Glucose-dependent Insulinotropic Peptide Responses Research Articles

Isomaltulose Enhances GLP-1 and PYY Secretion to a Mixed Meal in People With or Without Type 2 Diabetes as Compared to Saccharose.

Secretion of the gut hormones glucagon-like peptide (GLP-1) and peptide YY (PYY) are induced by nutrients reaching the lower small intestine which regulate insulin and glucagon release, inhibit appetite, and may improve β-cell regeneration. The aim is to test the effect of a slowly digested isomaltulose (ISO) compared to the rapidly digested saccharose (SAC) as a snack given 1h before a standardized mixed meal test (MMT) on GLP-1, PYY, glucose-dependent insulinotropic peptide (GIP), and metabolic responses in participants with or without type 2 diabetes (T2DM). Fifteenhealthy volunteers and 15 patients with T2DM consumed either 50g ISO or SAC 1h preload of MMT on nonconsecutive days. Clinical parameters and incretin hormones are measured throughout the whole course of MMT. Administration of 50g ISO as compared to SAC induced a significant increase in GLP-1, GIP, and PYY responses over 2h after intake of a typical lunch in healthy controls. Patients with T2DM showed reduced overall responses of GLP-1 and delayed insulin release compared to controls while ISO significantly enhanced the GIP and almost tripled the PYY response compared to SAC. A snack containing ISO markedly enhances the release of the metabolically advantageous gut hormones PYY and GLP-1 and enhances GIP release in response to a subsequent complex meal.

Bone metabolism and incretin hormones following glucose ingestion in young adults with pancreatic insufficient cystic fibrosis

BackgroundGut-derived incretin hormones, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), regulate post-prandial glucose metabolism by promoting insulin production. GIP, GLP-1, and insulin contribute to the acute bone anti-resorptive effect of macronutrient ingestion by modifying bone turnover. Cystic fibrosis (CF) is associated with exocrine pancreatic insufficiency (PI), which perturbs the incretin response. Cross-talk between the gut and bone (“gut-bone axis”) has not yet been studied in PI-CF. The objectives of this study were to assess changes in biomarkers of bone metabolism during oral glucose tolerance testing (OGTT) and to test associations between incretins and biomarkers of bone metabolism in individuals with PI-CF. MethodsWe performed a secondary analysis of previously acquired blood specimens from multi-sample OGTT from individuals with PI-CF ages 14–30 years (n = 23). Changes in insulin, incretins, and biomarkers of bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) and formation (procollagen type I N-terminal propeptide [P1NP]) during OGTT were computed. ResultsCTX decreased by 32% by min 120 of OGTT (P < 0.001), but P1NP was unchanged. Increases in GIP from 0 to 30 mins (rho = -0.48, P = 0.03) and decreases in GIP from 30 to 120 mins (rho = 0.62, P = 0.002) correlated with decreases in CTX from mins 0–120. Changes in GLP-1 and insulin were not correlated with changes in CTX, and changes in incretins and insulin were not correlated with changes in P1NP. ConclusionsIntact GIP response was correlated with the bone anti-resorptive effect of glucose ingestion, represented by a decrease in CTX. Since incretin hormones might contribute to development of diabetes and bone disease in CF, the “gut-bone axis” warrants further attention in CF during the years surrounding peak bone mass attainment.

Glucose-Dependent Insulinotropic Polypeptide Plasma Level Influences the Effect of n-3 PUFA Supplementation

