pancreastatin and Hypertension

Pancreastatin (PST) is a regulatory peptide containing 49 amino acids, first isolated from porcine pancreas. Intracellular and extracellular processing of the prohormone Chromogranin A (Chga) results various bioactive peptides of which PST has dysglycemic activity. PST regulates glucose, lipid, and protein metabolism in liver and adipose tissues. It also regulates the secretion of leptin and expression of leptin and uncoupling protein 2 in adipose tissue. In Chga knockout mice, PST induces gluconeogenesis in the liver. PST reduces glucose uptake in mice hepatocytes and adipocytes. In rat hepatocytes, PST induces glycogenolysis and glycolysis and inhibits glycogen synthesis. In rat adipocytes, PST inhibits lactate production and lipogenesis. These metabolic effects are confirmed in humans. In the dual signaling mechanism of PST receptor, mostly PST activates Gαq/11 protein leads to the activation of phospholipase C β3-isoform, therefore increasing cytoplasmic free calcium and stimulating protein kinase C. PST inhibits the cell growth in rat HTC hepatoma cells, mediated by nitric oxide and cyclic GMP production. Elevated levels of PST correlating with catecholamines have been found in gestational diabetes and essential hypertension. Rise in the blood PST level in Type 2 diabetes suggests that PST is a negative regulator of insulin sensitivity and glucose homeostasis.

Topics: Adipocytes; Amino Acid Sequence; Animals; Chromogranin A; Diabetes Mellitus; Diabetes, Gestational; Female; Glucose; Homeostasis; Humans; Hypertension; Liver; Molecular Sequence Data; Muscle Cells; Mutation; Pancreatic Hormones; Phylogeny; Pregnancy

Pancreastatin (PST), a chromogranin A-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a nonsynonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic disease states in Indian populations (n = 4,300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure, and catecholamines in Gly/Ser subjects as compared with wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (∼1.3-1.6-fold) for type 2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secretion, and greater inhibition of insulin-stimulated glucose uptake) than the wild-type peptide. Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor than the wild-type peptide, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and insulin receptor. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Catecholamines; Cell Line; Cell Line, Tumor; Chromogranin A; Coronary Artery Disease; Diabetes Mellitus, Type 2; Endoplasmic Reticulum Chaperone BiP; Genetic Association Studies; Genetic Predisposition to Disease; Hep G2 Cells; Humans; Hypertension; India; Metabolic Diseases; Peptides; Polymorphism, Single Nucleotide; Rats; Receptor, Insulin

Pancreastatin is a regulatory peptide known to inhibit insulin secretion and insulin action with a glycogenolytic effect in the liver. This peptide is present in and secreted by many endocrine and chromaffin cells. Abnormalities of glucose, insulin and lipoprotein metabolism are common in patients with hypertension, as well as their first-degree relatives. We have recently studied a group of non-obese hypertensive subjects in which pancreastatin-like levels were increased compared with controls, and correlated with norepinephrine levels. We hypothesized that pancreastatin alongside the sympathoadrenal system might have a part in the insulin resistance of these patients, and this metabolic syndrome could play a role in the pathogenesis and complications of hypertension. In this article, we studied the normotensive offspring of these nonobese hypertensive patients and looked for metabolic abnormalities as well as plasma pancreastatin, glucagon and catecholamine levels. The subjects were separated into two groups: (1) offspring from non-insulin-resistant patients and (2) offspring from insulin-resistant patients. We found that after an intravenous glucose load, offspring from insulin-resistant patients were already hyperinsulinemic, although glucose clearance was normal, suggesting an early alteration in insulin sensitivity, whereas pancreastatin and catecholamine levels were normal compared with matched controls. However, offspring from non-insulin-resistant patients had no differences with controls. These results suggest that pancreastatin and catecholamines may not play an important role in triggering insulin resistance, although they may be important once the syndrome is established.

Topics: Adult; Blood Glucose; Catecholamines; Cholesterol, HDL; Chromogranin A; Female; Glucose Tolerance Test; Humans; Hypertension; Insulin; Insulin Resistance; Male; Metabolic Clearance Rate; Pancreatic Hormones; Triglycerides

Pancreastatin (PST), a 49 amino acid peptide originally isolated from porcine pancreas, is derived from chromogranin A (Cg A), an acidic protein co-released with catecholamines from sympathetic nerve terminals and chromaffin cells. Extracellular processing of Cg A yields PST as well as other biological active peptides. Measurement of Cg A and PST-like immunoreactivity (PST-LI) has been used to investigate patients with pheochromocytoma and other neuroendocrine neoplasia. Some studies have found increased plasma norepinephrine (NE) levels in essential hypertension. We therefore measured venous plasma PST-LI and catecholamines in patients with essential hypertension. We employed a radioimmunoassay developed with commercially available reagents for measuring plasma PST-like immunoreactivity, and HPLC with electrochemical detection for measurement of plasma catecholamines. The correlation of PST-LI with epinephrine (E) was very weak. However, its correlation with NE was highly significant. Thus, venous plasma PST-LI immunoreactivity may reflect sympathetic nerve activity in essential hypertension.

Topics: Adult; Animals; Chromogranin A; Cross Reactions; Dose-Response Relationship, Immunologic; Epinephrine; Humans; Hypertension; Middle Aged; Norepinephrine; Pancreatic Hormones; Radioimmunoassay; Rats; Swine

Pancreastatin, a novel peptide, is known to inhibit insulin secretion and to have a glycogenolytic effect, and is present in many endocrine and chromaffin cells. Both the plasma insulin levels and the adrenergic activity accompanying insulin resistance have been shown to be increased in hypertensive subjects. Our working hypothesis was that pancreastatin might play a role in these pathological phenomena.. We studied the plasma pancreastatin level in non-obese essential hypertensive patients in response to an intravenous glucose load. We further measured the responses to the glucose challenge of insulin, glucagon, catecholamines and free fatty acids, as well as other factors related to insulin resistance (i.e. lipoproteins and apolipoproteins). We separated the hypertensive patients into three groups according to their response to an oral glucose-tolerance test: normoinsulinaemic, hyperinsulinaemic and glucose-intolerant. Matched normotensive control subjects were also studied.. Pancreastatin levels did not change in the control group after the glucose challenge. However, all hypertensive patients showed an increase in plasma pancreastatin levels after glucose loading. The normoinsulinaemic hypertensive patients also had elevated basal pancreastatin levels. The increase in pancreastatin levels was in the ranking: normoinsulinaemic > hyperinsulinaemic > glucose-intolerant. The pancreastatin: insulin ratio showed that the secretion of pancreastatin and insulin may be regulated differently. Basal free fatty acid and glucagon levels were found to be elevated both in the hyperinsulinaemic and in the glucose-intolerant group. Fasting triglycerides levels were increased in all of the hypertensive patients. Other risk factors for coronary artery disease were also found to be altered: elevated very low-density lipoprotein-cholesterol and decreased high-density lipoprotein-cholesterol, with ranking: normoinsulinaemic < hyperinsulinaemic < glucose-intolerant.. These results show an increase in pancreastatin levels in hypertensive patients, suggesting that pancreastatin might play a role in the pathophysiology of essential hypertension.

Topics: Adult; Antibodies; Chromogranin A; Fasting; Female; Glucose; Glucose Tolerance Test; Humans; Hypertension; Male; Middle Aged; Pancreatic Hormones; Radioimmunoassay