Fasting Glucose-dependent Insulinotropic Polypeptide Research Articles

Fasting and post prandial pancreatic and enteroendocrine hormone levels in obese and non-obese participants

Circulating insulin levels are known to be increased in people with higher body mass index (BMI) due to effects of adiposity on insulin resistance, whilst gut hormones have a more complex relationship, with fasting peptideYY (PYY) reported to be inversely related to BMI. This study aimed to further explore fasting and post prandial pancreatic and gut hormone concentrations in plasma samples from obese and non-obese participants. Participants with healthy BMI (n=15), overweight BMI (n=29) and obesity (n=161) had samples taken fasting and 30 min post mixed liquid meal for analysis of glucagon-like peptide-1 (GLP-1), PYY, glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. Data visualiation used linear discriminant analysis for dimensionality reduction, to visualise the data and assess scaling of each hormone. Fasting levels of insulin, GIP and PYY were shown to be key classifiers between the 3 groups on ANCOVA analysis, with an observation of increased GIP levels in overweight, but not obese participants. In non-obese subjects, fasting GIP, PYY and insulin correlated with BMI, whereas in subjects with obesity only the pancreatic hormones glucagon and insulin correlated with BMI. Concentrations of total GLP-1 in the fasting state correlated strongly with glucagon levels, highlighting potential assay cross-reactivities. The study, which included a relatively large number of subjects with severe obesity, supported previous evidence of BMI correlating negatively with fasting PYY and positively with fasting insulin. The observation of increased fasting GIP levels in overweight but not obese participants deserves further validation and mechanistic investigation.

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

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

Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region.

There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials.

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

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

Effects of Gender-Affirming Hormone Therapy on Insulin Sensitivity and Incretin Responses in Transgender People.

The long-term influences of sex hormone administration on insulin sensitivity and incretin hormones are controversial. We investigated these effects in 35 transgender men (TM) and 55 transgender women (TW) from the European Network for the Investigation of Gender Incongruence (ENIGI) study. Before and after 1 year of gender-affirming hormone therapy, body composition and oral glucose tolerance tests (OGTTs) were evaluated. In TM, body weight (2.8 ± 1.0 kg; P < 0.01), fat-free mass (FFM) (3.1 ± 0.9 kg; P < 0.01), and waist-to-hip ratio (-0.03 ± 0.01; P < 0.01) increased. Fasting insulin (-1.4 ± 0.8 mU/L; P = 0.08) and HOMA of insulin resistance (HOMA-IR) (2.2 ± 0.3 vs. 1.8 ± 0.2; P = 0.06) tended to decrease, whereas fasting glucose (-1.6 ± 1.6 mg/dL), glucose-dependent insulinotropic polypeptide (GIP) (-1.8 ± 1.0 pmol/L), and glucagon-like peptide 1 (GLP-1) (-0.2 ± 1.1 pmol/L) were statistically unchanged. Post-OGTT areas under the curve (AUCs) for GIP (2,068 ± 1,134 vs. 2,645 ± 1,248 [pmol/L] × min; P < 0.01) and GLP-1 (2,352 ± 796 vs. 2,712 ± 1,015 [pmol/L] × min; P < 0.01) increased. In TW, body weight tended to increase (1.4 ± 0.8 kg; P = 0.07) with decreasing FFM (-2.3 ± 0.4 kg; P < 0.01) and waist-to-hip ratio (-0.03 ± 0.01; P < 0.01). Insulin (3.4 ± 0.8 mU/L; P < 0.01) and HOMA-IR (1.7 ± 0.1 vs. 2.4 ± 0.2; P < 0.01) rose, fasting GIP (-1.4 ± 0.8 pmol/L; P < 0.01) and AUC GIP dropped (2,524 ± 178 vs. 1,911 ± 162 [pmol/L] × min; P < 0.01), but fasting glucose (-0.3 ± 1.4 mg/dL), GLP-1 (1.3 ± 0.8 pmol/L), and AUC GLP-1 (2,956 ± 180 vs. 2,864 ± 93 [pmol/L] × min) remained unchanged. In this cohort of transgender persons, insulin sensitivity but also post-OGTT incretin responses tend to increase with masculinization and to decrease with feminization.

Longitudinal Changes in Fasting and Glucose-Stimulated GLP-1 and GIP in Healthy Older Subjects.

It is not known whether glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels correlate within individuals, nor whether levels change with age. Previous studies have all been cross-sectional in design. To evaluate longitudinal changes in fasting and glucose-stimulated incretin hormone concentrations in healthy older subjects. Forty-one healthy older subjects had measurements of plasma GLP-1 and GIP while fasting and after a 75-g oral glucose load on two occasions separated by 5.9 ± 0.1 years [mean age at the initial study: 71.2 ± 3.8 (SD) years]. Breath samples were collected to calculate the gastric 50% emptying time (T50). For GLP-1, both fasting concentrations (P < 0.001) and area under the curve 0 to 120 minutes (P = 0.001) were decreased at followup. Fasting GIP was also lower (P = 0.03) at follow up, but there was no change in the area under the curve 0 to 120 minutes (P = 0.26). The gastric emptying T50 was slower at followup (P = 0.008). Neither the change in T50 nor the body mass index at the initial study was a determinant of the change in incretin responses. Between the two study days, fasting GIP (r = 0.72, P < 0.001) correlated well, but not fasting GLP-1 (r = 0.23, P = 0.18). However, both glucose-stimulated GLP-1 (r = 0.50, P = 0.002) and GIP (r = 0.60, P < 0.001) showed correlations between the initial and follow-up studies. Fasting GIP and glucose-stimulated GLP-1 and GIP concentrations correlate within individuals over a follow-up period of ∼5.9 years. Aging is associated with reductions in fasting GLP-1 and GIP, and glucose-stimulated GLP-1, which may predispose to the development of glucose intolerance and type 2 diabetes.

Impact of short-term exercise training intensity on β-cell function in older obese adults with prediabetes.

The effect of work-matched exercise intensity on β-cell function is unknown in people with prediabetes before clinical weight loss. We determined if short-term moderate continuous (CONT) vs. high-intensity interval (INT) exercise increased β-cell function. Thirty-one subjects (age: 61.4 ± 2.5 yr; body mass index: 32.1 ± 1.0 kg/m2) with prediabetes [American Diabetes Association criteria, 75-g oral glucose tolerance test (OGTT)] were randomized to work-matched CONT (70% HRpeak) or INT (3 min 90% HRpeak and 3 min 50% HRpeak) exercise for 60 min/day over 2 wk. A 75-g 2-h OGTT was conducted after an overnight fast, and plasma glucose, insulin, C-peptide, and free fatty acids were determined for calculations of skeletal muscle [oral minimal model (OMM)], hepatic (homeostatic model of insulin resistance), and adipose (Adipose-IR) insulin sensitivity. β-Cell function was defined from glucose-stimulated insulin secretion (GSIS, deconvolution modeling) and the disposition index (DI). Glucagon-like polypeptide-1 [GLP-1(active)] and glucose-dependent insulinotropic polypeptide (GIP) were also measured during the OGTT, along with peak oxygen consumption and body composition. CONT and INT increased skeletal muscle- but not hepatic- or adipose-derived DI ( P < 0.05). Although both treatments tended to reduce fasting GLP-1(active) ( P = 0.08), early phase GLP-1(active) increased post-CONT and INT training ( P < 0.001). Interestingly, CONT exercise increased fasting GIP compared with decreases in INT ( P = 0.02). Early and total-phase skeletal muscle DI correlated with decreased total glucose area under the curve ( r = -0.52, P = 0.002 and r = -0.50, P = 0.003, respectively). Independent of intensity, short-term training increased pancreatic function adjusted to skeletal muscle in relation to improved glucose tolerance in adults with prediabetes. Exercise also uniquely affected GIP and GLP-1(active). Further work is needed to elucidate the dose-dependent mechanism(s) by which exercise impacts glycemia. NEW & NOTEWORTHY Exercise is cornerstone for reducing blood glucose, but whether high-intensity interval training is better than moderate continuous exercise is unclear in people with prediabetes before weight loss. We show that 2 wk of exercise training, independent of intensity, increased pancreatic function in relation to elevated glucagon-like polypeptide-1 secretion. Furthermore, β-cell function, but not insulin sensitivity, was also correlated with improved glucose tolerance. These data suggest that β-cell function is a strong predictor of glycemia regardless of exercise intensity.

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

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

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.

Glucose-Dependent Insulinotropic Polypeptide Is Associated With Lower Low-Density Lipoprotein But Unhealthy Fat Distribution, Independent of Insulin: The ADDITION-PRO Study.

Glucose-dependent insulinotropic polypeptide (GIP) may increase lipid clearance by stimulating lipid uptake. However, given that GIP promotes release of insulin by the pancreas and insulin is anti-lipolytic, the effect may be indirect. In this study we examined the association between GIP and lipid metabolism in individuals with low to high risk of type 2 diabetes and assessed whether the associations were modified by or mediated through insulin. Analyses were based on the Danish cross-sectional ADDITION-PRO study (n = 1405). Lipid metabolism was measured by fasting plasma lipids and obesity including abdominal fat distribution assessed by ultrasonography. GIP and insulin were measured during an oral glucose tolerance test (0, 30 and 120 min). Linear regression analysis was used to study the associations between GIP, plasma lipids, and obesity measures. A doubling in fasting GIP levels was associated with lower low-density lipoprotein in both men (mean [95% CI] -0.10 mmol/l [-0.18--0.03]) and women (-0.14 mmol/l [-0.23--0.04]) and with higher high-density lipoprotein in women (0.06 mmol/l [-0.02-0.10]). In men, a doubling in stimulated GIP was associated with 0.13 cm less 0.01-0.25 sc fat but with more visceral abdominal fat (0.45 cm [0.12-0.78]) and higher waist-hip ratio (0.011 [0.004-0.019]). Contrary to what was previously thought, GIP may be associated with improved low-density lipoprotein clearance but with an unhealthy fat distribution independent of insulin. The effect of GIP on obesity measures was substantially different between men and women. The potential effect of GIP on visceral and sc adipose tissue physiology warrants further examination.

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

Phenotyping of type 2 diabetes mellitus at onset on the basis of fasting incretin tone: Results of a two-step cluster analysis.

According to some authors, in type 2 diabetes there is a reduced postprandial action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, little is known about the role of fasting incretins in glucose homeostasis. Our aim was to evaluate, through a two-step cluster analysis, the possibility of phenotyping patients with type 2 diabetes at onset on the basis of fasting GLP-1, GIP and ghrelin. A total of 96 patients with type 2 diabetes within 6 months of onset (mean age 62.40 ± 6.36 years) were cross-sectionally studied. Clinical, anthropometric and metabolic parameters were evaluated. At fasting the following were carried out: assay of GLP-1, GIP, ghrelin, insulin, C-peptide, glucagon and a panel of adipocytokines (visfatin, resistin, leptin, soluble leptin receptor and adiponectin). The analysis resulted in two clusters: cluster 1 (63 patients) had significantly lower levels of GLP-1 (4.93 ± 0.98 vs 7.81 ± 1.98 pmol/L; P < 0.001), GIP (12.73 ± 9.44 vs 23.88 ± 28.56 pmol/L; P < 0.001) and ghrelin (26.54 ± 2.94 vs 39.47 ± 9.84 pmol/L; P < 0.001) compared with cluster 2 (33 patients). Between the two clusters, no differences in age, duration of disease, sex, clinical-anthropometric parameters, insulin sensitivity and adipocytokines were highlighted. However, cluster 1 was associated with significantly higher levels of glycated hemoglobin (7.4 ± 0.61 vs 6.68 ± 0.57%, P = 0.007), glucagon (232.02 ± 37.27 vs 183.33 ± 97.29 ng/L; P = 0.001), fasting glucose (7.85 ± 1.60 vs 6.93 ± 1.01 mmol/L; P = 0.003) and significantly lower levels of C-peptide (0.12 ± 0.11 vs 0.20 ± 0.20 nmol/L; P = 0.017). The present study suggests that fasting incretins play an important role in the pathophysiology of type 2 diabetes, which requires to further investigation.

Effect of caloric restriction with or without n-3 polyunsaturated fatty acids on insulin sensitivity in obese subjects: A randomized placebo controlled trial

BackgroundCaloric restriction and n-3 polyunsaturated fatty acid (PUFA) supplementation protect from some of the metabolic complications. The aim of this study was to assess the influence of a low calorie diet with or without n-3 PUFA supplementation on glucose dependent insulinotropic polypeptide (GIP) output and insulin sensitivity markers in obese subjects. MethodsObese, non-diabetic subjects (BMI 30–40kg/m2) and aged 25–65yr. were put on low calorie diet (1200–1500kcal/day) supplemented with either 1.8g/day n-3 PUFA (DHA/EPA, 5:1) (n=24) or placebo capsules (n=24) for three months in a randomized placebo controlled trial. Insulin resistance markers and GIP levels were analysed from samples obtained at fasting and during an oral glucose tolerance test (OGTT). ResultsCaloric restriction with n-3 PUFA led to a decrease of insulin resistance index (HOMA-IR) and a significant reduction of insulin output as well as decreased GIP secretion during the OGTT. These effects were not seen with caloric restriction alone. Changes in GIP output were inversely associated with changes in red blood cell EPA content whereas fasting GIP level positively correlated with HOMA-IR index. Blood triglyceride level was lowered by caloric restriction with a greater effect when n-3 PUFA were included and correlated positively with fasting GIP level. ConclusionsThree months of caloric restriction with DHA+EPA supplementation exerts beneficial effects on insulin resistance, GIP and triglycerides. General significanceCombining caloric restriction and n-3 PUFA improves insulin sensitivity, which may be related to a decrease of GIP levels.

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.

Metabolic and Hormonal Alterations with Diacylglycerol and Low Glycemic Index Starch during Canine Weight Loss

Obesity increases insulin resistance and disregulation of glucose homeostasis. This study investigated low glycemic index starch (LGIS)/diacylglycerol (DAG) diet on plasma insulin and circulating incretin hormones during canine weight loss. Obese Beagle dogs were fed one of four starch/oil combination diets (LGIS/DAG; LGIS/triacylglycerol (TAG); high glycemic index starch (HGIS)/DAG; and HGIS/TAG) for 9 weeks during the weight loss period. At weeks 1 and 8, fasting plasma insulin, glucose, nonesterified fatty acid (NEFA), glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) were determined. Weight loss did not affect fasting insulin, glucose, and NEFA, but fasting GIP increased and GLP-1 decreased. LGIS affected postprandial insulin at both times and glucose was similar to insulin, except 60 min postprandially with DAG at week 8. NEFA lowering was less with the LGIS diets initially but not thereafter. At 60 min postprandially on week 8, GIP was significantly elevated by DAG, while GLP-1 was increased only with the HD diet. LGIS suppressed insulin and glucose responses up to 180 min postprandially at both sample times. DAG increased incretin hormones as did the DAG/HGIS combination but only at week 8. This latter finding appeared to be related to the glucose response but not to insulin at 60 min.

Incretin and pancreatic hormone secretion in Caucasian non‐diabetic carriers of the TCF7L2 rs7903146 risk T allele

We characterised 62 non-diabetic, middle-aged, Caucasians with and without the T risk allele of rs7903146 in transcription factor 7-like 2 (TCF7L2) with regard to secretion of insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) as well as insulin sensitivity and endogenous glucose production. All participants had a 3-h oral glucose tolerance test (OGTT), an intravenous glucose tolerance test and a euglycaemic, hyperinsulinaemic clamp. After adjustment for age and sex, risk T allele carriers had higher haemoglobin A1c levels (p = 0.030), reduced first-phase insulin response (p = 0.048), higher peripheral insulin sensitivity (p = 0.050) and lower fasting GIP concentrations (p = 0.003) than CC allele carriers. The latter was also reflected by lower total GIP secretion during the OGTT (p = 0.018). We found no significant differences in endogenous glucose production, hepatic insulin sensitivity or fasting concentrations of glucose, insulin, glucagon and GLP-1 between the groups. The findings suggest that the effect of TCF7L2 on diabetes risk may include reduced secretion of GIP.

PS6 - 30. Fasting and postprandial GLP-1 and GIP in relation to alanine aminotransterase and lipid metabolism in the general population

Hypertriglyceridaemia and increased amounts of liver fat are acknowledged cardiovascular risk factors, especially among type 2 diabetes patients. The incretins glucagonlike peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known from their insulinotropic effects, but recent studies have shown effects on lipid metabolism and liver fat.

Increased levels of serum glucose-dependent insulinotropic polypeptide as a novel risk factor for human colorectal adenoma

Obesity and insulin resistance are thought to be risk factors for colorectal adenoma. Glucose-dependent insulinotropic polypeptide (GIP) stimulates insulin secretion from the pancreas and promotes fat accumulation in adipocytes. The association between serum GIP and the risk of colorectal adenoma has not been examined previously. We investigated this association in 370 subjects who underwent total colonoscopy during thorough physical checkups between January and December 2008. We used a cross-sectional design and classified the subjects into a colorectal adenoma group and a control group without adenoma according to their endoscopic findings. Serum GIP concentrations in samples of venous blood obtained after an overnight fast were measured using a sandwich enzyme-linked immunosorbent assay kit. The mean levels of fasting GIP (34.9 ± 49.5 vs 25.0 ± 20.1 pg/mL, P = .04), triglyceride, glucose, and insulin and the values of the homeostasis model assessment of insulin resistance in the colorectal adenoma group were significantly higher than those in the control group. Multiple logistic regression analysis showed that the highest quartile of fasting GIP levels was associated with a significantly high risk of colorectal adenoma (odds ratio, 2.1; 95% confidence interval, 1.08-3.96; P = .01) in comparison with the lowest quartile. Quartile analysis demonstrated that increased levels of GIP were related to increased levels of fasting insulin and values of homeostasis model assessment β-cell. These results suggest that an increased level of fasting GIP is associated with an increased risk of colorectal adenoma.

Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease.

BackgroundGlucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.MethodsTo examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).ResultsFasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.ConclusionCirculating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

Dissociated incretin response to oral glucose at 1 year after restrictive vs. malabsorptive bariatric surgery

Compare the response to oral glucose of the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) at 1 year after restrictive vs. malabsorptive bariatric surgery. Vertical banded gastroplasty (VBG, n = 7) or jejunoileal bypass (JIB, n = 5) was performed in 12 women, aged 26-39 years, with severe obesity [body mass index (BMI) 46.6 +/- 2.3 kg/m(2)]. After 1 year, 75 g glucose was administered and plasma levels of glucose, insulin, GIP and GLP-1 were determined regularly during the following 2 h. At 1 year after operation, reduction in body weight, actual body weight, fasting glucose or insulin, or the glucose and insulin responses to oral glucose did not differ significantly between the groups. Similarly, fasting GIP and GLP-1 levels did not differ significantly between the groups. In contrast, the GIP and GLP-1 responses to oral glucose were different between the groups in a dissociated pattern. Thus, AUC(GIP) was significantly higher after VBG than after JIB (53 +/- 8 vs. 26 +/- 6 pmol/l/min, p = 0.003). In contrast, AUC(GLP-1) was significantly higher after JIB than after VBG (49 +/- 5 vs. 20 +/- 3 pmol/l/min, p = 0.007). We conclude that at 1 year after bariatric surgery, the two incretins show dissociated responses in that the GIP secretion is higher after VBG whereas GLP-1 secretion is higher after JIB. This dissociated incretin response is independent from reduction in body weight, glucose tolerance or insulin secretion.