Deficiency of adrenomedullin induces insulin resistance by increasing oxidative stress

Abstract

Hypertension, insulin resistance, and obesity are common age-related metabolic disorders that are often associated with increased oxidative stress and the resultant vascular damage. Underlying mechanisms have been suggested, and age-related overproduction of oxidative stress is one possible candidate. Since we recently found a vasoactive peptide, adrenomedullin, to be an endogenous antioxidant that potently inhibits oxidative stress-induced vascular damage, in the current study we evaluated oxidative stress-induced changes in aged mice. Insulin sensitivities in young and aged adrenomedullin-deficient mice were measured by means of the hyperinsulinemic-euglycemic clamp method; insulin resistance was apparent in aged adrenomedullin-deficient mice with increased urinary excretion of 8-iso-prostaglandin F2alpha, a marker of oxidative stress, but not in young adrenomedullin-deficient mice. Concomitantly, only aged adrenomedullin-deficient mice not only showed increased production of muscular reactive oxygen species, as demonstrated by the electron spin resonance method, but also had significantly decreased insulin-stimulated glucose uptake into the soleus muscle associated with impairment of insulin signals such as insulin receptor substrate-1,2 and phosphatidylinositol-3 kinase activities. In turn, these abnormalities could be nearly reversed by either treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a membrane-permeable superoxide dismutase mimetic, or adrenomedullin supplementation. Evidence presented in this report suggests that age-related accumulation of oxidative stress is involved in blood pressure regulation and insulin resistance in aged adrenomedullin-deficient mice, and adrenomedullin is thus an endogenous substance counteracting oxidative stress-induced insulin resistance associated with aging.