Insulin resistance and non-alcoholic fatty liver disease: a review of the pathophysiology and the potential targets for drug actions

Taoreed Adegoke Azeez(1*), Morenike Osundina(2)

(1) Endocrinology, Metabolism and Diabetes Unit Department of Medicine, University College Hospital, Ibadan, Nigeria
(2) Gatroenterology & Hepatology Unit, Department of Medicine, University College Hospital, Ibadan, Nigeria.
(*) Corresponding Author


Insulin resistance refers to the reduced physiological effects of insulin on various tissues. Insulin resistance has been implicated in the pathophysiology of non-alcoholic fatty liver disease (NAFLD), which is a spectrum of diseases ranging from hepatic steatosis on one end to steatohepatitis, liver cirrhosis and hepatocellular carcinoma on the other end. In most parts of the developed world, it is now the most commoncause of chronic liver disease and the most commonindication for liver transplantation. A similar findingis emerging in the developing world due to the rising prevalence of obesity and widespread adoption of Western lifestyles. Despite these epidemiological data, there are no universally approved medications for the treatment of NAFLD. The pathophysiological mechanisms of NAFLD essentially include adipose tissue insulin resistance, hepatic insulin resistance, inflammation and fibrosis. At the subcellular level, mitochondrial dysfunction, oxidative changes and endoplasmic reticulum dysfunction have been documented. Several drugs have been tested in vitro and in animal studies to target these pathophysiological mechanisms. Some are presently going through clinical trials, while others have already gone through clinical trials with variable results. Other potential target sites of drug development for the treatment of NAFLD are based on the complex pathophysiology of the disease. Insulin resistance plays an important role in the development of NAFLD. There are potential targets in the pathophysiology of NAFLD that can be explored in the development of medications for the disease.


hepatic insulin resistance; athophysiology; treatment; potential new drugs; NAFLD;

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  1. Reaven G. The metabolic syndrome or the insulin resistance syndrome? Different names, different concepts, and different goals. Endocrinol Metab Clin North Am 2004; 33(2):283-303.
  2. Wilcox G. Insulin and insulin resistance. Clin Biochem Rev 2005; 26(2): 19-39.
  3. Angulo P, Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2002; 17 Suppl(1):S186-90
  4. Maurice J, Manousou P. Non-alcoholic fatty liver disease. Clin Med (Lond) 2018; 18(3): 245-50.
  5. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64(1):73-84.
  6. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015; 149(2):367-78.
  7. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362(18):1675-85.
  8. Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J, et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes 2002; 51(Suppl 1):S83-S90.
  9. Soria B, Quesada I, Ropero AB, Pertusa JA, Martín F, Nadal A. Novel players in pancreatic islet signaling: from membrane receptors to nuclear channels. Diabetes 2004; 53(Suppl 1):S86-91.
  10. Kido Y, Nakae J, Accili D. Clinical review 125: the insulin receptor and its cellular targets. J Clin Endocrinol Metab. 2001; 86(3):972-9.
  11. Withers DJ, White M. Perspective: the insulin signaling system-a common link in the pathogenesis of type 2 diabetes. Endocrinology 2000; 141(6):1917-21.
  12. Burks DJ, White MF. IRS proteins and beta-cell function. Diabetes 2001; 50(Suppl 1):S140-5.
  13. Smith U. Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance--is insulin resistance initiated in the adipose tissue? Int J Obes Relat Metab Disord 2002; 26(7):897-904.
  14. Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest 2016; 126(1):12-22.
  15. Devaraj S, Rosenson RS, Jialal I. Metabolic syndrome: an appraisal of the pro-inflammatory and procoagulant status. Endocrinol Metab Clin North Am 2004; 33(2):431-53.
  16. Herman MA, Peroni OD, Villoria J, Schön MR, Abumrad NA, Blüher M, et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 2012; 484(7394):333-8.
  17. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89(6):2548-56.
  18. Asano T, Watanabe K, Kubota N, Gunji T, Omata M, Kadowaki T, et al. Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. J Gastroenterol Hepatol 2009; 24(10):1669-76.
  19. Carr RM, Oranu A, Khungar V. Non-alcoholic fatty liver disease: pathophysiology and management. Gastroeneterol Clin North Am 2016; 45(4):639-52.
  20. Yu J, Marsh S, Hu J, Feng W, Wu C. The pathogenesis of nonalcoholic fatty liver disease: interplay between diet, gut microbiota, and genetic background. Gastroenterol Res Pract 2016; 2016:2862173.
  21. Dumas ME, Kinross J, Nicholson JK. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 2014; 146(1):46-62.
  22. Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev 2012; 249(1):218-38.
  23. Barbuio R, Milanski M, Bertolo BM, Saad MJ, Velloso LA. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. J Endocrinol 2007; 194(3):539-50.
  24. Hasenour CM, Berglund ED, Wasserman DH. Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver. Mol Cellular Endocrinol 2013; 366(2):152-62.
  25. Day CP. Non-alcoholic fatty liver disease: current concepts and management strategies. Clin Med 2006; 6(1):19-25.
  26. Sharifnia T, Antoun J, Verriere TGC. Hepatic TLR4 signaling in obese NAFLD. Am J Physiol-Gastrointest Liver Physiol 2015; 309(4):G270-78.
  27. Federico A, Zulli C, de Sio I, Del Prete A, Dallio M, Masarone M, et al. Focus on emerging drugs for the treatment of patients with non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20(45):16841-57.
  28. Tilg H, Moschen A. Weight loss: cornerstone in the treatment of non-alcoholic fatty liver disease. Minerva Gastroenterol Dietol 2010; 56(2):159-67.
  29. Zelber-Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M et al. A double-blind randomized placebo-controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006; 4(5):639-44.
  30. Wierzbicki AS, Pendleton S, McMahon Z, Dar A, Oben J, Crook MA, et al. Rimonabant improves cholesterol, insulin resistance and markers of non-alcoholic fatty liver in morbidly obese patients: a retrospective cohort study. Int J Clin Pract 2011; 65(6):713-5.
  31. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305(16):1659-68.
  32. Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol 2011; 4(4):249-63.
  33. Nseir W, Mograbi J, Ghali M. Lipid-lowering agents in nonalcoholic fatty liver disease and steatohepatitis: human studies. Dig Dis Sci 2012; 57(7):1773-81.
  34. Loguercio C, Federico A, Trappoliere M, Tuccillo C, de Sio I, Di Leva A, Niosi M, et al. The effect of a silybin-vitamin e-phospholipid complex on nonalcoholic fatty liver disease: a pilot study. Dig Dis Sci 2007; 52(9):2387-95.
  35. Imajo K, Yoneda M, Ogawa Y, Wada K, Nakajima A. Microbiota and nonalcoholic steatohepatitis. Semin Immunopathol 2014; 36(1):115-32.
  36. Barbuio R, Milanski M, Bertolo MB, Saad MJ, Velloso LA. Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet. J Endocrinol 2007; 194(3):539-50.
  37. Paschos P, Tziomalos K. Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. World J Hepatol 2012; 4(12):327-31.


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