Glucose-dependent Insulinotropic Polypeptide Responses Research Articles

The relationship between plasma GIP and GLP-1 levels in individuals with normal and impaired glucose tolerance.

Glucose-dependent insulinotropic polypeptide (GIP) is released primarily from the proximal small intestine and glucagon-like peptide-1 (GLP-1) from the more distal small intestine and colon. Their relative importance to the incretin effect in health has been contentious in the past, although it now appears that GIP has the dominant role. It is uncertain whether there is a relationship between GIP and GLP-1 secretion. We aimed to evaluate the relationship between plasma GIP and GLP-1 responses to a 75-g oral glucose load in individuals with normal (NGT) and impaired glucose tolerance (IGT). One hundred healthy subjects had measurements of blood glucose, serum insulin, plasma GIP and GLP-1 concentrations for 240min after a 300mL drink containing 75g glucose. Fifty had NGT and 41 IGT; 9 had type 2 diabetes and were excluded from analysis. In both groups, there were increases in plasma GIP and GLP-1 following the glucose drink, with no difference in the magnitude of the responses between t = 0-240min. There was a weak relationship between the iAUC0-240min for GIP and GLP-1 in the combined (r = 0.23, P = 0.015) and in the IGT (r = 0.34, P = 0.01), but not in the NGT (r = 0.15, P = 0.14) group. There is a weak relationship between oral glucose-induced GIP and GLP-1 secretions in non-diabetic subjects.

The role of GIP and pancreatic GLP-1 in the glucoregulatory effect of DPP-4 inhibition in mice.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two peptides that function to promote insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors increase the bioavailability of both GLP-1 and GIP but the dogma continues to be that it is the increase in GLP-1 that contributes to the improved glucose homeostasis. We have previously demonstrated that pancreatic rather than intestinal GLP-1 is necessary for improvements in glucose homeostasis in mice. Therefore, we hypothesise that a combination of pancreatic GLP-1 and GIP is necessary for the full effect of DPP-4 inhibitors on glucose homeostasis. We have genetically engineered mouse lines in which the preproglucagon gene (Gcg) is absent in the entire body (GcgRAΔNull) or is expressed exclusively in the intestine (GcgRAΔVilCre) or pancreas and duodenum (GcgRAΔPDX1Cre). These mice were used to examine oral glucose tolerance and GLP-1 and GIP responses to a DPP-4 inhibitor alone, or in combination with incretin receptor antagonists. Administration of the DPP-4 inhibitor, linagliptin, improved glucose tolerance in GcgRAΔNull mice and control littermates and in GcgRAΔVilCre and GcgRAΔPDX1Cre mice. The potent GLP-1 receptor antagonist, exendin-[9-39] (Ex9), blunted improvements in glucose tolerance in linagliptin-treated control mice and in GcgRAΔPDX1Cre mice. Ex9 had no effect on glucose tolerance in linagliptin-treated GcgRAΔNull or in GcgRAΔVilCre mice. In addition to GLP-1, linagliptin also increased postprandial plasma levels of GIP to a similar degree in all genotypes. When linagliptin was co-administered with a GIP-antagonising antibody, the impact of linagliptin was partially blunted in wild-type mice and was fully blocked in GcgRAΔNull mice. Taken together, these data suggest that increases in pancreatic GLP-1 and GIP are necessary for the full effect of DPP-4 inhibitors on glucose tolerance.

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.

Glycaemic, gastrointestinal, hormonal and appetitive responses to pearl millet or oats porridge breakfasts: a randomised, crossover trial in healthy humans.

