Effect of Dehydroepiandrosterone on Insulin Sensitivity and Adipocyte Growth in Otsuka Long-Evans Tokushima-Fatty Rats

Dehydroepiandrosterone (DHEA) (1) is the major adrenal androgen of young adults. However, serum concentration of DHEA in 60 yearold men shows a gradual decrease, when compared with young men aged 25-30 years old. This decrease occurs as the incidence of atherosclerosis (2), obesity (3), and diabetes increases (4), suggesting that administration of DHEA may protect against the development of these disorders. Previously, we reported that in vitro DHEA treatment increased glucose uptake and activation of PI 3-kinase in native rat adipocytes (5). Protein kinase C (PKC) is a family of serine/threonine kinases, which play key functions in cellular signal transduction. Three categories of PKC, conventional, novel, and atypical PKCs, have been described depending on their mechanisms of activation. Moreover, it is known that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is the hub of many signaling pathways, which phosphorylate many downstream kinases of phosphatidylinositol 3-kinase (PI 3-kinase), such as Akt kinase, S6 kinase and PKC. Previous studies suggested that atypical PKC (aPKC/) isoforms are required for insulin stimulation of glucose uptake (6), and PDK1 is necessary for activation of aPKCs (7). It has been reported that DHEA treatment reduces fat accumulation and protects against insulin resistance via an increase in PI 3-kinase after immunoprecipitation with insulin receptor substrate-1 (IRS-1) in male rats (8). We have investigated the in-vitro and in-vivo effects of DHEA on insulin-induced glucose uptake in adipocytes of Otsuka Log-Evans Tokushima fatty (OLETF) (9) and LETO rats. Moreover, we have shown the DHEA-induced glucose uptake by activation of PI 3-kinase/atypaical PKC siganlling without association with IRS-1 (10). In vivo treatment with DHEA affects on a decrease of adipose tissue via downregulation of peroxisome proliferator-activated receptor  (PPAR) expression (11). Based on above results, we have searched more precise mechanism of DHEA-induced amelioration of insulin sensitivity and clinical application of DHEA in diabetic animal models and human male adults.