Streptozotocin diabetes

MDL 25637 16, and MDL 73945 17 (Figure 16.8), are effective in delaying the hyperglycemic response to oral starch and sucrose in normal and diabetic (streptozotocin-induced) rats and mice [62]. 

Diets containing n-3 PUFA have also been observed to decrease body weight of diabetic (streptozotocin-treated) rats. Such diets increased responsiveness of muscle glucose transport to insulin (22), and raised plasma leptin levels which, in turn, is associated with decreased food intake (23). 

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. 

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. 

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. 

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. 

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. 

The importance of insulin as a mediator of the hypercalciuric effect of arginine infusion was also evident from studies conducted in chronically diabetic rats, where diabetes was induced by strepto-zotocin (23). Animals were injected with streptozotocin prior to arginine infusion 100 mg/kg i.p. was given on the seventh day before, followed by 25 mg/kg six days before the arginine infusion and renal clearance studies. In contrast to non-diabetic controls, diabetic animals did not increase their urinary calcium excreted (per ml glomerular filtrate) in response to the arginine infusion, nor did the arginine stimulate insulin secretion. 

The above experiments strongly suggest to us that a linear relationship exists between serum or plasma insulin levels over a wide physiological range, and urinary calcium excretion. The calciuric response to arginine or glucose infusion does not occur if insulin secretion is prevented, as evidenced by the data obtained from animals made acutely insulinopenic by mannoheptulose, or more chronically diabetic by streptozotocin. 

Klinkhammer, C., Popowa, P. and Gleichmann, H. (1988). Specific immunity to the diabetogen streptozotocin cellular requirements for induction of lymphoproliferation. Diabetes 37 74— 80. 

Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289 2126—2128 Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107 137-148 Mabley JG, Suarez-Pinzon WL, Hasko G, Salzman AL, Rabinovitch A, Kun E, Szabo C (2001) Inhibition of poly (ADP-ribose) synthetase by gene disruption or inhibition with 5-iodo-6-amino-l,2-benzopyrone protects mice from multiple-low-dose-streptozotocin-induced diabetes. Br J Pharmacol 133 909-919... 

Aniya Y, Ojiri Y, Sunagawa R, et al. 1989. Glutathione s-transferases and chloroform toxicity in streptozotocin-induced diabetic rats. Jpn J Pharmacol 50 263-269. 

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