Effect of diabetogenic nitrosourea on the activity of the pentose phosphate shunt in isolated islets

Abstract

Summary

The effect of streptozotocin (STZ) on the activity of the pentose phosphate shunt in islets was studied. Isolated rat islets were pre-incubated with glucose (1.7 mM) alone or with streptozotocin (STZ) or N-methyl-N-nitrosourea (MNU). The effects of these pretreatments on glucose metabolism and insulin secretion were assessed during subsequent incubation with either (1-¹⁴C)-, (6-¹⁴C)- or (U-¹⁴C)-glucose (16.7 mM) alone or plus phenazine methosulfate (PMS). Islets pretreated with STZ (1–5 mM) metabolized less (1-¹⁴C)- and (U-¹⁴C)-glucose. The order of inhibition by STZ of (¹⁴C)-glucose metabolism by islets was: (1-¹⁴C)->(U-¹⁴C)->(6-¹⁴C)-glucose. Whereas PMS (0.5 mM) increased the metabolism of both (U-¹⁴C)- and (1-¹⁴C)-glucose, the metabolism of (6-¹⁴C)-glucose by STZ-pretreated islets was not increased by PMS. In a separate series of experiments, the total NADP⁺ + NADPH, but not the NAD content of the islets decreased after 2 min exposure of islets to STZ. At 30-min exposure, the levels of both pyridine coenzymes and that of 6-phosphogluconate were significantly decreased. The level of NADP⁺ + NADPH in islets was decreased more than the level of NAD. Insulin secretion was suppressed by the nitrosoureas. PMS (0.5 mM) increased the level of NADP⁺ + NADPH content of islets and augmented insulin secretion. It is concluded that the pentose phosphate pathway is inhibited on brief exposure of islets to STZ or MNU. Such inhibition may contribute to the suppression of insulin secretion caused by these nitrosoureas.