Skip to main content
  • Diabetes, Other Diseases, and New Complications: Emerging Associations (JJ Nolan, Section Editor)
  • Published:

Nonalcoholic Fatty Liver Disease and Type 2 Diabetes: Common Pathophysiologic Mechanisms

Current Diabetes Reports volume 15, Article number: 34 (2015) Cite this article

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for advanced liver disease, type 2 diabetes (T2DM), and cardiovascular diseases. The prevalence of NAFLD in the general population is around 30 %, but it is up to three times higher in those with T2DM. Among people with obesity and T2DM, the NAFLD epidemic also is worsening. Therefore, it is important to identify early metabolic alterations and to prevent these diseases and their progression. In this review, we analyze the pathophysiologic mechanisms leading to NAFLD, particularly, those common to T2DM, such as liver and muscle insulin resistance. However, it is mainly adipose tissue insulin resistance that results in increased hepatic de novo lipogenesis, inflammation, and lipotoxicity. Although genetics predispose to NAFLD, an unhealthy lifestyle, including high-fat/high-sugar diets and low physical activity, increases the risk. In addition, alterations in gut microbiota and environmental chemical agents, acting as endocrine disruptors, may play a role.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract. 2011;94:311–21.

    PubMed  Google Scholar 

  2. Gaggini M, Morelli M, Buzzigoli E, et al. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients. 2013;5:1544–60. This review analyzes the mechanisms relating NAFLD to CVD, including the role of ectopic fat accumulation, dyslipidemia, and lipotoxicity.

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56:1384–91.

    PubMed  Google Scholar 

  4. Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–60.

    PubMed  Google Scholar 

  5. Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73.

    CAS  PubMed  Google Scholar 

  6. Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–9.

    PubMed  Google Scholar 

  7. Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol. 2013;10:330–44. This article highlights the evidence that NAFLD is a multisystem disease and T2DM and CVD are factors that might determine interindividual variation in the development and progression of hepatic damage.

    CAS  PubMed  Google Scholar 

  8. Zezos P, Renner EL. Liver transplantation and non-alcoholic fatty liver disease. World J Gastroenterol: WJG. 2014;20:15532–8.

    PubMed Central  PubMed  Google Scholar 

  9. Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014;59:2188–95. By analyzing the United Network for Organ Sharing/Organ Procurement and Transplantation Network database (more than 61,000 patients, 16% of whom received liver transplants), the authors found that NAFLD is the second leading cause of liver transplantation, but more importantly, it is the most rapidly growing indication for transplantation.

    PubMed  Google Scholar 

  10. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23. These are the most recently published guidelines for the diagnosis and management of NAFLD.

    PubMed  Google Scholar 

  11. Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2014;2(11):901–10.

    CAS  PubMed  Google Scholar 

  12. Ghouri N, Preiss D, Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology. 2010;52:1156–61.

    PubMed  Google Scholar 

  13. Lattuada G, Ragogna F, Perseghin G. Why does NAFLD predict type 2 diabetes? Curr Diabetes Rep. 2011;11:167–72.

    CAS  Google Scholar 

  14. Targher G, Byrne CD. Clinical review: nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J Clin Endocrinol Metab. 2013;98:483–95.

    CAS  PubMed  Google Scholar 

  15. Stefan N, Haring HU. The metabolically benign and malignant fatty liver. Diabetes. 2011;60:2011–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012;142:711–25.

    CAS  PubMed  Google Scholar 

  17. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–85.

    CAS  PubMed  Google Scholar 

  18. Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133:496–506.

    CAS  PubMed  Google Scholar 

  19. Kotronen A, Juurinen L, Hakkarainen A, Westerbacka J, Corner A, Bergholm R, et al. Liver fat is increased in type 2 diabetic patients and underestimated by serum alanine aminotransferase compared with equally obese nondiabetic subjects. Diabetes Care. 2008;31:165–9.

