Correlation Between Plasma 12,13-diHOME And Metabolic Index In Patients With Type 2 Diabetes Mellitus And Nonalcoholic Fatty Liver Disease

Background:With the improvement of social and economic development and the improvement of people’s quality of life,the prevalence of diabetes has been on the rise all over the world,which has seriously affected people’s health and quality of life.The total number of people dying from diabetes and its complications has reached an astonishing number of millions every year.Nowadays,the vast majority of patients with diabetes is type 2 diabetes mellitus(T2DM)patients.Domestic studies in the past two years have shown that the prevalence rate of T2DM in adults over the age of 20 is as high as 9.7%.Insulin resistance is the core characteristic of T2DM,which plays a dominant role in the occurrence and development of the disease and is associated with multiple complications.T2DM is often associated with a variety of complications,such as hypertension,hyperlipidemia,hyperuricemia,overweight,non-alcoholic fatty liver disease(NAFLD),and even has a close relationship with each other.NAFLD is one of the most common type of chronic liver disease at present,it is to point to by the excessive intake of alcohol or other clear etiology,the lipid excessive deposition in the liver cells and reach a certain proportion of the own liver weight(>5%).NAFLD is a pathological syndrome characterized by diffuse bullae hepatocellular steatosis under the microscope.And NAFLD is the liver manifestation of metabolic syndrome and includes a range of liver diseases such as simple steatosis(SS),nonalcoholic steatohepatitis(NASH),cirrhosis,and hepatocellular carcinoma.Liver biopsy is the "gold standard" of the NAFLD diagnosis,but its clinical application is limited and difficult to carry out because of its invasive,high cost,complicated operation,postoperative complications.Imaging examination,such as magnetic resonance(MR),becomes a common clinical diagnosis way because of its easy operation,noninvasive,more sensitive.However,MR is expensive and occupies too much public health resources,which is often not the first choice for patients with chronic diseases with a large base.Ultrasound has a series of advantages,such as low cost,simple operation,noninvasive,low risk and high degree of recognition and the gradually improving computer aided quantitative methods in recent years so that it can become more accurate measurements of the liver fat content to some extent and has gradually become a new research field of NAFLD.The incidence of NAFLD is increasing year by year,and it has become one of the most common metabolic diseases in the world.So far,the specific pathogenesis of NAFLD has not been thoroughly studied,among which the theory of "second strike" is one of the hypotheses supported by many experts and scholars.The first strike is the excessive accumulation of lipids in liver cells caused by various metabolic risk factors,such as insulin resistance.The second strike refers to the formation and development of inflammatory liver lesions and liver fibrosis caused by factors related to oxidative stress in vivo.Its pathogenesis is closely related to inflammatory response,oxidative stress,glucose and lipid metabolic disorders,lipotoxicity and insulin resistance.Among them,insulin resistance is not only the central link of T2DM,but also a key factor that cannot be ignored in NAFLD,and may even become an important bridge between the two.Adipose tissue is not only an important energy storage warehouses of the human body,but also a more active endocrine organs which can secrete a variety of biological signal molecules called adipokines.These adipokines affect body functions through autocrine or paracrine,and regulate biological functions such as energy homeostasis,glucose and lipid metabolism,food intake,inflammation and immunity.The secretion balance disorder and dysfunction of adipokines are involved in the pathogenesis of various metabolic diseases such as obesity,diabetes,non-alcoholic fatty liver disease and atherosclerosis.The study of the relationship between components of metabolic syndrome and related complications will open up new ideas and broad application prospects for the diagnosis and treatment of metabolic diseases.Among them,12,13-dihydroxy-9z-18 carbon olefine acid(12,13-dihydroxy-9z-octadecenoic acid,12,13-diHOME)is a newly discovered adipokine which can be produced in a small amount in various tissues of the body,such as white adipose tissue,cardiac muscle,skeletal muscle,brain and bone marrow,and its most important source is brown adipose tissue.Studies have shown that 12,13-diHOME is closely related to blood glucose homeostasis,fatty acid and other lipid metabolic balance,quality index,liver transaminase level,and metabolic heat production in brown adipose tissue.12,13-diHOME can increase the intake of fatty acid and glucose in brown adipose tissue,and has certain effects on cardiopulmonary function,body immunity and inflammatory response.Animal experiments showed that the experimental group mice treated with exogenous 12,13-diHOME had better tolerance to cold exposure than the control group mice,and the experimental group mice had enhanced lipid oxidation and decreased circulating triglyceride levels.A recent study examined the effects of cold exposure on lipid signaling factors in human plasma and found that the concentration of 12,13-diHOME in human plasma was inversely proportional to body mass index,insulin resistance(represented by HOMA-IR),fasting plasma insulin and glucose levels,and liver transaminase levels.12,13-diHOME is the ligand of peroxisome proliferators-activated receptor receptors(PPAR-receptors).PPAR-receptors and its activators/inhibitors play an extremely important role in fat metabolism,various types of inflammation and immune response,which indirectly indicates that 12,13-diHOME has the potential to be developed into an important agent for the treatment of metabolism-related diseases in the future.A number of clinical studies have shown that 12,13-diHOME is closely related to glucose and lipid metabolism,but there are no reports on 12,13-diHOME in T2DM patients with NAFLD.The purpose of this study was to investigate the correlation between plasma 12,13-diHOME level and metabolic indexes in T2DM patients with NAFLD through a cross-sectional study,and to provide a new theoretical basis and method for the prevention and treatment of clinical diseases.Objective:To investigate the relationship between plasma 12,13-diHOME level and