The mechanisms of alloxan- and streptozotocin-induced diabetes

Abstract

Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive oxygen species (ROS) in a cyclic redox reaction with its reduction product, dialuric acid. Autoxidation of dialuric acid generates superoxide radicals, hydrogen peroxide and, in a final iron-catalysed reaction step, hydroxyl radicals. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent 'alloxan diabetes'. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Following its uptake into the beta cells, streptozotocin is split into its glucose and methylnitrosourea moiety. Owing to its alkylating properties, the latter modifies biological macromolecules, fragments DNA and destroys the beta cells, causing a state of insulin-dependent diabetes. The targeting of mitochondrial DNA, thereby impairing the signalling function of beta cell mitochondrial metabolism, also explains how streptozotocin is able to inhibit glucose-induced insulin secretion.

Investigation of hypoglycemic, hypolipidemic and antioxidant activities of aqueous extract of Terminalia paniculata bark in diabetic rats

“…Moreover, STZ is potential to act as an intracellular nitric oxide (NO) donor and generates reactive oxygen species (ROS). The synergistic action of both NO and ROS may also contribute to DNA fragmentation and other deleterious changes caused by STZ [15] . In our study, elevated blood glucose level and decreased insulin level were observed in STZ-induced diabetic rats and it may be due to above stated mechanism of STZ.…”

“…STZ utilizes low-affinity glucose transporter 2 in the plasma membrane and is selectively accumulated in pancreatic beta cells and also it damages other organs which can express this transporter, particularly kidney and liver [15] . In STZ-induced diabetic rats, elevated levels of SGPT and SGOT were observed and it may be due to STZ mediated liver damages which may cause leakage of above enzymes into the blood [20] .…”

Antidiabetic and hypolipidemic activities of Kigelia pinnata flowers extract in streptozotocin induced diabetic rats

“…STZ is a nitrosourea compound produced by Streptomyces achromogenes, which specifically induces DNA strand breakage in 毬 -cells causing diabetes mellitus [15][16][17][18] . This leads to insulin deficiency which in turn increases the blood sugar level.…”

Sevoflurane does not alter norepinephrine-induced intracellular Ca2+ changes in the diabetic rat aorta

“…Almost all of these studies were conducted using experimental animals treated with diabetogenic drugs, such as STZ, that destroys the beta cell in the pancreas due to its alkylating properties and subsequently depletes the insulin secretion. 15 Therefore, STZ-induced DM is considered as a model of type 1 DM. By contrast, OLETF rats spontaneously develop hyperinsulinemia from 25-60 weeks of age and have been characterized as a genetic model of type 2 DM.…”