Glucose-dependent Insulinotropic Polypeptide Levels Research Articles

Incretin and islet hormone responses to meals of increasing size in healthy subjects.

Postprandial glucose homeostasis is regulated through the secretion of glucagon-like peptide 1 (GLP-1) through the stimulation of insulin secretion and inhibition of glucagon secretion. However, how these processes dynamically adapt to demands created by caloric challenges achieved during daily life is not known. The objective of the study was to explore the adaptation of incretin and islet hormones after mixed meals of increasing size in healthy subjects. Twenty-four healthy lean subjects ingested a standard breakfast after an overnight fast followed, after 4 hours, by a lunch of a different size (511, 743, and 1034 kcal) but with identical nutrient composition together with 1.5 g paracetamol. Glucose, insulin, C-peptide, glucagon, intact GLP-1, and glucose-dependent insulinotropic polypeptide (GIP) and paracetamol were measured after the meals. Area under the 180-minute curve (AUC) for insulin, C-peptide, glucagon, GLP-1, and GIP and model-derived β-cell function and paracetamol appearance were calculated. Glucose profiles were similar after the two larger meals, whereas after the smaller meal, there was a postpeak reduction below baseline to a nadir of 3.8 ± 0.1 mmol/L after 75 minutes (P < .001). The AUC for GLP-1, GIP, insulin, and C-peptide were significantly higher by increasing the caloric load as was β-cell sensitivity to glucose. In contrast, the AUC glucagon was the same for all three meals, although there was an increase in glucagon after the postpeak glucose reduction in the smaller meal. The 0- to 20-minute paracetamol appearance was increased by increasing meal size. Mixed lunch meals of increasing size elicit a caloric-dependent insulin response due to increased β-cell secretion achieved by increased GIP and GLP-1 levels. The adaptation at larger meals results in identical glucose excursions, whereas after a lower caloric lunch, the insulin response is high, resulting in a postpeak suppression of glucose below baseline.

Nutritional strategy to prevent fatty liver and insulin resistance independent of obesity by reducing glucose-dependent insulinotropic polypeptide responses in mice.

High intake of carbohydrates, particularly sucrose, in western societies is associated with the development of non-alcoholic fatty liver (NAFL) and diabetes mellitus. It is unclear whether this is related primarily to the carbohydrate quantity or to the hormonal responses, particularly glucose-dependent insulinotropic polypeptide (GIP), which is released in the proximal intestine. Therefore, we investigated the role of GIP by comparing two glucose-fructose dimers, sucrose and Palatinose (isomaltulose), resorbed proximally or distally. The glycaemic and incretin responses to sucrose and Palatinose were studied by oral gavage and meal tests. We then analysed phenotypic and metabolic diet-induced changes in C57Bl/6J mice exposed to isoenergetic diets differing in carbohydrate type. Studies were repeated in GIP receptor knockout (Gipr(-/-)) mice and their wild-type littermates. Compared with sucrose, Palatinose intake resulted in slower glucose absorption and reduced postprandial insulin and GIP levels. After 22 weeks, Palatinose feeding prevented hepatic steatosis (48.5%) compared with sucrose and improved glucose tolerance, without differences in body composition and food intake. Ablation of GIP signalling in Gipr(-/-) mice completely prevented the deleterious metabolic effects of sucrose feeding. Furthermore, our microarray analysis indicated that sucrose increased 2.3-fold the hepatic expression of Socs2, which is involved in the growth hormone signalling pathway and participates in the development of NAFL. Our results suggest that the site of glucose absorption and the GIP response determine liver fat accumulation and insulin resistance. GIP may play a role in sucrose induced fatty liver by regulating the expression of Socs2.

RNA-Seq analysis of enteroendocrine cells reveals a role for FABP5 in the control of GIP secretion.

