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 * ,‡ ,1 and Radhika H. Muzumdar * ,§ * Department of Medicine, † Department of Obstetrics and Gynecology and Women’s Health, ‡ Molecular Genetics and the Institute for Aging Research, and § Department of Pediatrics, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA 1 Correspondence: Institute for Aging Research, Departments of Medicine and Molecular Biology, Belfer Building, Suite 701, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. E-mail: barzilai@aecom.yu.edu 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.—Einstein, F. H., Fishman, S., Bauman, J., Thompson, R. F., Huffman, D. M., Atzmon, G., Barzilai, N., Muzumdar, R. H. Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance. Key Words: hexosamine biosynthetic pathway • calorie restriction
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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.
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, Volume 22 (10): 3450
Fed of American Socs for Experimental Biology – Oct 1, 2008
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