Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease

To the Editor: Shulman (Sept. 18 issue)1 theorized that ectopic fat plays a major role in the development of insulin resistance. We speculate, however, that insulin resistance may be caused by another major pathway, in which glucose itself, at high levels, plays a critical role. Reasonable evidence has shown that when glucose levels are elevated, glucose molecules may randomly bind to proteins similar to the insulin receptor on the plasma membrane of the cell and in time become advanced glycation end products.2 Circulating insulin levels would easily fail to dock properly with the advanced glycation end product deposited on the insulin receptor and would therefore fail to initiate the glucose-transport process, effectively causing insulin resistance.3 This pathway for glycation-induced insulin resistance would explain why insulin resistance often develops in persons who are not obese and who probably do not have substantial ectopic fat.