In response to fat intake, enteroendocrine K cells release the hormone glucose-dependent insulinotropic polypeptide (GIP). GIP acts on adipocytes to increase lipid uptake and enhance adipokine secretion, promoting weight gain and insulin resistance. Modulation of intestinal GIP release could therefore represent a therapeutic strategy for the treatment and prevention of obesity and diabetes. However, the prospects of using drugs to effectively target specific enteroendocrine cell types have been tempered by the realization that these cells share similar transcriptional programs and frequently employ common mechanisms of hormone secretion. To gain novel insights into the regulation of GIP release, we generated knock-in mice expressing green fluorescent protein (GFP) under the control of the endogenous GIP promoter that enable the isolation of a purified population of small intestine K cells. Using RNA sequencing, we comprehensively characterized the transcriptomes of GIP(GFP) cells as well as the entire enteroendocrine lineage derived from Neurogenin3-expressing progenitors. Among the genes differentially expressed in GIP(GFP) cells, we identified and validated fatty acid-binding protein 5 (FABP5) as a highly expressed marker of GIP-producing cells that is absent in other enteroendocrine cell types. FABP5 promotes intracellular transport and inactivation of endocannabinoids, including anandamide, which inhibits GIP release. Remarkably, we found that circulating levels of GIP were significantly decreased in FABP5-deficient mice in the fasting state and in response to acute, oral fat diet administration. Our findings highlight the power of RNA sequencing to uncover molecular signatures of specific enteroendocrine cell types that can potentially be exploited for therapeutic purposes in the treatment of metabolic disorders.

Glucometabolic hormones and cardiovascular risk markers in antipsychotic-treated patients.

Treatment with antipsychotic drugs is widely associated with metabolic side effects such as weight gain and disturbed glucose metabolism, but the pathophysiologic mechanisms are unclear. Fifty nondiabetic (fasting plasma glucose ≤ 7.0 mmol/L), antipsychotic-treated male patients (ICD-10 diagnosis code F20, F21, F22, F25, F28, or F60; mean ± SD age = 33.0 ± 6.7 years; body mass index [BMI; kg/m²] = 26.0 ± 4.7; waist circumference = 95.9 ± 13.3 cm; glycated hemoglobin A1c [HbA1c] = 5.7% ± 0.3%) and 93 age- and waist circumference-matched healthy male controls (age = 33 ± 7.3 years; BMI = 26.1 ± 3.9; waist circumference = 94.6 ± 11.9 cm; HbA1c = 5.7% ± 0.3%) participated in this cross-sectional study. Blood was sampled in the fasting state and 90 minutes after ingestion of a standardized liquid meal (2,268 kJ). The primary outcomes were glucometabolic hormones and cardiovascular risk markers. Data were collected between March 2008 and February 2010. Compared to healthy controls, patients were characterized by elevated fasting levels of proinsulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) (P < .05) and higher postprandial levels of insulin, proinsulin, C-peptide, and GIP (P ≤ .02). Also, patients exhibited elevated plasma levels of C-reactive protein and signs of dyslipidemia. Fasting plasma levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), ghrelin, leptin, adiponectin, tumor necrosis factor-α, plasminogen activator inhibitor-1, and interleukin-6 and postprandial levels of glucagon, GLP-1, ghrelin, leptin, and adiponectin did not differ between groups. Presenting with an insulin resistant-like pattern, including beta cell hypersecretion and elevated GIP levels, nondiabetic antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised cardiovascular risk profile. The appetite-regulating hormones GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment. Our findings provide new clinical insight into the pathophysiology associated with metabolic side effects of antipsychotic treatment and put emphasis on the importance of implementing metabolic screening into psychiatric practice. ClinicalTrials.gov identifier NCT00627757.

Postprandial gallbladder emptying in patients with type 2 diabetes: potential implications for bile-induced secretion of glucagon-like peptide 1.

Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1(GCG)) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility. In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender- and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined. Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals. In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.

The impact of dipeptidyl peptidase 4 inhibition on incretin effect, glucose tolerance, and gastrointestinal-mediated glucose disposal in healthy subjects.

