Effects of endogenous GIP in patients with type 2 diabetes

Abstract

Objective The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved. Design A randomized, double-blinded, placebo-controlled, crossover study. Methods Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed. Results Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; −14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; −11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; −4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content. Conclusions Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.

Thrice daily consumption of a novel, premeal shot containing a low dose of whey protein increases time in euglycemia during 7 days of free-living in individuals with type 2 diabetes

“…Although the free-living nature of our study makes it difficuilt to discern mechanisms associated with our findings, prior literature has demonstrated that a WP preload of similar amounts (15–20 g) elevates GLP-1 above preprandial concentrations for ~180 min following ingestion of a meal 12 13 23. The ingestion of WP also modestly stimulates the secretion of glucose-dependent insulinotropic polypeptide (GIP)12; though the relevance of this to the observed improvement in glycemic control is likely minimal since endogenous GIP has little to no effect on PPG in individuals with T2D 34. Herein, it is possible that diurnal increases in GLP-1 secretion from thrice daily WP supplementation may have enhanced β-cell glucose sensitivity and delayed the rate of gastric emptying, thereby slowing the systemic appearance of meal-derived glucose and augmenting an efficient islet response 35 36.…”

Acute concomitant glucose‐dependent insulinotropic polypeptide receptor antagonism during glucagon‐like peptide 1 receptor agonism does not affect appetite, resting energy expenditure or food intake in patients with type 2 diabetes and overweight/obesity

“…The study was registered at http://www.clinicaltrials.gov (NCT03702660). Data from two separate experimental days involving GIP(3‐30)NH 2 and saline infusions have previously been published 5 …”

“…Optimized glycaemic control improves the insulinotropic effect of exogenous GIP in patients with type 2 diabetes, suggesting that diabetic GIP resistance is a reversible phenomenon 3,4 . Furthermore, we recently showed that endogenous GIP has insulinotropic properties in type 2 diabetes 5 . Several GLP‐1 receptor (GLP‐1R) agonists (GLP‐1RAs) are now approved for the treatment of type 2 diabetes and obesity 6 .…”

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

“…In the N-terminal segment (1-15), positions (1,3,5,8-11, and 15) displayed a high degree of conservation across species (Figure 4A). In the core segment (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), the hydrophobic positions 22,23,26, and 27, complementing a binding groove in the GIPR (57), showed the highest degree of conservation (CS < -1.328). The C-terminal segment (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) represents the C-terminal tail, which is unique for GIP(1-42) and structurally less ordered than the closely related class B1 peptides (58).…”

“…Supporting this, administration of the selective GIPR antagonist GIP(3-30)NH 2 resulted in inhibition of GIP actions on the bone cells ( 6 , 7 , 14 – 16 ). In contrast to the reduced insulinotropic actions of GIP in patients with T2D, the suppression of bone resorption by endogenous GIP seems conserved in patients with T2D ( 17 ). Supporting an important role for GIP in bone remodeling, mutations in the GIPR have been associated with increased fracture risk and decreased bone mineral density ( 18 ).…”