Carnosine protects stimulus-secretion coupling through prevention of protein carbonyl adduction events in cells under metabolic stress

Lavilla, CJ, Billacura, MP, Hanna, K, Boocock, DJ, Coveney, C, Miles, AK, Foulds, GA, Murphy, A, Tan, A, Jackisch, L, Sayers, SR, Caton, PW, Doig, CL, McTernan, PG, Colombo, SL, Sale, C ORCID: https://orcid.org/0000-0002-5816-4169 and Turner, MD (2021) Carnosine protects stimulus-secretion coupling through prevention of protein carbonyl adduction events in cells under metabolic stress. Free Radical Biology and Medicine, 175. pp. 65-79. ISSN 0891-5849

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Abstract

Type 2 diabetes is characterised by failure to control glucose homeostasis, with numerous diabetic complications attributable to the resulting exposure of cells and tissues to chronic elevated concentrations of glucose and fatty acids. This, in part, results from formation of advanced glycation and advanced lipidation end-products that are able to modify protein, lipid, or DNA structure, and disrupt normal cellular function. Herein we used mass spectrometry to identify proteins modified by two such adduction events in serum of individuals with obesity, type 2 diabetes, and gestational diabetes, along with similar analyses of human and mouse skeletal muscle cells and mouse pancreatic islets exposed to glucolipotoxic stress. We also report that carnosine, a histidine containing dipeptide, prevented 65–90% of 4-hydroxynonenal and 3-nitrotyrosine adduction events, and that this in turn preserved mitochondrial function and protected stimulus-secretion coupling in cells exposed to metabolic stress. Carnosine therefore offers significant therapeutic potential against metabolic diseases.

Item Type:	Article
Peer-reviewed:	Yes
Date Deposited:	24 Oct 2022 11:46
Publisher:	Elsevier
Additional Information:	This is an Accepted Manuscript of an article which appeared in Free Radical Biology and Medicine, published by Elsevier
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Endocrinology & Metabolism, Type 2 diabetes, Obesity, Gestational diabetes, Glucolipotoxicity, Reactive species scavenging, GLUT4 translocation, ENDOPLASMIC-RETICULUM, OXIDATIVE STRESS, SKELETAL-MUSCLE, SIGNALING PATHWAYS, INSULIN-RESISTANCE, SYNAPTOTAGMIN III, GRANULE DYNAMICS, FUNCTIONAL-ROLE, BETA-ALANINE, GLUCOSE, Animals, Mice, Diabetes Mellitus, Type 2, Diabetes Complications, Carnosine, Oxidative Stress, Protein Carbonylation, Glycation End Products, Advanced, GLUT4 translocation, Gestational diabetes, Glucolipotoxicity, Obesity, Reactive species scavenging, Type 2 diabetes, Animals, Carnosine, Diabetes Complications, Diabetes Mellitus, Type 2, Glycation End Products, Advanced, Mice, Oxidative Stress, Protein Carbonylation, 0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology
URI:	https://e-space.mmu.ac.uk/id/eprint/630599
DOI:	https://doi.org/10.1016/j.freeradbiomed.2021.08.233
ISSN	0891-5849
e-ISSN	1873-4596

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