Inhibition of dipeptidyl peptidase 4 (DPP4) is thought to intensify the physiological effects of the incretin hormones. We investigated the effects of DPP4 inhibition on plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1), incretin effect, glucose tolerance, gastrointestinal-mediated glucose disposal (GIGD) and gastric emptying in healthy subjects. A randomised, controlled and open-labelled study. Ten healthy subjects (six women; age, 40±5 years (mean±s.e.m.); BMI, 24±3 kg/m(2); fasting plasma glucose, 5.1±0.2 mmol/l and HbA1c, 34±1 mmol/mol (5.3±0.1%)) were randomised to two-paired study days comprising a 4-h 50 g oral glucose tolerance test (OGTT) with paracetamol (A) and an isoglycaemic intravenous (i.v.) glucose infusion (B), with (A1+B1) and without (A2+B2) preceding administration of the DPP4 inhibitor sitagliptin. Isoglycaemia was obtained in all subjects on the paired study days. Significant increases in fasting levels and OGTT-induced responses of active GLP1 and GIP were seen after DPP4 inhibition. No significant impact of DPP4 inhibition on fasting plasma glucose (5.1±0.1 vs 4.9±0.1 mmol/l, P=0.3), glucose tolerance (area under the curve (AUC) for plasma glucose, 151±35 vs 137±26 mmol/l×min, P=0.7) or peak plasma glucose during OGTT (8.5±0.4 vs 8.1±0.3 mmol/l, P=0.3) was observed. Neither incretin effect (40±9% (without DPP4 inhibitor) vs 40±7% (with DPP4 inhibitor), P=1.0), glucagon responses (1395±165 vs 1223±195 pmol/l×min, P=0.41), GIGD (52±4 vs 56±5%, P=0.40) nor gastric emptying (Tmax for plasma paracetamol: 86±9 vs 80±12 min, P=0.60) changed following DPP4 inhibition. These results suggest that acute increases in active incretin hormone levels do not affect glucose tolerance, GIGD, incretin effect, glucagon responses or gastric emptying in healthy subjects.

GIP Contributes to Islet Trihormonal Abnormalities in Type 2 Diabetes

Research and clinical treatments on type 2 diabetes mainly focus on insulin deficiency with little attention paid to other islet hormones. This study tested the hypothesis that glucose-dependent insulinotropic polypeptide (GIP) is involved in diabetes-associated multiislet hormone dysregulation. This paper included a case-control study involving 92 community-based volunteers from the Baltimore Longitudinal Study of Aging (BLSA): 23 with type 2 diabetes on glucose-lowering agents, 25 with newly diagnosed drug-naïve type 2 diabetes, 19 with prediabetes, and 25 with normal glucose tolerance; a separate intervention study with 13 non-BLSA volunteers with type 2 diabetes treated with diet alone, metformin, and/or metformin/sulfonylurea combination; a rodent study; and an in vitro cell line study. An oral glucose tolerance test was performed in the BLSA participants. For the intervention study, saline (0.9% NaCl) or synthetic human GIP (20 ng · kg(-1) · min(-1)) was administered to type 2 diabetes subjects for 180 minutes together with a meal, and plasma samples were obtained at predetermined intervals for 360 minutes. A bolus of GIP or placebo was given to C57BL/6 mice. Plasma glucose, insulin, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and GIP were measured. After an oral glucose tolerance test, glucose, glucagon, PP, GLP-1, and GIP levels were significantly elevated in type 2 diabetes groups, compared with normal and prediabetes groups. GIP infusion in type 2 diabetes subjects was associated with significantly elevated PP levels compared with placebo. The GIP bolus given to C57BL/6 mice was followed by increased PP levels. GIP receptors were found in both human and mouse PP cells. Up-regulation of GIP production may play an important role in multihormonal dysregulation in type 2 diabetes, most likely through interaction with GIP receptors on islets.

Elimination and Degradation of Glucagon-like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide in Patients with End-Stage Renal Disease

The affect of the kidneys in elimination and degradation of intact incretin hormones and their truncated metabolites is unclear. To evaluate elimination and degradation of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in patients with dialysis-dependent kidney failure. Twelve non-diabetic patients treated with chronic hemodialysis and 12 control subjects were examined in a double-blind, randomized, matched observational study at the Department of Nephrology, Rigshospitalet, University of Copenhagen, Denmark. Over 4 separate study days, synthetic human GIP or GLP-1 was infused with or without concurrent inhibition of dipeptidyl peptidase 4 using sitagliptin or placebo. Plasma concentrations of glucose, insulin, glucagon, and intact and total forms of GLP-1 or GIP were measured repeatedly. Plasma half-life (T1/2), metabolic clearance rate (MCR), area under curve, and volume of distribution for intact and metabolite levels of GLP-1 and GIP were calculated. Fasting concentrations of intact GLP-1 and GIP were increased in dialysis patients (P < .001) whereas fasting levels of GLP-1 and GIP metabolites did not differ between groups (P > .738). MCRs of intact GLP-1 and GIP, and the GLP-1 metabolite were reduced in dialysis patients on the placebo day (P < .009), and T1/2 of intact and metabolite forms of GLP-1 and GIP were comparable between groups (P > .121). Unexpectedly, degradation and elimination of the intact and metabolite forms of GLP-1 and GIP seemed preserved, although reduced, in patients with dialysis-dependent kidney failure.

