Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.
Atherosclerosis is increased in type 2 diabetic patients but the precise mechanisms underlying this predisposition remain vague. Mice deficient for insulin receptor substrate 2 (IRS2) develop type 2-like diabetes and thus, provide a model to explore the molecular connection between deranged carbohydrate metabolism and atherosclerosis. To explore the relationship between defective insulin signalling and atherosclerosis, we have examined the development of atherosclerosis in the following groups of fat-fed mice: wild-type, diabetic Irs2-null (Irs2-/-), atherosclerosis-prone apolipoprotein E-null (apoE-/-), and doubly-deficient apoE-/- Irs2-/-. Surprisingly, glucose levels of apoE-/- Irs2-/-mice were comparable to those seen in wild-type and apoE-/- and significantly lower than in Irs2-/- mice. Irs2-/- and apoE-/- Irs2-/-were hyperinsulinemic compared to wild-type and apoE-/- mice. Atherosclerotic lesions were barely detectable in wild-type and Irs2-/- mice, which displayed moderate hypercholesterolemia (approximately 280 mg/dL). Notably, atherosclerosis was significantly enhanced in apoE-/- Irs2-/- compared with apoE-/- mice, although both models displayed similar levels of severe hypercholesterolemia (>600 mg/dL). Circulating insulin levels predicted atherosclerotic lesion burden in apoE-/- Irs2-/- mice. Our results suggest that hyperinsulinemia as a result of Irs2 genetic ablation contributes to increased atherosclerosis when combined with severe hypercholesterolemia in the absence of hyperglycaemia (apoE-/- Irs2-/- mice), thus implicating IRS2 as an important modulator of murine hypercholesterolemia-dependent atherosclerosis. Future studies are necessary to determine whether IRS2 dysfunction may promote atherosclerosis in normoglycemic, pre-diabetic patients with clinical manifestations of hyperinsulinemia and insulin resistance.