Streptozotocin

Usual dose schedules of streptozotocin involve 500 mg/m2 i.v. during five consecutive days. The major toxicity is renal tubular damage. Treatment of metastatic insulinomas may result in the release of insulin from the tumor and subsequent hypoglycemic coma. Less severe toxicities include diarrhea, anemia, and mild alterations in glucose tolerance or liver function tests. 

The temporal correlation between in vitro and in vivo release of insulin was quite good. To induce diabetes, two groups of rats were administered 65 mg/kg of streptozotocin in 0.1 M citrate buffer, pH 4.5. Within several days, the animals had become diabetic, as evidenced by blood glucose levels of approximately 400 mg/dl, and substantial output of glucose in their urine. One group of these animals was then injected subcutaneously with 40-50 mg of 15% insulin-loaded PCPP-SA 50 50 microspheres, 850-1000 pm in diameter. A third group of animals receiving no treatment served as a control. 

FIGURE 12 Effect of insulin released from microspheres of PCPP-SA 50 50 injected subcutaneously in streptozotocin-diabetic rats. Details were as described in the text. 

CHOI J H, CHA B K and RHEE s J (1998) Effects of green tea catechin on hepatic microsomal phospholipase A2 activities and changes of hepatic phospholipid species in streptozotocin-induced diabetic rats , JNutr Sci Vitaminol (Tokyo), 44 (5), 673-83. 

LAI M-H, LIN Y-j, HUNG M-L, CHENG H-H (2001) Dietary rice bran improves the glycemic response in rats with Streptozotocin-induced diabetes. Nutritional Sciences Journal, 26(3) 159-70. 

Mnrngan, P. and Pari, L., Antioxidant effect of tetrahydroxyenrenmin streptozotocin-nicotinamide indneed diabetic rats. Life Set, 79, 1720, 2006. 

Katsumata, K., Katsumata, K. Jr and Katsumata Y. (1992). Protective efiect of diltiazem hydrochloride on the occurrence of alloxan- or streptozotocin-induced diabetes in rats. Horm. Metab. Res. 24, 508-510. 

Schein, P.S., Cooney, D.A. and Veron, M.L. (1967). The use of nicotinamide to modify the toxicity of streptozotocin diabetes without loss of antitumour activity Cancer Res. 27, 2324-2332. 

Yew, M.S. (1983). Effect of streptozotocin diabetes on tissue ascorbic acid and dehydroascorbic acid. Horm. Metab. Res. 15, 158. 

SOZ Serum-opsonized zymosan SP Sulphapyridine SR Systemic reaction sr Sarcoplasmic reticulum SRBC Sheep red blood cells SRS Slow-reacting substance SRS-A Slow-reacting substance of anaphylaxis STZ Streptozotocin Sub P Substance P... 

Diabetic Rats-Phase I. Laboratory rats (CD strain, 250-300g, male) were made diabetic by a single injection of streptozotocin (STZ), 50 mg/kg, into the tail vein. Nondiabetic controls received an equal volume of citrate buffer. Twenty-four hours after the STZ injection, each rat was individually housed for urine collection. The appearance of glucose in the urine (Ames test strips) and a predictable weight loss or depression of the growth curve were taken as confirming evidence of diabetes. 

JM Weissbrod. A comprehensive approach to whole body pharmacokinetics in mammalian systems Applications to methotrexate, streptozotocin and zinc. DSc Eng dissertation, Columbia University, New York, 1979, pp 110-112. 

M. Yusuf, B.T. Kwong Huat, A. Hsu, M. Whiteman, M. Bhatia, and P.K. Moore, Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem. Biophys. Res. Comm. 333, 1146-1152 (2005). 

Some flavonoids, such as procyanidins, have antidiabetic properties because they improve altered glucose and oxidative metabolisms of diabetic states (Pinent and others 2004). Extract of grape seed procyanidins (PE) administered orally to streptozotocin-induced diabetic rats resulted in an antihyperglycemic effect, which was significantly increased if PE administration was accompanied by a low insulin dose (Pinent and others 2004). The antihyperglycemic effect of PE may be partially due to the insuli-nomimetic activity of procyanidins on insulin-sensitive cell lines. 

Pinent M, Blay M, Blade MC, Salvado MJ, Arola L and Ardevol A. 2004. Grape seed-derived procyanidins have an antihyperglycemic effect in streptozotocin-induced diabetic rats and insuhnomimetic activity in insulin-sensitive cell lines Endocrinology 145(11) 4985 1990. 

Antioxidant enzymes also protect against free radical-mediated DNA degradation. For example, SOD and catalase as well as PARS inhibitors suppressed alloxan- and streptozotocin-induced islet DNA strand breaks [122], Uric acid inhibited single-strand DNA breaks induced... 

It should be mentioned that the inhibition of superoxide overproduction and lipid peroxidation by lipoic acid has been recently shown in animal models of diabetes mellitus. The administration of LA to streptozotocin-diabetic rats suppressed the formation of lipid peroxidation products [213], In another study the supplementation of glucose-fed rats with lipoic acid suppressed aorta superoxide overproduction as well as an increase in blood pressure and insulin resistance [214]. 

Lipid peroxidation is another free radical-mediated process enhanced in diabetes mellitus. It should be noted that some data obtained in animal models of diabetes could be misleading and not related to real diabetic state. For example, the enhanced intracellular generation of hydroxyl radicals has been shown in widely applied streptozotocin-induced model of diabetes in rats [121]. However, Lubec et al. [122] later showed that streptozotocin itself and not the diabetic state is responsible for the formation of hydroxyl radicals in this model. 

As in the case of other cardiovascular diseases, the possibility of antioxidant treatment of diabetes mellitus has been studied in both animal models and diabetic patients. The treatment of streptozotocin-induced diabetic rats with a-lipoic acid reduced superoxide production by aorta and superoxide and peroxynitrite formation by arterioles providing circulation to the region of the sciatic nerve, suppressed lipid peroxidation in serum, and improved lens glutathione level [131]. In contrast, hydroxyethyl starch desferrioxamine had no effect on the markers of oxidative stress in diabetic rats. Lipoic acid also suppressed hyperglycemia and mitochondrial superoxide generation in hearts of glucose-treated rats [132],... 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Only a few drugs have been identified as being capable of inducing autoimmune phenomena in mice. Among these are D-penicillamine, quinidine, streptozotocin (an anti-neoplastic drug that is also used as a model compound to induce diabetes) and procainamide. 

Leiter, E.H., Multiple low-dose streptozotocin-induced hyperglycemia and insulitis in C57BL mice Influence of inbred background, sex, and thymus. Proc. Natl. Acad. Sci. USA, 79, 630, 1982. 

Herold, K.C. et al., Regulation of cytokine production during development of autoimmune diabetes induced with multiple low doses of streptozotocin. J. Immunol., 156,3521,1996. 

Albers, R. et al., Selective immunomodulation by the autoimmunity-inducing xenobiotics streptozotocin and HgC12. Eur. J. Immunol., 28, 1233, 1998. 

Nierkens, S. et al., The reactive d-glucopyranose moiety of Streptozotocin is responsible for activation of macrophages and subsequent stimulation of CD8(+) T Cells. Chem. Res. Toxicol., 18, 872, 2005... 

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