Duodenal-Jejunal Bypass and Jejunectomy Improve Insulin Sensitivity in Goto-Kakizaki Diabetic Rats Without Changes in Incretins or Insulin Secretion

Gastric bypass surgery can dramatically improve type 2 diabetes. It has been hypothesized that by excluding duodenum and jejunum from nutrient transit, this procedure may reduce putative signals from the proximal intestine that negatively influence insulin sensitivity (SI). To test this hypothesis, resection or bypass of different intestinal segments were performed in diabetic Goto-Kakizaki and Wistar rats. Rats were randomly assigned to five groups: duodenal-jejunal bypass (DJB), jejunal resection (jejunectomy), ileal resection (ileectomy), pair-fed sham-operated, and nonoperated controls. Oral glucose tolerance test was performed within 2 weeks after surgery. Baseline and poststimulation levels of glucose, insulin, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured. Minimal model analysis was used to assess SI. SI improved after DJB (SI = 1.14 ± 0.32 × 10(-4) min(-1) ⋅ pM(-1)) and jejunectomy (SI = 0.80 ± 0.14 × 10(-4) min(-1) ⋅ pM(-1)), but not after ileectomy or sham operation/pair feeding in diabetic rats. Both DJB and jejunal resection normalized SI in diabetic rats as shown by SI levels equivalent to those of Wistar rats (SI = 1.01 ± 0.06 × 10(-4) min(-1) ⋅ pM(-1); P = NS). Glucose effectiveness did not change after operations in any group. While ileectomy increased plasma GIP levels, no changes in GIP or GLP-1 were observed after DJB and jejunectomy. These findings support the hypothesis that anatomic alterations of the proximal small bowel may reduce factors associated with negative influence on SI, therefore contributing to the control of diabetes after gastric bypass surgery.

Cotreatment with the α-glucosidase inhibitor miglitol and DPP-4 inhibitor sitagliptin improves glycemic control and reduces the expressions of CVD risk factors in type 2 diabetic Japanese patients

ObjectiveIn this study, we examined whether inhibition of postprandial hyperglycemia by combination therapy with two drugs for reducing postprandial hyperglycemia, i.e., α-glucosidase inhibitor miglitol and dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin, improves glycemic control and reduces the risk of cardiovascular disease (CVD) development. Materials/MethodsWe enrolled 32 type 2 diabetic Japanese patients with hemoglobin A1c (HbA1c) levels ranging from 6.9% to 10.5%, who had been treated for at least 2 months with 50mg miglitol (t.i.d.) or 50mg sitagliptin (q.d.). Following a monotherapy period with either miglitol (Group-M) or sitagliptin (Group-S) for 1 month, the patients were subjected to combination therapy with sitagliptin and miglitol for 3 months. Meal tolerance tests were performed at the end of the monotherapy and combination therapy. ResultsCombination therapy for 3 months after monotherapy reduced HbA1c (changes: Group-M: −1.3%±0.7%, P<0.001; Group-S: −0.6%±0.5%, P<0.001) and glycoalbumin levels and increased 1,5-anhydroglucitol concentrations in the blood. In the meal tolerance tests, circulating active glucagon-like peptide-1 levels were elevated in both groups, while active glucose-dependent insulinotropic polypeptide levels were reduced by combination therapy in the group with add-on miglitol therapy. The plasma protein concentrations of interleukin (IL)-8 and adhesion molecules (sE-selectin and sVCAM-1) were reduced by switching to the combination therapy, in particular with the add-on miglitol therapy. ConclusionsOur results suggest that combination therapy with miglitol and sitagliptin improves glycemic control and reduces the circulating protein concentrations of IL-8, sE-selectin, and sVCAM-1 in type 2 diabetic Japanese patients.

