(1) The effects of diazoxide on the conversion of oral doses of glucose-U-C-14 to fatty acids in adipose tissue, and to fatty acids and glycogen in liver have been studied in intact mice.
(2) Diazoxide in a subcutaneous dose of 10 mg. per kilogram inhibited conversion of the glucose-U-C-14 to fatty acids of epididymal fat approximately 50 per cent. The inhibition in conversion of isotopic glucose to fatty acids in liver was slightly less than that found for adipose tissue. These inhibitory effects as well as hyperglycemia occurred within twenty minutes after drug administration and ten minutes after the glucose-U-C-14 was given.
(3) In spite of the sensitivity of the system, insulin overcame the inhibitory effects of 200 mg. per kilogram diazoxide on all these parameters. This large dose of diazoxide did not antagonize the action of exogenous insulin.
(4) Although diazoxide inhibited conversion of glucose-U-C-14 to liver fatty acids, net incorporation into liver glycogen was stimulated one-hundredfold. A net increase in the weight of total liver glycogen also was found. The significance of the striking elevation in glycogen synthesis in terms of proposed mechanisms of action for diazoxide will be discussed.
(5) The inhibition in conversion of the glucose-U-C-14 to fatty acid and the hyperglycemia were accompanied by an increase rather than a decrease in the specific activity of the plasma glucose. This, combined with the fact that no antagonism to the action of exogenous insulin was observed, is consistent with the hypothesis that diazoxide-mediated hyperglycemia, at least at low doses, results primarily from an inhibition in insulin secretion. At higher doses adrenergic mechanism could also become involved in potentiating the hyperglycemia.