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 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.

In Vivo Rodent Models of Type 2 Diabetes and Their Usefulness for Evaluating Flavonoid Bioactivity

“…Genetic engineering of pigs represents an approach for diabetes mellitus research, including transgenic pigs expressing a dominant-negative glucose-dependent insulinotropic polypeptide receptor (GIPR) [27] and ubiquitous expression of a dominant-negative human hepatocyte nuclear factor 1α (HNF1A) [28]. High fat and cholesterol (HFC) diets with or without STZ have been adapted for the establishment of pig models for T2D [29,30]. While pigs are increasingly used as models for obesity and diabetes mellitus research, dogs remain an important model in this field.…”

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

“…Guinea pig models of type 2 diabetes based on high‐fat–high‐carbohydrate feeding have been developed, and exhibit impaired glucose tolerance and compensatory hyperinsulinaemia (Podell et al . ). There is some evidence for programming of glucose metabolism by maternal nutrition in guinea pigs, as occurs in humans (Ravelli et al .…”

The Generation of a Comprehensive Spectral Library for the Analysis of the Guinea Pig Proteome by SWATH‐MS

“…The guinea pig is an excellent experimental model for many aspects of human physiology and pathophysiology—including maternal and fetal adaptations to pregnancy cardiac excitation‐contraction coupling, asthma and airway drug responsiveness, auditory somatosensory processes, type 2 diabetes, and vitamin C deficiency—yet there is limited experimental information regarding the proteome available for this species. In an effort to overcome this obstacle, we therefore sought to generate a detailed spectral library of the guinea pig proteome.…”