Xenin-25 delays gastric emptying and reduces postprandial glucose levels in humans with and without Type 2 diabetes

Xenin-25 (Xen) is a neurotensin-related peptide secreted by a subset of glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine cells. In animals, Xen regulates gastrointestinal function and glucose homeostasis, typically by initiating neural relays. However, little is known about Xen action in humans. This study determines whether exogenously administered Xen modulates gastric emptying and/or insulin secretion rates (ISRs) following meal ingestion. Fasted subjects with normal (NGT) or impaired (IGT) glucose tolerance and Type 2 diabetes mellitus (T2DM; n = 10-14 per group) ingested a liquid mixed meal plus acetaminophen (ACM; to assess gastric emptying) at time zero. On separate occasions, a primed-constant intravenous infusion of vehicle or Xen at 4 (Lo-Xen) or 12 (Hi-Xen) pmol · kg(-1) · min(-1) was administered from zero until 300 min. Some subjects with NGT received 30- and 90-min Hi-Xen infusions. Plasma ACM, glucose, insulin, C-peptide, glucagon, Xen, GIP, and glucagon-like peptide-1 (GLP-1) levels were measured and ISRs calculated. Areas under the curves were compared for treatment effects. Infusion with Hi-Xen, but not Lo-Xen, similarly delayed gastric emptying and reduced postprandial glucose levels in all groups. Infusions for 90 or 300 min, but not 30 min, were equally effective. Hi-Xen reduced plasma GLP-1, but not GIP, levels without altering the insulin secretory response to glucose. Intense staining for Xen receptors was detected on PGP9.5-positive nerve fibers in the longitudinal muscle of the human stomach. Thus Xen reduces gastric emptying in humans with and without T2DM, probably via a neural relay. Moreover, endogenous GLP-1 may not be a major enhancer of insulin secretion in healthy humans under physiological conditions.

Laparoscopic Greater Curvature Plication in Morbidly Obese Women with Type 2 Diabetes: Effects on Glucose Homeostasis, Postprandial Triglyceridemia and Selected Gut Hormones

Laparoscopic greater curvature plication (LGCP) is an emerging bariatric procedure that reduces the gastric volume without implantable devices or gastrectomy. The aim of this study was to explore changes in glucose homeostasis, postprandial triglyceridemia, and meal-stimulated secretion of selected gut hormones [glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, and obestatin] in patients with type 2 diabetes mellitus (T2DM) at 1 and 6 months after the procedure. Thirteen morbidly obese T2DM women (mean age, 53.2 ± 8.76 years; body mass index, 40.1 ± 4.59 kg/m2) were prospectively investigated before the LGCP and at 1- and 6-month follow-up. At these time points, all study patients underwent a standardized liquid mixed-meal test, and blood was sampled for assessment of plasma levels of glucose, insulin, C-peptide, triglycerides, GIP, GLP-1, ghrelin, and obestatin. All patients had significant weight loss both at 1 and 6 months after the LGCP (p ≤ 0.002), with mean percent excess weight loss (%EWL) reaching 29.7 ± 2.9% at the 6-month follow-up. Fasting hyperglycemia and hyperinsulinemia improved significantly at 6 months after the LGCP (p < 0.05), with parallel improvement in insulin sensitivity and HbA1c levels (p < 0.0001). Meal-induced glucose plasma levels were significantly lower at 6 months after the LGCP (p < 0.0001), and postprandial triglyceridemia was also ameliorated at the 6-month follow-up (p < 0.001). Postprandial GIP plasma levels were significantly increased both at 1 and 6 months after the LGCP (p < 0.0001), whereas the overall meal-induced GLP-1 response was not significantly changed after the procedure (p > 0.05). Postprandial ghrelin plasma levels decreased at 1 and 6 months after the LGCP (p < 0.0001) with no significant changes in circulating obestatin levels. During the initial 6-month postoperative period, LGCP induces significant weight loss and improves the metabolic profile of morbidly obese T2DM patients, while it also decreases circulating postprandial ghrelin levels and increases the meal-induced GIP response.