Whole-grain cereal breakfast consumption has been associated with beneficial effects on glucose and insulin metabolism as well as satiety. Pearl millet is a popular ancient grain variety that can be grown in hot, dry regions. However, little is known about its health effects. The present study investigated the effect of a pearl millet porridge (PMP) compared with a well-known Scottish oats porridge (SOP) on glycaemic, gastrointestinal, hormonal and appetitive responses. In a randomised, two-way crossover trial, twenty-six healthy participants consumed two isoenergetic/isovolumetric PMP or SOP breakfast meals, served with a drink of water. Blood samples for glucose, insulin, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP), peptide YY, gastric volumes and appetite ratings were collected 2 h postprandially, followed by an ad libitum meal and food intake records for the remainder of the day. The incremental AUC (iAUC2h) for blood glucose was not significantly different between the porridges (P > 0·05). The iAUC2h for gastric volume was larger for PMP compared with SOP (P = 0·045). The iAUC2h for GIP concentration was significantly lower for PMP compared with SOP (P = 0·001). Other hormones and appetite responses were similar between meals. In conclusion, the present study reports, for the first time, data on glycaemic and physiological responses to a pearl millet breakfast, showing that this ancient grain could represent a sustainable alternative with health-promoting characteristics comparable with oats. GIP is an incretin hormone linked to TAG absorption in adipose tissue; therefore, the lower GIP response for PMP may be an added health benefit.

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.

389-P: Comparison of Hormonal Response to a Mixed-Meal Challenge in Individuals with Hypoglycemia after Sleeve Gastrectomy vs. Gastric Bypass

Objective: Exaggerated post-prandial incretin and insulin responses are well-documented in post-bariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). Thus, we sought to compare meal-stimulated hormonal response in those with PBH after SG vs. RYGB. Methods: We enrolled 20 RYGB (7 with and 13 without PBH) and 23 SG (12 with and 11 without PBH) who underwent bariatric surgery at our institution. PBH was defined as a postprandial interstitial or plasma glucose <55 mg/dl on continuous glucose monitor (5-days as outpatient, Dexcom) or 4-hour mixed meal tolerance test (MTT). Plasma samples from MTT were used to measure glucose, insulin, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). We used Kruskal Wallis Test to compare the difference in glucose or hormones across 4 groups (with and without PBH after SG or RYGB). Results: Participants (N=43) were on average 5 years since surgery, with mean age of 50 years, mean preoperative BMI of 48 kg/m2, 81% female, 61% Caucasian, 53% post SG. There were no differences in fasting glucose (p=0.38) or fasting insulin (p=0.34) across the 4 groups. Among those with PBH, the SG group showed a lower peak glucose (131.8 mg/dl, p<0.01), similar nadir glucose (59.6 mg/dl, p=0.18), peak insulin (68.7 mU/L, p<0.01) and peak GLP-1 (15.3 pM, p<0.01) and differed in overall hormonal response (AUC 0-240min) with lower insulin (3956.1 mU/L/min, p<0.01), lower GLP-1 (2498.9 pM/min, p<0.01) and higher GIP (51335.4 pM/min, p=0.05) compared to RYGB with PBH group. Conclusion: Among those with PBH, the SG group showed less glycemic excursion and different hormonal profiles including lower insulin, GLP-1 and higher GIP responses to MTT compared to the RYGB group. Future studies are needed to better understand the differential contribution of insulin and non-insulin mediated mechanisms behind PBH after SG vs. RYGB. Disclosure C. Lee: Consultant; Self; XOMA Corporation. Research Support; Self; Eiger BioPharmaceuticals. T. Brown: None. M. Schweitzer: Consultant; Self; Ethicon, Inc. T. Magnuson: None. J. Clark: None. Funding National Institutes of Health

Postprandial glucose, insulin and incretin responses differ by test meal macronutrient ingestion sequence (PATTERN study)

