Obesity-Related Insulin Resistance: The Central Role of Adipose Tissue Dysfunction.
Adipose tissue insulin resistance
Ceramides
Diacylglycerols
Hepatic insulin resistance
Lipidomic remodeling
Lipotoxicity
Muscle insulin resistance
Journal
Handbook of experimental pharmacology
ISSN: 0171-2004
Titre abrégé: Handb Exp Pharmacol
Pays: Germany
ID NLM: 7902231
Informations de publication
Date de publication:
2022
2022
Historique:
pubmed:
23
2
2022
medline:
26
7
2022
entrez:
22
2
2022
Statut:
ppublish
Résumé
Obesity is a key player in the onset and progression of insulin resistance (IR), a state by which insulin-sensitive cells fail to adequately respond to insulin action. IR is a reversible condition, but if untreated leads to type 2 diabetes alongside increasing cardiovascular risk. The link between obesity and IR has been widely investigated; however, some aspects are still not fully characterized.In this chapter, we introduce key aspects of the pathophysiology of IR and its intimate connection with obesity. Specifically, we focus on the role of adipose tissue dysfunction (quantity, quality, and distribution) as a driver of whole-body IR. Furthermore, we discuss the obesity-related lipidomic remodeling occurring in adipose tissue, liver, and skeletal muscle. Key mechanisms linking lipotoxicity to IR in different tissues and metabolic alterations (i.e., fatty liver and diabetes) and the effect of weight loss on IR are also reported while highlighting knowledge gaps.
Identifiants
pubmed: 35192055
doi: 10.1007/164_2021_573
doi:
Substances chimiques
Insulins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
145-164Informations de copyright
© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.
Références
Abdul-Ghani MA, Matsuda M, Balas B, DeFronzo RA (2007) Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care 30(1):89–94. https://doi.org/10.2337/dc06-1519
doi: 10.2337/dc06-1519
pubmed: 17192339
Adams JM 2nd, Pratipanawatr T, Berria R et al (2004) Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 53(1):25–31. https://doi.org/10.2337/diabetes.53.1.25
doi: 10.2337/diabetes.53.1.25
pubmed: 14693694
Alligier M, Gabert L, Meugnier E et al (2013) Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men. J Clin Endocrinol Metab 98(2):802–810. https://doi.org/10.1210/jc.2012-3289
doi: 10.1210/jc.2012-3289
pubmed: 23284008
Amati F, Dube JJ, Alvarez-Carnero E et al (2011) Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes 60(10):2588–2597. https://doi.org/10.2337/db10-1221
doi: 10.2337/db10-1221
pubmed: 21873552
pmcid: 3178290
Anastasiou CA, Kavouras SA, Lentzas Y, Gova A, Sidossis LS, Melidonis A (2009) Diabetes mellitus is associated with increased intramyocellular triglyceride, but not diglyceride, content in obese humans. Metabolism 58(11):1636–1642. https://doi.org/10.1016/j.metabol.2009.05.019
doi: 10.1016/j.metabol.2009.05.019
pubmed: 19615699
Anderson RL, Hamman RF, Savage PJ et al (1995) Exploration of simple insulin sensitivity measures derived from frequently sampled intravenous glucose tolerance (FSIGT) tests. The insulin resistance atherosclerosis study. Am J Epidemiol 142(7):724–732. https://doi.org/10.1093/aje/142.7.724
doi: 10.1093/aje/142.7.724
pubmed: 7572943
Arner E, Westermark PO, Spalding KL et al (2010) Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes 59(1):105–109. https://doi.org/10.2337/db09-0942
doi: 10.2337/db09-0942
pubmed: 19846802
Arner P, Bernard S, Salehpour M et al (2011) Dynamics of human adipose lipid turnover in health and metabolic disease. Nature 478(7367):110–113. https://doi.org/10.1038/nature10426
doi: 10.1038/nature10426
pubmed: 21947005
pmcid: 3773935
Azzu V, Vacca M, Virtue S, Allison M, Vidal-Puig A (2020) Adipose tissue-liver cross talk in the control of whole-body metabolism: implications in nonalcoholic fatty liver disease. Gastroenterology 158(7):1899–1912. https://doi.org/10.1053/j.gastro.2019.12.054