Elevated glucose-dependent insulinotropic peptide (GIP) levels in obesity may predict the metabolic benefits of n-3 PUFA supplementation. This placebo-controlled trial aimed to analyze fasting and postprandial GIP response to 3-month n-3 PUFA supplementation (1.8 g/d; DHA:EPA, 5:1) along with caloric restriction (1200–1500 kcal/d) in obese subjects. Compliance was confirmed by the incorporation of DHA and EPA into red blood cells (RBCs). Blood analyses of glucose, insulin, non-esterified fatty acids (NEFAs), GIP and triglycerides were performed at fasting, and during an oral glucose tolerance test and a high fat mixed-meal tolerance test. Fatty acid composition of RBC was assessed by gas chromatography and total plasma fatty acid content and composition was measured by gas–liquid chromatography. The DHA and EPA content in RBCs significantly increased due to n-3 PUFA supplementation vs. placebo (77% vs. −3%, respectively). N-3 PUFA supplementation improved glucose tolerance and decreased circulating NEFA levels (0.750 vs. 0.615 mmol/L), as well as decreasing plasma saturated (1390 vs. 1001 µg/mL) and monounsaturated (1135 vs. 790 µg/mL) fatty acids in patients with relatively high GIP levels. The effects of n-3 PUFAs were associated with the normalization of fasting (47 vs. 36 pg/mL) and postprandial GIP levels. Obese patients with elevated endogenous GIP could be a target group for n-3 PUFA supplementation in order to achieve effects that obese patients without GIP disturbances can achieve with only caloric restriction.

Lean Subjects with Fatty Liver Show Decreased GLP-1 and GIP Response during OGTT

Subjects with nonalcoholic fatty liver disease (NAFLD) are at high risk of type 2 diabetes even if they are not obese and recent studies have indicated that liver fat (LF)&amp;gt;2.5% was already associated with alteration in glucose and insulin metabolism. Our aim was to investigate if having LF as low as 2.5% was associated to impairment in insulin sensitivity, secretion (ISR) and/or incretin hormones glucagon-like peptide (GLP) 1 and glucose-dependent insulinotropic peptide (GIP) released during an oral glucose tolerance test (OGTT). We studied 49 nondiabetic non-obese subjects (age 52±4; BMI 24.2±0.4 kg/m2). All subjects underwent a 2 h OGTT with plasma insulin, C-peptide, GLP-1, and GIP concentrations were measured every 15-30 min and ISR was quantitated by C-peptide deconvolution. Insulin sensitivity was quantified by HOMA and Matsuda index. Liver fat (LF) accumulation was quantified by magnetic resonance spectroscopy (MRS). In this group of non-obese subjects the great majority were non-NAFLD (31 had LF&amp;lt;2.5%), while 18 had NAFLD (9 had LF 2.5-5% and 9 had LF&amp;gt;5%). Age, BMI, HOMA (1.4±0.2 vs. 1.1±0.2), Matsuda index (7.3±0.7 vs. 10.6±1.3), fasting glucose (5.2±0.1 vs. 5.2±0.1 mmol/l), insulin (6.1±0.7 vs. 4.7±0.7 mU/l), ALT (20±1 vs. 19±1 U/l) and TG (96±22 vs. 88±6 mg/dl) were similar in NAFLD and non-NAFLD. Subjects with LF&amp;gt;2.5% had lower GLP-1 [GLP-1_AUC0-120 was 2.8±0.3 vs. 3.7±0.3, p=0.03], insulin secretion [ISR_AUC60-120 was 61±5 vs. 78±5 nmol, p=0.03] and insulin clearance [MCRI0-120 69±6 vs. 91±7 ml/kg/min, p=0.01] but not GIP [GIP_AUC0-120 was 4.6±0.3 vs. 5.3±0.3, p=ns] response compared to NAFLD; glucose and insulin concentrations during OGTT were similar [Glu0-120 6.7±0.3 vs. 7.3±0.3 mmol/l; Ins0-120 39.9±3.7 vs. 37.5±3.3 mU/l]. Conclusions: Liver fat accumulation (LF&amp;gt;2.5%) is associated with reduced GLP-1, ISR and MCRI; this can help to explain the increased risk of T2D of subjects with NAFLD. Disclosure A. Gastaldelli: Advisory Panel; Self; Gilead Sciences, Inc.. Other Relationship; Self; European Foundation for the Study of Diabetes. Consultant; Self; INVENTIVA SA. J. Garduno-Garcia: Speaker's Bureau; Self; Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., AstraZeneca. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. N. Musi: None.

