Improvement in insulin resistance and the restoration of reduced phosphodiesterase 3B gene expression by pioglitazone in adipose tissue of obese diabetic KKAy mice

Phosphodiesterase (PDE) 3B is a key enzyme in the mediation of the antilipo lytic action of insulin in adipocytes, and activation of this molecule resu lts in a reduced output of free fatty acids (FFAs). An elevation of serum F FAs is known to cause insulin resistance in skeletal muscle and liver, whic h could be the primary cause of type 2 diabetes. To elucidate whether PDE3B is involved in this disease, we examined the PDE3B gene expression in epid idymal fat tissues of obese insulin-resistant diabetic KKAy mice. We also e xamined the effect of an insulin-sensitizing drug, pioglitazone, on this ge ne expression. In adipose tissue of KKAy mice, PDE3B mRNA and its correspon ding protein were reduced to 48 and 43% of those in C57BL/6J control mice. Basal and insulin-stimulated membrane-bound PDE activities were also decrea sed to 50 and 36% of those in the controls, respectively. Pioglitazone incr eased both PDE3B mRNA and protein levels by 1.8-fold of those in untreated KKAy mice. Basal and insulin-induced membrane-bound PDE activities were als o increased by 1.6- and 2.0-fold, respectively. Pioglitazone reduced the el evated levels of serum insulin, glucose, FFAs, and triglyceride in KKAy mic e. Thus, the reduced PDE3B gene expression in adipose tissues could be the primary event in the development of insulin resistance in KKAy mice, which was improved by pioglitazone possibly because of the restoration of the red uced PDE3B gene expression.