glucose and lipid metabolism in T2DM patients with NAFLD,and further analyze its potential role in the metabolic process of the body.Methods:From September 2018 to April 2019,202 patients with T2DM who met the inclusion criteria were selected from the patients hospitalized in our hospital.According to the result of liver ultrasound examination,patients can be divided into:T2DM group(63 cases,23 males and 40 females;average age:61.22±13.41 years;average duration of diabetes:13(8,18)years);the NAFLD group with T2DM(139 cases,64 males and 75 females;average age:55.86±13.57years;average duration of diabetes:10(1,13.25)years).The Chinese guidelines for the prevention and treatment of type 2 diabetes(2017 edition)were used as the reference standard for the diagnosis of T2DM patients,and the Chinese guidelines for the diagnosis and treatment of non-alcoholic fatty liver disease(2010 revised edition)were used as the reference standard for the diagnosis of NAFLD patients.Age,gender,height,weight and other general information of the patients were recorded.Glucose and lipid metabolism,other biochemical indicators and 12,13-diHOME level of the patients were measured,and the liver fat content of the two groups was measured by computer-assisted ultrasound quantitative method.The differences in general data and various test indicators between the two groups were compared.Binary logistic regression was used to analyze the risk factors of the occurrence of T2DM with NAFLD.Spearman correlation analysis was used to explore the correlation between plasma 12,13-diHOME level and each indicator,and multiple steps regression analysis was used to further test the relationship between 12,13-diHOME level and other study variables.SPSS 25.0 was used for statistical analysis.Results:(1)Comparison of general information between the two groupsCompared with T2DM group,the weight,mass index,diastolic blood pressure and heart rate of the group with T2DM patients with NAFLD were significantly increased,while the age and duration of diabetes were significantly decreased(all P<0.05).There was no significant statistical difference in gender,height,waist circumference,hip circumference,waist-to-hip ratio,systolic blood pressure between the two groups(all P>0.05).(2)The quantitative results of 12,13-diHOME and other indicators were compared between the two groupsCompared with T2DM group,serum aspertate aminotransferase,triglycerides,small dense low-density lipoprotein cholesterol,fasting blood glucose,glomerular filtration rate,urine creatinine,visceral fat area,C peptide and insulin resistance index,liver/kidney ultrasound echo intensity ratio,the liver were significantly higher in fat and high density lipoprotein cholesterol significantly decreased in T2DM patients with NAFLD(P<0.05).Serum uric acid,glutamyl transpeptidase,total cholesterol,low-density lipoprotein cholesterol,urinary bladder,protease inhibitors C,blood urea nitrogen,serum creatinine,c-reactive protein and free fatty acids,urine trace albumin,urine trace albumin/creatinine ratio,serum glycosylated hemoglobin,fasting insulin,12,13-diHOME and liver ultrasound echo intensity attenuation in two groups were no significant statistical difference(P>0.05).(3)Binary Logistic regression analysis of influencing factors associated with T2DM patients with NAFLDWith T2DM patients with NAFLD or not as the dependent variable,age,duration of diabetes,weight,quality index,diastolic blood pressure,heart rate,serum alanine aminotransferase,serum aspertate aminotransferase,triglycerides,high-density lipoprotein cholesterol,small and low-density lipoprotein cholesterol,fasting glucose,glomerular filtration rate,urine creatinine,visceral fat area,C peptide,insulin resistance index,liver/kidney ultrasound echo intensity ratio,liver fat content and 12,13-diHOME were independent variables and we conducted the binary Logistic regression analysis.The results showed that fasting blood glucose,urine creatinine and liver fat content had significant statistical significance(all P<0.05).(4)Correlation analysis between 12,13-diHOME and other indicatorsSpearman correlation analysis showed that,the plasma level of 12,13-diHOME was positively correlated with the serum aminotransferase,total cholesterol,high density lipoprotein cholesterol,blood urea nitrogen,free fatty acids,c-peptide,fasting insulin and insulin resistance index and was negatively correlated with height,weight,glomerular filtration rate,and serum hemoglobin alc(all P<0.05).However,there was no significant correlation with diabetes course,mass index,waist to hip ratio,diastolic blood pressure,systolic blood pressure,heart rate,serum uric acid,serum alanine aminotransferase,glutamyl transpeptidase,triglyceride,low density lipoprotein cholesterol and urinary cystease inhibitor C(all P>0.05).(5)Multiple stepwise regression analysis of 12,13-dihomeThe plasma level of 12,13-diHOME was used as the dependent variable,and general data of patients and the indicators measured in the laboratory were used as the independent variables for the multivariate stepwise regression analysis.The results showed that hip circumference,free fatty acids and visceral fat area were the independent influencing factors of plasma 12,13-diHOME level(all P<0.05).Then,the multiple linear regression equation was obtained:12,13-diHOME(ng/ml)=-2.193+0.059*hip circumference(cm)+1.643*free fatty acid(mmol/L)-0.021*visceral fat area(cm2).Conclusion:There was no significant statistical difference in plasma level of 12,13-diHOME between T2DM and T2DM patients with NAFLD,indicating that the body has certain self-control regulation ability for certain metabolic abnormalities in order to maintain the stability of internal environment.The plasma level of 12,13-diHOME was positively correlated with the serum aminotransferase,total cholesterol,high density lipoprotein cholesterol,blood urea nitrogen,free fatty acids,C-peptide,fasting insulin and insulin resistance index,and was significantly negatively correlated with height,weight,glomerular filtration rate,and serum hemoglobin a1c.Hip circumference,free fatty acids and visceral fat area were independent influencing factors for plasma 12,13-diHOME level.It indicates that 12,13-diHOME is closely related to a variety of metabolic indexes in the body,and it may play a certain role in the management of body weight and body type,lipid metabolism,liver and kidney function regulation,and changes in blood glucose level.Finally,the internal mechanism and relationship of this role need to be further studied.