Analysis of individuals with rare, molecularly defined defects in the signaling pathway activated by the hormone insulin (which controls blood glucose levels), by a team of researchers at the University of Cambridge, United Kingdom, has provided new insight that might be applicable to the many individuals with obesity-related resistance to insulin, something that predisposes individuals to type 2 diabetes.
The importance of such studies and the questions that they raise are discussed in an accompanying commentary by Robert Hegele and Karen Reue.
The team, led by Robert Semple and David Savage, found that patients with generalized resistance to insulin because they either carry mutations in the insulin receptor gene or have inhibitory antibodies that bind the insulin receptor, have low levels of fats known as triglycerides in their blood and normal levels of "good" cholesterol (HDL cholesterol).
By contrast, two patients with mutations in the AKT2 gene, which generates a protein that is part of one of the signaling pathways activated when insulin binds the insulin receptor, were found to have increased levels of triglycerides in their blood and low levels of HDL cholesterol.
These and other human data reported here by the authors are consistent with current hypotheses, generated from mouse studies, that abnormal fat and cholesterol levels in individuals with obesity-related resistance to insulin are in fact caused by partial postreceptor liver insulin resistance, i.e., defects in only some signaling pathways downstream of the insulin receptor on liver cells.
- Semple et al. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. Journal of Clinical Investigation, Jan 29, 2009; DOI: 10.1172/JCI37432
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