Functional and morphological modifications induced in rat islets by pentamidine and other diamidines in vitro

Abstract

The antiprotozoal drug pentamidine can be toxic to islet cells in vivo and in vitro. Rat islets were exposed to pentamidine (mesylate and isethionate salts) and six other structurally related diamidines. The beta-cell response to arginine + theophylline was suppressed by pentamidine (10(-2) mmol/l) while the glucagon and somatostatin secretions persisted. All diamidines tested suppressed the beta-cell function, with a log-dose-response proportionality, the mesylate compound being more potent than pentamidine isethionate, and the lipophilic analogs more than the hydrosoluble diamidines. Electron microscopy revealed distinct morphological alterations in islets exposed to pentamidine, the intensity of these changes being dose-and time-dependent, and the beta cells more severely damaged than the non-beta cells. 51Cr-labelled islet cells and RIN 5 F cells consistently appeared more sensitive to pentamidine cytotoxicity than rat fibroblasts, myeloma cells and hepatocytes. The pentamidine-induced suppression of beta-cell function was not, in conditions tested, affected by the presence of nicotinamide and the hexose concentration in the medium. The kinetics of islet damage were slower than those of streptozotocin and alloxan-induced islet damage. The present study confirms that pentamidine is selectively toxic to islet beta cells, with some features distinct from the alloxan and streptozotocin toxicities to these cells. The mechanism of this process and its precipitating factors in vivo need clarification.

Insulin-dependent diabetes mellitus following pentamidine therapy in a patient with AIDS

“…While this was the case with the shortest duration of therapy (9 days), the one with the longest duration (21 days) was accompanied by severe pancreatitis [14]. These clinical observations support the results of animal models in which the toxicity of pentamidine on the ß-cells of the pancreas appeared time dependent, dose dependent, and irreversible [2,3,11]. Renal insufficiency has been shown to increase toxicity, but liver damage does not seem to affect toxicity of the drug [2].…”

“…Persistent IDDM following pentamidine has been reported in about 25 cases so far [3,4,7,8,10,14]. There are 12 case reports from India on patients treated for kala-azar [8].…”

Pharmacological Agents That Directly Modulate Insulin Secretion

“…There is a dose-dependent toxicity with a threshold total dose, which appears to be in the range of 4 to 9 gm, at which irreversible damage to the ␤-cells may occur (Perronne et al, 1990). This damage is probably similar to that seen with streptozotocin in that the cells having a high energy requirement and highly active mitochondria are more susceptible to the oxidative damage of these compounds (Boillot et al, 1985).…”

Medications affecting glycemic control

“…Pentamidine induced hyperglycemia is attributed to either hyperamylasemia causing an increase in glucagon release or decreased insulin release, especially after a meal [47]. In vitro studies found that pentamidine induces irreversible β cell damage, secretory defect and necrosis precipitating the development of DM [48][49][50]. Risk factors associated with hyperglycemia include higher cumulative or single pentamidine dose and renal impairment [46].…”