The impact of high fat diet on islet function: the benefits from unsaturated fatty acids

Abstract

The prevalence of obesity and Type 2 Diabetes (T2D) is increasing worldwide. A Western diet is associated with the increased risks of obesity and T2D. Chronic consumption of a high saturated-fat diet (HSFD) in animals causes β-cell dysfunction due to lipotoxicity. However, lipotoxicity in vivo in human islets is currently unproven.

This thesis aimed to interrogate the impacts of chronic high polyunsaturated fat (PUFD), monounsaturated fat (MUFD), and high saturated fat (HSFD) diets and healthy chow in mice and their effects on mouse islet function. Then the effect of MUFD and HSFD on human islet function were assessed in vivo using an islet transplant model. To test human islet, we induced diabetes in immunocompromised Recombination Activating Gene 1 (RAG1)-null mice by streptozotocin or alloxan. Human islets were then transplanted under the mouse kidney capsule. Mice went on to diet for 16 weeks. Human islet transplanted mice then had their islet graft removed to confirm glucose regulation was solely driven by human islets.

Normal mice and human-islet transplanted mice gained excess weight on HSFD but not MUFD. PUFD had intermediate effects in mice and was not studied in human islets. In mice, there was significantly impaired glucose tolerance on HSFD, with intermediate effects of MUFD and PUFD. MUFD caused no deterioration in glucose tolerance in human-islet mice compared to chow-fed mice.

Overall, there were significant differences between donor islets (p<0.0001), diets (p<0.001) and as well as a significant diet-donor-preparation interaction (p=0.001). However, every human donor showed deterioration in GTT with HSFD. This work has important implications for diet in human diabetes and in people after pancreas- or islet-transplantation.