Age-Dependent Protection of Insulin Secretion in Diet Induced Obese Mice

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 beta-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 beta-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 beta-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.