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

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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 β-cell response to arginine+theophylline was suppressed by pentamidine (10−2 mmol/l) while the glucagon and somatostatin secretionspersisted. All diamidines tested suppressed the β-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 β cells more severely damaged than the non-β 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 β-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 β 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.