AENDO June 41/6

Gupta, Gaurav, Jane A. Cases, Li She, Xiao-Hui Ma, Xiao-Man Yang, Meizu Hu, Jeanie Wu, Luciano Rossetti, and Nir Barzilai. Ability of insulin to modulate hepatic glucose production in aging rats is impaired by fat accumulation. Am J Physiol Endocrinol Metab 278: E985– E991, 2000.—Increased total fat mass (FM) and visceral fat (VF) may account in part for age-associated decrease in hepatic insulin action. This study determined whether preventing the changes in body fat distribution abolished this defect throughout aging. We studied the F1 hybrid of Brown Norway-Fischer 344 rats (n 5 29), which we assigned to caloric restriction (CR) or fed ad libitum (AL). CR (55% of the calories consumed by AL) was initiated and used at 2 mo to prevent age-dependent increases in FM and VF. AL rats were studied at 2, 8, and 20 mo; CR rats were studied at 8 and 20 mo. VF and FM remained unchanged throughout aging in CR rats. AL-fed rats at 8 and 20 mo had over fourfold higher FM and VF compared with both CR groups. Insulin clamp studies (3 mU·kg21 ·min21 with somatostatin) were performed to assess hepatic insulin sensitivity. Prevention of fat accretion resulted in a marked improvement in insulin action in the suppression of hepatic glucose production (HGP) (6.3 6 0.3 and 7.2 6 1.2 mg·kg21 ·min21 in 8and 20-mo CR rats vs. 8.3 6 0.5 and 10.8 6 0.9 mg·kg21 ·min21 in 8and 20-mo AL rats, respectively). The rate of gluconeogenesis (by enrichment of hepatic uridine diphosphate glucose and phosphoenolpyruvate pools by [14C]lactate) was unchanged in all groups. The improvement in hepatic insulin action in the CR group was mostly due to effective suppression of glycogenolysis (4.4 6 0.3 and 4.9 6 0.3 mg·kg21 ·min21 in 8and 20-mo CR rats vs. 5.8 6 0.6 and 8.2 6 1.0 mg·kg21 ·min21 in 8and 20-mo AL rats, respectively). The results demonstrated the preservation of hepatic insulin action in aging CR rats. Therefore, body fat and its distribution are major determinants of age-associated hepatic insulin resistance.