Published Online
on March 31, 2003

A more recent version of this article appeared on May 1, 2003

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Submitted on October 21, 2002
Revised on November 15, 2002

Deficiency of Adrenomedullin Induces Insulin Resistance by Increasing Oxidative Stress

Tatsuo Shimosawa; Takehide Ogihara; Hiromitsu Matsui; Tomoichiro Asano; Katsuyuki Ando; and Toshiro Fujita^*

From the Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: fujita-dis{at}h.u-tokyo.ac.jp.

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 F₂, 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.

Key words: insulin resistance • oxidative stress • aging • diabetes mellitus • adrenomedullin

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