Introduction Insulin resistance (IR), a hallmark of obesity and precursor of type 2 diabetes, is an independent risk factor for the development of cardiovascular atherosclerosis. An early step in the development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioavailable nitric oxide (NO). IR is associated with endothelial dysfunction but the mechanistic relationship between these abnormalities and the role of impaired endothelial insulin signalling versus global IR requires elucidation.
Methods To examine the effects of IR specific to the endothelium, we generated a transgenic mouse with endothelium-targeted overexpression of a mutant human insulin receptor (ESMIRO mouse). This dysfunctional receptor has a mutation (alanine–threonine1134) in its tyrosine kinase domain that disrupts normal insulin signaling. Humans with the Thr1134 mutation have severe IR. Male ESMIRO mice aged 8–10 weeks were compared with age-matched wild-type (WT) littermates. Metabolic and vascular phenotypes were examined.
Results ESMIRO mice demonstrated preserved glucose homeostasis, normal lipid profiles and were both lean and normotensive. However, they had significant endothelial dysfunction in conduit vessels demonstrated by impaired vasomotor responses to insulin and blunted maximal aortic vasorelaxant responses to acetylcholine (Emax ESMIRO 68 ± 6%, WT 102 ± 6%, p<0.01, n = 8) and the calcium ionophore A23187 (Emax ESMIRO 51 ± 12%, WT 79 ± 8%, p<0.05). Relaxation responses to the endothelium-independent vasodilator sodium nitroprusside were similar in ESMIRO and WT. Acetylcholine-induced relaxation in ESMIRO mice was normalised by incubation with the superoxide dismutase mimetic, MnTMPyP. Furthermore, coronary microvascular endothelial cells from ESMIRO mice showed increased superoxide generation compared with WT as assessed by lucigenin-enhanced chemiluminescence and dihydroxyergotamine fluorescence. ESMIRO superoxide generation was inhibited by a flavoprotein inhibitor, diphenyleneiodonium, and was associated with increased messenger RNA expression of the nicotinamide adenine dinucleotide phosphate, reduced form, oxidase catalytic subunits Nox2 and Nox4. Expression levels of endothelial NO synthase mRNA and protein were similar in the ESMIRO and WT mice.
Discussion These results indicate that selective endothelial IR in the absence of a global defect in responses to insulin is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction, secondary to increased generation of superoxide. However, endothelial insulin signalling does not play a critical role in normal glucose homeostasis in vivo.
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