Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics
Abstract
:1. Introduction
2. Insulin Resistance, Disrupted Fat Partitioning and Hepatic Steatosis
3. Intrahepatic Fat Quality More than Quantity Impacts on Insulin Resistance
4. Lesson from the Animal Model
5. The Real-Life Scenario
6. Conclusions
Conflicts of Interest
References
- Manco, M. Metabolic syndrome in childhood from impaired carbohydrate metabolism to nonalcoholic fatty liver disease. J. Am. Coll. Nutr. 2011, 30, 295–303. [Google Scholar] [CrossRef] [PubMed]
- Buzzetti, E.; Pinzani, M.; Tsochatzis, E.A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 2016, 65, 1038–1048. [Google Scholar] [CrossRef] [PubMed]
- Marchesini, G.; Brizi, M.; Morselli Labate, A.M.; Bianchi, G.; Bugianesi, G.; McCullough, A.J.; Forlani, G.; Melchionda, N. Association of non-alcoholic fatty liver disease to insulin resistance. Am. J. Med. 1999, 107, 450–455. [Google Scholar] [CrossRef]
- Marchesini, G.; Brizi, M.; Bianchi, G.; Tomassetti, S.; Bugianesi, E.; Lenzi, M.; McCullough, A.J.; Natale, S.; Forlani, G.; Melchionda, N. Nonalcoholic fatty liver disease: A feature of the metabolic syndrome. Diabetes 2001, 50, 1844–1850. [Google Scholar] [CrossRef] [PubMed]
- Schwimmer, J.B.; Deutsch, R.; Rauch, J.B.; Behling, C.; Newbury, R.; Lavine, J.E. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fattyliver disease. J. Pediatr. 2003, 143, 500–505. [Google Scholar] [CrossRef]
- Shashaj, B.; Luciano, R.; Contoli, B.; Morino, G.S.; Spreghini, M.R.; Rustico, C.; Sforza, R.W.; Dallapiccola, B.; Manco, M. Reference ranges of HOMA-IR in normal-weight and obese young Caucasians. Acta Diabetol. 2016, 53, 251–260. [Google Scholar] [CrossRef] [PubMed]
- Petersen, M.C.; Shulman, G.I. Roles of diacylglycerols and ceramides in hepatic insulin resistance. Trends Pharmacol. Sci. 2017, 38, 649–665. [Google Scholar] [CrossRef] [PubMed]
- DeFronzo, R.A.; Tobin, J.D.; Andres, R. Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am. J. Physiol. 1979, 237, G214–G223. [Google Scholar]
- Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28, 412–419. [Google Scholar] [CrossRef] [PubMed]
- Katz, A.; Nambi, S.S.; Mather, K.; Baron, A.D.; Follmann, D.A.; Sullivan, G.; Quon, M.J. Quantitative insulin sensitivity check index: A simple, accurate method for assessing insulin sensitivity in humans. J. Clin. Endocrinol. Metab. 2000, 85, 2402–2410. [Google Scholar] [CrossRef] [PubMed]
- Matsuda, M.; DeFronzo, R.A. Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic insulin clamp. Diabetes Care 1999, 22, 1462–1470. [Google Scholar] [CrossRef] [PubMed]
- Mari, A.; Pacini, G.; Murphy, E.; Ludvik, B.; Nolan, J.J. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 2001, 24, 539–548. [Google Scholar] [CrossRef] [PubMed]
- Tripathy, D.; Almgren, P.; Tuomi, T.; Groop, L. Contribution of insulin-stimulated glucose uptake and basal hepatic insulin sensitivity to surrogate measures of insulin sensitivity. Diabetes Care 2004, 27, 2204–2210. [Google Scholar] [CrossRef] [PubMed]
- Petta, S.; Gastaldelli, A.; Rebelos, E.; Bugianesi, E.; Messa, P.; Miele, L.; Svegliati-Baroni, G.; Valenti, L.; Bonino, F. Pathophysiology of non alcoholic fatty liver disease. Int. J. Mol. Sci. 2016, 17, 2082. [Google Scholar] [CrossRef] [PubMed]
- Manco, M.; Marcellini, M.; Devito, R.; Comparcola, D.; Sartorelli, M.R.; Nobili, V. Metabolic syndrome and liver histology in paediatric non-alcoholic steatohepatitis. Int. J. Obes. (Lond.) 2008, 32, 381–387. [Google Scholar] [CrossRef] [PubMed]
- Shashaj, B.; Bedogni, G.; Graziani, M.P.; Tozzi, A.E.; DiCorpo, M.L.; Morano, D.; Tacconi, L.; Veronelli, P.; Contoli, B.; Manco, M. Origin of cardiovascular risk in overweight preschool children: A cohort study of cardiometabolic risk factors at the onset of obesity. JAMA Pediatr. 2014, 168, 917–924. [Google Scholar] [CrossRef] [PubMed]
- Danforth, E., Jr. Failure of adipocyte differentiation causes type II diabetes mellitus? Nat. Genet. 2000, 26, 13. [Google Scholar] [CrossRef] [PubMed]
- Virtue, S.; Vidal-Puig, A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome—An allostatic perspective. Biochim. Biophys. Acta 2010, 1801, 338–349. [Google Scholar] [CrossRef] [PubMed]
