Srinivasan K, Viswanad B, Asrat Lydia, Kaul C L, Ramarao P
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, Phase X, S.A.S. Nagar, Mohali 160 062, Punjab, India.
Pharmacol Res. 2005 Oct;52(4):313-20. doi: 10.1016/j.phrs.2005.05.004.
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.
本研究的目的是建立一种大鼠模型，该模型能复制人类2型糖尿病的自然病程和代谢特征，且适用于药理学筛选。将雄性Sprague-Dawley大鼠（160 - 180 g）分为两组，分别给予市售正常颗粒饲料（NPD）（脂肪提供12%的热量）或自制高脂饲料（HFD）（脂肪提供58%的热量），持续2周。与喂食NPD的对照大鼠相比，喂食HFD的大鼠体重、基础血浆葡萄糖（PGL）、胰岛素（PI）、甘油三酯（PTG）和总胆固醇（PTC）水平显著升高。此外，在静脉注射胰岛素葡萄糖耐量试验（IVIGTT）中，HFD大鼠的葡萄糖消失率（K值）显著降低。高胰岛素血症与降低的葡萄糖消失率（K值）表明，喂食HFD可诱导大鼠胰岛素抵抗。经过2周的饮食干预后，两组中的一部分大鼠腹腔注射低剂量链脲佐菌素（STZ）（35 mg kg⁻¹）。胰岛素抵抗的HFD喂养大鼠在注射STZ后出现明显的高血糖，然而，NPD喂养的大鼠注射STZ后PGL仅轻度升高。虽然HFD大鼠注射STZ后PI水平显著降低，但降低后的水平仅与NPD喂养的对照大鼠相当。此外，HFD喂养的大鼠在STZ治疗后PTG和PTC水平进一步升高。相比之下，STZ（35 mg kg⁻¹，腹腔注射）未能显著改变NPD喂养大鼠的PI、PTG和PTC水平。因此，这些高脂喂养/STZ处理的大鼠模拟了由于胰岛素抵抗和肥胖而患2型糖尿病风险增加的个体的自然疾病进展和典型代谢特征。此外，发现高脂喂养/STZ处理的大鼠对胰岛素增敏剂（吡格列酮）和促胰岛素分泌剂（格列吡嗪）的降糖作用敏感。此外，在这些糖尿病大鼠中显示了吡格列酮和格列吡嗪对血浆脂质参数（PTG和PTC）的影响。本研究表明，高脂喂养和低剂量STZ处理的大鼠组合可作为2型糖尿病的替代动物模型，模拟人类综合征，也适用于测试治疗2型糖尿病的抗糖尿病药物。
