The Cause of Insulin Resistance in Type 2 Diabetes

With more than 29 million Americans currently living with type 2 diabetes understanding the root cause of the insulin resistance which the majority experience has been a mystery. Insulin which is the peptide hormone secreted by the islet cells in the pancreas is responsible for the body’s ability to effectively process sugar.  For people with type 2 diabetes, the problem of insulin resistance means that there is plenty of insulin, however, the body does not respond to it effectively.  This resistance is associated with high sugar levels in the blood as determined by high H1C levels, but diabetes is also a problem of high levels of fat, especially inside skeletal muscle which leads to insulin resistance.
Researchers lead by Dr. Zoltan Arany at the University of Pennsylvania have identified the underlying cause of insulin resistance found in type 2 diabetics which was recently reported in Nature Medicine (  A new link has been determined between 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of branched chain amino acid (BCCA) valine as a new paracrine regulator of trans endothelial fatty acid transport.  3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake, and promotes lipid accumulation in muscle leading to insulin resistance in mice. 3-HIB levels are elevated in muscle from both mice and humans with diabetes as compared to those without diabetes.  Coupled with other results from this article, the researchers propose a mechanism that the metabolite, 3-HIC, regulates trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, which in turn provides a mechanistic explanation for how increased BCCA catabolic flux can cause type 2 diabetes.

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