Modulation of insulin secretion and glycemia by selective inhibition of cyclic AMP phosphodiesterase III

The effects of selective inhibition of cyclic AMP phosphodiesterase type III on insulin and glucose levels during an oral glucose challenge were evaluated in obese, diabeticob/obmice and in lean, non-diabetic littermates using the selective inhibitor, milrinone. Oral administration of milrinone increased plasma insulin levels both inob/oband in lean mice. Glucose tolerance was improved in lean, but not inob/obmice, where glucose levels were increased by milrinone treatment. In isolated hepatocytes from normal rats incubation with 200μM milrinone caused a 30% increase in glucose release with a corresponding depletion of glycogen stores. Stimulation of isolated rat adipocytes with 200μM milrinone increased glycerol release 7-fold. We conclude that selective inhibitors of cyclic AMP phosphodiesterase III are effective insulin secretagogues, but their therapeutic utility may be limited by their concurrent stimulation of lipolysis and hepatic glucose output.