doi: 10.1053/j.gastro.2019.12.054
pubmed: 32061598
Bastard JP, Faraj M, Karelis AD et al (2007) Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test: response to Abdul-Ghani et al. Diabetes Care 30(7):e83; author reply e84. https://doi.org/10.2337/dc07-0622
doi: 10.2337/dc07-0622
pubmed: 17596506
Bedogni G, Gastaldelli A, Manco M et al (2012) Relationship between fatty liver and glucose metabolism: a cross-sectional study in 571 obese children. Nutr Metab Cardiovasc Dis 22(2):120–126. https://doi.org/10.1016/j.numecd.2010.05.003
doi: 10.1016/j.numecd.2010.05.003
pubmed: 20880682
Belfiore F, Iannello S, Volpicelli G (1998) Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels. Mol Genet Metab 63(2):134–141. https://doi.org/10.1006/mgme.1997.2658
doi: 10.1006/mgme.1997.2658
pubmed: 9562967
Bell LN, Wang J, Muralidharan S et al (2012) Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. Hepatology 56(4):1311–1318. https://doi.org/10.1002/hep.25805
doi: 10.1002/hep.25805
pubmed: 22532269
Boden G, Shulman GI (2002) Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest 32(Suppl 3):14–23. https://doi.org/10.1046/j.1365-2362.32.s3.3.x
doi: 10.1046/j.1365-2362.32.s3.3.x
pubmed: 12028371
Boden G, Chen X, Iqbal N (1998) Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects. Diabetes 47(10):1609–1612. https://doi.org/10.2337/diabetes.47.10.1609
doi: 10.2337/diabetes.47.10.1609
pubmed: 9753299
Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA (1990) Obesity and insulin resistance in humans: a dose-response study. Metabolism 39(5):452–459. https://doi.org/10.1016/0026-0495(90)90002-t
doi: 10.1016/0026-0495(90)90002-t
pubmed: 2186255
Bourbon NA, Sandirasegarane L, Kester M (2002) Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest. J Biol Chem 277(5):3286–3292. https://doi.org/10.1074/jbc.M110541200
doi: 10.1074/jbc.M110541200
pubmed: 11723139
Brandon AE, Liao BM, Diakanastasis B et al (2019) Protein kinase C epsilon deletion in adipose tissue, but not in liver, improves glucose tolerance. Cell Metab 29(1):183–191 e187. https://doi.org/10.1016/j.cmet.2018.09.013
doi: 10.1016/j.cmet.2018.09.013
pubmed: 30318338
Bril F, Barb D, Portillo-Sanchez P et al (2017) Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology 65(4):1132–1144. https://doi.org/10.1002/hep.28985
doi: 10.1002/hep.28985
pubmed: 27981615
Brouwers B, Schrauwen-Hinderling VB, Jelenik T et al (2017) Metabolic disturbances of non-alcoholic fatty liver resemble the alterations typical for type 2 diabetes. Clin Sci (Lond) 131(15):1905–1917. https://doi.org/10.1042/CS20170261
doi: 10.1042/CS20170261
Bugianesi E, Gastaldelli A, Vanni E et al (2005) Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48(4):634–642. https://doi.org/10.1007/s00125-005-1682-x
doi: 10.1007/s00125-005-1682-x
pubmed: 15747110
Camastra S, Gastaldelli A, Mari A et al (2011) Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes. Diabetologia 54(8):2093–2102. https://doi.org/10.1007/s00125-011-2193-6
doi: 10.1007/s00125-011-2193-6
pubmed: 21614570
Chaurasia B, Kaddai VA, Lancaster GI et al (2016) Adipocyte ceramides regulate subcutaneous adipose browning, inflammation, and metabolism. Cell Metab 24(6):820–834. https://doi.org/10.1016/j.cmet.2016.10.002
doi: 10.1016/j.cmet.2016.10.002
pubmed: 27818258
Chavez JA, Knotts TA, Wang LP et al (2003) A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J Biol Chem 278(12):10297–10303. https://doi.org/10.1074/jbc.M212307200
doi: 10.1074/jbc.M212307200
pubmed: 12525490
Choromanska B, Mysliwiec P, Razak Hady H et al (2019) Metabolic syndrome is associated with ceramide accumulation in visceral adipose tissue of women with morbid obesity. Obesity (Silver Spring) 27(3):444–453. https://doi.org/10.1002/oby.22405
