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

Kalyanasundaram, S.; Viswanad, Bhoomi; Asrat, Lydia; Kaul, C. L.; Ramarao, P.

doi:10.1016/j.phrs.2005.05.004

Cited by 1,496 publications

(1,168 citation statements)

References 23 publications

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“…2A). In addition, the plasma levels of triglycerides, total cholesterol, LDL cholesterol, and FFA were elevated significantly in DM rats compared with the NC group (Table 1), which confirmed previous observations (27,37). In contrast, after a 1-wk PDTC treatment, fasting blood glucose levels showed a significant reduction compared with the DM group (P Ͻ 0.01; Fig.…”

Section: Pdtc Restored Fasting Blood Glucose and Hepatic Glycogen Depsupporting

confidence: 89%

Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats

Zhu

Zhang

Bernier

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC) on hepatic glycogen synthesis and FoxO1 transcriptional activity in type 2 diabetic rats and the mechanism underlying these effects. Fasting blood glucose and glycogen deposition, together with expressions of two key genes related to gluconeogenesis, were studied in the liver of rats fed a normal diet (NC), high-fat diet (HFD)-induced insulin-resistant rats made type 2 diabetic by a single intraperitoneal injection of streptozotocin (DM), and a DM with intervention of PDTC (DM + PDTC) for 1 wk. The phosphorylation of Akt, GSK-3β, and FoxO1 was assessed in liver extracts of fasted rats by Western blot, whereas indirect immunofluorescence staining was performed to determine the cellular distribution of FoxO1. The DM rats exhibited obvious increases in fasting blood glucose as well as decreased hepatic glycogen content compared with the NC group. Activation of the Akt/GSK-3β pathway and inactivating phosphorylation of FoxO1 were reduced greatly in DM rat livers ( P < 0.01). By contrast, PDTC treatment protected DM rats against high fasting blood glucose and hepatic glycogen deposition loss. PDTC also elicited an increase in Akt/GSK-3β signaling and subsequent inactivation and nuclear export of FoxO1 in DM rat livers, which translated into a significant reduction in the expression of two FoxO1 target genes, phospho enolpyruvate carboxykinase and glucose-6-phosphatase. This study suggests that PDTC enhances hepatic glycogen synthesis, whereas it reduces FoxO1 transcriptional activity in DM rats.

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Section: Pdtc Restored Fasting Blood Glucose and Hepatic Glycogen Depsupporting

confidence: 89%

Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats

Zhu

Zhang

Bernier

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…The OGTT results showed that DM rats had significantly higher serum glucose and lower insulin concentrations induced by glucose loading than CON rats and HFD rats, resulting in significant increases in AUC values of glucose and decreases in AUC of insulin ( Figure 1). These indexes were similar to the physiopathological state of type 2 diabetes, indicating that the DM rats may be considered as having type 2 diabetes [31,32] . Insulin resistance also occurred in HFD rats, in which the insulin and glucose levels induced by glucose loading were higher than those in CON rats (Figure 1).…”

Section: Establishment Of the Diabetic Rat Modelsupporting

confidence: 54%

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes. Methods: Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR. Results: After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp. Conclusion: Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake.

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“…Low-dose STZ is known to induce a mild impairment of insulin secretion that is similar to a feature of late-stage type 2 DM [16,24] . In the present study, at week 10, the rats fed a HFD combined with low-dose STZ exhibited hyperglycemia, hyperlipidemia and hyperinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

“…After acclimatization, rats were randomly assigned to receive a standardized diet (18% fat, 25% protein, and 57% carbohydrate) as the normal control group or a high-fat diet (HFD, 40% fat, 13% protein, and 47% carbohydrate) for 6 weeks. At the end of 6 weeks, as previously described [16,17] , control rats were injected (ip) with vehicle [0.1 mol/L citric acid buffer (pH 4.5)] once and given a standard diet sequentially. HFD rats were injected (ip) with low-dose (30 mg/kg) of STZ (Sigma-Aldrich, St Louis, MO, USA) and given a high-fat diet sequentially.…”

Section: Experimental Animalsmentioning

confidence: 99%

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Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

Zhou

Wang

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate whether activation of RhoA/Rho kinase (ROCK) is involved in myocardial fibrosis in diabetic hearts. Methods: A rat model of type 2 diabetes was established using high fat diet combined with streptozotocin (30 mg/kg, ip). Animals were randomly divided into 3 groups: control rats, untreated diabetic rats that received vehicle and treated diabetic rats that received Rhokinase inhibitor fasudil hydrochloride hydrate (10 mg·kg -1 ·d -1 , ip, for 14 weeks). Cardiac contractile function was evaluated in vivo. The morphological features of cardiac fibrosis were observed using immunohistochemistry and TEM. The mRNA expression of JNK, TGFβ1, type-I, and type-III procollagen was assessed with RT-PCR. The phosphorylation of MYPT1, JNK and Smad2/3, as well as the protein levels of TGFβ1 and c-Jun, were evaluated using Western blotting. Results: In untreated diabetic rats, myocardial fibrosis was developed and the heart contractility was significantly reduced as compared to the control rats. In the hearts of untreated diabetic rats, the mRNA expression level and activity of JNK were upregulated; the expression of TGFβ1 and phosphorylation of Smad2/3 were increased. In the hearts of treated diabetic rat, activation of JNK and TGFβ/Smad was significantly decreased, myocardial fibrosis was reduced, and cardiac contractile function improved. Conclusion: The data suggest that fasudil hydrochloride hydrate ameliorates myocardial fibrosis in rats with type 2 diabetes at least in part through inhibiting the JNK and TGFβ/Smad pathways. Inhibition of RhoA/ROCK may be a novel therapeutic target for prevention of diabetic cardiomyopathy.

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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

Cited by 1,496 publications

References 23 publications

Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats

Pyrrolidine dithiocarbamate enhances hepatic glycogen synthesis and reduces FoxO1-mediated gene transcription in type 2 diabetic rats

Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes

Involvement of RhoA/ROCK in myocardial fibrosis in a rat model of type 2 diabetes

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