    CAS  PubMed  Google Scholar 

  20. Portillo Sanchez P, Bril F, Maximos M, Lomonaco R, Biernacki D, Orsak B, Subbarayan S, Webb A, Hecht J, Cusi K (2014) High prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and normal plasma aminotransferase levels. The Journal of Clinical Endocrinology and Metabolism 2014:jc20142739

  21. Fracanzani AL, Valenti L, Bugianesi E, Andreoletti M, Colli A, Vanni E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792–8.

    CAS  PubMed  Google Scholar 

  22. Loomba R, Abraham M, Unalp A, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology. 2012;56:943–51. This analysis of 1069 NAFLD patients participating in the PIVENS trial and NAFLD Database Study showed that both a personal and a family history of diabetes are associated with the presence of NASH and fibrosis.

    PubMed Central  PubMed  Google Scholar 

  23. Zelber-Sagi S, Lotan R, Shibolet O, Webb M, Buch A, Nitzan-Kaluski D, et al. Non-alcoholic fatty liver disease independently predicts prediabetes during a 7-year prospective follow-up. Liver Int : Off J Int Assoc Study Liver. 2013;33:1406–12.

    CAS  Google Scholar 

  24. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.

    PubMed  Google Scholar 

  25. Ruhl CE, Everhart JE. Fatty liver indices in the multiethnic United States National Health and Nutrition Examination Survey. Aliment Pharmacol Ther. 2015;41:65–76.

    CAS  PubMed  Google Scholar 

  26. Margariti E, Deutsch M, Manolakopoulos S, et al. Non-alcoholic fatty liver disease may develop in individuals with normal body mass index. Ann Gastroenterol. 2012;25:45–51. This study showed that about one in eight NAFLD patients referred to a tertiary liver center has a normal BMI (<25 kg/m 2). These patients have higher levels of ALT/AST than overweight or obese NAFLD patients.

  27. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine. 2012;91:319–27. In this analysis of NHANES III, the authors show that the prevalence of diabetes is higher in people with NAFLD, independent of obesity, although there is a higher prevalence among overweight/obese than lean subjects.

    PubMed  Google Scholar 

  28. Chang Y, Jung HS, Yun KE, Cho J, Cho YK, Ryu S. Cohort study of non-alcoholic fatty liver disease, NAFLD fibrosis score, and the risk of incident diabetes in a Korean population. Am J Gastroenterol. 2013;108:1861–8.

    CAS  PubMed  Google Scholar 

  29. Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R, et al. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA. 2012;308:1150–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  30. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53:1270–87.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Lomonaco R, Ortiz-Lopez C, Orsak B, et al. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology. 2012;55:1389–97. These authors found that in patients with NAFLD, adipose tissue insulin resistance was associated with liver fibrosis, increased liver enzymes and TGs, and reduced HDL and adiponectin but found no association with NAFLD activity score.

    CAS  PubMed  Google Scholar 

  32. Armstrong MJ, Hazlehurst JM, Hull D, Guo K, Borrows S, Yu J, et al. Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis. Diabetes Obes Metab. 2014;16:651–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Kelsey MM, Forster JE, Van Pelt RE, Reusch JE, Nadeau KJ. Adipose tissue insulin resistance in adolescents with and without type 2 diabetes. Pediatr Obes. 2014;9:373–80.

    CAS  PubMed  Google Scholar 

  34. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005;48:634–42.

    CAS  PubMed  Google Scholar 

  35. Stefan N, Staiger H, Haring HU. Dissociation between fatty liver and insulin resistance: the role of adipose triacylglycerol lipase. Diabetologia. 2011;54:7–9.

    CAS  PubMed  Google Scholar 

  36. Lambert JE, Ramos-Roman MA, Browning JD, et al. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–35. This study measured DNL in vivo in subjects with NAFLD by using deuterated water and found that DNL increased up to three times compared with controls.

