The Randle hypothesis was proposed to explain the acquisition of insulin resistance associated with central adiposity. Which of the following statements best reflects the basis of the Randle hypothesis?

Question

Quizplus · Accepted Answer

The Randle hypothesis suggests that increased circulating free fatty acids in obese individuals impair insulin's ability to stimulate glucose uptake in skeletal muscle, contributing to insulin resistance.  The Randle hypothesis states that elevations in circulating free fatty acids (FFAs) interfere with insulin action in liver and skeletal muscle. Increased FFA uptake and metabolism by the liver results in an increased production of acetyl-CoA. All of the acetylCoA cannot be oxidized completely in the TCA cycle. The elevated acetyl-CoA levels result in inhibition of pyruvate dehydrogenase resulting in increased citrate transport to the cytosol. Increased cytosolic citrate inhibits 6-phosphofructokinase-1 (PFK1) resulting in reduced glucose oxidation and an increase in glucose- 6-phosphate levels. Increases in glucose 6-phosphate lead to inhibition of skeletal muscle hexokinase resulting in reduced glucose utilization. In addition, the elevated plasma FFAs impair insulin receptor tyrosine phosphorylation of IRS1 resulting in defects in insulinmediated signaling events in target cells, primarily skeletal muscle. Loss of insulin signaling in skeletal muscle prevents glucose transporter (GLUT4) mobilization to the cell surface with a resultant block to glucose uptake. The overall consequences of a high-fat diet are a progressive impairment in hepatic glucose homeostasis, impairment of insulin-mediated glucose uptake by skeletal muscle, and pancreatic b-cell decompensation. The latter leads to reduced insulin secretion and, thus, further impairment of the role of insulin in regulation of blood glucose.

The Randle Hypothesis Was Proposed to Explain the Acquisition of Insulin