Abstract
Type 2 diabetes is an age-and-obesity associated disease driven by impairments in glucose homeostasis that ultimately result in defective insulin secretion from pancreatic β-cells. To deconvolve the effects of age and obesity in an experimental model of prediabetes, we fed young and aged mice either chow or a short-term high-fat/high-sucrose Western diet (WD) and examined how weight, glucose tolerance, and β-cell function were affected. Although WD induced a similar degree of weight gain in young and aged mice, a high degree of heterogeneity was found exclusively in aged mice. Weight gain in WD-fed aged mice was well-correlated with glucose intolerance, fasting insulin, and in vivo glucose-stimulated insulin secretion, relationships that were not observed in young animals. Although β-cell mass expansion in the WD-fed aged mice was only three-quarters of that observed in young mice, the islets from aged mice were resistant to the sharp WD-induced decline in ex vivo insulin secretion observed in young mice. Our findings demonstrate that age is associated with the protection of islet function in diet-induced obese mice, and furthermore, that WD challenge exposes variability in the resilience of the insulin secretory pathway in aged mice.
Highlights
Prospective studies in mice, where obesity can be readily induced, allow the strict separation of the effects of age and obesity and have the potential to shed light on the human condition
We examined the susceptibility of both young (4 months of age) and aged (22 months of age) mice to weight gain and prediabetes during Western diet (WD) feeding
Fig. 2) during a glucose tolerance test found that weight was strongly correlated with impaired glucose tolerance (IGT) in aged mice (R2 = 0.51, P < 0.0001); there was no such correlation in young mice (R2 = 0.01, P = 0.61) (Fig. 1e)
Summary
To deconvolve the effects of age and obesity in an experimental model of prediabetes, we fed young and aged mice either chow or a short-term high-fat/high-sucrose Western diet (WD) and examined how weight, glucose tolerance, and β-cell function were affected. Weight gain in WD-fed aged mice was well-correlated with glucose intolerance, fasting insulin, and in vivo glucose-stimulated insulin secretion, relationships that were not observed in young animals. In aged mice, but not in young mice, we discovered that WD-induced glucose intolerance and weight gain is highly correlated with the hypersecretion of insulin. This in vivo effect is further correlated with an age-dependent enhancement of islet function, suggesting that WD. Challenge exposes variability in the resilience of the insulin secretory pathway – the capacity to recover from or respond to stressors24 – in aged mice
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