The Effect of a Benzothiadiazine, Diazoxide, on Carbohydrate Metabolism

Abstract

After the oral, intraperitoneal, or intravenous administration of an antihypertensive, antidiuretic benzothiadiazine, diazoxide, to dogs, rabbits, mice, and rats, rapid hyperglycemia is promptly elicited, but of short duration, and reversible. The hyperglycemia is accompanied by increased hepatic glycogenolysis, serum lactate and pyruvate, and blood urea nitrogen (BUN). The hyperglycemia is obtained in depancreatized dogs, alloxanized mice, propylthiouracil treated mice, and nephrectomized mice, suggesting that the pancreas, thyroid and kidneys are not the primary locus of action of diazoxide. Modification of diazoxide hyperglycemia by hypophysectomy suggests that the pituitary plays a role in the hyperglycemic phenomenon. However, this view must be tempered by the realization that hypophysectomy causes partial inanition, perhaps sufficient to prevent hyperglycemia. The partial suppression of diazoxide hyperglycemia by adrenalectomy and BW 61–43 (isopropyl methoxamine), a specific inhibitor of the metabolic effects of epinephrine, suggests that the metabolic effects of diazoxide are mediated, at least in part, by adrenergic hormones. Preliminary experiments wherein diazoxide hyperglycemia was markedly attenuated in adrenalectomized mice treated with a ganglionic blocking agent, chlorisondamine, tend to support this concept. However, some doubt is cast upon this concept since reserpine treated mice respond to diazoxide and differences were observed in the hyperglycemic responses to epinephrine and diazoxide in hypophysectomized mice. Further work is underway to elucidate the mechanism(s) and locus of action of the metabolic effects of diazoxide.

Benzothiadiazine suppression of insulin release from normal and abnormal islet tissue in man.

“…Only the finding of decreased levels of insulin in portal blood after administration of benzothiadiazines could furnish direct proof for such an effect in vivo. Nevertheless, our in-terpretation is strongly supported by the report of Frerichs and Creutzfeldt that diazoxide inhibits insulin release from pancreatic slices in vitro (20 (9).…”

“…dogs (9), b) plasma levels of insulin-like activity do not decrease in normal or diabetic subjects (10), or in rats (11) made hyperglycemic by administration of diazoxide, and c) in patients with metastatic insulin-secreting tumors, the hyperglycemic response to diazoxide and other benzothiadiazines occurs without apparent reduction in plasma levels of insulin (12,13). Other additional evidence has been presented to indicate that diazoxide hyperglycemia is an extrapancreatic phenomenon (9,11).…”

Indapamide in the treatment of hypertension in non-insulin-dependent diabetes.

“…The exact mechanism by which thiazide diuretics may worsen glucose tolerance is not completely understood, but postulations include either an inhibition of insulin secretion 6 or diminished sensitivity to insulin. 7 Moreover, insulin secretion may be decreased by thiazide-induced hypokalemia per se, 8 9 with a defect in beta cell responsiveness to glucose stimulus. It is interesting that hypokalemia appears to interfere with the conversion of proinsulin to insulin in the beta cell, so that larger amounts of the less active proinsulin are released in the blood.…”

Furosemide decreases the sensitivity of glucose transport to insulin in skeletal muscle in vitro

“…Hydrochlorothiazide, a diuretic which has been shown in vivo to induce glucose intolerance (1,3,(5)(6)(7)9), inhibits glucose transport in rat adipocytes by a mechanism similar to that of furosemide (14). The concentration of furosemide that was used is higher than that observed in the serum of patients receiving the usual therapeutic doses of the drug (5).…”

“…Although a decrease in the secretion of insulin has been reported (4,8), additional mechanisms may be involved since these drugs cause hyperglycemia in pancreatectomized dogs or alloxan-diabetic mice (9). Skeletal muscle is quantitatively most important for glucose disposal in response to insulin (10).…”