Insulin sensitivity is mediated by glucose in the hepatoportal region in the rat

Abstract

Obesity is associated with insulin resistance, the primary characteristic underlying the development of type 2 diabetes mellitus. The relationship between insulin resistance and obesity is the focus of much research yet the molecular mechanisms by which excess adiposity cause impaired insulin action remain poorly defined. Nutrition is fundamental to overall health and is implicated in the pathogenesis of obesity and insulin resistance. This is exemplified in rodent models, where high fat feeding induces insulin resistance in just three weeks. Previous studies have established a rat model of diet-induced insulin resistance where substituting one high-glucose meal for the usual fat meal in rats restores insulin sensitivity. The exact mechanisms of this improvement are unknown but are of interest as they provide insight into the physiological regulation of insulin action and may lead to novel treatment strategies. The aim of the experiments in this thesis is to further understanding of the mechanisms involved in the glucose regulated improvement of insulin sensitivity. High fat fed rats were given either a glucose meal, a systemic glucose infusion or a portal glucose infusion and insulin sensitivity was assessed by hyperinsulinemic euglycemic clamp. A glucose meal consistently improved insulin sensitivity in high fat fed rodents establishing that the model is reproducible. Further, a systemic glucose infusion did not affect insulin sensitivity indicating that the mechanism is not glucose flux or lipid withdrawal. A portal glucose infusion significantly improved insulin sensitivity, implying that the hepatoportal region mediates the improvement rather than gastrointestinal factors. These results further our understanding of the mechanism of the glucose mediated improvement of insulin sensitivity and provide new insight into the role of nutrition in the acute regulation of whole-body metabolism.