Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release

Abstract

Glucose-6-phosphatase (G6Pase) and glucokinase activities can be demonstrated in pancreatic islets from mammalian species [1±4]. Glucokinase appears to be the rate limiting enzyme of glycolysis in the beta-cell, regulating the dose-response relationship between glucose utilization and insulin release [4]. Since G6Pase opposes the action of glucokinase, a possible role for G6Pase in the metabolic regulation of insulin release was postulated [2,3]. There are several reports of relatively low G6Pase activity in homogenates of normal mammalian islets [1±4], one of activity exceeding that in liver [5] and one of no activity [6]. We found low activity in permeabilized and sonicated islets from normal rats and mice [7]. Sweet et al. [8] also found low G6Pase activity in intact islets from normal rats.Glucose cycling is the simultaneous phosphorylation of glucose to glucose-6-P and dephosphorylation of glucose-6-P to glucose with the resulting consumption of ATP [9]. In accordance with reports of low G6Pase activity, we demonstrated a low rate of glucose cycling in intact islets from normal mice, dephosphorylation occurring at only 3 % of the rate of phosphorylation [10]. However, in islets from ob/ob mice, 30±40 % of phosphorylated glucose was dephosphorylated [10]. Glucose cycling was also increased in islets from other animal models of Type II diabetes [11,12]. In accordance with these results, G6Pase activity was several fold higher in islets from diabetic than normal animals [7,13] and islet G6Pase gene expression was increased during the development of diabetes in Zucker rats [14]. Diabetologia (1998) Summary Glucose-6-phosphatase (G6Pase) activity and the rate of glucose cycling are increased in islets from animal models of Type II (non-insulin-dependent) diabetes mellitus. Glucocorticoid treatment further stimulates these processes and inhibits glucose-induced insulin release. To determine whether these effects result from a direct action of glucocorticoids on the beta-cells, we used isolated islets. The islets were from transgenic mice overexpressing the glucocorticoid receptor in their beta-cells to increase the cells' sensitivity to glucocorticoid. Islets from transgenic and non-transgenic control mice utilized and oxidized the same amount of glucose. In contrast, islet G6Pase activity was 70 % higher, glucose cycling was increased threefold and insulin release was 30 % lower in islets from transgenic mice. Hepatic G6Pase activity was the same in transgenic and control mice. Dexamethasone administration increased G6Pase activity and glucose cycling and decreased insulin release in both transgenic and control mouse islets. We conclude that glucocorticoids stimulate islet G6Pase activity and glucose cycling by acting directly on the beta-cell. That activity may be linked to the inhibition of insulin release. [Diabetologia (1998) 41: 634±639]

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

“…We thus selected women with insulin sensitivity in the highest quartile of insulin sensitivity in their age group. Glucocorticoids are also known to inhibit insulin secretion by a direct effect on the beta cells [33,34]. Hence, the increase in insulin secretion during dexamethasone-induced insulin resistance is most likely to be due to the adaptive mechanisms rather than to a direct effect of the steroid.…”

11?-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes

“…In contrast to the well-known secondary hyperinsulinaemia in response to acute cortisol exposure in healthy subjects [72], glucocorticoids even in physiological concentrations directly inhibit insulin secretion from pancreatic islets in vitro and in vivo [10,73,74,75,76]. 11β-HSD1 is expressed in islet cells and 11-oxo glucocorticoids activated by 11β-HSD1 diminish insulin secretion [76].…”

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

“…However, when the increment in insulin release between 5.5 mM and 16.7 mM glucose is calculated, a higher insulin response in DEX-treated animals as compared to vehicle treated mice is noted. As blood glucose and insulinemia were not determined in this experiment (Ling et al, 1998), which could indicate any deleterious GC effects on glucose homeostasis, caution should be exerted as to making conclusions about GC effects in normal mice.…”

“…In an attempt to extrapolate these observations and determine whether they are caused by direct islet effects of GC in vivo, a transgenic mouse that overexpresses the GR specifically in -cells was generated (Delaunay et al, 1997). These mice also displayed increased glucose cycling, mild glucose intolerance, decreased insulinogenic index and GSIS, but remained normoglycaemic (Delaunay et al, 1997;Ling et al, 1998). DEX treatment increased glucose cycling and the impairment of GSIS in this transgenic model.…”