Insulin signaling components predict diabetes, atherosclerosis risk
MedWire News: Insulin resistance and subclinical atherosclerosis are associated with reduction in components of insulin signal transduction pathways and genetic modifiers of insulin action, say researchers.
Monocyte cells from offspring of individuals with Type 2 diabetes have reduced gene expression of insulin receptor substrate 2 (IRS2) and tissue inhibitor of metalloproteinase 3 (TIMP3), they report.
As reported in the journal Diabetes, Massimo Federici (University of Rome Tor Vergata, Italy) and colleagues measured insulin sensitivity and intima-media thickness (IMT) in 41 first-degree relatives of patients with Type 2 diabetes.
They also took blood samples from all participants and measured monocyte levels of insulin signal transduction pathway components (such as the insulin receptor and its substrates) and genetic modifiers of insulin action (such as the TIMP3/ADAM17 pathway).
Compared with individuals in the highest tertile of expression of IRS2, those in the lowest tertile had significantly higher insulin resistance by homeostatic model assessment (2.20 vs 1.73) and higher IMT (0.74 vs 0.63 mm).
Those in the lowest tertile also had increased fasting plasma glucose (5.2 vs 4.8 mmol/l), increased glycated hemoglobin levels (5.46 vs 5.15%), and reduced levels of high-density lipoprotein cholesterol (1.39 vs 1.73 mmol/l).
Analysis of IRS2 protein levels in the lowest versus highest tertiles of insulin resistance confirmed that IRS2 protein was significantly decreased in insulin-resistant individuals.
The researchers also report that individuals in the highest tertile of insulin resistance had significantly reduced TIMP3 expression compared with those in the lowest tertile and that TIMP3 expression was negatively correlated with IMT.
"The inflammatory behavior of monocytes is controlled by TIMP3 which restrains the release of the soluble fraction of transmembrane proteins through their ectodomain shedding," they explain.
Gene expression and protein activity of IRS2 and expression of TIMP3 negatively correlate with insulin resistance and atherosclerosis in individuals at high risk for diabetes and atherosclerosis, concludes the team.
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By Sally Robertson