doi: 10.1002/oby.22405
Coen PM, Dube JJ, Amati F et al (2010) Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content. Diabetes 59(1):80–88. https://doi.org/10.2337/db09-0988
doi: 10.2337/db09-0988
pubmed: 19833891
Coen PM, Hames KC, Leachman EM et al (2013) Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity. Obesity (Silver Spring) 21(11):2362–2371. https://doi.org/10.1002/oby.20381
doi: 10.1002/oby.20381
Cusi K, Maezono K, Osman A et al (2000) Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest 105(3):311–320. https://doi.org/10.1172/JCI7535
doi: 10.1172/JCI7535
pubmed: 10675357
pmcid: 377440
Dadson P, Ferrannini E, Landini L et al (2017) Fatty acid uptake and blood flow in adipose tissue compartments of morbidly obese subjects with or without type 2 diabetes: effects of bariatric surgery. Am J Physiol Endocrinol Metab 313(2):E175–E182. https://doi.org/10.1152/ajpendo.00044.2017
doi: 10.1152/ajpendo.00044.2017
pubmed: 28400411
Davidson LE, Yu W, Goodpaster BH et al (2018) Fat-free mass and skeletal muscle mass five years after bariatric surgery. Obesity 26(7):1130–1136. https://doi.org/10.1002/oby.22190
doi: 10.1002/oby.22190
pubmed: 29845744
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237(3):E214–E223. https://doi.org/10.1152/ajpendo.1979.237.3.E214
doi: 10.1152/ajpendo.1979.237.3.E214
pubmed: 382871
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115(5):1343–1351. https://doi.org/10.1172/JCI23621
doi: 10.1172/JCI23621
pubmed: 15864352
pmcid: 1087172
Duncan MH, Singh BM, Wise PH, Carter G, Alaghband-Zadeh J (1995) A simple measure of insulin resistance. Lancet 346(8967):120–121. https://doi.org/10.1016/s0140-6736(95)92143-5
doi: 10.1016/s0140-6736(95)92143-5
pubmed: 7603193
Fabbrini E, Magkos F, Mohammed BS et al (2009) Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A 106(36):15430–15435. https://doi.org/10.1073/pnas.0904944106
doi: 10.1073/pnas.0904944106
pubmed: 19706383
pmcid: 2741268
Fabbrini E, Sullivan S, Klein S (2010a) Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51(2):679–689. https://doi.org/10.1002/hep.23280
doi: 10.1002/hep.23280
pubmed: 20041406
Fabbrini E, Tamboli RA, Magkos F et al (2010b) Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Gastroenterology 139(2):448–455. https://doi.org/10.1053/j.gastro.2010.04.056
doi: 10.1053/j.gastro.2010.04.056
pubmed: 20457158
Fabbrini E, Magkos F, Conte C et al (2012) Validation of a novel index to assess insulin resistance of adipose tissue lipolytic activity in obese subjects. J Lipid Res 53(2):321–324. https://doi.org/10.1194/jlr.D020321
doi: 10.1194/jlr.D020321
pubmed: 22147838
pmcid: 3269158
Fredrikson G, Tornqvist H, Belfrage P (1986) Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid. Metabolism 876(2):288–293. https://doi.org/10.1016/0005-2760(86)90286-9
doi: 10.1016/0005-2760(86)90286-9
Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A (2013) Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 5(5):1544–1560. https://doi.org/10.3390/nu5051544
doi: 10.3390/nu5051544
pubmed: 23666091
pmcid: 3708335
Gaggini M, Carli F, Gastaldelli A (2017) The color of fat and its central role in the development and progression of metabolic diseases. Horm Mol Biol Clin Invest 31(1). https://doi.org/10.1515/hmbci-2017-0060
Garg A (2011) Clinical review#: lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 96(11):3313–3325. https://doi.org/10.1210/jc.2011-1159
doi: 10.1210/jc.2011-1159
pubmed: 21865368
pmcid: 7673254
Gastaldelli A (2011) Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Diabetes Res Clin Pract 93(Suppl 1):S60–S65. https://doi.org/10.1016/S0168-8227(11)70015-8
doi: 10.1016/S0168-8227(11)70015-8
pubmed: 21864753
