Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance

Francine H. Einstein, Sigal Fishman, Jeffery Bauman, Reid F. Thompson, Derek M. Huffman, Gil Atzmon, Nir Barzilai, Radhika H. Muzumdar

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Calorie restriction improves life span whereas nutrient excess leads to obesity and unfavorable metabolic consequences, supporting the role for a cellular "nutrient sensor" in aging. Hexosamine biosynthetic pathway (HBP) is a candidate nutrient-sensing pathway. We hypothesized that altered nutrient sensing (by HBP) with age may provide a link among aging, nutrient flux, and insulin resistance. Using a hyperinsulinemic clamp in young rats, we show that experimental activation of HBP, through the systemic infusion of glucosamine, induced severe insulin resistance (36% decline in peripheral insulin action; P<0.05), increased adipose tissue gene expression of fat-derived peptides (PAI-1 by 4-fold, angiotensinogen 3-fold, leptin 2-fold, resistin 4-fold, and adiponectin 4-fold; P<0.01 compared with young saline-infused), and enhanced glycosylation of transcription factors, thus mimicking a physiological and biological phenotype of aging. We further demonstrate a greater activation of nutrient-sensing HBP with age in both old ad libitum-fed and calorie-restricted rats. Interestingly, old calorie-restricted animals rapidly develop insulin resistance when exposed to glucosamine, despite their "young" phenotype. These results suggest that altered nutrient sensing by HBP with age may be the link among nutrients, insulin resistance, and age-related diabetes.

Original languageEnglish (US)
Pages (from-to)3450-3457
Number of pages8
JournalFASEB Journal
Volume22
Issue number10
DOIs
StatePublished - Oct 2008

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Nutrients
Insulin Resistance
Hexosamines
Chemical activation
Insulin
Biosynthetic Pathways
Food
Aging of materials
Glucosamine
Rats
Glycosylation
Resistin
Phenotype
Angiotensinogen
Adiponectin
Plasminogen Activator Inhibitor 1
Clamping devices
Medical problems
Leptin
Gene expression

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

Einstein, F. H., Fishman, S., Bauman, J., Thompson, R. F., Huffman, D. M., Atzmon, G., ... Muzumdar, R. H. (2008). Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance. FASEB Journal, 22(10), 3450-3457. https://doi.org/10.1096/fj.08-109041

Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance. / Einstein, Francine H.; Fishman, Sigal; Bauman, Jeffery; Thompson, Reid F.; Huffman, Derek M.; Atzmon, Gil; Barzilai, Nir; Muzumdar, Radhika H.

In: FASEB Journal, Vol. 22, No. 10, 10.2008, p. 3450-3457.

Research output: Contribution to journalArticle

Einstein, FH, Fishman, S, Bauman, J, Thompson, RF, Huffman, DM, Atzmon, G, Barzilai, N & Muzumdar, RH 2008, 'Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance', FASEB Journal, vol. 22, no. 10, pp. 3450-3457. https://doi.org/10.1096/fj.08-109041
Einstein, Francine H. ; Fishman, Sigal ; Bauman, Jeffery ; Thompson, Reid F. ; Huffman, Derek M. ; Atzmon, Gil ; Barzilai, Nir ; Muzumdar, Radhika H. / Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance. In: FASEB Journal. 2008 ; Vol. 22, No. 10. pp. 3450-3457.
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