    CAS  PubMed  Google Scholar 

  37. Kotronen A, Seppanen-Laakso T, Westerbacka J, Kiviluoto T, Arola J, Ruskeepaa AL, et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes. 2009;58:203–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Strable MS, Ntambi JM. Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit Rev Biochem Mol Biol. 2010;45:199–214.

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118:829–38.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002;51:2005–11.

    CAS  PubMed  Google Scholar 

  41. Trauner M, Arrese M, Wagner M. Fatty liver and lipotoxicity. Biochim Biophys Acta. 1801;2010:299–310.

    Google Scholar 

  42. Marra F, Gastaldelli A, Svegliati Baroni G, Tell G, Tiribelli C. Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med. 2008;14:72–81.

    CAS  PubMed  Google Scholar 

  43. Gastaldelli A, Miyazaki Y, Pettiti M, Buzzigoli E, Mahankali S, Ferrannini E, et al. Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. J Clin Endocrinol Metab. 2004;89:3914–21.

    CAS  PubMed  Google Scholar 

  44. Gastaldelli A. Role of beta-cell dysfunction, ectopic fat accumulation and insulin resistance in the pathogenesis of type 2 diabetes mellitus. Diabetes Res Clin Pract. 2011;93 Suppl 1:S60–5.

    CAS  PubMed  Google Scholar 

  45. Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes. 2011;18:139–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Fon Tacer K, Rozman D. Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation. J Lipids. 2011;2011:783976.

    PubMed Central  PubMed  Google Scholar 

  47. Ramos-Arellano LE, Munoz-Valle JF, De la Cruz-Mosso U, Salgado-Bernabe AB, Castro-Alarcon N, Parra-Rojas I. Circulating CD36 and oxLDL levels are associated with cardiovascular risk factors in young subjects. BMC Cardiovasc Disord. 2014;14:54.

    PubMed Central  PubMed  Google Scholar 

  48. Koenig W, Karakas M, Zierer A, Herder C, Baumert J, Meisinger C, et al. Oxidized LDL and the risk of coronary heart disease: results from the MONICA/KORA Augsburg Study. Clin Chem. 2011;57:1196–200.

    CAS  PubMed  Google Scholar 

  49. Gastaldelli A, Miyazaki Y, Pettiti M, Santini E, Ciociaro D, Defronzo RA, et al. The effect of rosiglitazone on the liver: decreased gluconeogenesis in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91:806–12.

    CAS  PubMed  Google Scholar 

  50. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009;48:1–26.

    CAS  PubMed  Google Scholar 

  51. Brehm A, Krssak M, Schmid AI, Nowotny P, Waldhausl W, Roden M. Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes. 2006;55:136–40.

    CAS  PubMed  Google Scholar 

  52. Belfort R, Mandarino L, Kashyap S, Wirfel K, Pratipanawatr T, Berria R, et al. Dose–response effect of elevated plasma free fatty acid on insulin signaling. Diabetes. 2005;54:1640–8.

    CAS  PubMed  Google Scholar 

  53. Eriksson JW. Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance. FEBS Lett. 2007;581:3734–42.

    CAS  PubMed  Google Scholar 

  54. Del Prato S. Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies. Diabet Med. 2009;26:1185–92.

    PubMed  Google Scholar 

  55. Dela Pena A, Leclercq I, Field J, George J, Jones B, Farrell G. NF-kappaB activation, rather than TNF, mediates hepatic inflammation in a murine dietary model of steatohepatitis. Gastroenterology. 2005;129:1663–74.

    CAS  PubMed  Google Scholar 

  56. Grasselli E, Voci A, Demori I, De Matteis R, Compalati AD, Gallo G, et al. Effects of binge ethanol on lipid homeostasis and oxidative stress in a rat model of nonalcoholic fatty liver disease. J Physiol Biochem. 2014;70:341–53.

