Ability of insulin to modulate hepatic glucose production in aging rats isimpaired by fat accumulation

Increased total fat mass (FM) and visceral fat (VF) may account in part for age-associated decrease in hepatic insulin action. This study determined w hether preventing the changes in body fat distribution abolished this defec t throughout aging. We studied the F-1 hybrid of Brown Norway-Fischer 344 r ats (n = 29), which we assigned to caloric restriction (CR) or fed ad libit um (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 stud ies (3 mU . kg(-1) . min(-1) with somatostatin) were performed to assess he patic insulin sensitivity. Prevention of fat accretion resulted in a marked improvement in insulin action in the suppression of hepatic glucose produc tion (HGP) (6.3 +/- 0.3 and 7.2 +/- 1.2 mg . kg(-1) . min(-1) in 8- and 20- mo CR rats vs. 8.3 +/- 0.5 and 10.8 +/- 0.9 mg . kg(-1) . min(-1) in 8- and 20-mo AL rats, respectively). The rate of gluconeogenesis (by enrichment o f hepatic uridine diphosphate glucose and phosphoenolpyruvate pools by [C-1 4]lactate) was unchanged in all groups. The improvement in hepatic insulin action in the CR group was mostly due to effective suppression of glycogeno lysis (4.4 +/- 0.3 and 4.9 +/- 0.3 mU . kg(-1) . min(-1) in 8- and 20-mo CR rats vs. 5.8 +/- 0.6 and 8.2 +/- 1.0 mg . kg(-1) . min(-1) in 8- and 20-mo AL rats, respectively). The results demonstrated the preservation of hepat ic insulin action in aging CR rats. Therefore, body fat and its distributio n are major determinants of age-associated hepatic insulin resistance.