Insulin resistance often accompanies hypertension in human disease independent of obesity or frank diabetes. Mechanisms have been proposed for this phenomenon, including insulin-mediated sympathetic nerve activation and blunted insulin-induced vasodilatation in insulin-resistant states. A growing body of evidence suggests that the catecholamine vesicle protein chromogranin A (or CgA) functions as a pro-hormone and is proteolytically cleaved into a dysglycemic peptide, named pancreastatin (PST). PST counters the effects of insulin in cell lines and animal models, and elevated levels of the peptide are found in both diabetics and patients with essential hypertension. Moreover, plasma PST levels in humans correlate with those of norepinephrine, suggesting a novel mechanism linking hypertension to insulin resistance. However, the biological activity of PST in humans in vivo has not been studied. In this proposal, the investigators will examine the effects of PST on glucose uptake in humans in vivo, utilizing the human forearm model. They have developed a program in which they obtain and administer purified, synthetic PST according to the regulations of the U.S. Food and Drug Administration (FDA) and their local Institutional Review Board (IRB). Following cannulation of the brachial arterial and antecubital venous glucose levels), they will determine whether PST exerts effects that are hemodynamic and/or metabolic. Preliminary data suggests that PST alters forearm glucose uptake by decreasing [A-V]glucose, but does not affect FBF. In addition to physiological studies of the human forearm, they will attempt to better characterize the link of PST to human disease. Specifically, they will use plasma from approximately n=400 individuals, stratified by age, sex, ethnicity, genetic risk of hypertension, and presence/absence of hypertension. Plasma PST will be measured with the purpose of better characterizing the statistical correlation with disease states such as hypertension and diabetes.
| Cadman, Peter E; O'Connor, Daniel T (2003) Pharmacogenomics of hypertension. Curr Opin Nephrol Hypertens 12:61-70 |