Previous studies have shown that the sequential order of consuming different food components significantly impacts postprandial glucose and insulin excursions in prediabetes and type 2 diabetes, but the causative mechanisms in healthy humans remain ill-defined. Using a typical Asian meal comprising vegetables, protein (chicken breast), and carbohydrate (white rice), the aim of this study was to examine the effect of food intake sequence on postprandial glucose, insulin and incretin secretions in healthy adults. Sixteen healthy Chinese adults participated in a randomized, controlled, crossover meal trial. Subjects consumed in random order 5 experimental isocaloric meals that differed in the food intake sequence of vegetables, protein and carbohydrate. Glucose, insulin, incretins and satiety markers were measured over 3h. There were significant food intake sequence×time interaction effects on plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) concentrations (P<0.001). In comparison with rice consumed first followed by vegetable and meat (R-VM), the overall postprandial glucose response was significantly attenuated after the food intake sequence of vegetable first, followed by meat and rice (V-MR) or meat first, followed by vegetable and rice (M-VR) or vegetable first followed by meat and rice (V-M-R) or vegetable, meat and rice consumed together (VMR). The insulin iAUC (0-60) was significant lower after V-M-R than M-VR, VMR and R-VM. V-M-R food intake sequence stimulated higher GLP-1 release than other meal sequences. However, GIP response was lower after V-MR and V-M-R than M-VR and R-MR food intake sequences. Food macronutrient intake sequence can considerably influence its glycemic, insulinemic and incretin responses. V-M-R food intake sequence attenuates the glycemic response to a greater degree with accentuated GLP-1 stimulation without any increased demand for insulin. The sequence of food intake has great potential as a novel and simple behavioral strategy to modulate glycemic response in healthy adults. The trial was registered at clinicaltrials.gov as NCT03533738.

Zinc-induced activation of GPR39 regulates glucose homeostasis through glucose-dependent insulinotropic polypeptide secretion from enteroendocrine K-cells.

The role of Zn2+-sensing receptor GPR39 on glucose homeostasis and incretin regulation was assessed in enteroendocrine L- and K-cells. Anti-hyperglycaemic, insulinotropic and incretin secreting properties of Zn2+ were explored in normal, diabetic and incretin receptor knockout mice. Compared to intraperitoneal injection, oral administration of Zn2+ (50 μmol/kg body weight) with glucose (18 mmol/kg) in lean mice reduced the glycaemic excursion by 25-34% (p < 0.05-p < 0.001) and enhanced glucose-induced insulin release by 46-48% (p < 0.05-p < 0.01). In diabetic mice, orally administered Zn2+ lowered glucose by 24-31% (p < 0.01) and augmented insulin release by 32% (p < 0.01). In glucagon like peptide-1 (GLP-1) receptor knockout mice, Zn2+ reduced glucose by 15-28% (p < 0.05-p < 0.01) and increased insulin release by 35-43% (p < 0.01). In contrast Zn2+ had no effect on responses of glucose-dependent insulinotropic polypeptide (GIP) receptor knockout mice. Consistent with this, Zn2+ had no effect on circulating total GLP-1 whereas GIP release was stimulated by 26% (p < 0.05) in lean mice. Immunocytochemistry demonstrated GPR39 expression on mouse enteroendocrine L- and K-cells, GLUTag cells and pGIP/Neo STC-1 cells. Zn2+ had a direct effect on GIP secretion from pGIPneo STC-1 cells, increasing GIP secretion by 1.3-fold. GPR39 is expressed on intestinal L- and K-cells, and stimulated GIP secretion plays an integral role in mediating enhanced insulin secretion and glucose tolerance following oral administration of Zn2+. This suggests development of potent and selective GPR39 agonists as a therapeutic approach for diabetes.

Incretin Hormones, Thyroid Stimulating Hormone and Human Growth Hormone Responses During Ogtt in Newly Diagnosed T2DM Patients

