Dose‐dependent efficacy of the glucose‐dependent insulinotropic polypeptide (GIP) receptor antagonist GIP(3‐30)NH₂ on GIP actions in humans

Abstract

The glucose‐dependent insulinotropic polypeptide (GIP) fragment GIP(3‐30)NH2 is a selective, competitive GIP receptor antagonist, and doses of 800 to 1200 pmol/kg/min inhibit GIP‐induced potentiation of glucose‐stimulated insulin secretion by >80% in humans. We evaluated the effects of GIP(3‐30)NH2 across a wider dose range in eight healthy men undergoing six separate and randomized 10‐mmol/L hyperglycaemic clamps (A–F) with concomitant intravenous infusion of GIP (1.5 pmol/kg/min; A–E) or saline (F). Clamps A to E involved double‐blinded, infusions of saline (A) and GIP(3‐30)NH2 at four rates: 2 (B), 20 (C), 200 (D) and 2000 pmol/kg/min (E), respectively. Mean plasma concentrations of glucose (A–F) and GIP (A–E) were similar. GIP‐induced potentiation of glucose‐stimulated insulin secretion was reduced by 44 ± 10% and 84 ± 10% during clamps D and E, respectively. Correspondingly, the amounts of glucose required to maintain the clamp during D and E were not different from F. GIP‐induced suppression of bone resorption and increase in heart rate were lowered by clamps D and E. In conclusion, GIP(3‐30)NH2 provides extensive, dose‐dependent inhibition of the GIP receptor in humans, with most pronounced effects of the doses 200 to 2000 pmol/kg/min within the tested range.

Treatment of Type 2 Diabetes and Obesity on the Basis of the Incretin System: The 2021 Banting Medal for Scientific Achievement Award Lecture

“…For GIP, the doses of the antagonist employed have been demonstrated to block 80% of exogenous GIP when the latter was given in doses resulting in physiological elevations of GIP concentrations in plasma. A subsequent dose-response investigation gave similar results ( 12 ). Regarding GLP-1, the use of an antagonist as a tool for analyzing its actions is much more complicated.…”

Worsening Postural Tachycardia Syndrome Is Associated With Increased Glucose-Dependent Insulinotropic Polypeptide Secretion

“…11 Given that the GIP peak incidentally coincided with the decrease in upright SV; we hypothesize that this peptide, by increasing the splanchnic blood pooling, could contribute to the SV reduction and consequently to the worsening upright tachycardia. Indeed, a previous study 34 reported a significant increase in HR during infusion of the GIPR agonist GIP (1-42) and this effect was inhibited by the GIPR antagonist (GIP(3-30)N 2 ).…”

Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment

“…However, in T2DM patients, further studies to explore this problem were unable to be carried out due to the lack of appropriate GIP receptor antagonists. Recent studies have shown that GIP can improve glycemic control in patients with T2DM [ 39 , 40 ] and have revived studies on the development of novel antagonists [ 41 , 42 ]. These studies have led to a re-evaluation of the role of GIP in the anti-hyperglycemia of DPP4i.…”