Pre-Meal Effect of Whey Proteins on Metabolic Parameters in Subjects with and without Type 2 Diabetes: A Randomized, Crossover Trial.

Diabetic dyslipidemia with elevated postprandial triglyceride (TG) responses is characteristic in type 2 diabetes (T2D). Diet and meal timing can modify postprandial lipemia (PPL). The impact of a pre-meal of whey proteins (WP) on lipid metabolism is unidentified. We determined whether a WP pre-meal prior to a fat-rich meal influences TG and apolipoprotein B-48 (ApoB-48) responses differentially in patients with and without T2D. Two matched groups of 12 subjects with and without T2D accomplished an acute, randomized, cross-over trial. A pre-meal of WP (20 g) or water (control) was consumed 15 min before a fat-rich meal (supplemented with 20 g WP in case of water pre-meal). Postprandial responses were examined during a 360-min period. A WP pre-meal significantly increased postprandial concentrations of insulin (P < 0.0001), glucagon (P < 0.0001) and glucose-dependent insulinotropic peptide (GIP) (P < 0.0001) in subjects with and without T2D. We detected no effects of the WP pre-meal on TG, ApoB-48, or non-esterified fatty acids (NEFA) responses to the fat-rich meal in either group. Paracetamol absorption i.e., gastric emptying was delayed by the WP pre-meal (P = 0.039). In conclusion, the WP pre-meal induced similar hormone and lipid responses in subjects with and without T2D. Thus, the WP pre-meal enhanced insulin, glucagon and GIP responses but did not influence lipid or glucose responses. In addition, we demonstrated that a WP pre-meal reduced gastric emptying in both groups.

Pro-inflammatory gene expression profile in obese adults with high plasma GIP levels.

Glucose-dependent insulinotropic peptide (GIP) provides a novel link between the immune system and the gut, although results from different experimental and observational studies are contradictory, ranging from anti-inflammatory, through neutral to pro-inflammatory action of GIP. Thus, the aim of this study was to analyze inflammatory pathways on the level of gene expression and circulating inflammatory markers in relation to plasma GIP level. The study included 128 obese adults. Two groups of obese subjects were created according to fasting GIP levels, with cutoff point at the 66th percentile and compared in respect with molecular and circulating markers of inflammation. GIP, interleukin (IL)-6 and adipokines: leptin, adiponectin, visfatin were measured by enzyme-linked immunosorbent assay. Inflammatory markers: monocyte chemoattractant protein-1 (MCP-1), sE-Selectin, sVCAM-1, sPECAM-1 were studied at fasting and after nutrient challenges. Gene expression in blood cells was determined by human gene microarray. Obese patients with high GIP levels had elevated fasting glucose (Q2 (Q1-Q3): 5.6 (5.0-6.0) vs 5.0 (4.8-5.4), P<0.001), homeostasis model assessment of insulin resistance (Q2 (Q1-Q3): 3.68 (2.72-5.42) vs 2.70 (2.13-4.33), P=0.021), thus increased markers of insulin resistance as well as elevated inflammatory markers Il-6 (Q2 (Q1-Q3): 1.34 (1.0-2.04) vs 1.12 (0.76-1.64), P=0.045), MCP-1 (Q2 (Q1-Q3): 363 (287-447) vs 323 (263-389), P=0.026). Leptin to adiponectin ratio was significantly associated with fasting plasma GIP levels (β (95% CI): 0.84 (0.10-1.59)) independently of glucose levels. sE-Selectin was found to be a factor influencing GIP response to oral glucose intake (β (95% CI): 0.47 (0.14-0.81)) and sVCAM was found to be a factor influencing GIP response to high-fat meal intake (β (95% CI): 0.19 (0.01-0.37)). We identified 32 genes of inflammatory pathways differentially expressed in subjects with a high plasma GIP level compared to low GIP. Most upregulated genes play a role in leukocyte chemotaxis and tissue infiltration. These findings support the hypothesis that increased GIP signaling has a role in chronic low-grade inflammation.

