Age-related changes in body composition are associated with hepatic insulin resistance in conscious rats

Age-dependent changes in body composition and hepatic ([³H]glucose) glucose metabolism were examined in 2-, 4-, and 14-mo-old (n = 26) conscious Sprague-Dawley rats. Hepatic glucose production (HGP) and hepatic glucose-6- phosphatase maximum velocity were decreased 18 and 30%, respectively, between 2 and 4 mo but were unchanged with further aging. However, between 4 and 14 mo, twofold higher plasma insulin levels were required to maintain similar HGP, suggesting that hepatic insulin resistance develops with age. Utilizing hepatic-pancreatic clamp technique, we showed that a much higher rate of insulin infusion (1.6 ± 0.1 vs. 0.8 ± 0.1 mU · kg^-1 · min^-1) was needed to achieve similar plasma glucose levels and HGP. Furthermore, when 4- mo-old rats were infused with insulin at similar rates as the 14-mo-old rats, HGP was decreased by ~30%. Because hepatic insulin sensitivity was inversely related to the increase in body weight (r² = 0.876) and free fatty acid levels (r² = 0.843), we suggest that age-related changes in body composition may lead to the impairment of hepatic glucose metabolism.