Gastaldelli A, Ferrannini E (2014) Chapter 3: pathophysiology of prediabetes: role of lipotoxicity? In: Bergman M (ed) Global health perspectives in prediabetes and diabetes prevention, vol 1. World Scientific, Hackensack, pp 31–48
doi: 10.1142/9789814603324_0003
Gastaldelli A, Baldi S, Pettiti M et al (2000) Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49(8):1367–1373. https://doi.org/10.2337/diabetes.49.8.1367
doi: 10.2337/diabetes.49.8.1367
pubmed: 10923639
Gastaldelli A, Miyazaki Y, Pettiti M et al (2002) Metabolic effects of visceral fat accumulation in type 2 diabetes. J Clin Endocrinol Metab 87(11):5098–5103. https://doi.org/10.1210/jc.2002-020696
doi: 10.1210/jc.2002-020696
pubmed: 12414878
Gastaldelli A, Sironi AM, Ciociaro D et al (2005) Visceral fat and beta cell function in non-diabetic humans. Diabetologia 48(10):2090–2096. https://doi.org/10.1007/s00125-005-1891-3
doi: 10.1007/s00125-005-1891-3
pubmed: 16086140
Gastaldelli A, Cusi K, Pettiti M et al (2007) Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 133(2):496–506. https://doi.org/10.1053/j.gastro.2007.04.068
doi: 10.1053/j.gastro.2007.04.068
pubmed: 17681171
Gastaldelli A, Harrison SA, Belfort-Aguilar R et al (2009) Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 50(4):1087–1093. https://doi.org/10.1002/hep.23116
doi: 10.1002/hep.23116
pubmed: 19670459
Gastaldelli A, Gaggini M, DeFronzo RA (2017) Role of adipose tissue insulin resistance in the natural history of type 2 diabetes: results from the San Antonio metabolism study. Diabetes 66(4):815–822. https://doi.org/10.2337/db16-1167
doi: 10.2337/db16-1167
pubmed: 28052966
Gastaldelli A, Sabatini S, Carli F et al (2021) PPAR-gamma-induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH. Liver Int. https://doi.org/10.1111/liv.15005
Greco AV, Mingrone G, Giancaterini A et al (2002) Insulin resistance in morbid obesity: reversal with intramyocellular fat depletion. Diabetes 51(1):144–151. https://doi.org/10.2337/diabetes.51.1.144
doi: 10.2337/diabetes.51.1.144
pubmed: 11756334
Griffin JL, Atherton H, Shockcor J, Atzori L (2011) Metabolomics as a tool for cardiac research. Nat Rev Cardiol 8(11):630–643. https://doi.org/10.1038/nrcardio.2011.138
doi: 10.1038/nrcardio.2011.138
pubmed: 21931361
Groop LC, Bonadonna RC, DelPrato S et al (1989) Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84(1):205–213. https://doi.org/10.1172/JCI114142
doi: 10.1172/JCI114142
pubmed: 2661589
pmcid: 303971
Guo ZK, Cella LK, Baum C, Ravussin E, Schoeller DA (2000) De novo lipogenesis in adipose tissue of lean and obese women: application of deuterated water and isotope ratio mass spectrometry. Int J Obes Relat Metab Disord 24(7):932–937. https://doi.org/10.1038/sj.ijo.0801256
doi: 10.1038/sj.ijo.0801256
pubmed: 10918543
Haemmerle G, Zimmermann R, Hayn M et al (2002) Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem 277(7):4806–4815. https://doi.org/10.1074/jbc.M110355200
doi: 10.1074/jbc.M110355200
pubmed: 11717312
Haemmerle G, Lass A, Zimmermann R et al (2006) Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312(5774):734–737. https://doi.org/10.1126/science.1123965
doi: 10.1126/science.1123965
pubmed: 16675698
Hansen T, Drivsholm T, Urhammer SA et al (2007) The BIGTT test: a novel test for simultaneous measurement of pancreatic beta-cell function, insulin sensitivity, and glucose tolerance. Diabetes Care 30(2):257–262. https://doi.org/10.2337/dc06-1240
doi: 10.2337/dc06-1240
pubmed: 17259491
Hanson RL, Pratley RE, Bogardus C et al (2000) Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol 151(2):190–198. https://doi.org/10.1093/oxfordjournals.aje.a010187
doi: 10.1093/oxfordjournals.aje.a010187
pubmed: 10645822
Holland WL, Brozinick JT, Wang LP et al (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5(3):167–179. https://doi.org/10.1016/j.cmet.2007.01.002
