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

Gaurav Gupta, Jane A. Cases, Li She, Xiao Hui Ma, Xiao Man Yang, Meizu Hu, Jeanie Wu, Luciano Rossetti, Nir Barzilai

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55 Scopus citations

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 F1 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 [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 ± 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.

Original languageEnglish (US)
Pages (from-to)E985-E991
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume278
Issue number6 41-6
StatePublished - Jun 1 2000

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Keywords

  • Caloric restriction
  • Obesity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Gupta, G., Cases, J. A., She, L., Ma, X. H., Yang, X. M., Hu, M., Wu, J., Rossetti, L., & Barzilai, N. (2000). Ability of insulin to modulate hepatic glucose production in aging rats is impaired by fat accumulation. American Journal of Physiology - Endocrinology and Metabolism, 278(6 41-6), E985-E991.