Roles of insulin resistance and beta-cell dysfunction in dexamethasone-induced diabetes.

Abstract

The roles of insulin resistance and fl-cell dysfunction in glucocorticoid-induced diabetes were determined in Wistar and Zucker (fa/fa) rats. All Wistar rats treated with 5 mg/kg per d of dexamethasone for 24 d exhibited increased f-cell mass and basal and arginine-stimulated insulin secretion, indicating insulin resistance, but only 16% became diabetic. The insulin response to 20 mM glucose was normal in the perfused pancreas of all normoglycemic dexamethasone-treated rats but absent in every diabetic rat. Immunostainable high K. f-cell transporter, GLUT-2, was present in -100% of f-cells of normoglycemic rats, but in only 25% of f, cells of diabetic rats.GLUT-2 mRNA was not reduced. All Zucker (fia/fa) rats treated with 0.2-0.4 mg/kg per d of dexamethasone for 24 d became diabetic and glucose-stimulated insulin secretion was absent in all. High K. glucose transport in islets was 50% below nondiabetic controls. Only 25% of cells of diabetic rats were GLUT-2-positive compared with -100% in controls. Total pancreatic GLUT-2 mRNA was increased twofold suggesting a posttranscriptional abnormality. We conclude that dexamethasone induces insulin resistance, whether or not it induces hyperglycemia. Whenever hyperglycemia is present, GLUT-2-positive fi cells are reduced, high K. glucose transport into cells is attenuated and the insulin response to glucose is absent. (J. Clin. Invest. 1992. 90:497-504.)

Insufficient adaptive capability of pancreatic endocrine function in dexamethasone-treated ageing rats

“…Glucocorticoid-induced insulin resistance is usually associated with a compensatory increase in -cell mass (Ogawa et al 1992) and pancreatic insulin content (Bonner-Weir et al 1981). Our data on pancreatic and islet insulin stores fully confirm this latter observation for DEX-treated young rats only.…”

“…It is worth noticing that our results confirm that the antilipolytic effect of insulin is blunted by DEX treatment (Venkatesan et al 1996). The present study clearly indicates that the variable effects of glucocorticoid treatment on blood glucose concentrations are not only genetically determined as suggested by Ogawa et al (1992), but also dependent on acquired factors such as age, overweight or both. Taking into account the hypothetical involvement of abundant lipid availability in the pathogenesis of hyperglycaemia in insulin resistant states such as obesity (Unger 1995), it is possible that the elevation of blood glucose in older rats could be mediated, at least in part, by the DEX-induced rise in circulating FFA levels, which interferes with glucose uptake and utilization particularly in muscles (Venkatesan et al 1987, Groop et al 1991, Roden et al 1996.…”

Irreversible loss of normal beta-cell regulation by glucose in neonatally streptozotocin diabetic rats

“…To properly evaluate such an influence and to provide information on the validity of the transplantation protocol, we studied in parallel insulin secretion from islets isolated from nondiabetic rats. The transplanted islets from normal to normal rats showed a typical biphasic secretion of insulin in response to glucose, which was very similar to that of perfused pancreata of the Wistar rats [23]. Furthermore, the islet grafts from normal to diabetic rats showed somewhat reduced responses to glucose but enhanced responses to arginine.…”

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

“…In these contexts, b-cell function does not correspond to the peripheral insulin demand, and the deregulation of glucose homeostasis becomes more pronounced, reinforcing that individual background is a critical factor. Indeed, this susceptibility to b-cell failure after treatment with dexamethasone has also been observed in animal models with an obesity background, such as fa/fa rats (Ogawa et al 1992) and ob/ob mice (Khan et al 1992).…”