Several research groups have reported variable results about incretin effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1), altered thyroid stimulating hormone (TSH) status, human growth hormone (hGH) deficiency and perturbed cytokines balances in type 2 diabetes mellitus (T2DM).The present case-control prospective interventional study was conducted investigating responses of incretin hormones (GIP, GLP-1), TSH and hGH to oral glucose tolerance test (OGTT) in newly diagnosed Bangladeshi T2DM patient. Blood samples were collected from 36 OGTT positive newly diagnosed T2DM patients as cases and 30 normal adults as controls at '0' minute (fasting) and at 2 hours after OGTT. Laboratory investigations were done and special parameters in serum, i.e. hGH, TSH, Insulin, GIP and GLP-1 were analyzed using enzyme immunoassay (EIA) kits. Statistical analyses were made by Student's 't' test using SPSS programm. T2DM patients (cases) had FBG and BG2Hr levels much higher than controls (p&lt;0.001). No significant differences were observed between controls and cases for F-TSH (p=0.927), TSH2HrA (p=0.413), F-hGH (p=0.532) and hGH2HrA (p=0.773) levels. It was observed that F-GIP (p=0.309) and F-GLP-1 (p=0.984) levels were similar between cases and controls. Interestingly, control subjects responded to OGTT by increasing GIP2HA and GLP-1, 2HR levels about 3 times compared to F-GIP and F-GLP-1 (p&lt;0.001). In cases, F-GIP and F-GLP-1 levels were also raised responding to OGTT but by about 1.5 times only compared to F-GIP and F-GLP-1 (p&lt;0.025). Although no significant differences were observed for F-TSH, TSH2HrA, F-hGH and hGH2HrA between cases and controls, F-GIP and F-GLP-1 levels were raised responding to OGTT in cases by about 1.5 times only compared to about 3.0 times in controls subjects. But responses of GIP and GLP-1 to glucose load were lower leading to reduced insulin levels in these T2DM patients reported earlier. Further studies with a larger sample size including cytokines are warranted.&#x0D; Bangladesh J Med Biochem 2018; 11(1): 9-16

Effects of starvation and short-term refeeding on gastric emptying and postprandial blood glucose regulation in adolescent girls with anorexia nervosa.

Postprandial glucose is reduced in malnourished patients with anorexia nervosa (AN), but the mechanisms and duration for this remain unclear. We examined blood glucose, gastric emptying, and glucoregulatory hormone changes in malnourished patients with AN and during 2 wk of acute refeeding compared with healthy controls (HCs). Twenty-two female adolescents with AN and 17 age-matched female HCs were assessed after a 4-h fast. Patients were commenced on a refeeding protocol of 2,400 kcal/day. Gastric emptying (13C-octanoate breath test), glucose absorption (3-O-methylglucose), blood glucose, plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide, and glucagon responses to a mixed-nutrient test meal were measured on admission and 1 and 2 wk after refeeding. HCs were assessed once. On admission, patients had slower gastric emptying, lower postprandial glucose and insulin, and higher glucagon and GLP-1 than HCs ( P < 0.05). In patients with AN, the rise in glucose (0-30 min) correlated with gastric emptying ( P < 0.05). With refeeding, postprandial glucose and 3-O-methylglucose were higher, gastric emptying faster, and baseline insulin and C-peptide less ( P < 0.05), compared with admission. After 2 wk of refeeding, postprandial glucose remained lower, and glucagon and GLP-1 higher, in patients with AN than HCs ( P < 0.05) without differences in gastric emptying, baseline glucagon, or postprandial insulin. Delayed gastric emptying may underlie reduced postprandial glucose in starved patients with AN; however, postprandial glucose and glucoregulatory hormone changes persist after 2 wk of refeeding despite improved gastric emptying. Future research should explore whether reduced postprandial glucose in AN is related to medical risk by examining associated symptoms alongside continuous glucose monitoring during refeeding.

Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses

BackgroundPatients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG (rs36210421 and rs1805123) on QT interval and plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon during an oral glucose tolerance test (OGTT).We used two population-based cohorts for evaluation of the effect of common variants in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1, GIP, insulin and glucagon during an OGTT.ResultsCarriers of either the minor A-allele of rs36210421 or the minor G-allele of rs1805123 had ~ 2 ms shorter QT interval per risk allele (p = 0.025 and p = 1.9 × 10− 7). Additionally, both variants were associated with alterations in pancreatic and gut hormone release among carriers. The minor A- allele of rs36210421 was associated with increased GLP-1 and decreased GIP response to oral glucose stimulation, whereas the minor G-allele of rs1805123 is associated with decreased fasting plasma insulin and glucagon release. A genetic risk score combining the two gene variants revealed reductions in glucose-stimulated GIP, as well as suppressed glucagon response to increased glucose levels during an OGTT.ConclusionsTwo common missense polymorphisms of the Kv11.1 voltage-gated hERG potassium channel are associated with alterations in circulating levels of GIP and glucagon, suggesting that hERG potassium channels play a role in fasting and glucose-stimulated release of GIP and glucagon.Trial registrationClinicalTrials.gov (NCT00289237). Trial retrospectively registered at February 9, 2006. Studies were approved by the Ethical Committee of the Central Denmark Region (journal no. 20080229) and by the Copenhagen County Ethical Committee (KA 98155).

