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


BACKGROUND
Clinicaltrials.gov NCT02235584.
Department of Endocrinology, Bispebjerg University Hospital, Bispebjerg Bakke 23, DK-2400, Copenhagen, Denmark, mi.eriksen1@gmail.com.
Marie
M
Eriksen
David H
DH
Jensen
Siri
S
Tribler
Jens J
JJ
Holst
Sten
S
Madsbad
Thure
T
Krarup
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D012307:Risk Factors
D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D003907:Dexamethasone; D052216:Glucagon-Like Peptide 1