Hyperglycemia modulates angiotensinogen gene expression.
Elevated plasma angiotensinogen (AGT) levels have been demonstrated in insulin-resistant states such as obesity and type 2 diabetes mellitus (DM2), conditions that are directly correlated to hypertension. We examined whether hyperinsulinemia or hyperglycemia may modulate fat and liver AGT gene expression and whether obesity and insulin resistance are associated with abnormal AGT regulation. In addition, because the hexosamine biosynthetic pathway is considered to function as a biochemical sensor of intracellular nutrient availability, we hypothesized that activation of this pathway would acutely mediate in vivo the induction of AGT gene expression in fat and liver. We studied chronically catheterized lean (approximately 300 g) and obese (approximately 450 g) Sprague-Dawley rats in four clamp studies (n = 3/group), creating physiological hyperinsulinemia (approximately 60 microU/ml, by an insulin clamp), hyperglycemia (approximately 18 mM, by a pancreatic clamp using somatostatin to prevent endogenous insulin secretion), or euglycemia with glucosamine infusion (GlcN; 30 micromol. kg(-1). min(-1)) and equivalent saline infusions (as a control). Although insulin infusion suppressed AGT gene expression in fat and liver of lean rats, the obese rats demonstrated resistance to this effect of insulin. In contrast, hyperglycemia at basal insulin levels activated AGT gene expression in fat and liver by approximately threefold in both lean and obese rats (P < 0.001). Finally, GlcN infusion simulated the effects of hyperglycemia on fat and liver AGT gene expression (2-fold increase, P < 0.001). Our results support the hypothesis that physiological nutrient "pulses" may acutely induce AGT gene expression in both adipose tissue and liver through the activation of the hexosamine biosynthetic pathway. Resistance to the suppressive effect of insulin on AGT expression in obese rats may potentiate the effect of nutrients on AGT gene expression. We propose that increased AGT gene expression and possibly its production may provide another link between obesity/insulin resistance and hypertension.
Gabriely
I
I
Diabetes Research and Training Center, Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Yang
X M
XM
Cases
J A
JA
Ma
X H
XH
Rossetti
L
L
Barzilai
N
N
D000273:Adipose Tissue / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005944:Glucosamine / Q000008:administration & dosage; D015309:Glucose Clamp Technique; D006595:Hexosamines / Q000096:biosynthesis; D006943:Hyperglycemia / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D006595:Hexosamines; D007328:Insulin; D000808:Angiotensinogen; D005944:Glucosamine