Metabolic Adaptations to Dexamethasone‐Induced Insulin Resistance in Healthy Volunteers

Abstract

NICOD, NATHALIE, VITTORIO GIUSTI, CHRISTINE BESSE, AND LUC TAPPY. Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers. Obes Res. 2003;11:625-631. Objective: Insulin resistance is observed in individuals with normal glucose tolerance. This indicates that increased insulin secretion can compensate for insulin resistance and that additional defects are involved in impaired glucose tolerance or type 2 diabetes. The objective of this study was to evaluate a procedure aimed at assessing the compensatory mechanisms to insulin resistance. Research Methods and Procedures: Eight healthy nonobese female patients were studied on two occasions, before and after administration of 2 mg/d dexamethasone for 2 days during a two-step hyperglycemic clamp. Insulin secretion was assessed from plasma insulin concentrations. Insulin sensitivity was assessed from the ratio of whole-body glucose use (6,6 2 H 2 glucose) to plasma insulin concentrations. This procedure is known to induce a reversible impairment of glucose tolerance and insulin resistance. Results: In all subjects, dexamethasone induced a decrease in insulin sensitivity and a proportionate increase in firstphase insulin secretion and in insulin concentrations at both steps of glycemia. The resulting hyperinsulinemia allowed the restoration of normal whole-body glucose uptake and the suppression of plasma free fatty acids and triglycerides. In contrast, the suppression of endogenous glucose production was impaired after dexamethasone (p Ͻ 0.01). Discussion: Increased insulin secretion fully compensates dexamethasone-induced insulin resistance in skeletal muscle and adipose tissue but not in the liver. This suggests that failure to overcome hepatic insulin resistance can impair glucose tolerance. The compensatory insulin secretion in response to insulin resistance can be assessed by means of a hyperglycemic clamp after a dexamethasone challenge.

Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes

“…Importantly, in most of these studies, volunteers developed hyperinsulinaemia. In fact, during glucose challenging with a hyperglycaemic-clamp (Beard et al 1984, Nicod et al 2003 or an oGTT (Schneiter & Tappy 1998, Hollindgal et al 2002, Willi et al 2002, insulin release was significantly higher in GC-treated individuals compared with control groups. The plasma C-peptide values were also elevated after treatment with prednisolone in healthy men at basal conditions (Hollindgal et al 2002) and during a meal tolerance test (van Raalte et al 2010).…”

“…However, in contrast to the above-mentioned inhibitory effects observed in both acute and long-term GC incubation, chronic in vivo administration of these steroids leads to up-regulation of b-cell function as a result of the compensatory adaptation to GC-induced IR. Administration of high doses of prednisolone (30 mg) or dexamethasone (2-15 mg) to healthy individuals for prolonged periods (up to 15 days and up to 4 days respectively) resulted in normoglycaemia or a modest increase in fasting glycaemia (Beard et al 1984, Schneiter & Tappy 1998, Hollindgal et al 2002, Willi et al 2002, Nicod et al 2003, Ahrén 2008, van Raalte et al 2010, Petersons et al 2013. Importantly, in most of these studies, volunteers developed hyperinsulinaemia.…”

“…The ability of GCs to produce peripheral IR is central to explain their impact on glucose homeostasis. It is well known that any reduction in peripheral insulin sensitivity, e.g., when GCs are administered, is adaptively compensated by augmented pancreatic b-cell function (Beard et al 1984, Nicod et al 2003, Ahrén 2008. This islet compensation meets the principle of the disposition index, the product of insulin secretion and peripheral insulin sensitivity.…”

Experimental model of glucocorticoid-induced insulin resistance

“…Several studies show that glucocorticoids induce peripheral insulin resistance, in vivo and in vitro 5,8,[23][24][25][26] , by increasing hepatic glucose output and decreasing the peripheral glucose uptake. There are evidences that ROS' production plays a fundamental role on developing insulin resistance by being responsible for the smaller capture of glucose on muscle 27 and on adipose tissue 28 .…”

Changes in Insulin Secretion and Glucose Metabolism Induced by Dexamethasone in Lean and Obese Females

“…For this purpose, a two-step hyperglycemic glu-cose clamp was performed, and insulin secretion was assessed from plasma insulin concentrations at each plateau of glycemia, whereas the stimulation of glucose metabolism secondary to hyperglycemia and hyperinsulinemia was evaluated from whole body glucose use measured with 6,6 2 H 2 glucose. In these healthy lean women, whole body glucose use was maintained unchanged because insulin secretion increased to compensate for dexamethasone-induced insulin resistance (9).…”