doi: 10.1016/j.cmet.2007.01.002
pubmed: 17339025
Hyotylainen T, Jerby L, Petaja EM et al (2016) Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease. Nat Commun 7:8994. https://doi.org/10.1038/ncomms9994
doi: 10.1038/ncomms9994
pubmed: 26839171
pmcid: 4742839
Itani SI, Ruderman NB, Schmieder F, Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51(7):2005–2011. https://doi.org/10.2337/diabetes.51.7.2005
doi: 10.2337/diabetes.51.7.2005
pubmed: 12086926
Jo J, Gavrilova O, Pack S et al (2009) Hypertrophy and/or hyperplasia: dynamics of adipose tissue growth. PLoS Comput Biol 5(3):e1000324. https://doi.org/10.1371/journal.pcbi.1000324
doi: 10.1371/journal.pcbi.1000324
pubmed: 19325873
pmcid: 2653640
Johannsen DL, Tchoukalova Y, Tam CS et al (2014) Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the "adipose tissue expandability" hypothesis. Diabetes Care 37(10):2789–2797. https://doi.org/10.2337/dc14-0761
doi: 10.2337/dc14-0761
pubmed: 25011943
pmcid: 4170127
Kahn D, Perreault L, Macias E et al (2021) Subcellular localisation and composition of intramuscular triacylglycerol influence insulin sensitivity in humans. Diabetologia 64(1):168–180. https://doi.org/10.1007/s00125-020-05315-0
doi: 10.1007/s00125-020-05315-0
pubmed: 33128577
Katz A, Nambi SS, Mather K et al (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85(7):2402–2410. https://doi.org/10.1210/jcem.85.7.6661
doi: 10.1210/jcem.85.7.6661
pubmed: 10902785
Kelley D, Mitrakou A, Marsh H et al (1988) Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. J Clin Invest 81(5):1563–1571. https://doi.org/10.1172/JCI113489
doi: 10.1172/JCI113489
pubmed: 3130396
pmcid: 442590
Kim JY, van de Wall E, Laplante M et al (2007) Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest 117(9):2621–2637. https://doi.org/10.1172/JCI31021
doi: 10.1172/JCI31021
pubmed: 17717599
pmcid: 1950456
Kim-Dorner SJ, Deuster PA, Zeno SA, Remaley AT, Poth M (2010) Should triglycerides and the triglycerides to high-density lipoprotein cholesterol ratio be used as surrogates for insulin resistance? Metabolism 59(2):299–304. https://doi.org/10.1016/j.metabol.2009.07.027
doi: 10.1016/j.metabol.2009.07.027
pubmed: 19796777
Kissebah AH, Vydelingum N, Murray R et al (1982) Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 54(2):254–260. https://doi.org/10.1210/jcem-54-2-254
doi: 10.1210/jcem-54-2-254
pubmed: 7033275
Kolak M, Westerbacka J, Velagapudi VR et al (2007) Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity. Diabetes 56(8):1960–1968. https://doi.org/10.2337/db07-0111
doi: 10.2337/db07-0111
pubmed: 17620421
Krook A, Bjornholm M, Galuska D et al (2000) Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 49(2):284–292. https://doi.org/10.2337/diabetes.49.2.284
doi: 10.2337/diabetes.49.2.284
pubmed: 10868945
Kurek K, Miklosz A, Lukaszuk B, Chabowski A, Gorski J, Zendzian-Piotrowska M (2015) Inhibition of ceramide de novo synthesis ameliorates diet induced skeletal muscles insulin resistance. J Diabetes Res 2015:154762. https://doi.org/10.1155/2015/154762
doi: 10.1155/2015/154762
pubmed: 26380311
pmcid: 4562089
Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC (1996) Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest 98(2):378–385. https://doi.org/10.1172/JCI118803
doi: 10.1172/JCI118803
pubmed: 8755648
pmcid: 507441
Lean ME, Leslie WS, Barnes AC et al (2018) Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 391(10120):541–551. https://doi.org/10.1016/S0140-6736(17)33102-1
doi: 10.1016/S0140-6736(17)33102-1
pubmed: 29221645
Lean MEJ, Leslie WS, Barnes AC et al (2019) Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol 7(5):344–355. https://doi.org/10.1016/S2213-8587(19)30068-3
doi: 10.1016/S2213-8587(19)30068-3
pubmed: 30852132