The effect of diet, adiposity, and weight loss on the secretion of incretin hormones in cats

Degree of adiposity and dietary macronutrient composition affect incretin hormone secretion in humans and mice, but little is known about their effect in cats. In this study, 7 overweight cats were fed a maintenance diet (MD) for at least 2 wk followed by a reduced calorie diet (RCD), which was lower in fat and higher in carbohydrates and fiber. Cats were fed ad libitum initially, and then, food was restricted to achieve 1%–2% loss of body weight weekly (11 wk). When lean, cats were fed MD for 2 wk. A standardized meal test (SMT) using a third diet was performed after at least 7 d on each diet, before and after weight loss (four SMT's total). Glucose, insulin, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) concentrations were measured immediately before and over 6 h after feeding the SMT. Area under the curve (AUC) was compared for GLP-1, GIP, and insulin concentrations using 2-way analysis of variance. Leaner cats had increased GIPAUC compared to obese cats (P = 0.025). There was a trend toward increased GIPAUC on RCD compared to the MD (P = 0.085). There was a moderate negative correlation between body fat percentage and GLP-1AUC (r = −0.45; P = 0.05). There was no effect of diet on GLP-1AUC. In conclusion, degree of adiposity and dietary macronutrient content could be important in determining GIP responses not only acutely but also on a long-term basis. Further investigation of GIP responses in cats should take both diet and degree of adiposity into account.

Red wine enhances glucose-dependent insulinotropic peptide (GIP) and insulin responses in type 2 diabetes during an oral glucose tolerance test.

Ingestion of ethanol before a glucose challenge enhances the insulin response by an unknown mechanism. In addition, epidemiological studies consistently indicate that moderate alcohol consumption reduces the risk of developing type 2 diabetes (T2D). The purposes of this study were to evaluate the potential involvement of glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1) in alcohol-induced augmentation of the insulin response and to determine if red wine acutely improves glucose tolerance during an oral glucose tolerance test (OGTT). Nine subjects (eight T2D and one pre-diabetes) completed two OGTT 30min after consumption of 263ml water or red wine (28g ethanol). Blood samples were obtained for 3h and analyzed for glucose, insulin, C-peptide, GIP, and GLP-1. Compared with water, consumption of red wine increased the incremental area under the curve (iAUC) for insulin by 50% (14,837±4759 vs. 9885±2686 µU/ml×min; p<0.05) and for GIP by 25% (7729±1548 vs. 6191±1049pmol/l×min; p<0.05). Glucose and GLP-1 responses were not affected by red wine. Wine consumption before an OGTT augments the insulin response, which may be partially driven by a greater GIP response. Because glucose levels were not reduced, acute wine consumption may not be effective treatment for enhancing glycemic control or may need to be combined with therapy that improves insulin sensitivity.

Circulating irisin and glucose-dependent insulinotropic peptide are associated with the development of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by oligo- or anovulation, polycystic ovary, and/or hyperandrogenism. In addition, many PCOS patients present with dyslipidemia, insulin resistance, and obesity. Due to the complexity of this disorder, the causes of PCOS remain to be identified. Because many PCOS patients have a propensity to develop dyslipidemia, we hypothesized that the brown adipose-differentiation factor, irisin, and the glucose-dependent insulinotropic peptide (GIP) play a role in the development of PCOS. Serum hormone levels in 202 PCOS patients and 47 healthy women were investigated. Patients were stratified based on the presence/absence of metabolic syndrome risk factors, as defined by the National Cholesterol Education Program's Adult Treatment Panel III report (ATPIII [+] and ATPIII [-]), or body mass index (healthy-weight and overweight). We measured serum irisin, GIP, LH, anti-Mullerian hormone (AMH), and androgens as well as metabolic indices including homeostasis model assessment-insulin resistance, Matsuda's sensitivity index, and quantitative insulin-sensitivity check index. PCOS patients exhibited hyperandrogenism, dyslipidemia, and hyperinsulinism, as well as elevated LH and AMH levels. In addition, fasting irisin level (P < .001) and glucose-induced GIP response (P = .013) in PCOS patients were significantly elevated as compared to those of control women. Remarkably, levels of fasting irisin and glucose-induced GIP response remained significantly elevated in ATP III [-] PCOS and healthy-weight PCOS patients when compared to matched controls. Analysis of the effect size indicated that both fasting irisin and glucose-induced GIP response are significant risk factors for PCOS with odds ratios of 6.63 and 4.21, respectively. Although there is as yet no evidence for a causal link between irisin and/or GIP and PCOS, it is conceivable that irisin and GIP might contribute to the development of PCOS and may also represent novel PCOS biomarkers.

