Association Between Serum Cytokines And Type 2 Diabetes Mellitus With Non-alcoholic Fatty Liver Disease

BackgroundNon-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in China and the fastest growing cause of liver-related death worldwide.Type 2 diabetes mellitus(T2DM)has a higher prevalence of NAFLD and a more severe degree of hepatic fibrosis.Hepatic fibrosis is a major determinant of liver-related adverse outcomes.A variety of proinflammatory cytokines have been found to play an important role in the occurrence of NAFLD and the progression of hepatic fibrosis as inflammatory mediators.However,there are few studies on cytokines related to NAFLD and hepatic fibrosis in patients with type 2 diabetes mellitus.It is of great significance to explore the effects of cytokines on NAFLD and hepatic fibrosis in patients with T2DM.ObjectiveIn this study,a broad set of serum cytokines were evaluated in type 2 diabetic population,aiming to explore the cytokines closely related to NAFLD and significant hepatic fibrosis,to find potential biomarkers of NAFLD and significant hepatic fibrosis in type 2 diabetic patients,and to explore the potential mechanism of cytokines in the progression of hepatic fibrosis.MethodsA total of 185 patients with type 2 diabetes were selected from a community in Jinan,excluding excessive drinking and other liver damage.Detailed questionnaire survey,physical examination,clinical indicators,transient elastography(TE)test and cytokines profile were performed.According to the results of TE,the patients were divided into simple type 2 diabetes group(T2DM group),NAFLD without significant hepatic fibrosis group(no HF group),and NAFLD with significant hepatic fibrosis group(HF group).Comparing the cytokines of the three groups,screening serum cytokines can be used to identify NAFLD and significant hepatic fibrosis.After adjusting for clinical confounding factors,the association between NAFLD,significant hepatic fibrosis and cytokines was investigated.Mediating effect analysis was used to verify the possible mediating effect of cytokines.Results1.In patients with T2DM,body weight,BMI,waist circumference,fasting C-peptide,HOMA-IR and triglyceride are common risk factors for NAFLD and significant hepatic fibrosis.HDL-C is a protective factor for NAFLD and significant hepatic fibrosis.In addition,uric acid and systolic blood pressure are also associated with an increased risk of NAFLD.2.Serum IL-1ra in no HF and HF groups was significantly higher than that in T2DM group.The serum IP-10 level in HF group was significantly higher than that in T2DM and no HF groups.The levels of RANTES and MIP-1β in HF groups were higher than those in no HF group and T2DM group,respectively.The levels of IL-2 and IL-12p70 in HF group were lower than those in no HF group and T2DM group,respectively.Among the 27 cytokines,the area under the receiver operating characteristic curve(AUROC)of serum IL-1ra for screening NAFLD and serum IP-10 for screening significant hepatic fibrosis was the largest.3.Serum IL-1ra is independently associated with the development of NAFLD in patients with T2DM.Serum IP-10 was independently associated with an increased risk of significant hepatic fibrosis.The AUROC of serum IL-1ra combined with waist circumference in the diagnosis of NAFLD was 0.759,and the specificity was 92.7%.The AUROC of serum IP-10 for screening significant hepatic fibrosis in T2DM patients with NAFLD were 0.727.4.Aspartate transaminase,eGFR and liver stiffness measurement were independent factors affecting serum IP-10.The mediating effect of IP-10 between HOMA-IR and hepatic fibrosis was significant,with a mediating effect of 38.9%.ConclusionsSerum IL-1ra is independently associated with the occurrence of NAFLD in patients with T2DM.As a potential biomarker,it can improve the specificity of NAFLD diagnosis when combined with waist circumference.Serum IP-10 is a potential biomarker for screening significant hepatic fibrosis in patients with T2DM.Moreover,as an inflammatory mediator,it may be involved in mediating the promoting effect of insulin resistance on hepatic fibrosis in non-alcoholic fatty liver disease.