‘Classical’ and ‘new’ diabetogens—comparison of their effects on isolated rat pancreatic islets in vitro

Abstract

This study compares functional and morphological alterations caused by application of alloxan, streptozotocin, xanthine oxidase/hypoxanthine (generation of reactive oxygen species), or S-nitroso-N-acetyl-D,L-penicillamine (SNAP, liberation of nitric oxide) to isolated rat pancreatic islets in vitro. In perifusion experiments, membrane leakage--detected by non-stimulated insulin release--was found after application of all drugs, but showed a substance-specific time pattern. Twenty-four hours after application of the classical diabetogens (alloxan or streptozotocin), potassium chloride- and glucose-stimulated insulin secretion were markedly reduced, while a persistent reduction was observed neither after exposure to xanthine oxidase/hypoxanthine, nor to SNAP. Morphological analysis of the islets revealed that nearly all beta-cells were destroyed following alloxan or streptozotocin treatment, while the majority of beta-cells were configured regularly after application of xanthine oxidase/hypoxanthine or SNAP. Necrotic cells found after xanthine oxidase/hypoxanthine usually differed in morphology from those observed after application of the classical diabetogens. While the former cells were characterised by swollen nuclei, the latter had shrunken nuclei with irregular condensed chromatin. Apoptosis was found only following nitric oxide exposure. Due to these differences, it seems unlikely that alloxan, streptozotocin, xanthine oxidase/hypoxanthine, and nitrix oxide have a common major feature in their toxic action.

Protective effect of testosterone on early apoptotic damage induced by streptozotocin in rat pancreas

“…However, there exist some possibilities. The main effectors in STZ damage are free radicals, such as reactive oxygen species (ROS) and nitric oxide (NO) (Peschke et al 2000, González et al 2002. Androgens modulate enzymes that help cells to escape this type of damage (Ahlbom et al 1999, Aragno et al 1999.…”

“…During STZ metabolism, various toxic intermediates are produced, including methyl cations, methyl radicals, reactive oxygen species (ROS) and nitric oxide (NO) (Peschke et al 2000, González et al 2002. Beta cells are very susceptible to oxidative changes since they possess a low antioxidative capacity (Hotta et al 1998, Kajimoto & Kaneto 2004.…”

The mechanisms of alloxan- and streptozotocin-induced diabetes

“…In 1943, alloxan became of interest in diabetes research when Dunn and McLetchie reported that it could induce diabetes in animals [4] as a result of the specific necrosis of the pancreatic beta cells [5][6][7]. The resulting insulinopenia causes a state of experimental diabetes mellitus called 'alloxan diabetes' [4,8,9].…”

Improvement of insulin response in the streptozotocin model of insulin-dependent diabetes mellitus. Insulin response with and without a long-acting insulin treatment

“…Furthermore, the STZ-DM rat differs from other common experimental models of type 1 diabetes, such as pancreatectomized animals, dexamethasone-treated type 1 diabetic rat and alloxan-induced diabetes (Ader et al, 1998;Cheta, 1998;Qi et al, 2004). An explanation to this could be the different origins of the disease and in the different modes of actions of the diabetes-inducing substances (Cheta, 1998;Peschke et al, 2000;Gai et al, 2004). To improve the usefulness of the STZ-rat model, it is of vast importance that these differences are taken into account and minimized as much as possible.…”