Fat oxidation and diabetes of obesity: the Randle hypothesis revisited

Abstract

A hypothesis is presented that addresses the etiology of diabetes in the obese. Evidence from many areas of research suggests that ready availability of free fatty acids for oxidation by muscles and other tissues may lead to impairment of carbohydrate oxidation and lead to glucose intolerance as is seen in obesity and obese diabetics. In addition, free fatty acids can stimulate hepatic gluconeogenesis and alter pancreatic insulin release and subsequent metabolism, which may be the pathophysiological mechanism for these changes in obese diabetics. It is well-recognized that there are different anatomic forms of obesity and that risk of diabetes is much greater in those with abdominal rather than hip/thigh obesity. It may be that fat cells in abdominal depots (in these individuals) are more metabolically active, releasing greater amounts of free fatty acids (even after feeding when they should be suppressed), and the metabolism of these fatty acids leads to the changes described here, leading to overt diabetes.