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

Charlie J. Lavilla; Merell P. Billacura; Katie Hanna; David J. Boocock; Clare Coveney; Amanda K. Miles; Gemma A. Foulds; Alice Murphy; Arnold Tan; Laura Jackisch; Sophie R. Sayers; Paul W. Caton; Craig L. Doig; Philip G. McTernan; Sergio L. Colombo; Craig Sale; Mark D. Turner

doi:10.1016/j.freeradbiomed.2021.08.233

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

Charlie J. Lavilla, Merell P. Billacura, Katie Hanna, David J. Boocock, Clare Coveney, Amanda K. Miles, Gemma A. Foulds, Alice Murphy, Arnold Tan, Laura Jackisch, Sophie R. Sayers, Paul W. Caton, Craig L. Doig, Philip G. McTernan, Sergio L. Colombo, Craig Sale, Mark D. Turner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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.

Original language	English
Pages (from-to)	65-79
Number of pages	15
Journal	Free Radical Biology and Medicine
Volume	175
DOIs	https://doi.org/10.1016/j.freeradbiomed.2021.08.233
Publication status	Published - 1 Nov 2021

Keywords

Gestational diabetes
Glucolipotoxicity
GLUT4 translocation
Obesity
Reactive species scavenging
Type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.freeradbiomed.2021.08.233

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Lavilla, C. J., Billacura, M. P., Hanna, K., Boocock, D. J., Coveney, C., Miles, A. K., Foulds, G. A., Murphy, A., Tan, A., Jackisch, L., Sayers, S. R., Caton, P. W., Doig, C. L., McTernan, P. G., Colombo, S. L., Sale, C., & Turner, M. D. (2021). Carnosine protects stimulus-secretion coupling through prevention of protein carbonyl adduction events in cells under metabolic stress. Free Radical Biology and Medicine, 175, 65-79. https://doi.org/10.1016/j.freeradbiomed.2021.08.233

@article{a0e9b8299ffd4832b98ec7b228dea14c,

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

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.",

keywords = "Gestational diabetes, Glucolipotoxicity, GLUT4 translocation, Obesity, Reactive species scavenging, Type 2 diabetes",

author = "Lavilla, {Charlie J.} and Billacura, {Merell P.} and Katie Hanna and Boocock, {David J.} and Clare Coveney and Miles, {Amanda K.} and Foulds, {Gemma A.} and Alice Murphy and Arnold Tan and Laura Jackisch and Sayers, {Sophie R.} and Caton, {Paul W.} and Doig, {Craig L.} and McTernan, {Philip G.} and Colombo, {Sergio L.} and Craig Sale and Turner, {Mark D.}",

note = "Funding Information: This study was funded by grant awards from the British Council (grant award numbers: 209524711 ; 279698970 ) and Diabetes UK ( 11/0004417 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = nov,

day = "1",

doi = "10.1016/j.freeradbiomed.2021.08.233",

language = "English",

volume = "175",

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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 & 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, vol. 175, pp. 65-79. https://doi.org/10.1016/j.freeradbiomed.2021.08.233

TY - JOUR

T1 - Carnosine protects stimulus-secretion coupling through prevention of protein carbonyl adduction events in cells under metabolic stress

AU - Lavilla, Charlie J.

AU - Billacura, Merell P.

AU - Hanna, Katie

AU - Boocock, David J.

AU - Coveney, Clare

AU - Miles, Amanda K.

AU - Foulds, Gemma A.

AU - Murphy, Alice

AU - Tan, Arnold

AU - Jackisch, Laura

AU - Sayers, Sophie R.

AU - Caton, Paul W.

AU - Doig, Craig L.

AU - McTernan, Philip G.

AU - Colombo, Sergio L.

AU - Sale, Craig

AU - Turner, Mark D.

N1 - Funding Information: This study was funded by grant awards from the British Council (grant award numbers: 209524711 ; 279698970 ) and Diabetes UK ( 11/0004417 ). Publisher Copyright: © 2021 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/11/1

Y1 - 2021/11/1

N2 - 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.

AB - 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.

KW - Gestational diabetes

KW - Glucolipotoxicity

KW - GLUT4 translocation

KW - Obesity

KW - Reactive species scavenging

KW - Type 2 diabetes

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DO - 10.1016/j.freeradbiomed.2021.08.233

M3 - Article

AN - SCOPUS:85114160650

SN - 0891-5849

VL - 175

SP - 65

EP - 79

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

ER -

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

Abstract

Keywords

UN SDGs

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