Further studies on diazoxide suppression of insulin release from abnormal and normal islet tissue in man.

In previous reports,'j2 we described studies of the effects of diazoxide, given in combination with trichlormethiazide, on plasma insulin and blood glucose levels in healthy subjects and in patients with functioning islet cell tumors of the pancreas. From these studies, we have concluded: ( a ) that decreased insulin secretion, as well as a failure of appropriate increases in insulin secretion, are involved in the mechanisms by which diazoxide and trichlormethiazide induce hyperglycemia; (b) that these compounds inhibit insulin release induced by the administration of glucose and leucine; and (c) that these benzothiadiazines also increase blood glucose by mechanisms that do not involve alterations in plasma insulin. Graber and coworker^,^,^ Seltzer and Allen5 and Marks and coworkerss have also reported that diazoxide decreases plasma levels of insulin in patients with beta-cell tumors of the p a n ~ r e a s , ~ , ~ , ~ in healthy subjects4j5 and in diabetic pat i e n t ~ . ~ , ~ Frerichs and associate^,^ and Howell and TaylorE have shown by in vifro experiments that diazoxide causes an inhibition of insulin secretion induced by glucose. The studies described in this paper had the following objectives: 1. To extend observations of diazoxide's effect on plasma insulin and blood glucose in patients with pancreatic islet cell tumors. 2. To investigate in these patients the relation between any changes in plasma and urinary levels of catecholamines and changes in levels of plasma insulin during administration of diazoxide. 3. To ascertain the effect of diazoxide on insulin secretion induced by glucagon, tolbutamide and arginine in addition to that induced by glucose and leucine. The results of these studies indicate that: (a ) diazoxide is a potent, rapid, and consistent inhibitor of pancreatic insulin release, (b) diazoxide increases blood glucose by decreasing insulin secretion as well as by activating extrapancreatic mechanisms, (c) these effects of diazoxide on plasma insulin and blood glucose may be observed without concomitant increases in plasma or urinary levels of catecholamines, ( d ) diazoxide is an effective agent for the alleviation of hypoglycemia due to functioning pancreatic islet cell tumors, and (e) diazoxide is a useful agent for studying possible differences in mechanism by which nutrients, hormones and pharmacologic agents induce the release of insulin.