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Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders.
Allu, Prasanna K R; Kiranmayi, Malapaka; Mukherjee, Sromona D; Chirasani, Venkat R; Garg, Richa; Vishnuprabu, Durairajpandian; Ravi, Sudesh; Subramanian, Lakshmi; Sahu, Bhavani S; Iyer, Dhanya R; Maghajothi, Sakthisree; Sharma, Saurabh; Ravi, Marimuthu S; Khullar, Madhu; Munirajan, Arasambattu K; Gayen, Jiaur R; Senapati, Sanjib; Mullasari, Ajit S; Mohan, Viswanathan; Radha, Venkatesan; Naga Prasad, Sathyamangala V; Mahapatra, Nitish R.
Afiliación
  • Allu PKR; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Kiranmayi M; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Mukherjee SD; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
  • Chirasani VR; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Garg R; Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India.
  • Vishnuprabu D; Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.
  • Ravi S; Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.
  • Subramanian L; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Sahu BS; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Iyer DR; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Maghajothi S; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Sharma S; Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
  • Ravi MS; Department of Cardiology, Madras Medical College and Government General Hospital, Chennai, India.
  • Khullar M; Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
  • Munirajan AK; Department of Genetics, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.
  • Gayen JR; Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, India.
  • Senapati S; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
  • Mullasari AS; Institute of Cardiovascular Diseases, Madras Medical Mission, Chennai, India.
  • Mohan V; Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, India.
  • Radha V; Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, India.
  • Naga Prasad SV; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
  • Mahapatra NR; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India.
Diabetes ; 71(3): 538-553, 2022 03 01.
Article en En | MEDLINE | ID: mdl-34862200
ABSTRACT
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.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Predisposición Genética a la Enfermedad / Cromogranina A / Enfermedades Metabólicas Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Humans País/Región como asunto: Asia Idioma: En Año: 2022 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Enfermedades Cardiovasculares / Predisposición Genética a la Enfermedad / Cromogranina A / Enfermedades Metabólicas Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Humans País/Región como asunto: Asia Idioma: En Año: 2022 Tipo del documento: Article