    CAS  PubMed  Google Scholar 

  57. Ayala A, Munoz MF, Arguelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Med Cell Longev. 2014;2014:360438.

    Google Scholar 

  58. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11:98–107.

    CAS  PubMed  Google Scholar 

  59. Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013;2013:139239.

    PubMed Central  PubMed  Google Scholar 

  60. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.

    CAS  PubMed  Google Scholar 

  61. Anstee QM, Day CP. The genetics of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10:645–55. The authors review the genes involved in the pathogenesis of NAFLD.

    CAS  PubMed  Google Scholar 

  62. Grarup N, Sandholt CH, Hansen T, et al. Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia. 2014;57:1528–41. The authors review the genes involved in the development of T2DM.

    CAS  PubMed  Google Scholar 

  63. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38:320–3.

    CAS  PubMed  Google Scholar 

  64. Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007;117:2155–63.

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Musso G, Gambino R, Pacini G, Pagano G, Durazzo M, Cassader M. Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH. Hepatology. 2009;49:426–35.

    CAS  PubMed  Google Scholar 

  66. Li H, Xu R, Peng X, Wang Y, Wang T. Association of glucokinase regulatory protein polymorphism with type 2 diabetes and fasting plasma glucose: a meta-analysis. Mol Biol Rep. 2013;40:3935–42.

    CAS  PubMed  Google Scholar 

  67. Vaxillaire M, Cavalcanti-Proenca C, Dechaume A, Tichet J, Marre M, Balkau B, et al. The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes. 2008;57:2253–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  68. Liu YL, Reeves HL, Burt AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309. This article shows an association between the gene TM6SF2 and advanced hepatic fibrosis/cirrhosis independent of potential confounding factors (e.g., age, BMI, T2DM, and PNPLA3 rs738409 genotype).

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Gouda HN, Sagoo GS, Harding AH, Yates J, Sandhu MS, Higgins JP. The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol. 2010;171:645–55.

    PubMed Central  PubMed  Google Scholar 

  70. Naik A, Kosir R, Rozman D. Genomic aspects of NAFLD pathogenesis. Genomics. 2013;102:84–95.

    CAS  PubMed  Google Scholar 

  71. Ramya K, Ayyappa KA, Ghosh S, Mohan V, Radha V. Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in south Indian population. Gene. 2013;532:253–62.

    CAS  PubMed  Google Scholar 

  72. Dongiovanni P, Valenti L, Rametta R, Daly AK, Nobili V, Mozzi E, et al. Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease. Gut. 2010;59:267–73.

    CAS  PubMed  Google Scholar 

  73. Bodhini D, Radha V, Mohan V. Association study of IRS1 gene polymorphisms with type 2 diabetes in south Indians. Diabetes Technol Ther. 2011;13:767–72.

    CAS  PubMed  Google Scholar 

  74. Wilmot EG, Edwardson CL, Achana FA, Davies MJ, Gorely T, Gray LJ, et al. Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis. Diabetologia. 2012;55:2895–905.

    CAS  PubMed  Google Scholar 

  75. Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut. 2007;56:1760–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Zivkovic AM, German JB, Sanyal AJ. Comparative review of diets for the metabolic syndrome: implications for nonalcoholic fatty liver disease. Am J Clin Nutr. 2007;86:285–300.

    CAS  PubMed  Google Scholar 

  77. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62:3307–15.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Liu WY, Luda J, Du XM, Sun JQ, Ge J, Wang RW, et al. Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men--the role of gut microbiota composition: study protocol for the AELC randomized controlled tria. BMC Public Health. 2014;14:48.

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Zelber-Sagi S, Ratziu V, Oren R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J Gastroenterol : WJG. 2011;17:3377–89.

    PubMed Central  PubMed  Google Scholar 

  80. Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab: TEM. 2013;24:537–45. Microbiotal factors and products may be involved in the regulation of insulin sensitivity and metabolic inflammation and are driving forces of hepatic steatosis.

