TY - JOUR

T1 - GIP(3-30)NH2 is an efficacious GIP receptor antagonist in humans

T2 - a randomised, double-blinded, placebo-controlled, crossover study

AU - Gasbjerg, Lærke S

AU - Christensen, Mikkel B

AU - Hartmann, Bolette

AU - Lanng, Amalie R

AU - Sparre-Ulrich, Alexander H

AU - Gabe, Maria B N

AU - Dela, Flemming

AU - Vilsbøll, Tina

AU - Holst, Jens J

AU - Rosenkilde, Mette M

AU - Knop, Filip K

PY - 2018/2

Y1 - 2018/2

N2 - AIMS/HYPOTHESIS: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH2 in in vivo and in in vitro receptor studies.METHODS: In transiently transfected COS-7 cells, GIP(3-30)NH2 was evaluated with homologous receptor binding and receptor activation (cAMP accumulation) studies at the glucagon-like peptide 1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucagon, secretin and growth hormone-releasing hormone (GHRH) receptors. Ten healthy men (eligibility criteria: age 20-30 years, HbA1c less than 6.5% [48 mmol/mol] and fasting plasma glucose [FPG] less than 7 mmol/l) were included in the clinical study. Data were collected as plasma and serum samples from a cubital vein cannula. As primary outcome, insulin secretion and glucose requirements were evaluated together with in a randomised, four-period, crossover design by infusing GIP(3-30)NH2 (800 pmol kg(-1) min(-1)), GIP (1.5 pmol kg(-1) min(-1)), a combination of these or placebo during hyperglycaemic clamp experiments. The content of the infusions were blinded to the study participants and experimental personnel. No study participants dropped out.RESULTS: GIP(3-30)NH2 neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH2 in humans was 7.6 ± 1.4 min. Markedly larger amounts of glucose were required to maintain the clamp during GIP infusion compared with the other days. GIP-induced insulin secretion was reduced by 82% (p < 0.0001) during co-infusion with GIP(3-30)NH2, and the need for glucose was reduced to placebo levels. There were no effects of GIP(3-30)NH2 alone or of GIP with or without GIP(3-30)NH2 on plasma glucagon, GLP-1, somatostatin, triacylglycerols, cholesterol, glycerol or NEFA. GIP(3-30)NH2 administration was well tolerated and without side effects.CONCLUSIONS/INTERPRETATION: We conclude that GIP(3-30)NH2 is an efficacious and specific GIP receptor antagonist in humans suitable for studies of GIP physiology and pathophysiology.TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT02747472.FUNDING: The study was funded by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.

AB - AIMS/HYPOTHESIS: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH2 in in vivo and in in vitro receptor studies.METHODS: In transiently transfected COS-7 cells, GIP(3-30)NH2 was evaluated with homologous receptor binding and receptor activation (cAMP accumulation) studies at the glucagon-like peptide 1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucagon, secretin and growth hormone-releasing hormone (GHRH) receptors. Ten healthy men (eligibility criteria: age 20-30 years, HbA1c less than 6.5% [48 mmol/mol] and fasting plasma glucose [FPG] less than 7 mmol/l) were included in the clinical study. Data were collected as plasma and serum samples from a cubital vein cannula. As primary outcome, insulin secretion and glucose requirements were evaluated together with in a randomised, four-period, crossover design by infusing GIP(3-30)NH2 (800 pmol kg(-1) min(-1)), GIP (1.5 pmol kg(-1) min(-1)), a combination of these or placebo during hyperglycaemic clamp experiments. The content of the infusions were blinded to the study participants and experimental personnel. No study participants dropped out.RESULTS: GIP(3-30)NH2 neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH2 in humans was 7.6 ± 1.4 min. Markedly larger amounts of glucose were required to maintain the clamp during GIP infusion compared with the other days. GIP-induced insulin secretion was reduced by 82% (p < 0.0001) during co-infusion with GIP(3-30)NH2, and the need for glucose was reduced to placebo levels. There were no effects of GIP(3-30)NH2 alone or of GIP with or without GIP(3-30)NH2 on plasma glucagon, GLP-1, somatostatin, triacylglycerols, cholesterol, glycerol or NEFA. GIP(3-30)NH2 administration was well tolerated and without side effects.CONCLUSIONS/INTERPRETATION: We conclude that GIP(3-30)NH2 is an efficacious and specific GIP receptor antagonist in humans suitable for studies of GIP physiology and pathophysiology.TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT02747472.FUNDING: The study was funded by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.

KW - Journal Article

U2 - 10.1007/s00125-017-4447-4

DO - 10.1007/s00125-017-4447-4

M3 - Journal article

C2 - 28948296

VL - 61

SP - 413

EP - 423

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 2

ER -