angiotensinogen and Hyperinsulinism

Our paper is discussing the presence and intensity of metabolic, humoral and haemodynamic abnormalities in mild middle-aged essential hypertensives (EH) and in hereditary predisposed still normotensive offspring from hypertensive families and their possible association with candidate genes changes. Four groups of subjects were compared (middle-aged normotensive controls (n = 21), corresponding patients with EH (n = 21), normotensive offspring from hypertensive (SH) (n = 56) and normotensive families (SN) (n = 56). Our results demonstrate that middle-aged patients with EH in our country have the same indices of hyperinsulinemia, impared glucose tolerance and insulin-sensitivity as previously described for other populations. They are accompanied by higher plasma concentrations of vasopressor substance like catecholamines, endothelin and lower levels of vasodepressor substances as ANP and kallikrein. The finding of similar, but quantitatively less expressed metabolic and humoral changes in SH but not in SN support the evidence for hereditary background of these abnormalities. The humoral and metabolic abnormalities may participate in BP elevation and in morphological and functional changes of left ventricle seen in SH (higher LV mass index, impaired diastolic filling). We did not prove an association between BP and polymorphism of ACE and angiotensinogen genes, however, our findings of association of DD genotype for ACE and M235 for angiotensinogen with higher insulinemia, plasma catecholamines and plasma renin activity evoke the hypothesis, whether the bearers of these genotypes, exposed for long-time to the higher concentrations of vascoactive substances, are not the subset of hereditary threatened subjects in whom clinically evident EH will manifest during their life.

Topics: Adult; Angiotensinogen; C-Peptide; Disease Susceptibility; Echocardiography; Epinephrine; Genotype; Humans; Hyperinsulinism; Hypertension; Kallikreins; Male; Norepinephrine; Peptidyl-Dipeptidase A; Polymorphism, Genetic

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.

Topics: Adipose Tissue; Angiotensinogen; Animals; Blood Glucose; Body Composition; Body Weight; Gene Expression Regulation; Glucosamine; Glucose Clamp Technique; Hexosamines; Hyperglycemia; Hyperinsulinism; Infusions, Intravenous; Insulin; Insulin Resistance; Liver; Male; Obesity; Rats; Rats, Sprague-Dawley