Male grower pigs fed cereal soluble dietary fibres display biphasic glucose response and delayed glycaemic response after an oral glucose tolerance test.

Acute and sustained soluble dietary fibre (SDF) consumption are both associated with improved glucose tolerance in humans and animal models (e.g. porcine). However, the effects on glucose tolerance in grower pigs, adapted to diets with a combination of SDF have not been studied previously. In this experiment, cereal SDF wheat arabinoxylan (AX) and oat β-glucan (BG) were fed individually and in combination to determine the effect on glucose tolerance in jugular vein catheterized grower pigs. Five groups of Large White male grower pigs were fed highly digestible diets containing either 10% AX, 10% BG, 5% AX with 5% BG, a model cereal whole wheat flour (WWF), or a control wheat starch diet (WS) with no SDF. Blood was collected via jugular vein catheters over 240 minutes following a feed challenge and an oral glucose tolerance test (OGTT) on two separate days. Postprandial blood samples were used to determine plasma glucose, insulin, non-esterified fatty acids (NEFA), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), ghrelin, glucagon and cortisol concentrations. No dietary effects on glycaemic response were observed following the feed challenge or the OGTT as determined by the area under the curve (AUC). A biphasic glucose and insulin response was detected for all pigs following the OGTT. The current study showed male grower pigs have tight glycaemic control and glucose tolerance regardless of diet. In addition, pigs fed the combined SDF had a reduced GIP response and delayed insulin peak following the feed challenge. Incretin (GLP-1 and GIP) secretion appeared asynchronous reflecting their different enteroendocrine cell locations and response to nutrient absorption.

Comparing olive oil and C4-dietary oil, a prodrug for the GPR119 agonist, 2-oleoyl glycerol, less energy intake of the latter is needed to stimulate incretin hormone secretion in overweight subjects with type 2 diabetes

Background/objective After digestion, dietary triacylglycerol stimulates incretin release in humans, mainly through generation of 2-monoacylglycerol, an agonist for the intestinal G protein-coupled receptor 119 (GPR119). Enhanced incretin release may have beneficial metabolic effects. However, dietary fat may promote weight gain and should therefore be restricted in obesity. We designed C4-dietary oil (1,3-di-butyryl-2-oleoyl glycerol) as a 2-oleoyl glycerol (2-OG)-generating fat type, which would stimulate incretin release to the same extent while providing less calories than equimolar amounts of common triglycerides, e.g., olive oil.Subjects and methodsWe studied the effect over 180 min of (a) 19 g olive oil plus 200 g carrot, (b) 10.7 g C4 dietary oil plus 200 g carrot and (c) 200 g carrot, respectively, on plasma responses of gut and pancreatic hormones in 13 overweight patients with type 2 diabetes (T2D). Theoretically, both oil meals result in formation of 7.7 g 2-OG during digestion.ResultsBoth olive oil and C4-dietary oil resulted in greater postprandial (P ≤ 0.01) glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses (incremental area under curve (iAUC)): iAUCGLP−1: 645 ± 194 and 702 ± 97 pM × min; iAUCGIP: 4,338 ± 764 and 2,894 ± 601 pM × min) compared to the carrot meal (iAUCGLP−1: 7 ± 103 pM × min; iAUCGIP: 266 ± 234 pM × min). iAUC for GLP-1 and GIP were similar for C4-dietary oil and olive oil, although olive oil resulted in a higher peak value for GIP than C4-dietary oil.ConclusionC4-dietary oil enhanced secretion of GLP-1 and GIP to almost the same extent as olive oil, in spite of liberation of both 2-OG and oleic acid, which also may stimulate incretin secretion, from olive oil. Thus, C4-dietary oil is more effective as incretin releaser than olive oil per unit of energy and may be useful for dietary intervention.

