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

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 beta-cell mass (beta(m)), insulin, and glucose model to elucidate the dynamics of insulin sensitivity (S(I)), beta-cell secretory capacity (beta(sc)), and beta(m) in these four animal models. Both groups that remained normoglycemic with increasing obesity (mZF, LF-fZDF) exhibited increased beta(m) and constant beta(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 beta(m), with constant beta(sc). beta(sc) decreased after glucose levels rose above 20 mM. Taken together, these data suggest that excessive insulin resistance and insufficient beta(m) adaptation play a primary role in the pathogenesis of diabetes.

The Sodium Glucose Cotransporter Type 2 Inhibitor Empagliflozin Preserves β-Cell Mass and Restores Glucose Homeostasis in the Male Zucker Diabetic Fatty Rat

“…Hence, pharmacological inhibition of renal glucose reabsorption effectively reduces hyperglycemia with preserved b-cell secretory function and b-cell mass, which strongly suggests that improving glycemic control independent of insulin secretion may lead to b-cell sparing effects of empagliflozin. This interpretation is in good agreement with the hypothesis that glucolipotoxicity and progressive b-cell exhaustion caused by continued increased insulin demand, in combination, may lead to disease progression as a consequence of islet b-cell secretory defects, lowered b-cell proliferative rate, and augmented apoptotic b-cell death (Pick et al, 1998;Prentki and Nolan 2006;Topp et al, 2007;Paulsen et al, 2010). Correspondingly, the present study indicated that vehicletreated ZDF rats exhibited a significantly lower total islet and absolute b-cell mass with a concomitant significant reduction in the number of Ki-67-positive proliferating b cells as compared with baseline levels.…”

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

“…Therefore, as the β-cell mass increases to compensate for greater whole-body insulin demand, the feedback system is maintained by increasing β-cell turnover through controlled mechanisms of proliferation/ neogenesis and dampened β-cell death (Topp et al 2007). Numerous studies have shown that increased levels of free fatty acids and excessive glucose exposure (i.e.…”

Proteomics in diabetes research

“…The ZDF rat was developed by successive inbreeding of the most glucose intolerant ZF rats. The ZF rat remains normoglycaemic in the face of increasing obesity due to their ability to increase their β-cell mass and maintain a constant insulin secretory capacity despite a reduction in insulin sensitivity (Topp, et al 2007). These data indicate that β-cell proliferation and/or β-cell neogenesis from undifferentiated progenitor cells can occur if β-cell mass needs to be increased.…”