    CAS  PubMed  Google Scholar 

  81. Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–87.

    CAS  PubMed  Google Scholar 

  82. De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology. 2014;59:1738–49.

    PubMed  Google Scholar 

  83. Puddu A, Sanguineti R, Montecucco F, Viviani GL. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediat Inflamm. 2014;2014:162021.

    Google Scholar 

  84. Neel BA, Sargis RM. The paradox of progress: environmental disruption of metabolism and the diabetes epidemic. Diabetes. 2011;60:1838–48. This article discusses the epidemiologic links between chemical exposure and disorders of glucose metabolism, experimental data demonstrating chemical-induced changes in insulin action, and challenges facing the field of metabolic disruption, as well as approaches for addressing those challenges.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Newbold RR, Padilla-Banks E, Jefferson WN, Heindel JJ. Effects of endocrine disruptors on obesity. Int J Androl. 2008;31:201–8.

    CAS  PubMed  Google Scholar 

  86. Newbold RR. Impact of environmental endocrine disrupting chemicals on the development of obesity. Hormones (Athens). 2010;9:206–17.

    Google Scholar 

  87. Lind PM, Roos V, Ronn M, Johansson L, Ahlstrom H, Kullberg J, et al. Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women. Environ Health. 2012;11:21.

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Hatch EE, Nelson JW, Qureshi MM, Weinberg J, Moore LL, Singer M, et al. Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999–2002. Environ Health. 2008;7:27.

    PubMed Central  PubMed  Google Scholar 

  89. Desvergne B, Feige JN, Casals-Casas C. PPAR-mediated activity of phthalates: A link to the obesity epidemic? Mol Cell Endocrinol. 2009;304:43–8. EDCs, such as phthalates, might influence major factors controlling glucose and lipid metabolism in humans by activating PPARs.

    CAS  PubMed  Google Scholar 

  90. Lehrke M, Lazar MA. The many faces of PPARgamma. Cell. 2005;123:993–9.

    CAS  PubMed  Google Scholar 

  91. Lee DH, Lee IK, Song K, Steffes M, Toscano W, Baker BA, et al. A strong dose–response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999–2002. Diabetes Care. 2006;29:1638–44.

    CAS  PubMed  Google Scholar 

  92. Ruzzin J, Petersen R, Meugnier E, Madsen L, Lock EJ, Lillefosse H, et al. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect. 2010;118:465–71.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. Lee DH, Lee IK, Jin SH, Steffes M, Jacobs Jr DR. Association between serum concentrations of persistent organic pollutants and insulin resistance among nondiabetic adults: results from the National Health and Nutrition Examination Survey 1999–2002. Diabetes Care. 2007;30:622–8.

    CAS  PubMed  Google Scholar 

  94. Lind PM, Zethelius B, Lind L. Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Diabetes Care. 2012;35:1519–24. Plasma concentrations of several phthalate metabolites were found to be related to diabetes prevalence, as well as to markers of insulin secretion and resistance.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Bohte AE, van Werven JR, Bipat S, Stoker J. The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis. Eur Radiol. 2011;21:87–97.

    PubMed Central  PubMed  Google Scholar 

  96. Kwok R, Tse YK, Wong GL, Ha Y, Lee AU, Ngu MC, et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease—the role of transient elastography and plasma cytokeratin-18 fragments. Aliment Pharmacol Ther. 2014;39:254–69.

    CAS  PubMed  Google Scholar 

  97. de Ledinghen V, Vergniol J, Capdepont M, Chermak F, Hiriart JB, Cassinotto C, et al. Brigitte le B: Controlled attenuation parameter (CAP) for the diagnosis of steatosis: a prospective study of 5323 examinations. J Hepatol. 2014;60:1026–31.

    PubMed  Google Scholar 

  98. Singh S, Venkatesh SK, Wang Z, Miller FH, Motosugi U, Low RN, Hassanein T, Asbach P, Godfrey EM, Yin M, Chen J, Keaveny AP, Bridges M, Bohte A, Murad MH, Lomas DJ, Talwalkar JA, Ehman RL: Diagnostic Performance of Magnetic Resonance Elastography in Staging Liver Fibrosis: A Systematic Review and Meta-analysis of Individual Participant Data. Clin Gastroenterol Hepatol 2014.

  99. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 2005;288:E462–8.

    CAS  PubMed  Google Scholar 

  100. Fishbein MH, Gardner KG, Potter CJ, Schmalbrock P, Smith MA. Introduction of fast MR imaging in the assessment of hepatic steatosis. Magn Reson Imaging. 1997;15:287–93.

    CAS  PubMed  Google Scholar 

  101. Duman DG, Celikel C, Tuney D, Imeryuz N, Avsar E, Tozun N. Computed tomography in nonalcoholic fatty liver disease: a useful tool for hepatosteatosis assessment? Dig Dis Sci. 2006;51:346–51.

    PubMed  Google Scholar 

  102. Park SH, Kim PN, Kim KW, Lee SW, Yoon SE, Park SW, et al. Macrovesicular hepatic steatosis in living liver donors: use of CT for quantitative and qualitative assessment. Radiology. 2006;239:105–12.

    PubMed  Google Scholar 

  103. Wong VW, Vergniol J, Wong GL, Foucher J, Chan AW, Chermak F, et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2012;107:1862–71.

    PubMed  Google Scholar 

  104. Palmentieri B, de Sio I, La Mura V, Masarone M, Vecchione R, Bruno S, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Dig Liver Dis. 2006;38:485–9.

    CAS  PubMed  Google Scholar 

  105. Fraquelli M, Rigamonti C, Casazza G, Donato MF, Ronchi G, Conte D, et al. Etiology-related determinants of liver stiffness values in chronic viral hepatitis B or C. J Hepatol. 2011;54:621–8.

    PubMed  Google Scholar 

  106. Rifai K, Cornberg J, Mederacke I, Bahr MJ, Wedemeyer H, Malinski P, et al. Clinical feasibility of liver elastography by acoustic radiation force impulse imaging (ARFI). Dig Liver Dis. 2011;43:491–7.

    PubMed  Google Scholar 

  107. Goertz RS, Sturm J, Pfeifer L, Wildner D, Wachter DL, Neurath MF, et al. ARFI cut-off values and significance of standard deviation for liver fibrosis staging in patients with chronic liver disease. Ann Hepatol. 2013;12:935–41.

    PubMed  Google Scholar 

  108. Baranova A, Lal P, Birerdinc A, Younossi ZM. Non-invasive markers for hepatic fibrosis. BMC Gastroenterol. 2011;11:91.

    PubMed Central  PubMed  Google Scholar 

  109. Grandison GA, Angulo P. Can NASH be diagnosed, graded, and staged noninvasively? Clin Liver Dis. 2012;16:567–85.

    PubMed Central  PubMed  Google Scholar 

  110. Bedogni G, Kahn HS, Bellentani S, Tiribelli C. A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC Gastroenterol. 2010;10:98.

    PubMed Central  PubMed  Google Scholar 

  111. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.

    PubMed Central  PubMed  Google Scholar 

  112. Gastaldelli A, Kozakova M, Hojlund K, Flyvbjerg A, Favuzzi A, Mitrakou A, et al. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009;49:1537–44.

    CAS  PubMed  Google Scholar 

  113. Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42:503–8.

    CAS  PubMed  Google Scholar 

  114. Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137:865–72.

    CAS  PubMed  Google Scholar 

  115. Pearce SG, Thosani NC, Pan JJ. Noninvasive biomarkers for the diagnosis of steatohepatitis and advanced fibrosis in NAFLD. Biomark Res. 2013;1:7.

