Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease

被引:721
作者
Shulman, Gerald I. [1 ,2 ,3 ]
机构
[1] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA
[2] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA
[3] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA
关键词
PROTEIN-KINASE-C; MAGNETIC-RESONANCE-SPECTROSCOPY; MUSCLE GLYCOGEN-SYNTHESIS; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; GLUCOSE-TRANSPORT-PHOSPHORYLATION; INDUCED HEPATIC STEATOSIS; TYPE-2 DIABETIC PARENTS; SKELETAL-MUSCLE; LIVER-DISEASE; MITOCHONDRIAL DYSFUNCTION;
D O I
10.1056/NEJMra1011035
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Type 2 diabetes currently affects more than a third of a billion people worldwide and is the leading cause of end-stage renal disease, nontraumatic loss of limb, and blindness in working adults, with estimated annual worldwide health care costs exceeding half a trillion dollars. 1 Furthermore, the worldwide prevalence of type 2 diabetes is projected to increase by more than 75% during the next two decades, with the largest increases occurring in Asia and the Indian subcontinent. 1 Although impaired beta-cell function is ultimately responsible for the progression from normoglycemia to hyperglycemia, insulin resistance predates beta-cell dysfunction and plays a major role in the pathogenesis of type 2 diabetes. 2,3 After carbohydrate ingestion, glucose is deposited primarily in muscle and the liver as glycogen, and alterations in insulin responsiveness in these organs result in fasting and postprandial hyperglycemia. 4,5.; In this review, I focus on recent studies using magnetic resonance spectroscopy (MRS) that have implicated ectopic lipid accumulation in the pathogenesis of insulin resistance in muscle and the liver and have clarified the role of muscle-specific insulin resistance in promoting increased hepatic lipogenesis, nonalcoholic fatty liver disease, and atherogenic dyslipidemia. I then propose a potential link between inflammation and macrophage-induced lipolysis in the progression from ectopic lipid-induced insulin resistance to impaired glucose tolerance and type 2 diabetes. Copyright © 2014 Massachusetts Medical Society.
引用
收藏
页码:1131 / 1141
页数:11
相关论文
共 73 条
[1]   Dissociation Between Intrahepatic Triglyceride Content and Insulin Resistance in Familial Hypobetalipoproteinemia [J].
Amaro, Anastassia ;
Fabbrini, Elisa ;
Kars, Marleen ;
Yue, Pin ;
Schechtman, Kenneth ;
Schonfeld, Gustav ;
Klein, Samuel .
GASTROENTEROLOGY, 2010, 139 (01) :149-153
[2]   Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance Another Paradox in Endurance-Trained Athletes? [J].
Amati, Francesca ;
Dube, John J. ;
Alvarez-Carnero, Elvis ;
Edreira, Martin M. ;
Chomentowski, Peter ;
Coen, Paul M. ;
Switzer, Galen E. ;
Bickel, Perry E. ;
Stefanovic-Racic, Maja ;
Toledo, Frederico G. S. ;
Goodpaster, Bret H. .
DIABETES, 2011, 60 (10) :2588-2597
[3]   Nonalcoholic fatty liver disease [J].
Brunt, Elizabeth M. ;
Wong, Vincent W. -S. ;
Nobili, Valerio ;
Day, Christopher P. ;
Sookoian, Silvia ;
Maher, Jacquelyn J. ;
Bugianesi, Elisabetta ;
Sirlin, Claude B. ;
Neuschwander-Tetri, BrentA. ;
Rinella, Mary E. .
NATURE REVIEWS DISEASE PRIMERS, 2015, 1
[4]  
[Anonymous], 2014, IDF Diabetes Atlas, V6th
[5]   Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients [J].
Befroy, Douglas E. ;
Petersen, Kitt Falk ;
Dufour, Sylvie ;
Mason, Graeme F. ;
de Graaf, Robin A. ;
Rothman, Douglas L. ;
Shulman, Gerald I. .
DIABETES, 2007, 56 (05) :1376-1381
[6]   A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis [J].
Belfort, Renata ;
Harrison, Stephen A. ;
Brown, Kenneth ;
Darland, Celia ;
Finch, Joan ;
Hardies, Jean ;
Balas, Bogdan ;
Gastaldelli, Amalia ;
Tio, Fermin ;
Pulcini, Joseph ;
Berria, Rachele ;
Ma, Jennie Z. ;
Dwivedi, Sunil ;
Havranek, Russell ;
Fincke, Chris ;
DeFronzo, Ralph ;
Bannayan, George A. ;
Schenker, Steven ;
Cusi, Kenneth .
NEW ENGLAND JOURNAL OF MEDICINE, 2006, 355 (22) :2297-2307
[7]   Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy [J].
Boumezbeur, Fawzi ;
Mason, Graeme F. ;
de Graaf, Robin A. ;
Behar, Kevin L. ;
Cline, Gary W. ;
Shulman, Gerald I. ;
Rothman, Douglas L. ;
Petersen, Kitt F. .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2010, 30 (01) :211-221
[8]   Cellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice [J].
Camporez, Joao Paulo G. ;
Jornayvaz, Francois R. ;
Petersen, Max C. ;
Pesta, Dominik ;
Guigni, Blas A. ;
Serr, Julie ;
Zhang, Dongyan ;
Kahn, Mario ;
Samuel, Varman T. ;
Jurczak, Michael J. ;
Shulman, Gerald I. .
ENDOCRINOLOGY, 2013, 154 (09) :3099-3109
[9]   Cellular Mechanism by Which Estradiol Protects Female Ovariectomized Mice From High-Fat Diet-Induced Hepatic and Muscle Insulin Resistance [J].
Camporez, Joao Paulo G. ;
Jornayvaz, Francois R. ;
Lee, Hui-Young ;
Kanda, Shoichi ;
Guigni, Blas A. ;
Kahn, Mario ;
Samuel, Varman T. ;
Carvalho, Carla R. O. ;
Petersen, Kitt Falk ;
Jurczak, Michael J. ;
Shulman, Gerald I. .
ENDOCRINOLOGY, 2013, 154 (03) :1021-1028
[10]   CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance [J].
Cantley, Jennifer L. ;
Yoshimura, Toru ;
Camporez, Joao Paulo G. ;
Zhang, Dongyan ;
Jornayvaz, Francois R. ;
Kumashiro, Naoki ;
Guebre-Egziabher, Fitsum ;
Jurczak, Michael J. ;
Kahn, Mario ;
Guigni, Blas A. ;
Serr, Julie ;
Hankin, Joseph ;
Murphy, Robert C. ;
Cline, Gary W. ;
Bhanot, Sanjay ;
Manchem, Vara Prasad ;
Brown, J. Mark ;
Samuel, Varman T. ;
Shulman, Gerald I. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (05) :1869-1874