Deficiency of Adrenomedullin Induces Insulin Resistance by Increasing Oxidative Stress

• DOI: 10.1161/01.hyp.0000066846.46422.2c
• Publication Date: 2003-05-01T20:28:48Z
• Authors: Tatsuo Shimosawa; Takehide Ogihara; Hiromitsu Matsui; Tomoichiro Asano; Katsuyuki Ando; Toshiro Fujita
• Keywords: Male; Mice, Knockout; 0301 basic medicine; 2. Zero hunger; Aging; Genotype; Body Weight; Blood Pressure; Deoxyglucose; In Vitro Techniques; Isoprostanes; Antioxidants; 3. Good health; Cyclic N-Oxides; Adrenomedullin; Mice; Oxidative Stress; 03 medical and health sciences; Animals; Insulin; Female; Insulin Resistance; Muscle, Skeletal; Peptides

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 F 2α , 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.