Effects of Aerobic Exercise with or without Metformin on Plasma Incretins in Type 2 Diabetes

Despite positive effects of incretins on insulin secretion, little is known about the effect of exercise on these hormones. Metformin can affect incretin concentrations and is prescribed to a large proportion of people with diabetes. We, therefore, examined the effects of aerobic exercise and/or metformin on incretin hormones. Ten participants with type 2 diabetes were recruited for this randomized crossover study. Metformin or placebo was given for 28 days, followed by the alternate treatment for 28 days. On the last 2 days of each condition, participants were assessed during a non-exercise day and a subsequent exercise day. Aerobic exercise took place in the morning and blood samples were taken in the subsequent hours (before and after lunch). Aerobic exercise did not increase total plasma glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP) in the pre- or post-lunch periods (all p>0.1). GLP-1 was higher in the pre-lunch (p=0.016) and post-lunch (p=0.018) periods of the metformin conditions compared with the placebo. Total plasma GIP was higher in the pre-lunch period (p=0.05), but not in the post-lunch period (p=0.95), with metformin compared with placebo. In contrast to our hypothesis, aerobic exercise did not acutely increase total GLP-1 and GIP levels in patients with type 2 diabetes. Metformin, independent of exercise, significantly increased total plasma GLP-1 and GIP concentrations in these patients.

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Introduction: Insulin is used to treat hyperglycemia in critical illness, but can cause hypoglycaemia which is associated with poor outcomes. In health, glucose-dependent insulinotropic polypeptide (GIP) is a potent glucose-lowering hormone that does not induce hypoglycaemia. GIP may also accelerate gastric emptying and thereby improve nutrient absorption. Our objective was to determine whether exogenous GIP affects fasting or nutrient-stimulated glycaemia, glucose absorption and/or gastric emptying in critically ill patients. Methods: Twenty mechanically ventilated hyperglycaemic patients (Median age 61.5 range [22.0-79.0] years, BMI 27.9 [20.7-39.9] kg/m², HbA1c 5.9 [5.3-9.1] %), without known pre-existing diabetes, were studied on consecutive days in a randomised, double blind, placebo controlled, cross over fashion. Intravenous GIP (4 pmol/kg/min), or placebo (0.9% saline) was infused between T=0-360min. At T=60min, 100ml of liquid nutrient (2 kcal/ml), labeled with 3-O-Methylglucose (3-OMG) and 20 MBq 99mTc Calcium phytate was administered via a nasogastric tube. Blood glucose and serum 3-OMG (an index of glucose absorption) concentrations were measured. Gastric emptying was quantified using scintigraphy. Results are presented as medians (quartiles) and analysed using Wilcoxon paired tests. Results: Baseline glucose concentrations were comparable (T=0min; GIP 7.5 [6.5-9.5] vs. control 7.6 [7.0-9.4] mmol/L; P=0.68). GIP had no effect on fasting (T=60min, GIP 8.1 [6.3-9.0] vs. control 7.8 [6.8-9.5] mmol/L; P=0.53) or 'postprandial' glycaemia (AUC0-360: P=0.86). Neither gastric emptying (Gastric retention at T60min: GIP 80 [66-89] vs. control 84 [60-96] %; P=0.88. Gastric retention at T360min: GIP 26 [10-63] vs. control 37 [7-92] %; P=0.33) nor glucose absorption (3-OMG concentrations AUC60-360: GIP 50.6 [22.3-74.2] vs. control 64.3 [9.9-96.3] mmol/L/min; P=0.62) were affected by administration of GIP. Plasma GIP levels were significantly higher on days when GIP was infused. Serum insulin levels were not affected (P=0.76). Conclusions: Exogenous GIP does not affect glycaemia, glucose absorption or gastric emptying in the critically ill.

