The pathophysiology describing the intimate relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and less known. 

A paper reviewed these mechanisms in a unified manner. Individuals with NAFLD and T2DM have established insulin resistance (IR), which intensifies these comorbidities. IR increases free fatty acids (FFAs) accumulation in the liver, thus depleting NAFLD further. FFAs accumulation occurs due to its increased influx from peripheral adipose tissue by the activation of hormone-sensitive lipase. 

Additionally, there occurs de novo increased lipogenesis and triglycerides storage in the liver. 

Lipids accumulation in the liver causes chronic stress in the endoplasmic reticulum of the hepatocytes. Genetic variants associated with NAFLD severity has been determined but not related to IR. Especially, the alteration of patatin-like phospholipase domain-containing protein 3 increases the susceptibility to NAFLD. 

Furthermore, in T2DM, the lipotoxicity of ceramides and diacylglycerol initiates a chronic inflammatory process, promoting hepatic steatosis to steatohepatitis. 

Mitochondrial dysfunction produces Reactive oxygen species which leads to liver inflammation and beta-cells damage, further progressing NAFLD and T2DM. 

Thus NAFLD and T2DM association are bidirectional, in which T2DM initiates NAFLD onset and its progression, alongside NAFLD itself, offers the development of IR and T2DM. 

Future studies are warranted to identify newer therapeutic targets for the treatment of NAFLD, which are currently substantially absent.

Source: Acierno C, Caturano A, Pafundi PC, Nevola R, Adinolfi LE, Sasso FC. Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin. Explor Med. 2020;1:287-306. https://doi.org/10.37349/emed.2020.00019