Liebisch G, Fahy E, Aoki J et al (2020) Update on LIPID MAPS classification, nomenclature, and shorthand notation for MS-derived lipid structures. J Lipid Res 61(12):1539–1555. https://doi.org/10.1194/jlr.S120001025
doi: 10.1194/jlr.S120001025
pubmed: 33037133
pmcid: 7707175
Liggi S, Griffin JL (2017) Metabolomics applied to diabetes-lessons from human population studies. Int J Biochem Cell Biol 93:136–147. https://doi.org/10.1016/j.biocel.2017.10.011
doi: 10.1016/j.biocel.2017.10.011
pubmed: 29074437
Linge J, Heymsfield SB, Dahlqvist Leinhard O (2020) On the definition of sarcopenia in the presence of aging and obesity-initial results from UK Biobank. J Gerontol A Biol Sci Med Sci 75(7):1309–1316. https://doi.org/10.1093/gerona/glz229
doi: 10.1093/gerona/glz229
pubmed: 31642894
Listenberger LL, Han X, Lewis SE et al (2003) Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 100(6):3077–3082. https://doi.org/10.1073/pnas.0630588100
doi: 10.1073/pnas.0630588100
pubmed: 12629214
pmcid: 152249
Lomonaco R, Ortiz-Lopez C, Orsak B et al (2012) Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 55(5):1389–1397. https://doi.org/10.1002/hep.25539
doi: 10.1002/hep.25539
pubmed: 22183689
Luukkonen PK, Zhou Y, Sadevirta S et al (2016) Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol 64(5):1167–1175. https://doi.org/10.1016/j.jhep.2016.01.002
doi: 10.1016/j.jhep.2016.01.002
pubmed: 26780287
Luukkonen PK, Sadevirta S, Zhou Y et al (2018) Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care 41(8):1732–1739. https://doi.org/10.2337/dc18-0071
doi: 10.2337/dc18-0071
pubmed: 29844096
pmcid: 7082640
Mack E, Ziv E, Reuveni H et al (2008) Prevention of insulin resistance and beta-cell loss by abrogating PKCepsilon-induced serine phosphorylation of muscle IRS-1 in Psammomys obesus. Diabetes Metab Res Rev 24(7):577–584. https://doi.org/10.1002/dmrr.881
doi: 10.1002/dmrr.881
pubmed: 18613220
Magkos F, Fraterrigo G, Yoshino J et al (2016) Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab 23(4):591–601. https://doi.org/10.1016/j.cmet.2016.02.005
doi: 10.1016/j.cmet.2016.02.005
pubmed: 26916363
pmcid: 4833627
Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ (2001) A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 24(3):539–548
doi: 10.2337/diacare.24.3.539
Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22(9):1462–1470. https://doi.org/10.2337/diacare.22.9.1462
doi: 10.2337/diacare.22.9.1462
pubmed: 10480510
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419
doi: 10.1007/BF00280883
McQuaid SE, Hodson L, Neville MJ et al (2011) Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition? Diabetes 60(1):47–55. https://doi.org/10.2337/db10-0867
doi: 10.2337/db10-0867
pubmed: 20943748
Medina-Gomez G, Gray SL, Yetukuri L et al (2007) PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet 3(4):e64. https://doi.org/10.1371/journal.pgen.0030064
doi: 10.1371/journal.pgen.0030064
pubmed: 17465682
pmcid: 1857730
Mileti E, Kwok KH, Andersson DP et al (2021) Human white adipose tissue displays selective insulin resistance in the obese state. Diabetes. https://doi.org/10.2337/db21-0001
Mitrakou A, Kelley D, Veneman T et al (1990) Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39(11):1381–1390. https://doi.org/10.2337/diab.39.11.1381
doi: 10.2337/diab.39.11.1381
pubmed: 2121568
Mittendorfer B, Yoshino M, Patterson BW, Klein S (2016) VLDL triglyceride kinetics in Lean, overweight, and obese men and women. J Clin Endocrinol Metab 101(11):4151–4160. https://doi.org/10.1210/jc.2016-1500
doi: 10.1210/jc.2016-1500
pubmed: 27588438
pmcid: 5095238
Mota M, Banini BA, Cazanave SC, Sanyal AJ (2016) Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 65(8):1049–1061. https://doi.org/10.1016/j.metabol.2016.02.014
doi: 10.1016/j.metabol.2016.02.014
pubmed: 26997538
pmcid: 4931958