Effects of concentrated arabinoxylan and β-glucan compared with refined wheat and whole grain rye on glucose and appetite in subjects with the metabolic syndrome: a randomized study

Several studies emphasise that arabinoxylan and β-glucan have more beneficial effects on glucose metabolism than low-dietary fibre (DF) meals. Less attention has been paid to the effects of concentrated DF compared with whole grain. We compared the effects of DF and whole grain on glucose, hormone responses and appetite in subjects with the metabolic syndrome (MetS). Fifteen subjects with MetS participated in this acute, randomised, cross-over intervention study. The test breads provided 50 g of digestible carbohydrate: wheat bread with concentrated arabinoxylan (AX) or β-glucan (BG), rye bread with kernels (RK) and wheat bread (WB) as control. Blood samples were drawn for 270 min to determine glucose, insulin, glucagon-like peptide-1, glucose-dependent insulinotropic peptide (GIP) and ghrelin. Appetite score was addressed every 30 min. Ad libitum energy intake (EI) was measured 270 min after test meals. Compared with WB, BG and RK induced lower initial glycaemic responses (P<0.001), whereas AX only reduced the glucose peak value (P<0.001). RK reduced insulin (P<0.001) and GIP responses (P<0.001) compared with the other breads. BG lowered insulin responses more than AX (P<0.001). AX, BG and RK increased satiety feeling (P<0.001) more than WB, but did not differ significantly in terms of subsequent EI (P=0.089). BG and RK had beneficial impact on the glucose response, whereas AX had only effect on the postprandial glucose peak. The impact of the AX bread was influenced by higher protein content. Whether the metabolic effects of the breads are still present to mixed meals remains to be tested.

The effects of sitagliptin on gastric emptying in healthy humans – a randomised, controlled study

The rate of gastric emptying (GE) and subsequent release of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are critical determinants of postprandial glycaemia in health and type 2 diabetes. Slowing of GE may be the dominant mechanism by which exogenous GLP-1, and some GLP-1 analogues, improve postprandial glycaemia. To determine the effect of sitagliptin on GE in healthy subjects, and the relationships between GE with glycaemia and incretin hormone secretion. Fifteen volunteers (22.8 ± 0.7 years) were studied on two occasions following 2 days dosing with sitagliptin (100 mg/day) or placebo. GE (scintigraphy), glycaemia and plasma GLP-1 and GIP (total and intact), insulin and glucagon were measured for 240 min following a mashed potato meal (1808 kJ). There was no difference in GE between sitgaliptin and placebo [50% emptying time (T50): P = 0.4]. Mean blood glucose was slightly less (P = 0.02) on sitagliptin. Sitagliptin reduced plasma glucagon between 75 and 120 min (P < 0.05), and increased intact GLP-1 (P = 0.0002) and intact GIP (P = 0.0001) by approximately twofold, but reduced total GIP (P = 0.0003) and had no effect on total GLP-1 (P = 0.16) or insulin (P = 0.75). On sitagliptin the initial rise in blood glucose (r = -0.66, P = 0.008) and the intact GIP response (r = -0.66, P = 0.007) were inversely related, whereas the intact GLP-1 response was related directly (r = 0.52, P = 0.05) to the T50. While the effects of sitagliptin on glycaemic control are unlikely to relate to slowing of GE in healthy humans, the rate of GE is a significant determinant of postprandial glycaemia on sitagliptin.

