Streptozotocin–nicotinamide-induced diabetes in the rat. Characteristics of the experimental model

Abstract

Administration of both streptozotocin (STZ) and nicotinamide (NA) has been proposed to induce experimental diabetes in the rat. STZ is well known to cause pancreatic B-cell damage, whereas NA is administered to rats to partially protect insulin-secreting cells against STZ. STZ is transported into B-cells via the glucose transporter GLUT2 and causes DNA damage leading to increased activity of poly(ADP-ribose) polymerase (PARP-1) to repair DNA. However, exaggerated activity of this enzyme results in depletion of intracellular NAD(+) and ATP, and the insulin-secreting cells undergo necrosis. The protective action of NA is due to the inhibition of PARP-1 activity. NA inhibits this enzyme, preventing depletion of NAD(+) and ATP in cells exposed to STZ. Moreover, NA serves as a precursor of NAD(+) and thereby additionally increases intracellular NAD(+) levels. The severity of diabetes in experimental rats strongly depends on the doses of STZ and NA given to these animals. Therefore, in diabetic rats, blood glucose may be changed in a broad range--from slight hyperglycemia to substantial hyperglycemia compared with control animals. Similarly, blood insulin may be only slightly decreased or substantial hypoinsulinemia may be induced. In vitro studies demonstrated that the insulin-secretory response to glucose is attenuated in STZ-NA-induced diabetic rats compared with control animals. This is due to reduced B-cell mass as well as metabolic defects in the insulin-secreting cells. Results of numerous experiments have demonstrated that this model of diabetes is useful in studies of different aspects of diabetes.