The role of mitochondrial dysfunction in the pathogenesis of insulin resistance is a widely debated topic. It has been shown that young, lean, insulin-resistant offspring of parents with type 2 diabetes have reduced mitochondrial function. But the precise role of this decreased function in relation to insulin resistance and type 2 diabetes was not clear.
In a paper appearing online on November 10 in advance of print publication of the December issue of the Journal of Clinical Investigation, Gerald Shulman and colleagues from Yale University take muscle biopsies from these offspring and show that they have reduced mitochondrial content as assessed by electron microscopy. The subjects also have lower insulin-stimulated muscle glucose uptake and increased lipid content in muscle cells. However in contrast to two recent studies, the authors did not find any alterations in PGC-1a or PGC-1b or other downstream regulators of mitochondrial gene expression.
These results provide new insights into the earliest defects that may be responsible for the pathogenesis of type 2 diabetes. Moreover, reduced mitochondrial content could result in reduced mitochondrial function, which predisposes the offspring of type, 2 diabetic parents to muscle cell lipid accumulation, which then leads to defective insulin signaling and action.
TITLE: Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of Type 2 diabetic parents.
AUTHOR CONTACT:
Gerald Shulman
Yale Medical School, New Haven, CT USA
Phone: 203-737-1115
Fax: 203-737-4059
E-mail: gerald.shulman@yale.edu
Journal of Clinical Investigation