Chlorogenic acid differentially affects postprandial glucose and glucose-dependent insulinotropic polypeptide response in rats

Regular coffee consumption significantly lowers the risk of type 2 diabetes (T2D). Coffee contains thousands of compounds; however, the specific component(s) responsible for this reduced risk is unknown. Chlorogenic acids (CGA) found in brewed coffee inhibit intestinal glucose uptake in vitro. The objective of this study was to elucidate the mechanisms by which CGA acts to mediate blood glucose response in vivo. Conscious, unrestrained, male Sprague-Dawley rats were chronically catheterized and gavage-fed a standardized meal (59% carbohydrate, 25% fat, 12% protein), administered with or without CGA (120mg·kg(-1)), in a randomized crossover design separated by a 3-day washout period. Acetaminophen was co-administered to assess the effects of CGA on gastric emptying. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) were measured. GLP-1 response in the presence of glucose and CGA was further examined, using the human colon cell line NCI-H716. Total area under the curve (AUC) for blood glucose was significantly attenuated in rats fed CGA (p< 0.05). Despite this, no differences in plasma insulin or nonesterified fatty acids were observed, and gastric emptying was not altered. Plasma GIP response was blunted in rats fed CGA, with a lower peak concentration and AUC up to 180min postprandially (p< 0.05). There were no changes in GLP-1 secretion in either the in vivo or in vitro study. In conclusion, CGA treatment resulted in beneficial effects on blood glucose response, with alterations seen in GIP concentrations. Given the widespread consumption and availability of coffee, CGA may be a viable prevention tool for T2D.

The Incretin Effect and Secretion in Obese and Lean Women with Polycystic Ovary Syndrome: A Pilot Study

Insulin resistance is considered to play an important role in the pathogenesis of polycystic ovary syndrome (PCOS) and in the progression to type 2 diabetes. Recent reports concentrate on a possible relationship between incretin secretion and beta-cell function in PCOS. The aim of the present study is to investigate the incretin effect in obese and lean women with PCOS. Twenty women with PCOS and ten age-matched healthy women were recruited in the study. The oral glucose tolerance test (OGTT) and isoglycemic test were carried out on each participant after an overnight fast at 2-weeks interval. Plasma levels of insulin, glucose, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) were assayed. Obese women with PCOS demonstrated lower GIP concentrations (area under the curve [AUC]) in response to OGTT compared to the control group. The incretin effect was found significantly augmented in the obese women with PCOS compared to controls. This finding remained robust in the subgroup analysis including only body mass index (BMI)-matched healthy women. Increased insulinotropic effect could counteract the blunted GIP response to OGTT in obese women with PCOS. It is suggested that the pathology of PCOS may also include impaired activity of the enteroinsular axis.

Incretin responses to oral glucose load in Japanese non-obese healthy subjects

IntroductionRecently, incretin-related therapy has been developed for the new treatment of diabetes mellitus; however, incretin response to glucose ingestion in normal glucose tolerant (NGT) subjects has not been clarified in detail with special reference to the role of incretin hormones, glucagon, and a family history of diabetes.MethodsWe conducted a 75 g oral glucose tolerance test in 30 NGT subjects.ResultsThe total glucose-dependent insulinotropic peptide (GIP)-AUC0–120 (area under the curve over a period of 0–120 minutes) was correlated with immunoreactive insulin (IRI)-AUC0–120 (P<0.05), insulinogenic index (II; P<0.05), ΔIRI between 0 and 120 minutes (P<0.05). Active glucagon-like peptide-1 (GLP-1) AUC0–120 was correlated inversely both with Δ glucose between 0 and 30 minutes (P<0.01) and with Δ immunoreactive glucagon between 0 and 30 minutes (P<0.05). Δ Total GIP between 0 and 15 minutes (P<0.01), Δ total GIP between 0 and 30 minutes (P<0.05), and the total GIP-AUC0–120 (P<0.05) in the subjects with a family history of type 2 diabetes were significantly higher than those in the subjects without a family history.ConclusionThese results suggest that GIP possibly facilitates insulin secretion in response to oral glucose load directly and active GLP-1 may exert the glucoregulatory action via the suppression of glucagon secretion in NGT subjects. Notably, the subjects with a family history of diabetes exert significantly higher GIP response in the early phase of glucose load compared with those without a family history.

