**7.1 With or without 'T2DM and insulin resistance'**

Diabetes is highly prevalent in patients with NASH/NAFLD and vice versa.

Three studies using Fibroscan showed that 12–18% of diabetic patients are estimated to have significant liver fibrosis by different cut-offs [98–100]. Decreased levels of HbA1c [101] were more strongly associated with fibrosis improvement in 39 Japanese patients with diabetes and NAFLD who underwent sequential liver biopsies. Thus, these three clinical parameters, including ALT, body weight and HbA1c (ABC), can become the milestones for the treatment of NASH, although the appropriate goal of each parameter to ameliorate hepatic fibrosis will be established in the near future.

In a cross-sectional multicentre study conducted by JSGNAFLD, the presence of diabetes was found to be associated with advanced fibrosis in 1365 biopsy-proven NAFLD patients [102]. 'With or without T2DM' is a crucial problem for treating NAFLD/NASH patients because complicated T2DM itself modulates the clinical manifestations of NAFLD/NASH and affects the sensitivities to treatment procedures and the prognosis of each disease. If some effective treatments are developed and preferable improvement of NAFLD/NASH can be achieved, the control of T2DM will improve unexpectedly. Mounting evidence suggests that more experimental and clinical studies are needed to confirm or refute the claim that hepcidin has a role or relevance with T2DM complicated with NAFLD/NASH.

Recently, attention has been shifting towards the iron regulatory hormone hepcidin and its possible role in the etiopathogenesis of T2DM. Interpreting this critically, notably, hepcidin in the pancreas is expressed exclusively in the islets of Langerhans, which constitute merely a small compartment of the total pancreatic parenchyma. Very likely, the regulation of iron and glucose metabolism is distinctly coupled at least at the pancreatic level by the co-release of insulin and hepcidin [81].
