Evidence that autonomic mechanisms contribute to the adaptive increase in insulin secretion during dexamethasone-induced insulin resistance in humans

Abstract

Aims/hypothesis This study examined whether autonomic mechanisms contribute to adaptively increased insulin secretion in insulin-resistant humans, as has been proposed from studies in animals. Methods Insulin secretion was evaluated before and after induction of insulin resistance with or without interruption of neural transmission. Insulin resistance was induced by dexamethasone (15 mg given over 3 days) in nine healthy women (age 67 years, BMI 25.2±3.4 kg/m 2 , fasting glucose 5.1± 0.4 mmol/l, fasting insulin 46±6 pmol/l). Insulin secretion was evaluated as the insulin response to intravenous arginine (5 g) injected at fasting glucose and after raising glucose to 13 to15 mmol/l or to >28 mmol/l. Neural transmission across the ganglia was interrupted by infusion of trimethaphan (0.3-0.6 mg kg −1 min −1 ). Results As an indication of insulin resistance, dexamethasone increased fasting insulin (to 75±8 pmol/l, p<0.001) without significantly affecting fasting glucose. Arginine-induced insulin secretion was increased by dexamethasone at all glucose levels (by 64±12% at fasting glucose, by 80± 19% at 13-15 mmol glucose and by 43±12% at >28 mmol glucose; p<0.001 for all). During dexamethasone-induced insulin resistance, trimethaphan reduced the insulin response to arginine at all three glucose levels. The augmentation of the arginine-induced insulin responses by dexamethasoneinduced insulin resistance was reduced by trimethaphan by 48±6% at fasting glucose, 61±8% at 13-15 mmol/l glucose and 62±8% at >28 mmol/l glucose (p<0.001 for all). In contrast, trimethaphan did not affect insulin secretion before dexamethasone was given. Conclusions/interpretations Autonomic mechanisms contribute to the adaptative increase in insulin secretion in dexamethasone-induced insulin resistance in healthy participants.

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

“…However, these adaptations do not always guarantee an adequate glucose homeostasis. Although insulin hypersecretion observed after prolonged steroid treatment appears to be consistent in most experiments carried out in healthy volunteers (Beard et al 1984, Schneiter & Tappy 1998, Ahrén 2008, van Raalte et al 2010) and normal adult rats (Karlsson et al 2001, glucose intolerance is also present. In these studies, hyperinsulinaemia is normally associated with normoglycaemia or modest increases in blood glucose values, but the insulin (Schneiter & Tappy 1998 and C-peptide hypersecretion (van Raalte et al 2010) during glucose or meal challenges, respectively, do not prevent elevation in postprandial blood glucose levels.…”

“…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.…”

Functional and Molecular Aspects of Glucocorticoids in the Endocrine Pancreas and Glucose Homeostasis

“…The elevation of insulinemia indicates IR, a condition also confirmed after GC treatment (Pagano et al, 1983;Grill et al, 1990;Larsson & Ahren, 1999;Hollingdal et al, 2002;Willi et al, 2002;Nicod et al, 2003;Ahrén, 2008). The modest increase in fasting glycemia may be explained by direct effect of GCs on hepatic de novo glucose production or by a reduction of glucose uptake by peripheral tissues (e.g., muscle, liver and adipose tissue).…”

“…As GCs induce IR, pancreatic -cells initially also increase their insulin secretion capacity in response to GC treatment (Beard et al, 1984;Nicod et al, 2003;Ahrén, 2008;. However, it is also known that GCs, by direct effects, can cause pancreatic -cell dysfunction, which leads to attenuated GSIS (Lambillotte et al, 1997;Jeong et al, 2001;Ullrich et al, 2005;Zawalich et al, 2006;Roma et al, 2011).…”