Dynamics of insulin sensitivity, β-cell function, and β-cell mass during the development of diabetes in fa/fa rats

Open Access
Publisher Website
Google Scholar
Abstract
Both male Zucker Fatty (mZF) and lower-fat-fed female Zucker diabetic fatty (LF-fZDF) rats are obese but remain normoglycemic. Male ZDF (mZDF) and high-fat-fed female ZDF rats (HF-fZDF) are also obese but develop diabetes between 7 and 10 wk of age. Although these models have been well studied, the mechanisms governing the adaptations to obesity in the normoglycemic animals, and the failure of adaptation in the animals that develop diabetes, remain unclear. Here we use quantitative morphometry and our recently developed coupled β-cell mass (βm), insulin, and glucose model to elucidate the dynamics of insulin sensitivity (SI), β-cell secretory capacity (βsc), and βm in these four animal models. Both groups that remained normoglycemic with increasing obesity (mZF, LF-fZDF) exhibited increased βm and constant βsc in response to a falling SI. In rats that developed hyperglycemia (mZDF, HF-fZDF), there was a greater reduction in SI and slower expansion of βm, with constant βsc. βsc decreased after glucose levels rose above 20 mM. Taken together, these data suggest that excessive insulin resistance and insufficient β m adaptation play a primary role in the pathogenesis of diabetes.