Diabetogenic effect of pentamidine: In vitro and in vivo studies in a patient with malignant insulinoma

Abstract

Pentamidine can cause hypoglycemia followed by hyperglycemia. The mechanism of this biphasic response is not known but has been reported to be similar to that of streptozotocin and N-3-pyridyl-N-p-nitrourea (Vacor). Pentamidine (4 mg/kg per day for 12 days) was used in a patient with malignant insulinoma after several unsuccessful debulking procedures and chlorozotocin therapy. Mean glucose and immunoreactive insulin levels (± SEM) before and after therapy were 80 ± 40 mg/dl versus 70 ± 50 mg/dl and 216 ± 12 μU/ml versus 198 ± 22 μU/ml, respectively. These were not significantly different. The patient's five-month-old malignant insulinoma monolayer cell culture was incubated with pentamidine (60 μg/ml) in the presence or absence of supplemented stimulatory medium consisting of glucose (300 mg/dl) and theophylline (20 μg/ml). Chloroquine (60 μg/ml) was added to inhibit lysosomal degradation of immunoreactive insulin. Aliquots of media for immunoreactive insulin determination were obtained at 30 minutes, 20 hours, 72 hours, and three weeks. The cells were examined by high-power light microscopy at each time interval. At 30 minutes, pentamidine alone caused passive release of immunoreactive insulin, 23 percent higher than control (p < 0.01). Stimulatory medium increased immunoreactive insulin 45 percent greater than control (p < 0.01). Pentamidine plus stimulatory medium had no additive effect on immunoreactive insulin released within 30 minutes. At the end of 20 hours, immunoreactive insulin was no different with pentamidine and/or stimulatory medium. However, the addition of chloroquine increased immunoreactive insulin by 35 percent above the medium with pentamidine and stimulatory medium (p < 0.01). At 72 hours, pentamidine suppressed immunoreactive insulin by 100 percent in all the media, irrespective of the presence or absence of stimulatory medium and/or chloroquine. At the end of three weeks, there was 50 percent suppression of immunoreactive insulin in the control medium, but pentamidine again completely suppressed immunoreactive insulin. High-power microscopy demonstrated intact cells in the control medium, whereas no cell structure could be detected in the media containing pentamidine at three weeks. In summary, pentamidine had no acute in vivo effect in a patient with malignant insulinoma. However, when used in an in vitro monolayer system, pentamidine caused (1) acute immunoreactive insulin release followed by inhibition of immunoreactive insulin secretion and (2) cytolysis of human malignant insulinoma cells in vitro.