Pentamidine, a new diabetogenic drug in laboratory rodents

Abstract

The antiprotozoal drug, pentamidine, has been reported to induce hypoglycaemia associated with inappropriately high plasma insulin concentrations, followed by insulin-dependent diabetes mellitus. It has been suggested that this drug can be toxic to the islet B cell, inducing early cytolytic release of insulin leading to B cell destruction. In order to test this hypothesis, mouse and rat islets were incubated with pentamidine at concentration range of 5 x 10(-11) to 5 x 10(-3) mol/l and exposure times of 3-48 h. The B cell responses to glucose + theophylline and to arginine were suppressed by pentamidine, while insulin release in non-stimulatory conditions was increased. These effects were dose-dependent, time-dependent and irreversible. They were significant for 5 x 10(-7) mol/l pentamidine, which is a concentration relevant to therapeutic uses. These effects developed more slowly than the toxic effects of streptozotocin and alloxan at the same molar concentration in vitro. 51Chromium release and Trypan blue exclusion tests support the hypothesis that pentamidine produces islet cell necrosis.

Pentamidine-Induced Derangements of Glucose Homeostasis: Determinant roles of renal failure and drug accumulation: A study of 128 patients

“…The chronological sequence of early hypoglycemia and then diabetes may be due to early leakage of insulin and excessive plasma insulin levels, followed by extensive islet necrosis and insulinopenia, reminiscent of the early hypoglycemia (with hyperinsulinism) and then hyperglycemia (with insulinopenia), which follow the injection of streptozotocin to rats. Functional and morphological studies of rat islets exposed to pentamidine in vitro have shown that after initial exposure, B-cell injury is associated with insulin release; after prolonged exposure, permanent B-cell damage ensues, resulting in an irreversible Bcell secretory defect and necrosis, both effects being concentration-related (24)(25)(26). In rats rendered experimentally uremic, pentamidine treatment induced hypoglycemic episodes alternating with hyperglycemia associated with inappropriate plasma insulin levels (Fig.…”

“…Inappropriate plasma insulin levels were sometimes determined: they were excessive in the presence of hypoglycemia, and lower than normal in the diabetic patients treated with pentamidine (9). On the basis of these observations and the results of in vitro exposure of islets of Langerhans to pentamidine, we (9,15,24,25) and others (26,27) suggested that a dose-dependent toxicity of pentamidine to the islets of Langerhans can account for these opposite adverse metabolic effects: an early excessive insulin leakage from lesioned B-cells as a cause of hypoglycemia, and then B-cell death and insulinopenia causing diabetes.…”

“…Acute pancreatitis, associated with serious disruption of glucose homeostasis, was observed in a number of patients. Hypoglycemia and diabetes have also been reported after pentamidine isethionate (18) and pentamidine aerosol therapies (19)(20)(21)(22)(23)(24). Inappropriate plasma insulin levels were sometimes determined: they were excessive in the presence of hypoglycemia, and lower than normal in the diabetic patients treated with pentamidine (9).…”