Enhanced activation of a "nutrient-sensing" pathway with age contributes to insulin resistance.
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
Francine H
FH
Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461, USA.
Fishman
Sigal
S
Bauman
Jeffery
J
Thompson
Reid F
RF
Huffman
Derek M
DM
Atzmon
Gil
G
Barzilai
Nir
N
Muzumdar
Radhika H
RH
D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005944:Glucosamine / Q000494:pharmacology; D006031:Glycosylation; D006595:Hexosamines / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D052243:Resistin / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism
D052242:Adiponectin; D006595:Hexosamines; D007328:Insulin; D020738:Leptin; D017395:Plasminogen Activator Inhibitor 1; D052243:Resistin; D016329:Sp1 Transcription Factor; D000808:Angiotensinogen; D005944:Glucosamine