. For all three drinks, adding L-arabinose increased glucagon-like peptide 1 (GLP-1) responses and lowered Glucose-dependent insulinotropic polypeptide (GIP) responses. Despite adding large quantities of starch and fat to sugary drinks, L-arabinose significantly lowered postprandial glycemic and insulinemic responses in healthy subjects. These findings suggest that L-arabinose can be functional in more complex foods; however, the factors affecting its efficacy in solid food matrices need to be studied in more detail.

Associations between Postprandial Gut Hormones and Markers of Bone Remodeling.

Gut-derived hormones have been suggested to play a role in bone homeostasis following food intake, although the associations are highly complex and not fully understood. In a randomized, two-day cross-over study on 14 healthy individuals, we performed postprandial time-course studies to examine the associations of the bone remodeling markers carboxyl-terminal collagen type I crosslinks (CTX) and procollagen type 1 N-terminal propeptide (P1NP) with the gut hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) using two different meal types—a standardized mixed meal (498 kcal) or a granola bar (260 kcal). Plasma concentrations of total GIP, total GLP-1, total PYY, CTX, and P1NP were measured up to 240 min after meal intake, and the incremental area under the curve (iAUC) for each marker was calculated. The iAUC of CTX and P1NP were used to assess associations with the iAUC of GIP, GLP-1, and PYY in linear mixed effect models adjusted for meal type. CTX was positively associated with GIP and GLP-1, and it was inversely associated with PYY (all p < 0.001). No associations of P1NP with GIP or GLP-1 and PYY were found. In conclusion, the postprandial responses of the gut hormones GIP, GLP-1, and PYY are associated with the bone resorption marker CTX, supporting a link between gut hormones and bone homeostasis following food intake.

β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet-Fed Mice.

SUMOylation reduces oxidative stress and preserves islet mass at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme sentrin-specific protease 1 (SENP1) following metabolic stress, we put pancreas/gut-specific SENP1 knockout (pSENP1-KO) mice on a high-fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls but only in response to oral glucose. A similar phenotype was observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were identical in pSENP1-KO and wild-type littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and β-cell exocytotic responses to the GLP-1 receptor agonist exendin-4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we generated β-cell–specific SENP1 KO mice. These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired β-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca2+ levels. Thus, β-cell SENP1 limits oral glucose intolerance following HFD by ensuring robust insulin secretion at a point downstream of incretin signaling.

1179-P: Acute Physiological Effects of Gastric Aspiration for the Treatment of Obesity

AspireAssist® allows aspiration of ~30% of an ingested meal through a percutaneous gastrostomy tube thereby reducing caloric uptake. We evaluated the acute effects of aspiration therapy on postprandial glucose tolerance, responses of gluco-regulatory and appetite-regulating gut hormones, appetite sensations and food intake. Seven AspireAssist®-treated persons without diabetes (median [IQR] age 52 [44;54] years; BMI 35.6 [31.5;40.5] kg/m2) underwent two mixed meal tests on separate days with double-blinded aspiration (aspiration visit) and sham aspiration (sham visit), respectively. Seven age and BMI-matched controls (age 43 [42;54]; BMI 34.1 [31.6;38.7] kg/m2) underwent one meal test (control visit). All mixed meal tests were followed by an ad libitum meal for evaluation of food intake. Compared to sham visits, postprandial glucose tolerance was improved on aspiration visits (median [IQR] baseline-subtracted area under the curve (bsAUC) 170 [88;356] vs. 388 [239;456] mmol/L × min, P = 0.025). Postprandial responses (bsAUCs) of C-peptide, cholecystokinin (CCK) and glucose-dependent insulinotropic polypeptide (GIP) were reduced during aspiration vs. sham visits (113 [28;224] vs. 302 [215;433] nmol/L × min, P = 0.014; 223 [59.4;402] vs. 467 [416;546] pmol/L × min, P = 0.005; and 4,634 [1,488;9,044] vs. 15,382 [9,588;18,850] pmol/L × min, P = 0.025). Glucagon, gastrin, ghrelin and peptide YY, respectively, were similar on aspiration and sham visits. Appetite sensations and ad libitum food intake were similar on aspiration and sham visits. Responses of plasma glucose, gut hormones, appetite sensations and food intake were similar on sham and control visits. In this study, aspiration therapy acutely improved postprandial glucose tolerance without causing a compensatory increase in appetite sensations or food intake at a subsequent ad libitum meal; pointing to acute beneficial metabolic effect of aspiration therapy in addition to the long-term bodyweight-lowering effect of this treatment. Disclosure I. Gether: None. M. M. Jensen: None. T. Jorsal: None. C. Nexøe-larsen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L. P. S. Naver: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Augustinus Fonden

Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance.

Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found. In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.

Co-ingestion of NUTRALYS® pea protein and a high-carbohydrate beverage influences the glycaemic, insulinaemic, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses: preliminary results of a randomised controlled trial.

Plant-based proteins may have the potential to improve glycaemic and gastrointestinal hormone responses to foods and beverages. The aim of this study was to investigate the effect of two doses of pea protein on postprandial glycaemic, insulinaemic, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) response following a high-carbohydrate beverage intake in healthy individuals. In a single-blind, randomised, controlled, repeat measure, crossover design trial, thirty-one participants were randomly assigned to ingest 50g glucose (Control), 50g glucose with 25g pea protein (Test 1) and 50g glucose with 50g pea protein (Test 2) on three separate days. Capillary blood samples (blood glucose and plasma insulin measurements) and venous blood samples (GIP and GLP-1 concentrations) were taken before each test and at fixed intervals for 180min. The data were compared using repeated-measures ANOVA or the Friedman test. Glucose incremental Area under the Curve (iAUC180) was significantly lower (p < 0.001) after Test 2 compared with Control (- 53%), after Test 1 compared with Control (- 31%) and after Test 2 compared with Test 1 (-32%). Insulin iAUC 180 was significantly higher (p < 0.001) for Test 1 (+ 28%) and Test 2 (+ 40%) compared with Control and for Test 2 (+ 17%) compared with Test 1 (p = 0.003). GIP and GLP-1 release showed no clear difference between Control and Pea protein drinks. The consumption of pea protein reduced postprandial glycaemia and stimulated insulin release in healthy adults with a dose-response effect, supporting its role in regulating glycaemic and insulinaemic responses.

Characterization of the Meal-Stimulated Incretin Response and Relationship With Structural Brain Outcomes in Aging and Alzheimer's Disease.

BackgroundIndividuals with Alzheimer’s Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear.MethodsHere, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; n = 32) and AD (n = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging.ResultsThe meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions.ConclusionOur findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.

No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect.

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

Preserved postprandial suppression of bone turnover markers, despite increased fasting levels, in postmenopausal women.

Menopause leads to an increased bone turnover associated with a high risk of fractures. Bone turnover is inhibited by meal intake, to some extent mediated by gut hormones, and interventions based on these endocrine changes may have potential in future prevention of osteoporosis. To investigate whether postmenopausal women exhibit postprandial suppression of bone turnover markers to the same extent as premenopausal women, despite higher fasting levels. Furthermore, to assess whether menopausal differences in bone turnover markers are related to postmenopausal changes in plasma gut hormone levels. A cross-sectional study of 21 premenopausal, 9 perimenopausal, and 24 postmenopausal women between 45 and 60years of age. Serum/plasma levels of bone turnover markers and gut hormones were investigated during a 120min oral glucose tolerance test. Bone turnover markers included N-terminal propeptide of type-I procollagen (PINP, bone formation marker) and carboxyterminal collagen I crosslinks (CTX-I, bone resorption marker). Gut hormone secretion was evaluated from responses of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). Fasting levels of s-CTX-I were increased in peri- and postmenopausal women compared to premenopausal women (p=0.001). Despite higher fasting levels, the relative postprandial s-CTX-I suppression was comparable across menopausal status (p=0.14). Fasting levels of s-PINP were also increased in postmenopausal women compared to premenopausal women (p<0.001) with comparable and modest s-PINP suppression over menopause (p=0.13). Postprandial plasma GLP-1 (p=0.006) and GLP-2 (p=0.01) were significantly increased in postmenopausal women compared to premenopausal women while GIP responses were slightly increased in the perimenopausal group (p=0.02) but comparable between pre- and postmenopausal women. None of the postprandial gut hormone increases predicted postprandial bone turnover suppression in these women. Glucose-induced suppression of bone turnover markers is preserved in postmenopausal women, despite significantly higher fasting values, indicating that CTX-I lowering treatments based on these postprandial mechanisms might be a feasible strategy to prevent postmenopausal osteoporosis.