Differential effects of protein quality on postprandial lipemia in response to a fat-rich meal in type 2 diabetes: comparison of whey, casein, gluten, and cod protein

Background:Enhanced and prolonged postprandial triglyceride responses involve increased cardiovascular disease risk in type 2 diabetes. Dietary fat and carbohydrates profoundly influence postprandial hypertriglyceridemia, whereas little information exists on the effect of proteins. Objective:The objective was to compare the effects of the proteins casein, whey, cod, and gluten on postprandial lipid and incretin responses to a high-fat meal in persons with type 2 diabetes. Design:A crossover study was conducted in 12 patients with type 2 diabetes. Blood samples were collected over 8 h after ingestion of a test meal containing 100 g butter and 45 g carbohydrate in combination with 45 g casein (Cas-meal), whey (Whe-meal), cod (Cod-meal), or gluten (Glu-meal). We measured plasma concentrations of triglycerides, retinyl palmitate (RP), free fatty acids, insulin, glucose, glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide. Results:The incremental area under the curve for triglyceride was significantly lower after the Whe-meal than after the other meals. The RP response was lower after the Whe-meal than after the Cas-meal and Cod-meal in the chylomicron-rich fraction and higher after the Whe-meal than after Cod- and Glu-meals in the chylomicron-poor fraction. Free fatty acids were most pronouncedly suppressed after the Whe-meal. The glucose response was lower after the Whe-meal than after the other meals, whereas no significant differences were found in insulin, glucagon, glucagon-like peptide 1, and glucose-dependent insulinotropic peptide responses. Conclusion:The data suggest that as a supplement to a fat-rich meal in patients with type 2 diabetes, whey protein seems to outperform other proteins in terms of postprandial lipemia improvement, possibly because of the formation of fewer chylomicrons or increased clearance of chylomicrons. The trial was registered at clinicaltrials.gov as NCT00817973.

Preservation of the incretin effect after orthotopic pancreas transplantation in inbred rats

To establish whether the incretin effect is under neural control, insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) responses and hepatic insulin clearance were investigated after oral and “isoglycemic” intravenous glucose in 12 inbred rats after denervation of the pancreas by orthotopic transplantation with portal venous drainage (Tx group) and in 12 laparotomized controls (sham group). Effective pancreas denervation was documented by a decreased pancreatic polypeptide (PP) response to insulin-induced hypoglycemia and by decreased levels of norepinephrine and calcitonin gene—related peptide (CGRP) in pancreatic tissue. Basal and incremental arterial plasma glucose integrated over 180 minutes did not differ between oral and intravenous glucose, but the integrated insulin response (mean ± SEM) was significantly greater with oral versus intravenous glucose (Tx group, 104.9 ± 22.0 v 31.0 ± 4.9 nmol · L −1 · min, P < .01; sham group, 79.5 ± 10.6 v 36.6 ± 5.8 nmol · L −1 · min, P < .01). The integrated response of C-peptide was similar during both tests (Tx group, 105 ± 14 v 79 ± 8 pmol · mL −1 · min; sham group, 112 ± 10 v 121 ± 12 pmol · mL −1 · min). Hepatic insulin clearance was significantly decreased in both groups by oral compared with intravenous glucose administration (Tx group, 1.3 ± 0.2 v 3.3 ± 0.6 mmol/mmol, P < .01; sham group, 1.6 ± 0.1 v 3.9 ± 0.6 mmol/mmol, P < .02). The incretin effects for insulin (Tx group, 5.6 ± 2.7; sham group, 3.0 ± 0.8) and C-peptide (Tx group, 1.4 ± 0.2; sham group, 1.1 ± 0.2), calculated as the ratio of the integrated oral response and integrated intravenous response, and GIP responses to oral and intravenous glucose were not significantly different between the two groups. We conclude that there is preservation of the incretin effect in rats with orthotopically transplanted and hence extrinsically denervated pancreas, thus ruling out the possibility that the autonomic nervous system substantially contributes. Hepatic insulin clearance and insulinotropic hormones such as GIP appear to be more important.

Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut.

The ileal proglucagon-derived peptides (PGDPs) play important roles in the regulation of gastric function and insulin secretion. We have previously demonstrated the existence of a proximal-distal enteroendocrine loop mediated by glucose-dependent insulinotropic peptide (GIP), through which intestinal PGDP secretion is stimulated after placement of nutrients in the duodenum. To study the possible involvement of neuropeptides in this loop, we infused gastrin-releasing peptide (GRP) into anesthetized rats at 47, 235, or 470 ng/h. GRP stimulated secretion of the intestinal PGDPs only at the highest dose, from 250 +/- 18 to 321 +/- 9 pg/ml (P < 0.05). Gastrin secretion was also increased by GRP infusion (from 20 +/- 7 to 75 +/- 19 pg/ml; P < 0.05); however, GIP release was not altered from basal levels. Placement of fat into the duodenum stimulated the secretion of both the intestinal PGDPs and GIP (to 618 +/- 221 and 417 +/- 154 pg/ml above basal, respectively; P < 0.05). However, infusion of the GRP antagonist, BW10 (3 ng/h), completely abrogated the PGDP response to duodenal fat (P < 0.05). In contrast, the GIP response was reduced by 56 +/- 15% (P < 0.05) with BW10 administration, but remained elevated compared to the basal level (P < 0.05). Removal of the entire intestine distal to the fat-infused duodenal segment prevented the rise in intestinal PGDPs, but not that of GIP, demonstrating the distal and proximal origins of these peptides, respectively. Thus, placement of fat into the duodenum stimulated the release of the PGDPs from the distal intestine through a GRP-dependent mechanism. Although GIP plays a role in regulating intestinal PGDP secretion in the rat, GRP appears to exert its effects independent of changes in GIP.

Studies of the Entero‐insular Axis Following Pancreas Transplantation in Man: Neural or Hormonal Control?

To study the role of hormonal and neural factors in the control of the entero-insular axis the insulin, C-peptide, and glucose-dependent insulinotropic peptide (GIP) responses to oral and intravenous glucose were investigated in 5 patients who had received a combined kidney and paratopic pancreas transplant, with physiological portal venous drainage. The incremental areas under the insulin and C-peptide responses to oral glucose were significantly greater than the responses to intravenous glucose (insulin: patients 7983 +/- 1937 (+/- SE) vs 3513 +/- 2188 mU l-1 min, p less than 0.002, control subjects 5505 +/- 1035 vs 1066 +/- 484 mU l-1 min, p less than 0.004; C peptide: patients 440 +/- 80 vs 144 +/- 61 nmol l-1 min, p less than 0.01, control subjects 200 +/- 38 vs 63 +/- 16 nmol l-1 min, P less than 0.01). The incretin effects for insulin (patients 4.4 +/- 1.4, control subjects 7.7 +/- 1.8) and C-peptide (patients 4.4 +/- 0.9, control subjects 3.7 +/- 0.9) and the GIP responses to oral and intravenous glucose were not significantly different between transplant patients and control subjects. As the incretin effect was preserved, despite a denervated pancreas, hormonal rather than neural factors may be more important in mediating increased insulin secretion after oral carbohydrate. The normal GIP response is compatible with its proposed role as an insulinotropic hormone.