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      The Characterization of High-Fat Diet and Multiple Low-Dose Streptozotocin Induced Type 2 Diabetes Rat Model

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          Abstract

          Aim. Based on the previously established method, we developed a better and stable animal model of type 2 diabetes mellitus by high-fat diet combined with multiple low-dose STZ injections. Meanwhile, this new model was used to evaluate the antidiabetic effect of berberine. Method. Wistar male rats fed with regular chow for 4 weeks received vehicle (control groups), rats fed with high-fat diet for 4 weeks received different amounts of STZ once or twice by intraperitoneal injection (diabetic model groups), and diabetic rats were treated with berberine (100 mg/kg, berberine treatment group). Intraperitoneal glucose tolerance test and insulin tolerance test were carried out. Moreover, fasting blood glucose, fasting insulin, total cholesterol, and triglyceride were measured to evaluate the dynamic blood sugar and lipid metabolism. Result. The highest successful rate (100%) was observed in rats treated with a single injection of 45 mg/kg STZ, but the plasma insulin level of this particular group was significantly decreased, and ISI has no difference compared to control group. The successful rate of 30 mg/kg STZ twice injection group was significantly high (85%) and the rats in this group presented a typical characteristic of T2DM as insulin resistance, hyperglycemia, and blood lipid disorder. All these symptoms observed in the 30 mg/kg STZ twice injection group were recovered by the treatment of berberine. Conclusion. Together, these results indicated that high-fat diet combined with multiple low doses of STZ (30 mg/kg at weekly intervals for 2 weeks) proved to be a better way for developing a stable animal model of type 2 diabetes, and this new model may be suitable for pharmaceutical screening.

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          Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.

          The objective of the present study was to develop a rat model that replicates the natural history and metabolic characteristics of human type 2 diabetes and is also suitable for pharmacological screening. Male Sprague-Dawley rats (160-180 g) were divided into two groups and fed with commercially available normal pellet diet (NPD) (12% calories as fat) or in-house prepared high-fat diet (HFD) (58% calories as fat), respectively, for a period of 2 weeks. The HFD-fed rats exhibited significant increase in body weight, basal plasma glucose (PGL), insulin (PI), triglycerides (PTG) and total cholesterol (PTC) levels as compared to NPD-fed control rats. Besides, the HFD rats showed significant reduction in glucose disappearance rate (K-value) on intravenous insulin glucose tolerance test (IVIGTT). Hyperinsulinemia together with reduced glucose disappearance rate (K-value) suggested that the feeding of HFD-induced insulin resistance in rats. After 2 weeks of dietary manipulation, a subset of the rats from both groups was injected intraperitoneally with low dose of streptozotocin (STZ) (35 mg kg(-1)). Insulin-resistant HFD-fed rats developed frank hyperglycemia upon STZ injection that, however, caused only mild elevation in PGL in NPD-fed rats. Though there was significant reduction in PI level after STZ injection in HFD rats, the reduction observed was only to a level that was comparable with NPD-fed control rats. In addition, the levels of PTG and PTC were further accentuated after STZ treatment in HFD-fed rats. In contrast, STZ (35 mg kg(-1), i.p.) failed to significantly alter PI, PTG and PTC levels in NPD-fed rats. Thus, these fat-fed/STZ-treated rats simulate natural disease progression and metabolic characteristics typical of individuals at increased risk of developing type 2 diabetes because of insulin resistance and obesity. Further, the fat-fed/STZ-treated rats were found to be sensitive for glucose lowering effects of insulin sensitizing (pioglitazone) as well as insulinotropic (glipizide) agents. Besides, the effect of pioglitazone and glipizide on the plasma lipid parameters (PTG and PTC) was shown in these diabetic rats. The present study represents that the combination of HFD-fed and low-dose STZ-treated rat serves as an alternative animal model for type 2 diabetes simulating the human syndrome that is also suitable for testing anti-diabetic agents for the treatment of type 2 diabetes.
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            A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat.

            This study was initiated to develop an animal model of type 2 diabetes in a non-obese, outbred rat strain that replicates the natural history and metabolic characteristics of the human syndrome and is suitable for pharmaceutical research. Male Sprague-Dawley rats (n = 31), 7 weeks old, were fed normal chow (12% of calories as fat), or high-fat diet (40% of calories as fat) for 2 weeks and then injected with streptozotocin (STZ, 50 mg/kg intravenously). Before STZ injection, fat-fed rats had similar glucose concentrations to chow-fed rats, but significantly higher insulin, free fatty acid (FFA), and triglyceride (TG) concentrations (P < .01 to .0001). Plasma insulin concentrations in response to oral glucose (2 g/kg) were increased 2-fold by fat feeding (P < .01), and adipocyte glucose clearance under maximal insulin stimulation was significantly reduced (P < .001), suggesting that fat feeding induced insulin resistance. STZ injection increased glucose (P < .05), insulin (P < .05), FFA (P < .05), and TG (P < .0001) concentrations in fat-fed rats (Fat-fed/STZ rats) compared with chow-fed, STZ-injected rats (Chow-fed/STZ rats). Fat-fed/STZ rats were not insulin deficient compared with normal chow-fed rats, but had hyperglycemia and a somewhat higher insulin response to an oral glucose challenge (both P < .05). In addition, insulin-stimulated adipocyte glucose clearance was reduced in Fat-fed/STZ rats compared with both chow-fed and Chow-fed/STZ rats (P < .001). Finally, Fat-fed/STZ rats were sensitive to the glucose lowering effects of metformin and troglitazone. In conclusion, Fat-fed/STZ rats provide a novel animal model for type 2 diabetes, simulates the human syndrome, and is suitable for the testing of antidiabetic compounds.
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              Berberine improves glucose metabolism through induction of glycolysis.

              Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C2C12 myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3-O-methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser307/312), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for > or =16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.
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                Author and article information

                Journal
                Exp Diabetes Res
                EDR
                Experimental Diabetes Research
                Hindawi Publishing Corporation
                1687-5214
                1687-5303
                2008
                4 January 2009
                : 2008
                : 704045
                Affiliations
                Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
                Author notes

                Recommended by Timothy Kern

                Article
                10.1155/2008/704045
                2613511
                19132099
                dc01a779-e82e-40a5-bbe7-b4960694a519
                Copyright © 2008 Ming Zhang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 June 2008
                : 14 October 2008
                : 19 November 2008
                Categories
                Research Article

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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