Perry RJ, Camporez JG, Kursawe R et al (2015) Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160(4):745–758. https://doi.org/10.1016/j.cell.2015.01.012
doi: 10.1016/j.cell.2015.01.012
pubmed: 25662011
pmcid: 4498261
Petersen MC, Shulman GI (2018) Mechanisms of insulin action and insulin resistance. Physiol Rev 98(4):2133–2223. https://doi.org/10.1152/physrev.00063.2017
doi: 10.1152/physrev.00063.2017
pubmed: 30067154
pmcid: 6170977
Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI (2005) Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54(3):603–608. https://doi.org/10.2337/diabetes.54.3.603
doi: 10.2337/diabetes.54.3.603
pubmed: 15734833
Petkevicius K, Virtue S, Bidault G et al (2019) Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity. Elife 8. https://doi.org/10.7554/eLife.47990
Phillips DI, Caddy S, Ilic V et al (1996) Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. Metabolism 45(8):947–950. https://doi.org/10.1016/s0026-0495(96)90260-7
doi: 10.1016/s0026-0495(96)90260-7
pubmed: 8769349
Pietilainen KH, Rog T, Seppanen-Laakso T et al (2011) Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans. PLoS Biol 9(6):e1000623. https://doi.org/10.1371/journal.pbio.1000623
doi: 10.1371/journal.pbio.1000623
pubmed: 21666801
pmcid: 3110175
Polyzos SA, Perakakis N, Mantzoros CS (2019) Fatty liver in lipodystrophy: a review with a focus on therapeutic perspectives of adiponectin and/or leptin replacement. Metabolism 96:66–82. https://doi.org/10.1016/j.metabol.2019.05.001
doi: 10.1016/j.metabol.2019.05.001
pubmed: 31071311
Postic C, Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 118(3):829–838. https://doi.org/10.1172/JCI34275
doi: 10.1172/JCI34275
pubmed: 18317565
pmcid: 2254980
Powell DJ, Hajduch E, Kular G, Hundal HS (2003) Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol Cell Biol 23(21):7794–7808. https://doi.org/10.1128/MCB.23.21.7794-7808.2003
doi: 10.1128/MCB.23.21.7794-7808.2003
pubmed: 14560023
pmcid: 207567
Puri P, Baillie RA, Wiest MM et al (2007) A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46(4):1081–1090. https://doi.org/10.1002/hep.21763
doi: 10.1002/hep.21763
pubmed: 17654743
Ranganathan G, Unal R, Pokrovskaya I et al (2006) The lipogenic enzymes DGAT1, FAS, and LPL in adipose tissue: effects of obesity, insulin resistance, and TZD treatment. J Lipid Res 47(11):2444–2450. https://doi.org/10.1194/jlr.M600248-JLR200
doi: 10.1194/jlr.M600248-JLR200
pubmed: 16894240
Roden M, Stingl H, Chandramouli V et al (2000) Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans. Diabetes 49(5):701–707
doi: 10.2337/diabetes.49.5.701
Rosso C, Mezzabotta L, Gaggini M et al (2016) Peripheral insulin resistance predicts liver damage in nondiabetic subjects with nonalcoholic fatty liver disease. Hepatology 63(1):107–116. https://doi.org/10.1002/hep.28287
doi: 10.1002/hep.28287
pubmed: 26473614
Rosso C, Kazankov K, Younes R et al (2019) Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J Hepatol 71(5):1012–1021. https://doi.org/10.1016/j.jhep.2019.06.031
doi: 10.1016/j.jhep.2019.06.031
pubmed: 31301321
Samuel VT, Shulman GI (2012) Mechanisms for insulin resistance: common threads and missing links. Cell 148(5):852–871. https://doi.org/10.1016/j.cell.2012.02.017
doi: 10.1016/j.cell.2012.02.017
pubmed: 22385956
pmcid: 3294420
Samuel VT, Shulman GI (2018) Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab 27(1):22–41. https://doi.org/10.1016/j.cmet.2017.08.002
doi: 10.1016/j.cmet.2017.08.002
pubmed: 28867301
Samuel VT, Liu ZX, Wang A et al (2007) Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 117(3):739–745. https://doi.org/10.1172/JCI30400
doi: 10.1172/JCI30400
pubmed: 17318260
pmcid: 1797607
Simon TG, Roelstraete B, Khalili H, Hagstrom H, Ludvigsson JF (2020) Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut. https://doi.org/10.1136/gutjnl-2020-322786