Effect of short-term intensive insulin therapy on the incretin response in early type 2 diabetes

AimsShort-term intensive insulin therapy (IIT) and gastric bypass surgery are both interventions that can improve beta-cell function, reduce insulin resistance and induce remission of type 2 diabetes. Whereas gastric bypass yields an enhanced glucagon-like peptide-1 (GLP-1) response that may contribute to its metabolic benefits, the effect of short-term IIT on the incretin response is unclear. Thus, we sought to evaluate the impact of IIT on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretion in early type 2 diabetes. MethodsIn this study, 63 patients (age 59±8.3 years, baseline A1c 6.8±0.7%, diabetes duration 3.0±2.1 years) underwent 4 weeks of IIT (basal insulin detemir and pre-meal insulin aspart). GLP-1, GIP and glucagon responses were assessed by the area-under-the-curve (AUC) of these hormones on oral glucose tolerance tests at baseline and 1-day after the completion of therapy. Beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2), with insulin resistance measured by Homeostasis Model Assessment (HOMA-IR). ResultsAs expected, comparing the post-therapy oral glucose tolerance test to that at baseline, IIT increased ISSI-2 (P=0.02), decreased HOMA-IR (P<0.001), and reduced AUCglucagon (P<0.001). Of note, however, IIT had no significant impact on AUCGLP-1 (P=0.24) and reduced AUCGIP (P=0.02). ConclusionDespite improving beta-cell function, insulin resistance and glucagonemia, short-term IIT does not change GLP-1 secretion and decreases the GIP response to an oral glucose challenge in early type 2 diabetes. Thus, the beneficial impact of this therapy on glucose homeostasis is not attributable to its effects on incretin secretion.

Incretin Hormones and Insulin Responses During OGTT in Newly Diagnosed T2DM Patients

Several research groups have reported variable results about incretin effects of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(GLP-1) particularly, as well as cytokines balance in type 2 diabetes mellitus (T2DM). The present case-control prospective interventional study was conducted in 2014-2015 at Medical College for Women &amp; Hospital, Dhaka, investigating responses of incretin hormones and insulin to oral glucose tolerance test (OGTT) in Bangladeshi subjects. Blood samples were collected from 36 OGTT positive adult T2DM patients (Pt) and 30 normal adults (NC) at '0' minute (fasting) and at 2 hours after OGTT. Routine laboratory investigations in blood were done and special parameters in serum, i.e. insulin, HGH, TSH, GIP and GLP-1 were analyzed using enzyme immunoassay kits. Pt had FBG and BG2Hr levels much higher than NC (p&lt;0.001). In Pt, F-Insulin and Insulin2Hr were much lower than NC subjects (p&lt;0.001), although Insulin2Hr level was higher than F-Insulin level in Pt. F-GIP (p=0.309) and F-GLP-1(p=0.984) levels were similar between Pt and NC. Interestingly, NC responded to OGTT by increasing GIP2Hr and GLP-1,2Hr levels about 3 times, whereas Pt responded by raising about 1.5 times only compared to F-GIP and F-GLP-1 (p&lt;0.001). Reduced insulin levels, both fasting and postprandial, were possibly due to decreased responses of GIP and GLP-1 to glucose load in T2DM patients. Further studies with a larger sample size including cytokines are warranted.

Incretin secretion in humans is under the influence of cannabinoid receptors.

The mechanisms regulating incretin secretion are not fully known. Human obesity is associated with altered incretin secretion and elevated endocannabinoid levels. Since cannabinoid receptors (CBRs) are expressed on incretin-secreting cells in rodents, we hypothesized that endocannabinoids are involved in the regulation of incretin secretion. We compared plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) responses during oral glucose tolerance test (OGTT) in 20 lean and 20 obese participants from the Baltimore Longitudinal Study of Aging (BLSA). Next, we recruited 20 healthy men to evaluate GIP and GLP-1 responses during OGTT after administering placebo or nabilone (CBR agonist) in a randomized, double-blind, crossover fashion. Compared with the BLSA lean group, the BLSA obese group had significantly higher fasting and post-OGTT GIP levels, but similar fasting GLP-1 and significantly lower post-OGTT GLP-1 levels. In the nabilone vs. placebo study, when compared with placebo, nabilone resulted in significantly elevated post-dose fasting GIP levels and post-OGTT GIP levels, but no change in post-dose fasting GLP-1 levels together with significantly lower post-OGTT GLP-1 levels. Glucose levels were not different with both interventions. We conclude that elevated GIP levels in obesity are likely a consequence of increased endocannabinoid levels. CBRs exert tonic control over GIP secretion, which may have a homeostatic effect in suppressing GLP-1 secretion. This raises the possibility that gut hormones are influenced by endocannabinoids.

