MODULATION OF INSULIN-SECRETION AND GLYCEMIA BY SELECTIVE-INHIBITION OF CYCLIC-AMP PHOSPHODIESTERASE-III

The effects of selective inhibition of cyclic AMP phosphodiesterase ty pe III on insulin and glucose levels during an oral glucose challenge were evaluated in obese, diabetic ob/ob mice and in lean, non-diabetic littermates using the selective inhibitor, milrinone. Oral administra tion of milrinone increased plasma insulin levels both in ob/ob and in lean mice. Glucose tolerance was improved in lean, but not in ob/ob m ice, where glucose levels were increased by milrinone treatment. In is olated hepatocytes from normal rats incubation with 200 mu M milrinone caused a 30% increase in glucose release with a corresponding depleti on of glycogen stores. Stimulation of isolated rat adipocytes with 200 mu M milrinone increased glycerol release 7-fold. We conclude that se lective inhibitors of cyclic AMP phosphodiesterase III are effective i nsulin secretagogues, but their therapeutic utility may be limited by their concurrent stimulation of lipolysis and hepatic glucose output. (C) 1997 Academic Press.