TY - JOUR
T1 - Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance
AU - Einstein, Francine H.
AU - Fishman, Sigal
AU - Bauman, Jeffery
AU - Thompson, Reid F.
AU - Huffman, Derek M.
AU - Atzmon, Gil
AU - Barzilai, Nir
AU - Muzumdar, Radhika H.
PY - 2008/10
Y1 - 2008/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=54049127745&partnerID=8YFLogxK
U2 - 10.1096/fj.08-109041
DO - 10.1096/fj.08-109041
M3 - Article
C2 - 18566293
AN - SCOPUS:54049127745
SN - 0892-6638
VL - 22
SP - 3450
EP - 3457
JO - FASEB Journal
JF - FASEB Journal
IS - 10
ER -