Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders

Abstract

Pancreastatin (PST), a chromogranin A (CHGA)-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a non-synonymous 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 diseases states in Indian populations (n≈4300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure and catecholamines in Gly/Ser subjects as compared to 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, greater inhibition of insulin-stimulated glucose-uptake) than the wild-type peptide (PST-WT). Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor (IR) than PST-WT, 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 IR. 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.

The immunomodulatory functions of chromogranin A-derived peptide pancreastatin

“…These data were consistent with enhanced inhibition of insulin-stimulated glucose uptake from blood and increased expression of glucose-6-phosphatase (G6pc; mouse: G6pc) and phosphoenolpyruvate (mouse: Pck1), genes involved in gluconeogenesis, in wild-type mice treated with PST [32]. More recently, in silico and in vitro assays predicted a higher binding affinity of the Ser 297 variant with the glucose-regulated protein 78 (GRP78), an endoplasmic chaperon involved in multiple cellular processes, and the insulin receptor compared to wild-type PST [109,110]. Interestingly, experimentally deletion of three N-terminal amino acids (Pro-Glu-Gly) showed a decrease in plasma glucose and hepatic gluconeogenesis in diet-induced obesity mice [34].…”

“…Recently, PST has been shown to also bind to the Insulin receptor [110], a tyrosine kinase receptor. Treating insulin-sensitive HTC hepatoma cells with PST inhibited insulin action and signaling in a dose-dependent manner.…”

“…PST weakened downstream signaling of the Insulin receptor, including insulin-receptor substrate (IRS)− 1/IRS-2 and p62 phosphorylation. Recent in silico modeling and in vitro competitive binding assays using [125] I-Tyr insulin strengthened the interaction of PST with GRP78 and the Insulin receptor [110]. At least part of the metabolic and immunomodulatory effects of PST might be due to its binding to the Insulin receptor.…”