The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

被引:980
作者
Samuel, Varman T. [1 ,2 ]
Shulman, Gerald I. [1 ,3 ,4 ]
机构
[1] Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 USA
[2] Vet Affairs Med Ctr, West Haven, CT USA
[3] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA
[4] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA
关键词
FATTY LIVER-DISEASE; PROTEIN-KINASE-C; ELEMENT-BINDING PROTEIN; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; GLUCOSE-TRANSPORTER TRANSLOCATION; MAGNETIC-RESONANCE-SPECTROSCOPY; HEPATIC GLYCOGEN-SYNTHESIS; ADIPOSE-TISSUE LIPOLYSIS; TYPE-2 DIABETIC PARENTS; PITUITARY-ADRENAL AXIS;
D O I
10.1172/JCI77812
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetylCoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.
引用
收藏
页码:12 / 22
页数:11
相关论文
共 128 条
[41]   Adipose tissue as an endocrine organ [J].
Kershaw, EE ;
Flier, JS .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2004, 89 (06) :2548-2556
[42]   Physiological regulation of lipoprotein lipase [J].
Kersten, Sander .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2014, 1841 (07) :919-933
[43]   Obesity-associated improvements in metabolic profile through expansion of adipose tissue [J].
Kim, Ja-Young ;
De Wall, Esther Van ;
Laplante, Mathieu ;
Azzara, Anthony ;
Trujillo, Maria E. ;
Hofmann, Susanna M. ;
Schraw, Todd ;
Durand, Jorge L. ;
Li, Hua ;
Li, Guangyu ;
Jelicks, Linda A. ;
Mehler, Mark F. ;
Hui, David Y. ;
Deshaies, Yves ;
Shulman, Gerald I. ;
Schwartz, Gary J. ;
Scherer, Philipp E. .
JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (09) :2621-2637
[44]   Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle [J].
Kim, JK ;
Michael, MD ;
Previs, SF ;
Peroni, OD ;
Mauvais-Jarvis, F ;
Neschen, S ;
Kahn, BB ;
Kahn, CR ;
Shulman, GI .
JOURNAL OF CLINICAL INVESTIGATION, 2000, 105 (12) :1791-1797
[45]   Mechanism of insulin resistance in A-ZIP/F-1 fatless mice [J].
Kim, JK ;
Gavrilova, O ;
Chen, Y ;
Reitmann, ML ;
Shulman, GI .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (12) :8456-8460
[46]   Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance [J].
Kim, JK ;
Fillmore, JJ ;
Chen, Y ;
Yu, CL ;
Moore, IK ;
Pypaert, M ;
Lutz, EP ;
Kako, Y ;
Velez-Carrasco, W ;
Goldberg, IJ ;
Breslow, JL ;
Shulman, GI .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (13) :7522-7527
[47]   Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4 [J].
Kim, JK ;
Zisman, A ;
Fillmore, JJ ;
Peroni, OD ;
Kotani, K ;
Perret, P ;
Zong, HH ;
Dong, JY ;
Kahn, CR ;
Kahn, BB ;
Shulman, GI .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 108 (01) :153-160
[48]   Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans:: a 1H NMR spectroscopy study [J].
Krssak, M ;
Petersen, KF ;
Dresner, A ;
DiPietro, L ;
Vogel, SM ;
Rothman, DL ;
Shulman, GI ;
Roden, M .
DIABETOLOGIA, 1999, 42 (01) :113-116
[49]   Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease [J].
Kumashiro, Naoki ;
Erion, Derek M. ;
Zhang, Dongyan ;
Kahn, Mario ;
Beddow, Sara A. ;
Chu, Xin ;
Still, Christopher D. ;
Gerhard, Glenn S. ;
Han, Xianlin ;
Dziura, James ;
Petersen, Kitt Falk ;
Samuel, Varman T. ;
Shulman, Gerald I. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (39) :16381-16385
[50]   NF-κB is important for TNF-α-induced lipolysis in human adipocytes [J].
Laurencikiene, Jurga ;
van Harmelen, Vanessa ;
Nordstrom, Elisabet Arvidsson ;
Dicker, Andrea ;
Blomqvist, Lennart ;
Naslund, Erik ;
Langin, Dominique ;
Arner, Peter ;
Ryden, Mikael .
JOURNAL OF LIPID RESEARCH, 2007, 48 (05) :1069-1077