Increased oral sodium chloride intake in humans amplifies selectively postprandial GLP-1 but not GIP, CCK, and gastrin in plasma.

Human studies have demonstrated that physiologically relevant changes in circulating glucagon‐like peptide‐1 (GLP‐1) elicit a rapid increase in renal sodium excretion when combined with expansion of the extracellular fluid volume. Other studies support the involvement of various gastrointestinal hormones, e.g., gastrin and cholecystokinin (CCK) in a gut‐kidney axis, responsible for a rapid‐acting feed‐forward natriuretic mechanism. This study was designed to investigate the hypothesis that the postprandial GLP‐1 plasma concentration is sensitive to the sodium content in the meal. Under fixed sodium intake for 4 days prior to each experimental day, 10 lean healthy male participants were examined twice in random order after a 12‐hr fasting period. Arterial blood samples were collected at 10–20‐min intervals for 140 min after 75 grams of oral glucose + 6 grams of oral sodium chloride (NaCl) load versus 75 grams of glucose alone. Twenty‐four‐hour baseline urinary sodium excretions were similar between study days. Arterial GLP‐1 levels increased during both oral glucose loads and were significantly higher at the 40–80 min period during glucose + NaCl compared to glucose alone. The postprandial arterial responses of CCK, gastrin, and glucose‐dependent insulinotropic polypeptide as well as glucose, insulin, and C‐peptide did not differ between the two study days. Arterial renin, aldosterone, and natriuretic peptides levels did not change within subjects or between study days. Angiotensin II levels were significantly lower at the time GLP‐1 was higher (60–80 min) during glucose + NaCl. Sodium intake in addition to a glucose load selectively amplifies the postprandial GLP‐1 plasma concentration. Thus, GLP‐1 may be part of an acute feed‐forward mechanism for natriuresis.

Responses of gut and pancreatic hormones, bile acids, and fibroblast growth factor-21 differ to glucose, protein, and fat ingestion after gastric bypass surgery.

Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, FGF-21, and C-peptide were increased after glucose compared with the other meals. The neurotensin and bile acids responses were greater after fat, while the glucagon and CCK responses were greater after protein ingestion. Furthermore, compared with control subjects, RYGB subjects had greater responses of total PYY after glucose, glucagon after glucose and fat, glicentin after glucose and protein, and GLP-1 and neurotensin after all meals, while GIP and CCK responses were lower after fat. Ghrelin responses did not differ between meals or between groups. Orlistat reduced all hormone responses to fat ingestion, except for ghrelin in the RYGB group. In conclusion, after RYGB glucose is a more potent stimulator of most gut hormones, especially for the marked increased secretion of GLP-1 compared with fat and protein.NEW & NOTEWORTHY We investigated the impact of glucose, protein, and fat meals on intestinal and pancreatic hormones, bile acid, and fibroblast growth factor 21 (FGF-21) secretion in gastric bypass-operated patients compared with matched nonoperated individuals. The fat meal was administered with and without a pancreas lipase inhibitor. We found that the impact of the different meals on gut hormones, bile, and FGF 21 secretion differ and was different from the responses observed in nonoperated control subjects.