    PubMed Central  PubMed  Google Scholar 

  116. Otgonsuren M, Estep MJ, Hossain N, Younossi E, Frost S, Henry L, Hunt S, Fang Y, Goodman Z, Younossi ZM: A single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). J Gastroenterol Hepatol 2014.

  117. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010;59:1265–9.

    PubMed  Google Scholar 

  118. Shah AG, Lydecker A, Murray K, Tetri BN, Contos MJ, Sanyal AJ. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:1104–12.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.

    CAS  PubMed  Google Scholar 

  120. Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–7.

    CAS  PubMed  Google Scholar 

  121. Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117–23.

    CAS  PubMed  Google Scholar 

  122. Cales P, Laine F, Boursier J, Deugnier Y, Moal V, Oberti F, et al. Comparison of blood tests for liver fibrosis specific or not to NAFLD. J Hepatol. 2009;50:165–73.

    PubMed  Google Scholar 

  123. Fedchuk L, Nascimbeni F, Pais R, Charlotte F, Housset C, Ratziu V, et al. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2014;40:1209–22.

    CAS  PubMed  Google Scholar 

  124. Kahl S, Strassburger K, Nowotny B, Livingstone R, Kluppelholz B, Kessel K, et al. Comparison of liver fat indices for the diagnosis of hepatic steatosis and insulin resistance. PLoS ONE. 2014;9:e94059.

    PubMed Central  PubMed  Google Scholar 

  125. Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87:2784–91.

    CAS  PubMed  Google Scholar 

  126. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.

    CAS  PubMed  Google Scholar 

  127. Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51:445–53.

    CAS  PubMed  Google Scholar 

  128. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.

    PubMed Central  CAS  PubMed  Google Scholar 

  129. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.

    CAS  PubMed  Google Scholar 

  130. Armstrong MJ, Houlihan DD, Rowe IA, Clausen WH, Elbrond B, Gough SC, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther. 2013;37:234–42.

    CAS  PubMed  Google Scholar 

  131. Bergenstal RM, Li Y, Porter TK, Weaver C, Han J. Exenatide once weekly improved glycaemic control, cardiometabolic risk factors and a composite index of an HbA1c < 7 %, without weight gain or hypoglycaemia, over 52 weeks. Diabetes Obes Metab. 2013;15:264–71.

    PubMed Central  CAS  PubMed  Google Scholar 

  132. Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007;29:139–53.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by institutional grants of the CNR.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Chiara Saponaro is recipient of a research scholarship awarded by “Dottorato Pegaso Regione Toscana in Biochimica e Biologia Molecolare” she has no conflict of interest.

Melania Gaggini is recipient of a research fellowship awarded by Gilead.

Amalia Gastaldelli reports personal fees from Roche and Eli Lilly, and grants from Amylin-BMS-AstraZeneca.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Affiliations

  1. Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, via Moruzzi 1, 56100, Pisa, Italy

    Chiara Saponaro, Melania Gaggini & Amalia Gastaldelli

  2. Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Siena, Italy

    Chiara Saponaro

  3. Dipartimento di Patologia Chirurgica, Molecolare Medica e di Area Critica, Università di Pisa, Pisa, Italy

    Melania Gaggini

Authors
  1. Chiara Saponaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melania Gaggini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amalia Gastaldelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amalia Gastaldelli.

Additional information

This article is part of the Topical Collection on Diabetes, Other Diseases, and New Complications: Emerging Associations

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saponaro, C., Gaggini, M. & Gastaldelli, A. Nonalcoholic Fatty Liver Disease and Type 2 Diabetes: Common Pathophysiologic Mechanisms. Curr Diab Rep 15, 34 (2015). https://doi.org/10.1007/s11892-015-0607-4

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-015-0607-4

Keywords

  • Fatty liver
  • Glucose intolerance
  • De novo lipogenesis
  • Lipotoxicity
  • Gut microbiota
  • Endocrine disruptors
  • NASH