Pentamidine-induced beta cell toxicity is not preventable by high glucose.
The incidence of beta cell damage attributable to pentamidine treatment of pneumocystis pneumonia is increasing in frequency because of the AIDS epidemic. We carried out in vitro studies in perfused rat islets using insulin secretion as an index of beta cell damage to study the effects of pentamidine and to test whether glucose can prevent toxicity in this physiologic model. Isolated islets were cultured for 16-18 hours of static incubation, in a culture medium containing 100 mg/dl glucose, with or without pentamidine (10(-6) M, a therapeutic concentration). Islets were then perfused with media containing 60 mg/dl followed by 300 mg/dl glucose concentrations to study the insulin secretory response. Incubation of islets with pentamidine was associated with subsequent basal hypersecretion of insulin (0.40 +/- 0.05 microU/islet .5 minute vs. 0.18 +/- 0.04 microU/islet .5 minute, p less than .005), and an insulin secretory response to glucose which was completely abolished (0.05 +/- 0.04 microU/islet .5 minute versus 1.12 +/- 0.02 microU/islet .5 minute, p less than .005). To determine whether glucose may protect against the effects of pentamidine, islets were then exposed to high glucose concentrations during simultaneous incubation with pentamidine. Coincubation with high glucose did not prevent these insulin secretory defects. A more extended culture of pentamidine-treated islets in the absence of pentamidine and at a glucose concentration of 100 mg/dl did not result in any recovery of insulin secretion. We conclude that pentamidine-induced beta cell damage is irreversible, not preventable by incubation with high glucose concentrations, and may therefore result from a mechanism different to that of alloxan.
Zhou
D B
DB
Harbor-UCLA Medical Center, Department of Medicine, Torrance 90502.
Ipp
E
E
D000578:Amidines / Q000633:toxicity*; D000818:Animals; D005947:Glucose / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010419:Pentamidine / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D000578:Amidines; D007328:Insulin; D010419:Pentamidine; D005947:Glucose