- Hooper, A.J.; Adams, L.A.; Burnett, J.R. Genetic determinants of hepatic steatosis in man. J. Lipid Res. 2011, 52, 593–617. [Google Scholar] [CrossRef] [PubMed]
- Shulman, G.I. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N. Engl. J. Med. 2014, 371, 1131–1141. [Google Scholar] [CrossRef] [PubMed]
- Caprio, S.; Perry, R.; Kursawe, R. Adolescent obesity and insulin resistance: Roles of ectopic fat accumulation and adipose inflammation. Gastroenterology 2017, 152, 1638–1646. [Google Scholar] [CrossRef] [PubMed]
- D’Adamo, E.; Cali, A.M.; Weiss, R.; Santoro, N.; Pierpont, B.; Northrup, V.; Caprio, S. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescents. Diabetes Care 2010, 33, 1817–1822. [Google Scholar] [CrossRef] [PubMed]
- Kursawe, R.; Eszlinger, M.; Narayan, D.; Liu, T.; Bazuine, M.; Cali, A.M.; D’Adamo, E.; Shaw, M.; Pierpont, B.; Shulman, G.I.; et al. Cellularity and adipogenic profile of the abdominal subcutaneous adipose tissue from obese adolescents: Association with insulin resistance and hepatic steatosis. Diabetes 2010, 59, 2288–2296. [Google Scholar] [CrossRef] [PubMed]
- Rebrin, K.; Steil, G.M.; Mittelman, S.D.; Bergman, R.N. Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs. J. Clin. Investig. 1996, 98, 741–749. [Google Scholar] [CrossRef] [PubMed]
- Umano, G.R.; Martino, M.; Santoro, N. The association between pediatric NAFLD and common genetic variants. Children 2017, 4, 49. [Google Scholar] [CrossRef] [PubMed]
- Petäjä, E.M.; Yki-Järvinen, H. Definitions of normal liver fat and the association of insulin sensitivity with acquired and genetic NAFLD—A systematic review. Int. J. Mol. Sci. 2016, 17, 633. [Google Scholar] [CrossRef] [PubMed]
- Goffredo, M.; Caprio, S.; Feldstein, A.E.; D’Adamo, E.; Shaw, M.M.; Pierpont, B.; Savoye, M.; Zhao, H.; Bale, A.E.; Santoro, N. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology 2016, 63, 117–125. [Google Scholar] [CrossRef] [PubMed]
- Grandone, A.; Cozzolino, D.; Marzuillo, P.; Cirillo, G.; di Sessa, A.; Ruggiero, L.; di Palma, M.R.; Perrone, L.; Miraglia del Giudice, E. TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children. Pediatr. Obes. 2016, 11, 115–119. [Google Scholar] [CrossRef] [PubMed]
- Sookoian, S.; Pirola, C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 2011, 53, 1883–1894. [Google Scholar] [CrossRef] [PubMed]
- He, S.; McPhaul, C.; Li, J.Z.; Garuti, R.; Kinch, L.; Grishin, N.V.; Hobbs, H.H. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J. Biol. Chem. 2010, 285, 6706–6715. [Google Scholar] [CrossRef] [PubMed]
- Huang, Y.; Cohen, J.C.; Hobbs, H.H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J. Biol. Chem. 2011, 286, 37085–37093. [Google Scholar] [CrossRef] [PubMed]
- Kumari, M.; Schoiswohl, G.; Chitraju, C.; Paar, M.; Cornaciu, I.; Rangrez, A.Y.; Wongsiriroj, N.; Nagy, H.M.; Ivanova, P.T.; Scott, S.A.; et al. Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase. Cell Metab. 2012, 15, 691–702. [Google Scholar] [CrossRef] [PubMed]
- Luukkonen, P.K.; Zhou, Y.; Sädevirta, S.; Leivonen, M.; Arola, J.; Orešič, M.; Hyötyläinen, T.; Yki-Järvinen, H. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 2016, 64, 1167–1175. [Google Scholar] [CrossRef] [PubMed]
- Kozlitina, J.; Smagris, E.; Stender, S.; Nordestgaard, B.G.; Zhou, H.H.; Tybjærg-Hansen, A.; Vogt, T.F.; Hobbs, H.H.; Cohen, J.C. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2014, 46, 352–356. [Google Scholar] [CrossRef] [PubMed]
- Pirola, C.J.; Sookoian, S. The dual and opposite role of the TM6SF2-rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: A meta-analysis. Hepatology 2015, 62, 1742–1756. [Google Scholar] [CrossRef] [PubMed]
- Marzuillo, P.; Miraglia del Giudice, E.; Santoro, N. Pediatric fatty liver disease: Role of ethnicity and genetics. World J. Gastroenterol. 2014, 20, 7347–7355. [Google Scholar] [CrossRef] [PubMed]
- Azzout-Marniche, D.; Becard, D.; Guichard, C.; Foretz, M.; Ferre, P.; Foufelle, F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem. J. 2000, 350, 389–393. [Google Scholar] [CrossRef] [PubMed]