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.

Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia.

Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long-QT syndrome type 2 (LQT2) because of prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), respectively. These hormones are crucial for glucose regulation, and long-QT syndrome may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β-cell function and decreased α-cell function, and thus lower glucose levels. Eleven patients with LQT2 and 22 sex-, age-, and body mass index-matched control participants underwent a 6-hour 75-g oral glucose tolerance test with ECG recording and blood sampling for measurements of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP. In comparison with matched control participants, LQT2 patients had 56% to 78% increased serum insulin, serum C-peptide, plasma GLP-1, and plasma GIP responses (P=0.03-0.001) and decreased plasma glucose levels after glucose ingestion (P=0.02) with more symptoms of hypoglycemia (P=0.04). Sixty-three percent of LQT2 patients developed hypoglycemic plasma glucose levels (<70 mg/dL) versus 36% control participants (P=0.16), and 18% patients developed serious hypoglycemia (<50 mg/dL) versus none of the controls. LQT2 patients had defective glucagon responses to low glucose, P=0.008. β-Cell function (Insulin Secretion Sensitivity Index-2) was 2-fold higher in LQT2 patients than in controls (4398 [95% confidence interval, 2259-8562] versus 2156 [1961-3201], P=0.03). Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effect, and small interfering RNA inhibition of hERG in β and L cells increased insulin and GLP-1 secretion up to 50%. Glucose ingestion caused cardiac repolarization disturbances with increased QTc intervals in both patients and controls, but with a 122% greater increase in QTcF interval in LQT2 patients (P=0.004). Besides a prolonged cardiac repolarization phase, LQT2 patients display increased GLP-1, GIP, and insulin secretion and defective glucagon secretion, causing decreased plasma glucose and thus increased risk of hypoglycemia. Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients. URL: http://clinicaltrials.gov. Unique identifier: NCT02775513.

Effects of a high-fat meal on postprandial incretin responses, appetite scores and ad libitum energy intake in women with obesity.

Considering the possible role of triglycerides (TG), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the regulation of appetite, this study aimed to compare high fat meal-induced response of GIP and GLP-1, appetite scores and ad libitum energy intake in women with obesity, according to postprandial increment in triglyceridemia (∆TG). Methods: Thirty-three no-diabetic women (BMI = 35.0 ± 3.2 kg.m-2) were divided into two groups: Group with ∆TG ≤ median were called "Low TG change -LTG" and ∆TG > median, "High TG change - HTG". Plasma concentrations of GIP, GLP-1 and appetite sensations were measured prior to, and every 30 min for 180 min after ingestion of a high-fat breakfast. An ad libitum lunch was served 3 h after the test meal. The AUC incrementalGIP were significant lower in HTG vs. LTG group (p = 0.03). The same was observed for GIP levels at 150 min (p = 0.03) and at 180 min (p < 0.01). Satiety was lower in HTG at 120 min (p = 0.03) and 150 min (p < 0.01). The AUC totalGLP1 were similar between groups and there were no between-group differences for the GLP-1 at each time point. Ad libitum food intake were also similar between groups. The HTG group exhibited differences in satiety scores and lower postprandial secretion of GIP, however with no impact on ad libitum food intake in short term.

Fructose intervention for 12 weeks does not impair glycemic control or incretin hormone responses during oral glucose or mixed meal tests in obese men

Background and aimsIncretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. Methods and resultsAs many as 66 obese (BMI 26–40 kg/m2) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). ConclusionIn obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge.