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OR05-6 The Effect of the GLP1R Variant rs6923761 on Post-Prandial Glucose Levels during Treatment with Sitagliptin

ABSTRACT: Abstract BACKGROUND: Glucagon-like peptide-1 (GLP-1) functions to increase insulin production in a glucose-dependent manner. Endogenous GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP4), and GLP-1 receptor agonists and DPP4 inhibitors (DPP4Is) are now used in the treatment of diabetes. The GLP-1 receptor (GLP-1R) is a G-protein coupled receptor that is expressed widely, encoded for by GLP1R. The GLP1R variant rs6923761 (Gly168Ser) has been associated with increased weight loss in response to GLP-1 agonist therapy in some studies. This study tested the hypothesis that this variant would be associated with responsiveness to endogenous GLP-1 during DPP4I therapy. METHODS: Forty-seven subjects with hypertension and type 2 diabetes mellitus were assigned to one-week crossover therapy with placebo and the DPP4I sitagliptin (100 mg/d), and underwent a mixed meal study. Subjects were excluded for type 1 diabetes, poorly controlled diabetes with Hgb A1c ?8.7%, use of an anti-diabetic medication other than metformin for last 12 months, or presence of secondary hypertension. RESULTS: Post-prandial GLP-1 levels were increased during sitagliptin (AUC 11413, 95% CI [7113, 15712]) as compared with placebo treatment (AUC 5101, 95% CI [2254, 7949], p<0.05), and did not significantly differ by genotype. Peak post-prandial glucose was significantly higher in placebo as compared with sitagliptin treatment (146.6 +/- 35.8 mg/dL versus 133.0 +/- 26.5 mg/dL, respectively; t=90 minutes, p<0.01). Subjects with one or two copies of the wild-type allele (Gly/Gly or Gly/Ser) had increased post-prandial glucose excursion as compared with Ser/Ser subjects, in both the placebo and sitagliptin treatments (plasma glucose at 90 minutes: placebo Gly/- 150.1 +/- 38.0 mg/dL vs Ser/Ser 132.6 +/- 13.7 mg/dL, p<0.05; sitagliptin Gly/- 135.8 +/- 27.3 mg/dL vs Ser/Ser 117.4 +/- 14.7 mg/dL, p<0.05). Post-prandial insulin levels were not different in the placebo versus sitagliptin treatments (AUC 13264, 95% CI [9296,17232] vs 11996, 95% CI [8278, 15714], respectively), but there was a genotype by drug treatment interaction (p<0.05) such that Ser/Ser subjects had higher post-prandial insulin in the placebo treatment as compared with other genotypes. This difference was eliminated with sitagliptin therapy. CONCLUSIONS: Homozygosity for the Ser variant of GLP1R is associated with decreased glucose after a mixed meal without altering the effect of sitagliptin on post prandial GLP-1 concentrations. Further studies are needed to assess whether this variant confers increased sensitivity at the GLP-1R and whether it affects the long-term response to DPP4I.

SUBMITTER: Mashayekhi M

PROVIDER: S-EPMC6555090 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Project description:BackgroundAppetite is affected by many factors including the hormones leptin, ghrelin and adiponectin. Ghrelin stimulates hunger, leptin promotes satiety, and adiponectin affects insulin response. This study was designed to test whether the pre- and postprandial response of key appetite hormones differs in normal weight (NW) and severely obese (SO) women.MethodsTwenty three women ages 25-50 were recruited for this study including 10 NW (BMI = 23.1 ± 1.3 kg/m²) and 13 SO (BMI = 44.5 ± 7.1 kg/m²). The study was conducted in a hospital-based clinical research centre. Following a 12-hour fast, participants had a baseline blood draw, consumed a moderately high carbohydrate meal (60% carbohydrate, 20% protein, 20% fat) based on body weight. Postprandially, participants had six blood samples drawn at 0, 15, 30, 60, 90, and 120 minutes. Primary measures included pre- and post-prandial total ghrelin, leptin, adiponectin and insulin. A repeated measures general linear model was used to evaluate the hormone changes by group and time (significance p ? 0.05).ResultsThere were significant differences between the NW and the SO for all hormones in the preprandial fasting state. The postprandial responses between the SO versus NW revealed: higher leptin (p < 0.0001), lower adiponectin (p = 0.04), trend for lower ghrelin (p = 0.06) and insulin was not different (p = 0.26). Postprandial responses over time between the SO versus NW: higher leptin (p < 0.001), lower ghrelin and adiponectin (p = 0.004, p = 0.015, respectively), and trend for higher insulin (p = 0.06).ConclusionThis study indicates that significant differences in both pre- and selected post- prandial levels of leptin, ghrelin, adiponectin and insulin exist between NW and SO women. Improving our understanding of the biochemical mechanisms accounting for these differences in appetite hormones among individuals with varying body size and adiposity should aid in the development of future therapies to prevent and treat obesity.

Project description:BackgroundLower post-prandial glucose (PPG) and insulin (PPI) responses to foods are associated with reduced diabetes risk and progression. Several plant extracts have been proposed to reduce PPG or PPI by inhibiting enzymes or transporters involved in carbohydrate digestion and uptake. This study evaluates a range of such extracts, consumed with a carbohydrate load, for their effects on PPG, PPI and indicators of (gastrointestinal) tolerance.MethodsInterventions were extracts of mulberry fruit (MFE, 1.5 g), mulberry leaf (MLE, 1.0 g), white bean (WBE, 3.0 g), apple (AE, 2.0 g), elderberry (EE, 2.0 g), turmeric (TE, 0.18 g), AE + TE, and EE + TE. Each of these 8 individual extracts or combinations were added to a rice porridge containing ~ 50 g available carbohydrate (control). In a within-subject (randomised, balanced incomplete block) design, individual subjects received the control and a subset of 4 of the 8 extracts or combinations. Participants were 72 apparently healthy adults (mean [SD] age 31.2 [5.5] yr, body mass index 22.1 [2.0] kg/m2). The primary outcome was the percentage change in 2-h PPG (positive incremental area under the curve) relative to control. Secondary measures were the 2-h PPI response, 7-h breath hydrogen, measures of gastrointestinal discomfort, and urine glucose.ResultsIn the 65 subjects who completed the control and at least one intervention treatment, additions of AE, MFE and MLE produced statistically significant reductions in PPG vs control (p < 0.05; mean effect - 24.1 to - 38.1%). All extracts and combinations except TE and WBE significantly reduced PPI (p < 0.01; mean effect - 17.3% to - 30.4%). Rises in breath hydrogen > 10 ppm were infrequent, but statistically more frequent than control only for MLE (p = 0.02). Scores for gastrointestinal discomfort were extremely low and not different from control for any treatment, and no glucosuria was observed.ConclusionsAdditions of AE, MFE and MLE to rice robustly reduced PPG and PPI. EE significantly reduced only PPI, while TE and WBE showed no significant efficacy for PPG or PPI. Breath hydrogen responses to MLE suggest possible carbohydrate malabsorption at the dose used, but there were no explicit indications of intolerance to any of the extracts.Trial registrationClinicalTrials.gov identifier NCT04258501. Registered 6 February 2020 - Retrospectively registered.

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OR05-6 The Effect of the GLP1R Variant rs6923761 on Post-Prandial Glucose Levels during Treatment with Sitagliptin

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