Incretins, amylin and other gut‐brain axis hormones in children with coeliac disease

Previous research indicated that coeliac disease (CD) is associated with type 1 diabetes mellitus (T1DM). However, the gut-brain axis peptide hormones secretion has not been evaluated so far in patients with CD prior to treatment initiation or under treatment, irrespective of patients having concomitant T1DM or not. The aim of the study was therefore to evaluate these gut hormones at the preprandial levels of patients with CD before and under treatment. Of forty-seven CD children, 12 untreated (UCD), 22 treated with gluten-free diet (TCD) and 13 treated CD with coexisting T1DM (DCD), and 18 healthy controls (HC) were enrolled. Preprandial glucagon-like-peptide-1 (GLP-1), glucose-dependent-insulinotropic-polypeptide (GIP), active amylin, acylated ghrelin (AG), leptin, pancreatic polypeptide (PP) and peptide-tyrosine-tyrosine (PYY) were determined with hormone-map-array technology. We found in patients with CD compared with HC that the concentration of (i) GLP-1 was reduced remarkably in all patients with CD (P = 0.008), (ii) GIP was lower in patients with UCD (P = 0.008), (iii) amylin was remarkably reduced (P < 0.01) in all patients with CD, (iv) AG was significantly decreased in patients with DCD (P < 0.01), while (v) leptin, PP and PYY were not significantly different. GIP, GLP-1 and amylin levels correlated positively with insulin concentrations (P < 0.001, P = 0.004 and P < 0.01, respectively) in all patients. Amylin and GIP levels were strongly associated with triglycerides concentrations (P < 0.001, for both peptides) in children with CD. Our study revealed a different secretion pattern of gut-brain axis hormones in children with CD compared with HC. The alterations in the axis were more pronounced in children with both CD and T1DM.

Postprandial responses of incretin and pancreatic hormones in non-diabetic patients with end-stage renal disease

Patients with end-stage renal disease (ESRD) have glucometabolic disturbances resulting in a high prevalence of prediabetes. The underlying pathophysiology remains unclear, but may prove important for the strategies employed to prevent progression to overt diabetes. Meal-induced release of the insulinotropic gut-derived incretin hormones and pancreatic hormones play a critical role in the maintenance of a normal postprandial glucose tolerance. We studied patients with ESRD and either normal (n = 10) or impaired (n = 10) glucose tolerance, and control subjects (n = 11). Plasma concentrations of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and paracetamol were measured repeatedly during a standardized 4-h liquid meal including 1.5 g paracetamol (added for evaluation of gastric emptying). Fasting glucose and postprandial glucose responses were comparable between groups (P > 0.082). Patients with ESRD exhibited higher fasting levels of GIP and glucagon compared with controls (P < 0.001). Baseline-corrected GLP-1 and glucagon responses were enhanced (P < 0.002), baseline-corrected insulin responses and insulin excursions were reduced (P < 0.035), and paracetamol excursions were delayed (P < 0.024) in patients with ESRD compared with controls. None of the variables differed between the two ESRD subgroups. Non-diabetic patients with ESRD were characterized by reduced postprandial insulin responses despite increased secretion of the insulinotropic incretin hormone GLP-1. Fasting levels and baseline-corrected responses of glucagon were elevated and gastric emptying was delayed in the ESRD patients. These perturbations seem to be caused by uraemia per se and may contribute to the disturbed glucose metabolism in ESRD patients.

Preventive Effect of Dipeptidyl Peptidase-4 Inhibitor on Atherosclerosis Is Mainly Attributable to Incretin's Actions in Nondiabetic and Diabetic Apolipoprotein E-Null Mice

