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Insulin resistance (IR) is highly associated with NAFLD/NASH and NAFLD is present in up to 2/3 of patients with T2DM1. Also in lean patients with normal glucose tolerance there is an association between IR and NAFLD, which in this case could represent an initial stage of MetS2. There are also genetic variants that is strongly associated with NAFLD/NASH, but is not characterized by features of the metabolic syndrome, like the IR. One example of this is the polymorphism in PNPLA3 leading to the missense mutation I148M giving a susceptibility to NAFLD3.

Hepatic insulin resistance leads to an increase in glucose production and hyperglycemia and the hepatic lipid and lipoprotein metabolism is also severely affected. In NAFLD, insulin resistance contributes to increased hepatic fatty acids (FA) via de novo lipogenesis (DNL) and via increased lipolysis in white adipose tissue. Hepatic accumulation of lipids reduces hepatic responsiveness to insulin, resulting in an increase of glucose in circulation and thus of insulin, producing a state of chronic hyperinsulinemia. Whether IR triggers lipid accumulation in the liver, or whether fat deposition in the liver alters the hepatic response to insulin, is not clear. In obese and diabetic patients, peripheral IR may be initially responsible for the accumulation of fat in the liver, whilst diet can be the primary cause of hepatic steatosis and hepatic insulin resistance in non-obese patients4.

Immune cells, such as macrophages, contributes to the progression of NASH and dysregulation of macrophages are closely related to multiple metabolic disorders and among them NAFLD. Excessive hepatic lipid accumulation promotes the activation of macrophages/Kupffer cells to exacerbate IR, as well as hepatic inflammation and fibrogenesis 5.

HOMA-IR has recently been suggested to be a diagnostic tool for NAFLD, since the upper limit of HOMA-IR in population-based cohorts closely corresponds to that of normal liver fat6.

Multiple organs are involved in the development and progression of NAFLD and NASH and the IR plays a central role in all tissues4.


1.        Khan, R., Bril, F., Cusi, K. & Newsome, P. N. Modulation of Insulin Resistance in NAFLD. Hepatology hep.30429 (2018). doi:10.1002/hep.30429
2.        Marchesini, G. et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am. J. Med. 107, 450–5 (1999).
3.        Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
4.        Reccia, I. et al. Non-alcoholic fatty liver disease: A sign of systemic disease. Metabolism. 72, 94–108 (2017).
5.        Kitade, H., Chen, G., Ni, Y. & Ota, T. Nonalcoholic Fatty Liver Disease and Insulin Resistance: New Insights and Potential New Treatments. Nutrients 9, 387 (2017).
6.        Isokuortti, E. et al. Use of HOMA-IR to diagnose non-alcoholic fatty liver disease: a population-based and inter-laboratory study. Diabetologia 60, 1873–1882 (2017).