Diazoxide Causes Recovery of β-Cell Glucose Responsiveness in 90% Pancreatectomized Diabetic Rats

Abstract

Chronic hyperglycemia causes near-total disappearance of glucose-induced insulin secretion. The etiology has been suggested to be a nonsustainable stimulation of insulin release that causes beta-cells to become unresponsive to glucose through an undefined mechanism. We used an inhibitor of insulin secretion, diazoxide, to test this hypothesis in 90% pancreatectomized (Px) rats. Px rats were given 5 days of diazoxide (30 mg/kg orally twice a day) or tap water starting on postoperative day 8, 15, or 22. In vitro pancreas perfusions were conducted 36 h posttreatment (2, 3, or 4 weeks after surgery) using a protocol of 15 min of 16.7 mM glucose followed by 15 min of 16.7 mM glucose plus 10 mM arginine. In 2-week Px rats, insulin responses to 16.7 mM glucose and to glucose/arginine were both appropriate for the reduced beta-cell mass, i.e., no defect in beta-cell glucose responsiveness had yet occurred. Diazoxide had no affect on insulin release at this time. Between 2 and 3 weeks after pancreatectomy, insulin output to 16.7 mM glucose fell 75%, and that to glucose/arginine fell 50%. Diazoxide given at this time partially blocked the fall in glucose-induced insulin secretion and totally prevented that with arginine. The increased insulin secretion caused by diazoxide was accompanied by 1) lower nonfasting plasma glucose values, 2) improved glucose tolerance after oral glucose load, and 3) a 50% increase in pancreatic insulin content. Our results support the concept that excessive insulin secretion is a major cause of the hyperglycemia-induced loss of beta-cell glucose responsiveness. A leading candidate for the mechanism of this effect is depleted pancreatic insulin stores. Overstimulation of insulin secretion provides a new target for pharmacological therapy aimed at reducing glucose intolerance in non-insulin-dependent diabetes mellitus.

Distinct glucose lowering and beta cell protective effects of vanadium and food restriction in streptozotocin-diabetes

“…In humans, intensive insulin treatment for 2 weeks following recent-onset diabetes results in the preservation of residual beta cell function and insulin content for at least one year (23,24). This effect was attributed to a reduced insulin demand, as direct inhibition of insulin secretion by diazoxide also preserved beta cells in Type 1 diabetic patients (25), and reduced the incidence of diabetes in spontaneously diabetic BB (26) and 90% pancreatectomized rats (27).…”

Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

“…Similar to the individuals with T2DM, animal models like the diabetic Zucker fatty rat, the Goto Kakizaki (GK) rat, and the 90% pancreatectomized diabetic rat have perturbations in glucose and lipid handling resulting in elevated levels of glucose and fatty acids (Leahy et al 1986, Goto et al 1988, Unger 1995, Hosokawa et al 1996. When administered to the animal models, diazoxide improved plasma glucose values and oral glucose tolerance, suppressed circulating insulin levels, enhanced insulin sensitivity, and improved lipid metabolism (Leahy et al 1994, Bjorklund et al 1997, Alemzadeh & Tushaus 2005. b-cells from the diabetic Zucker fatty rat, the GK rat, and the 90% pancreatectomized diabetic rat have increased apoptosis, reduced insulin content, and deranged insulin secretory patterns including reduction of the initial glucose-induced rise and loss of regular pulsatility (Leahy et al 1986, Unger 1995, Hosokawa et al 1996, Maedler et al 2001, Lupi et al 2002, Prentki et al 2002, Ostenson et al 2007.…”

Too much of a good thing: why it is bad to stimulate the beta cell to secrete insulin

“…Treatment with the insulin secretion inhibitor diazoxide prevents impairment of beta cell function in rats administered a 48 h glucose infusion [22], in 90% pancreatectomised diabetic rats [23] and in streptozotocintreated rats [24]. Furthermore, treatment of patients with type 2 diabetes with diazoxide or somatostatin resulted in improved glucagon-and tolbutamide-induced insulin secretion [25] and restored insulin pulsatility and the insulin/ proinsulin ratio in vitro [26].…”