Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

TY - JOUR

T1 - Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

AU - Eriksen, Marie

AU - Jensen, David H

AU - Tribler, Siri

AU - Holst, Jens Juul

AU - Madsbad, Sten

AU - Krarup, Thure

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Aims/hypothesis: We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoid-induced insulin resistance. Methods: Nineteen healthy, glucose tolerant, first-degree relatives of type 2 diabetic patients underwent OGTT and 7 mmol/l and 15 mmol/l glucose clamps with concomitant infusions of GLP-1, GIP or NaCl and a final infusion of arginine for determination of maximum beta cell capacity before and after treatment with dexamethasone. In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l. Results: After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose concentrations, while beta cell function indices generally increased according to the increased resistance. First-phase insulin responses induced by GLP-1 and GIP at 7 mmol/l and maximal beta cell secretory capacity did not differ before and after dexamethasone, while second-phase responses to 7 mmol/l and first-phase responses to 15 mmol/l glucose were reduced equally for both hormones. Conclusions/interpretation: Glucocorticoid-induced insulin resistance in individuals at risk of type 2 diabetes leads to a reduced insulinotropic effect of the incretin hormones. This reduction was not associated with a decrease in the maximal beta cell secretory capacity, indicating that the reduced incretin effect in the developing dysglycaemia of the present experimental model is due to a specific early reduction of the insulinotropic effects of the incretin hormones. Trial registration: Clinicaltrials.gov

AB - Aims/hypothesis: We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoid-induced insulin resistance. Methods: Nineteen healthy, glucose tolerant, first-degree relatives of type 2 diabetic patients underwent OGTT and 7 mmol/l and 15 mmol/l glucose clamps with concomitant infusions of GLP-1, GIP or NaCl and a final infusion of arginine for determination of maximum beta cell capacity before and after treatment with dexamethasone. In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l. Results: After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose concentrations, while beta cell function indices generally increased according to the increased resistance. First-phase insulin responses induced by GLP-1 and GIP at 7 mmol/l and maximal beta cell secretory capacity did not differ before and after dexamethasone, while second-phase responses to 7 mmol/l and first-phase responses to 15 mmol/l glucose were reduced equally for both hormones. Conclusions/interpretation: Glucocorticoid-induced insulin resistance in individuals at risk of type 2 diabetes leads to a reduced insulinotropic effect of the incretin hormones. This reduction was not associated with a decrease in the maximal beta cell secretory capacity, indicating that the reduced incretin effect in the developing dysglycaemia of the present experimental model is due to a specific early reduction of the insulinotropic effects of the incretin hormones. Trial registration: Clinicaltrials.gov

U2 - 10.1007/s00125-015-3522-y

DO - 10.1007/s00125-015-3522-y

M3 - Journal article

C2 - 25748606

SN - 0012-186X

VL - 58

SP - 920

EP - 928

JO - Diabetologia

JF - Diabetologia

IS - 5

ER -