title: Ability of insulin to modulate hepatic glucose production in aging rats is impaired by fat accumulation.
abstract: 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 F(1) hybrid of Brown Norway-Fischer 344 rats (n = 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. kg(-1). min(-1) 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 +/- 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 of hepatic uridine diphosphate glucose and phosphoenolpyruvate pools by [(14)C]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 +/- 0.3 and 4.9 +/- 0.3 mg. 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 hepatic insulin action in aging CR rats. Therefore, body fat and its distribution are major determinants of age-associated hepatic insulin resistance.
authors.affiliation: Department of Medicine, and the Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, New York 10461, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gupta
authors.forename: J A
authors.initials: JA
authors.lastname: Cases
authors.forename: L
authors.initials: L
authors.lastname: She
authors.forename: X H
authors.initials: XH
authors.lastname: Ma
authors.forename: X M
authors.initials: XM
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Rossetti
authors.forename: N
authors.initials: N
authors.lastname: Barzilai
mesh_terms: D000273:Adipose Tissue; D000375:Aging; D000818:Animals; D001823:Body Composition; D002149:Energy Intake; D005943:Gluconeogenesis; D005947:Glucose / Q000096:biosynthesis*; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344
chemical_list: D007328:Insulin; D020738:Leptin; D006003:Glycogen; D005947:Glucose