Sondergaard E, Espinosa De Ycaza AE, Morgan-Bathke M, Jensen MD (2017) How to measure adipose tissue insulin sensitivity. J Clin Endocrinol Metab 102(4):1193–1199. https://doi.org/10.1210/jc.2017-00047
doi: 10.1210/jc.2017-00047
pubmed: 28323973
pmcid: 5460729
Spalding KL, Arner E, Westermark PO et al (2008) Dynamics of fat cell turnover in humans. Nature 453(7196):783–787. https://doi.org/10.1038/nature06902
doi: 10.1038/nature06902
pubmed: 18454136
Stenberg E, Thorell A (2020) Insulin resistance in bariatric surgery. Curr Opin Clin Nutr Metab Care 23(4):255–261. https://doi.org/10.1097/MCO.0000000000000657
doi: 10.1097/MCO.0000000000000657
pubmed: 32205577
Stratford S, DeWald DB, Summers SA (2001) Ceramide dissociates 3′-phosphoinositide production from pleckstrin homology domain translocation. Biochem J 354(Pt 2):359–368. https://doi.org/10.1042/0264-6021:3540359
doi: 10.1042/0264-6021:3540359
pubmed: 11171115
pmcid: 1221664
Stumvoll M, Mitrakou A, Pimenta W et al (2000) Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23(3):295–301. https://doi.org/10.2337/diacare.23.3.295
doi: 10.2337/diacare.23.3.295
pubmed: 10868854
Szendroedi J, Yoshimura T, Phielix E et al (2014) Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci U S A 111(26):9597–9602. https://doi.org/10.1073/pnas.1409229111
doi: 10.1073/pnas.1409229111
pubmed: 24979806
pmcid: 4084449
Ter Horst KW, Gilijamse PW, Versteeg RI et al (2017) Hepatic diacylglycerol-associated protein kinase Cepsilon translocation links hepatic steatosis to hepatic insulin resistance in humans. Cell Rep 19(10):1997–2004. https://doi.org/10.1016/j.celrep.2017.05.035
doi: 10.1016/j.celrep.2017.05.035
pubmed: 28591572
pmcid: 5469939
Thamer C, Machann J, Stefan N et al (2007) High visceral fat mass and high liver fat are associated with resistance to lifestyle intervention. Obesity 15(2):531–538. https://doi.org/10.1038/oby.2007.568
doi: 10.1038/oby.2007.568
pubmed: 17299127
Trites MJ, Clugston RD (2019) The role of adipose triglyceride lipase in lipid and glucose homeostasis: lessons from transgenic mice. Lipids Health Dis 18(1):204. https://doi.org/10.1186/s12944-019-1151-z
doi: 10.1186/s12944-019-1151-z
pubmed: 31757217
pmcid: 6874817
Turpin SM, Nicholls HT, Willmes DM et al (2014) Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab 20(4):678–686. https://doi.org/10.1016/j.cmet.2014.08.002
doi: 10.1016/j.cmet.2014.08.002
pubmed: 25295788
van Vliet S, Koh HE, Patterson BW et al (2020) Obesity is associated with increased basal and postprandial beta-cell insulin secretion even in the absence of insulin resistance. Diabetes. https://doi.org/10.2337/db20-0377
Vangipurapu J, Stancakova A, Kuulasmaa T et al (2011) A novel surrogate index for hepatic insulin resistance. Diabetologia 54(3):540–543. https://doi.org/10.1007/s00125-010-1966-7
doi: 10.1007/s00125-010-1966-7
pubmed: 21107521
Yang K, Han X (2016) Lipidomics: techniques, applications, and outcomes related to biomedical sciences. Trends Biochem Sci 41(11):954–969. https://doi.org/10.1016/j.tibs.2016.08.010
doi: 10.1016/j.tibs.2016.08.010
pubmed: 27663237
pmcid: 5085849
Yang J, Eliasson B, Smith U, Cushman SW, Sherman AS (2012) The size of large adipose cells is a predictor of insulin resistance in first-degree relatives of type 2 diabetic patients. Obesity 20(5):932–938. https://doi.org/10.1038/oby.2011.371
doi: 10.1038/oby.2011.371
pubmed: 22240722
Yki-Jarvinen H (2014) Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2(11):901–910. https://doi.org/10.1016/S2213-8587(14)70032-4
doi: 10.1016/S2213-8587(14)70032-4
pubmed: 24731669
Zimmermann R, Strauss JG, Haemmerle G et al (2004) Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306(5700):1383–1386. https://doi.org/10.1126/science.1100747
doi: 10.1126/science.1100747
pubmed: 15550674