Glucocorticoid induced insulin resistance impairs basal but not glucose entrained high-frequency insulin pulsatility in humans

Abstract

Insulin resistance and relative insulin deficiency are pronounced elements in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus [1,2]. It has long been debated whether insulin resistance or beta-cell dysfunction is the primary defect in Type II diabetes [3±8]. In this context insulin resistance has been established as a strong predictor for the development of Type II diabetes, whereas this seems to apply to a lesser extend to beta-cell dysfunction. This might in part be due to the insensitivity of tests for beta-cell dysfunction [6,9,10]. A dynamic relation between insulin resistance and a compensatory increase in beta-cell mass and beta-cell glucose metabolism has been suggested [11]. Insulin secretion is pulsatile and irregular insulin pulsatility has been re- Diabetologia (2002) Abstract Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is characterized by abnormal insulin secretion, which involves a disrupted basal and glucose-entrained insulin pulsatility, and by insulin resistance. The aim of this study was to examine the influence of glucocorticoid-mediated insulin resistance on the regularity of high frequency insulin pulsatility. Methods. Eight healthy men (means SD; age 24.4 0.5 years, BMI 23.2 0.7 kg/m 2 ) were examined after prednisolone treatment (30 mg/day) or placebo for 6 days in a double-blind, placebo controlled, cross-over study with a 6-week washout period. Blood was collected every minute for 60 min during baseline and glucose-entrainment. Time-series were assessed by spectral and autocorrelation analyses and a first-phase insulin secretion test was carried out. Results. Prednisolone treatment led to insulin resistance as expected (HOMA-S; prednisolone vs placebo; 1.85 0.26 vs 1.02 0.10; p < 0.01) with exaggerated first-phase insulin secretion (3016 468 pmol/l vs 1688 207 pmol/l; p < 0.01), suggesting a stable disposition index. During baseline, normalized spectral power of serum insulin concentration time-series was reduced during prednisolone exposure compared with placebo (8.40 0.95 vs 11.79 1.66; p < 0.05) indicating a disturbed high-frequency oscillatory insulin release. A similar trend was observed using autocorrelation analysis (0.23 0.04 vs 0.32 0.07; p = 0.12). During glucose entrainment no difference in normalized spectral power or in the autocorrelation coefficient between prednisolone and placebo (p > 0.1) was observed. Conclusion/interpretation. Six days of prednisolone treatment resulted in a pertubed high-frequency insulin release in the fasting state whereas the ability of glucose to entrain insulin secretion was preserved. This indicates a mechanism of pertubed glucose-insulin feedback mechanism which causes irregular oscillatory insulin release. [Diabetologia (2002) 45: 49±55]

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).…”

“…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). This enhanced b-cell function was also observed in adult rats treated for up to 13 consecutive days with dexamethasone (0.125-2.0 mg/kg) based on basal hyperinsulinaemia (Novelli et al 1999, Karlsson et al 2001 or in vivo glucose challenging (Rafacho et al , 2011.…”

“…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.…”

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).…”

“…Treatment of healthy subjects with high doses of DEX (2 to 4 days) or prednisolone (6 to 15 days) is associated with normoglycemia or modest increase in fasting blood glucose levels concomitant with significantly heightened circulating insulin concentrations during the post-absorptive state (Pagano et al, 1983;Beard et al, 1984;Grill et al, 1990;Schneiter & Tappy, 1998;Hollingdal et al, 2002;Willi et al, 2002;Nicod et al, 2003;Binnert et al, 2004;van Raalte et al, 2010), (see an overview in Table 1). 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).…”