Researchers have shown how two signalling mechanisms in the cell together create a situation that could trigger the thickening of arterial blood vessels or atherosclerosis1, a leading cause of cardiovascular diseases.
The two signalling mechanisms — that of oxidative stress and mitochondrial dysfunction — originating from hyperinsulinemia (increased endogenous insulin levels) promote the migration and proliferation of vascular smooth muscle cells (VSMCs), a hallmark of atherosclerosis.
Atherosclerosis is one of the major cardiovascular complications of diabetes and involves endothelial dysfunction and increased migration and proliferation of VSMCs. Several epidemiological studies point to the association between insulin resistance and atherosclerosis. Once the insulin resistance progresses, the pancreas produces increasing amounts of insulin (compensatory hyperinsulinemia) to maintain normal glucose levels. Although compensatory hyperinsulinemia may prevent the development of fasting hyperglycemia in insulin-resistant individuals, the price paid is the untoward physiologic effects and pro-atherogenic actions — the dark side of insulin.
To simulate hyperinsulinemia, the researchers treated the VSMCs with insulin for 6 days. They showed that hyperinsulinemia-mediated migration and proliferation of VSMCs was mediated by a cross-talk between mitochondrial dysfunction and oxidative stress. "We demonstrate the possible biochemical and molecular basis for the detrimental influence of hyperinsulinemia. This creates a state of increased mitogenic insulin signaling as against insulin's usual metabolic signaling actions," say lead researchers Muthuswamy Balasubramanyam and Viswanathan Mohan.
"Because hyperinsulinemia may exaggerate the detrimental influence of poor metabolic control and even be a causative factor for overweight or obesity, therapeutic interventions should be directed both to control glycemia as well as to control hyperinsulinemia in patients with type 2 diabetes," adds Balasubramanyam.
The authors of this work are from: Department of Cell and Molecular Biology, Madras Diabetes Research Foundation (MDRF) and Dr.Mohans' Diabetes Specialities Centre, Chennai & Department of Biotechnology, Indian Institute of Technology (IIT-M), Chennai, India.
