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

Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6

Submitted 4 September 2007 ; accepted in final form 19 September 2007

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 (β_m), insulin, and glucose model to elucidate the dynamics of insulin sensitivity (S_I), β-cell secretory capacity (β_sc), and β_m in these four animal models. Both groups that remained normoglycemic with increasing obesity (mZF, LF-fZDF) exhibited increased β_m and constant β_sc in response to a falling S_I. In rats that developed hyperglycemia (mZDF, HF-fZDF), there was a greater reduction in S_I and slower expansion of β_m, with constant β_sc. β_sc 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.

etiology; insulin secretory defects; insulin resistance; mathematical modeling

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