Dynamics of insulin sensitivity, [beta]-cell function, and [beta]-cell mass during the development of diabetes in falfa rats

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 [beta]-cell mass ([[beta].sub.m]), insulin, and glucose model to elucidate the dynamics of insulin sensitivity ([S.sub.I]), [beta]-cell secretory capacity ([[beta].sub.sc]), and [[beta].sub.m] in these four animal models. Both groups that remained normoglycernic with increasing obesity (mZF, LF-fZDF) exhibited increased [[beta].sub.m] and constant [[beta].sub.sc] in response to a falling [S.sub.I]. In rats that developed hyperglycemia (mZDF, HF-fZDF), there was a greater reduction in [S.sub.I] and slower expansion of [[beta].sub.m], with constant [[beta].sub.sc]. [[beta].sub.sc] decreased after glucose levels rose above 20 mM. Taken together, these data suggest that excessive insulin resistance and insufficient [[beta].sub.m] adaptation play a primary role in the pathogenesis of diabetes. etiology; insulin secretory defects; insulin resistance; mathematical modeling