In vivo kinetics of islet compensation and dysfunction in a mouse model of diet-induced obesity and insulin resistance

Aims: Pancreatic islets have been shown to compensate in function and mass during the development of obesity and insulin resistance (IR). However, the transition of successful islet compensation to islet cell dysfunction, which results in the development of type 2 diabetes (T2D), is largely unknown. In this study we aimed to assess the adaptation of islet cell mass and function during obesity induced IR in vivo to correlate these changes with systemic physiological parameters.

Methods: Obesity and IR were induced in mice by 3 months high-fat diet (HFD). Glucose homeostasis was assessed over the entire time course, while islets transplanted to the anterior chamber of the eye were repetitively monitored noninvasively in vivo. Islet morphology and function at single cell level were visualized by utilizing islets expressing different types of fluorescent protein.

Results: HFD feeding increased body weight of the mice, induced IR and impaired glucose tolerance. Stimulated insulin release was increased, however systemic insulin secretion capacity declined after 4 weeks. Total islet and β-cell volume continuously increased over the 3 month time course, mainly through islet cell hyperplasia rather than by hypertrophy. Intra-islet vessels adapted to islet changes by vessel dilation. Islet function, evidenced by in vivo recordings of glucose induced changes in intracellular Ca²⁺ concentrations, showed an initial hyper-function followed by dysfunction after 4 weeks.

Conclusion: In our model islets responded to obesity and systemic IR by β-cell hyperplasia and islet growth. Interestingly, while the mass increase persisted during the course of HFD feeding, islet function declined after 4 weeks. Our data indicate that HFD feeding initially leads to functional islet compensation which turns into islet dysfunction after a relatively short time period. Additionally, our results point to a dissociation of β-cell mass and secretory capacity during the development of obesity and IR.