Dehydroepiandrosterone sulfate and beta-cell function: enhanced glucose-induced insulin secretion and altered gene expression in rodent pancreatic beta-cells.

Abstract

Administration of dehydroepiandrosterone (DHEA), or its sulfated form (DHEAS), controls hyperglycemia in diabetic rodents without directly altering insulin sensitivity. We show that DHEAS enhanced glucose-stimulated insulin secretion when administered in vivo to rats or in vitro to ␤-cell lines, without changing cellular insulin content. Insulin secretion increased from 3 days of steroid exposure in vitro, suggesting that DHEAS did not directly activate the secretory processes. DHEAS selectively increased the ␤-cell mRNA expression of acyl CoA synthetase-2 and peroxisomal acyl CoA oxidase in a time-dependent manner. Although DHEAS is a peroxisomal proliferator, it did not alter the mRNA expression of peroxisomal proliferator-activated receptor (PPAR) ␣ or ␤, or enhance the activity of transfected PPAR ␣, ␤, or ␥ in vitro. Thus, DHEAS directly affected the ␤-cell to enhance glucose-stimulated insulin secretion and increased the mRNA expression of specific ␤-cell mitochondrial and peroxisomal lipid metabolic enzymes. This effect of DHEAS on insulin secretion may contribute to the amelioration of hyperglycemia seen in various rodent models of diabetes. Diabetes 49

Peroxisome proliferator-activated receptor α (PPARα) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

“…Such oleate-induced dysfunction was worsened by downregulation of PPARα. Among the different subtypes belonging to the PPAR nuclear receptor family, PPARα is relatively abundant in beta cells [34] and is similarly produced in primary rat islet beta cells and insulinoma INS-1 cells [35]. Our results indicate that endogenous PPARα levels exert some protective effects, although it might not be sufficient when there is a pathophysiological concentrations of oleate.…”

Two Years of Treatment With Dehydroepiandrosterone Does Not Improve Insulin Secretion, Insulin Action, or Postprandial Glucose Turnover in Elderly Men or Women

“…In vitro and animal experiments suggest that DHEA can improve insulin action (11)(12)(13)(14)(15)(16)(17). On the other hand, studies in humans have been less convincing, perhaps because many used indirect methods to assess insulin action (19,26) or involved young or middle-aged subjects who did not have documented DHEA deficiency (19,20,22,23,25,26,50).…”

“…In addition, plasma DHEA concentrations have been reported to be inversely correlated with BMI, visceral fat, plasma insulin concentrations, and insulin action (1,(7)(8)(9)(10). Furthermore, treatment with DHEA increases glucose uptake in vitro and improves glucose tolerance in mice, decreases body fat in fa/fa rats, prevents diabetes in ob/ob mice, and enhances glucose-induced insulin secretion in Wistar rats (11)(12)(13)(14)(15)(16)(17). These observations have led to speculation that the agerelated fall in DHEA concentrations either causes or exacerbates glucose intolerance and likely has contributed to the widespread empirical use of DHEA as a putative "anti-aging" drug.…”

Serum DHEA-S Level Is Associated with the Presence of Atherosclerosis in Postmenopausal Women with Type 2 Diabetes Mellitus

“…DHEA is known to improve insulin resistance [6] and to increase insulin secretion from the pancreas [18]. Several reports have indicated an association between diabetic control and the level of DHEA(-S) [19,20].…”