Podell Brendan K, Ackart David F, Richardson Michael A, DiLisio James E, Pulford Bruce, Basaraba Randall J
Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.
Dis Model Mech. 2017 Feb 1;10(2):151-162. doi: 10.1242/dmm.025593. Epub 2017 Jan 12.
Type 2 diabetes is a leading cause of morbidity and mortality among noncommunicable diseases, and additional animal models that more closely replicate the pathogenesis of human type 2 diabetes are needed. The goal of this study was to develop a model of type 2 diabetes in guinea pigs, in which diet-induced glucose intolerance precedes β-cell cytotoxicity, two processes that are crucial to the development of human type 2 diabetes. Guinea pigs developed impaired glucose tolerance after 8 weeks of feeding on a high-fat, high-carbohydrate diet, as determined by oral glucose challenge. Diet-induced glucose intolerance was accompanied by β-cell hyperplasia, compensatory hyperinsulinemia, and dyslipidemia with hepatocellular steatosis. Streptozotocin (STZ) treatment alone was ineffective at inducing diabetic hyperglycemia in guinea pigs, which failed to develop sustained glucose intolerance or fasting hyperglycemia and returned to euglycemia within 21 days after treatment. However, when high-fat, high-carbohydrate diet-fed guinea pigs were treated with STZ, glucose intolerance and fasting hyperglycemia persisted beyond 21 days post-STZ treatment. Guinea pigs with diet-induced glucose intolerance subsequently treated with STZ demonstrated an insulin-secretory capacity consistent with insulin-independent diabetes. This insulin-independent state was confirmed by response to oral antihyperglycemic drugs, metformin and glipizide, which resolved glucose intolerance and extended survival compared with guinea pigs with uncontrolled diabetes. In this study, we have developed a model of sequential glucose intolerance and β-cell loss, through high-fat, high-carbohydrate diet and extensive optimization of STZ treatment in the guinea pig, which closely resembles human type 2 diabetes. This model will prove useful in the study of insulin-independent diabetes pathogenesis with or without comorbidities, where the guinea pig serves as a relevant model species.
2型糖尿病是非传染性疾病中发病和死亡的主要原因，因此需要更多能更紧密模拟人类2型糖尿病发病机制的动物模型。本研究的目的是建立一种豚鼠2型糖尿病模型，其中饮食诱导的葡萄糖不耐受先于β细胞细胞毒性，这两个过程对人类2型糖尿病的发展至关重要。通过口服葡萄糖耐量试验测定，豚鼠在高脂、高碳水化合物饮食喂养8周后出现葡萄糖耐量受损。饮食诱导的葡萄糖不耐受伴有β细胞增生、代偿性高胰岛素血症和伴有肝细胞脂肪变性的血脂异常。单独使用链脲佐菌素（STZ）治疗在诱导豚鼠糖尿病性高血糖方面无效，豚鼠未能发展为持续性葡萄糖不耐受或空腹高血糖，且在治疗后21天内恢复正常血糖。然而，当高脂、高碳水化合物饮食喂养的豚鼠接受STZ治疗时，葡萄糖不耐受和空腹高血糖在STZ治疗后持续超过21天。饮食诱导的葡萄糖不耐受的豚鼠随后接受STZ治疗，其胰岛素分泌能力与非胰岛素依赖型糖尿病一致。通过对口服降糖药二甲双胍和格列吡嗪的反应证实了这种非胰岛素依赖状态，与未控制糖尿病的豚鼠相比，这两种药物改善了葡萄糖不耐受并延长了生存期。在本研究中，我们通过高脂、高碳水化合物饮食以及对豚鼠STZ治疗的广泛优化，建立了一种顺序性葡萄糖不耐受和β细胞丢失的模型，该模型与人类2型糖尿病非常相似。该模型将被证明在研究有无合并症的非胰岛素依赖型糖尿病发病机制中有用，其中豚鼠是一种相关的模型物种。