AimSeveral recent reports have revealed that dipeptidyl peptidase (DPP)-4 inhibitors have suppressive effects on atherosclerosis in apolipoprotein E-null (Apoe −/−) mice. It remains to be seen, however, whether this effect stems from increased levels of the two active incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).MethodsNontreated Apoe −/− mice, streptozotocin-induced diabetic Apoe −/− mice, and db/db diabetic mice were administered the DPP-4 inhibitor vildagliptin in drinking water and co-infused with either saline, the GLP-1 receptor blocker, exendin(9–39), the GIP receptor blocker, (Pro3)GIP, or both via osmotic minipumps for 4 weeks. Aortic atherosclerosis and oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages were determined.ResultsVildagliptin increased plasma GLP-1 and GIP levels without affecting food intake, body weight, blood pressure, or plasma lipid profile in any of the animals tested, though it reduced HbA1c in the diabetic mice. Diabetic Apoe −/− mice exhibited further-progressed atherosclerotic lesions and foam cell formation compared with nondiabetic counterparts. Nondiabetic and diabetic Apoe −/− mice showed a comparable response to vildagliptin, namely, remarkable suppression of atherosclerotic lesions with macrophage accumulation and foam cell formation in peritoneal macrophages. Exendin(9–39) or (Pro3)GIP partially attenuated the vildagliptin-induced suppression of atherosclerosis. The two blockers in combination abolished the anti-atherosclerotic effect of vildagliptin in nondiabetic mice but only partly attenuated it in diabetic mice. Vildagliptin suppressed macrophage foam cell formation in nondiabetic and diabetic mice, and this suppressive effect was abolished by infusions with exendin(9–39)+(Pro3)GIP. Incubation of DPP-4 or vildagliptin in vitro had no effect on macrophage foam cell formation.ConclusionsVildagliptin confers a substantial anti-atherosclerotic effect in both nondiabetic and diabetic mice, mainly via the action of the two incretins. However, the partial attenuation of atherosclerotic lesions by the dual incretin receptor antagonists in diabetic mice implies that vildagliptin confers a partial anti-atherogenic effect beyond that from the incretins.

Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth

Milk has been recognized to represent a functionally active nutrient system promoting neonatal growth of mammals. Cell growth is regulated by the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1). There is still a lack of information on the mechanisms of mTORC1 up-regulation by milk consumption. This review presents milk as a materno-neonatal relay system functioning by transfer of preferential amino acids, which increase plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) for mTORC1 activation. Importantly, milk exosomes, which regularly contain microRNA-21, most likely represent a genetic transfection system enhancing mTORC1-driven metabolic processes. Whereas human breast milk is the ideal food for infants allowing appropriate postnatal growth and species-specific metabolic programming, persistent high milk signaling during adolescence and adulthood by continued cow´s milk consumption may promote mTORC1-driven diseases of civilization.

Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

To i) compare incretin responses to oral glucose and mixed meal of diabetic patients with the normoglycaemic population and ii) to investigate whether incretin responses are associated with hypertriglyceridaemia and alanine aminotransferase (ALT) as liver fat marker. A population-based study. A total of 163 persons with normal glucose metabolism (NGM), 20 with intermediate hyperglycaemia and 20 with type 2 diabetes aged 40-65 years participated. Participants received a mixed meal and oral glucose load on separate occasions. Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon profiles were analysed as total area under the curve (tAUC) and incremental area under the curve. In diabetic patients compared with persons with NGM, we found increased GLP-1 secretion (tAUC per hour) following oral glucose (23.2 pmol/l (95% CI 17.7-28.7) vs 18.0 (95% CI 16.9-19.1), P<0.05) but not after the mixed meal. GIP secretion among diabetic patients was increased on both occasions (82.9 pmol/l (55.9-109.8) vs 47.1 (43.8-50.4) for oral glucose and 130.6 (92.5-168.7) vs 83.2 (77.5-88.9) for mixed meal, both P<0.05). After oral glucose, GLP-1 (tAUC per hour) was inversely related to fasting triglycerides. GIP (tAUC per hour) was positively related to fasting and postprandial triglycerides. Higher fasting GIP levels were related to higher fasting and postprandial triglyceride levels and ALT. This study confirms that in type 2 diabetes, GLP-1 secretion is generally preserved and that GIP secretion is exaggerated. The mechanism underlying the divergent associations of GLP-1 and GIP metabolism with fat metabolism and liver fat accumulation warrants further study.

Physiology of incretins and loss of incretin effect in type 2 diabetes and obesity

An important role in the regulation of glucose homeostasis is played by incretins, which are gut-derived hormones released in response to nutrient ingestion. In humans, the major incretin hormones are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), and together they fully account for the incretin effect (that is, higher insulin release in response to an oral glucose challenge compared to an equal intravenous glucose load). Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, and the loss of incretin effect is likely to contribute importantly to the postprandial hyperglycaemia in type 2 diabetes. However, the specific cause–effect relationship between disease and incretins is still unclear. This review focuses on several key studies elucidating the association of defective incretin action with obesity and T2DM and the effects of metformin and other anti-diabetic agents on the incretin system.