内分泌学
内科学
胰岛素
2型糖尿病
葡萄糖稳态
生物
代谢综合征
糖尿病
胰岛素抵抗
医学
作者
Prasanna K.R. Allu,Malapaka Kiranmayi,Sromona Mukherjee,Venkat R. Chirasani,Richa Garg,Vishnuprabu Durairaj Pandian,Ravi Sudesh,Lakshmi Subramanian,Bhavani S. Sahu,Dhanya R. Iyer,Sakthisree Maghajothi,Saurabh Sharma,Marimuthu Shanmugam Ravi,Madhu Khullar,Arasambattu Kannan Munirajan,Jiaur R. Gayen,Sanjib Senapati,Ajit S. Mullasari,Viswanathan Mohan,Venkatesan Radha
出处
期刊:Diabetes
[American Diabetes Association]
日期:2021-12-03
卷期号:71 (3): 538-553
被引量:5
摘要
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.
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