The Randle hypothesis was proposed to explain the correlation between carbohydrate and lipid metabolic homeostasis and the effect of disruptions in both processes on diabetes and obesity. Which of the following statements best reflects the basis of the Randle hypothesis?
A) an increase in adipocyte volume due to increased lipid storage causes adipocytes to lose their responsiveness to insulin
B) increased circulating free fatty acids in obese individuals impair the ability of insulin to stimulate skeletal muscle cell glucose uptake
C) long-term hyperlipidemia leads to permanent elevation in pancreatic insulin secretion that ultimately causes downregulation of insulin receptors
D) the high level of circulating free fatty acids stimulates the liver to shut off gluconeogenesis that then impairs pancreatic sensing of the need for insulin release
E) the hyperglycemia prevalent in obese individuals activates insulin release from the pancreas, leading to increased adipocyte lipolysis

Question

Quizplus · Accepted Answer

The Randle hypothesis, also known as the glucose-fatty acid cycle, suggests that increased levels of circulating free fatty acids can impair glucose uptake in skeletal muscle by inhibiting insulin action, which is a key factor in the development of 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 acetyl-CoA cannot be oxidized completely in the TCA cycle. The elevated acetyl-CoA levels result in inhibition of the PDHc, resulting in increased citrate transport to the cytosol. Increased cytosolic citrate inhibits 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, leading to defects in insulin-mediated 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 β-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 Correlation Between