- Browning, J.D.; Horton, J.D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Investig. 2004, 114, 147–152. [Google Scholar] [CrossRef] [PubMed]
- Akkaoui, M.; Cohen, I.; Esnous, C.; Lenoir, V.; Sournac, M.; Girard, J.; Prip-Buus, C. Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids. Biochem. J. 2009, 420, 429–438. [Google Scholar] [CrossRef] [PubMed]
- McGarry, J.D.; Mannaerts, G.P.; Foster, D.W. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J. Clin. Investig. 1977, 60, 265–270. [Google Scholar] [CrossRef] [PubMed]
- Jelenik, T.; Kaul, K.; Séquaris, G.; Flögel, U.; Phielix, E.; Kotzka, J.; Knebel, B.; Fahlbusch, P.; Hörbelt, T.; Lehr, S.; et al. Mechanisms of insulin resistance in primary and secondary non-alcoholic fatty liver. Diabetes 2017, 66, 2241–2253. [Google Scholar] [CrossRef] [PubMed]
- Neel, J.V. Diabetes mellitus: A “thrifty” genotype rendered detrimental by “progress”? Am. J. Hum. Genet. 1962, 14, 353–362. [Google Scholar] [PubMed]
- Romeo, S.; Kozlitina, J.; Xing, C.; Pertsemlidis, A.; Cox, D.; Pennacchio, L.A.; Boerwinkle, E.; Cohen, J.C.; Hobbs, H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008, 40, 1461–1465. [Google Scholar] [CrossRef] [PubMed]
- Yki-Järvinen, H. Diagnosis of non-alcoholic fatty liver disease (NAFLD). Diabetologia 2016, 59, 1104–1111. [Google Scholar] [CrossRef] [PubMed]
- Del Chierico, F.; Nobili, V.; Vernocchi, P.; Russo, A.; Stefanis, C.; Gnani, D.; Furlanello, C.; Zandonà, A.; Paci, P.; Capuani, G.; et al. Gut microbiota profiling of pediatric nonalcoholic fatty liver disease and obese patients unveiled by an integrated meta-omics-based approach. Hepatology 2017, 65, 451–464. [Google Scholar] [CrossRef] [PubMed]
- Manco, M.; Putignani, L.; Bottazzo, G.F. Gut microbiota, lipopolysaccharides, and innate immunity in the pathogenesis of obesity and cardiovascular risk. Endocr. Rev. 2010, 31, 817–844. [Google Scholar] [CrossRef] [PubMed]
- Stanhope, K.L. Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit. Rev. Clin. Lab. Sci. 2016, 53, 52–67. [Google Scholar] [CrossRef] [PubMed]
- Macdonald, I.A. A review of recent evidence relating to sugars, insulin resistance and diabetes. Eur. J. Nutr. 2016, 55, 17–23. [Google Scholar] [CrossRef] [PubMed]
- Yki-Järvinen, H. Nutritional modulation of non-alcoholic fatty liver disease and insulin resistance. Nutrients 2015, 7, 9127–9138. [Google Scholar] [CrossRef] [PubMed]
- Mosca, A.; Nobili, V.; De Vito, R.; Crudele, A.; Scorletti, E.; Villani, A.; Alisi, A.; Byrne, C.D. Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents. J. Hepatol. 2017, 66, 1031–1036. [Google Scholar] [CrossRef] [PubMed]
- Polyzos, S.A.; Kountouras, J.; Deretzi, G.; Zavos, C.; Mantzoros, C.S. The emerging role of endocrine disruptors in pathogenesis of insulin resistance: A concept implicating nonalcoholic fatty liver disease. Curr. Mol. Med. 2012, 12, 68–82. [Google Scholar] [CrossRef] [PubMed]
- Sampey, B.P.; Vanhoose, A.M.; Winfield, H.M.; Freemerman, A.J.; Muehlbauer, M.J.; Fueger, P.T.; Newgard, C.B.; Makowski, L. Cafeteria diet is a robust model of human metabolic syndrome with liver and adipose inflammation: Comparison to high-fat diet. Obesity 2011, 19, 1109–1117. [Google Scholar] [CrossRef] [PubMed]
- Petta, S.; Valenti, L.; Bugianesi, E.; Targher, G.; Bellentani, S.; Bonino, F.; Special Interest Group on Personalised Hepatology of the Italian Association for the Study of the Liver (AISF); Special Interest Group on Personalised Hepatology of Italian Association for Study of Liver AISF. A “systems medicine” approach to the study of non-alcoholic fatty liver disease. Dig. Liver Dis. 2016, 48, 333–342. [Google Scholar] [PubMed]
© 2017 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Manco, M. Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics. Children 2017, 4, 74. https://doi.org/10.3390/children4080074
Manco M. Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics. Children. 2017; 4(8):74. https://doi.org/10.3390/children4080074
Chicago/Turabian StyleManco, Melania. 2017. "Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics" Children 4, no. 8: 74. https://doi.org/10.3390/children4080074