Question

In patients with type 2 diabetes, cells no longer respond to the hormone insulin. What change has likely occurred in these cells to make them insulin resistant?

Answer 1

1. Decreased delivery of substrate or insulin to the tissue bed might be responsible for the insulin resistance in type 2 diabetes.

2. Increased plasma free fatty acid concentrations are typically associated with many insulin-resistant states, including obesity and type 2 diabetes mellitus.

An increase in fatty acids caused an increase in the intramitochondrial acetyl CoA/CoA and NADH/NAD+ ratios, with subsequent inactivation of pyruvate dehydrogenase. This in turn would cause intracellular citrate concentrations to increase, leading to inhibition of phosphofructokinase, a key rate-controlling enzyme in glycolysis. Subsequent accumulation of glucose-6-phosphate would inhibit hexokinase II activity, resulting in an increase in intracellular glucose concentrations and decreased glucose uptake.