A model of type 2 diabetes in the guinea pig using sequential diet-induced glucose intolerance and streptozotocin treatment

Abstract

Type 2 diabetes is a leading cause of morbidity and mortality among non-communicable 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 critical to the development of human type 2 diabetes. Guinea pigs developed impaired glucose tolerance after eight weeks of feeding 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 then 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 to 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.