Study On The Mechanism Of Diabetes And Diabetic Retinopathy Based On HGF And LH

Type 2 diabetes mellitus(T2DM)is a global public health disease,and the incidence rate is increasing year by year.The microvascular and macrovascular complications caused by this disease are the main cause of disability and death.Patients’ health and quality of life are being threatened.Therefore,it is particularly important to study the pathogenesis of type 2 diabetes and the risk factors for its complications.Insulin resistance is an important pathophysiological mechanism for type 2diabetes.Hepatic insulin resistance plays a very important role in systemic insulin resistance.Previous studies have demonstrated that the HGF/c-Met signaling pathway improves insulin resistance by inhibiting gluconeogenesis by lowering glycemic key genes such as PEPCK and G6 PASE.In our previous study,we used exogenous hepatocyte growth factor(HGF)to treat insulin resistance model mice,and observed that HGF can significantly reduce fasting blood glucose and fasting insulin levels,and relieve liver lipid deposition,which suggested that HGF/c-Met signaling pathway involved in the regulation of lipid metabolism.However,the mechanism by which HGF participates in lipid metabolism needs to be further clarified.Therefore,in this study,we conducted further study to confirm that HGF/c-Met signaling pathway can improve lipid metabolism by regulating lipid metabolism-related genes FXR-SHP/SREBP-1c and FXR/PPARα on the gene and protein levels,by which to relieve liver insulin resistance.In terms of diabetic complications,we found that in male patients with type 2diabetes,diabetic retinopathy(DR)is associated with diabetes duration,blood pressure,fasting blood glucose,glycosylated hemoglobin,body mass index(BMI),and urinary albumintocreatinine ratio(ACR).It is also associated with sex hormones,especially luteinizing hormone(LH).Our result showed that LH is also an independent risk factor for diabetic retinopathy.In the stratified analysis,we found that the incidence of DR increased with the increasing of LH.Therefore,in this study,we identified the mechanisms by which HGF/c-Met signaling pathway regulates lipid metabolism and risk factors for male diabetic retinopathy.HGF/c-Met signaling pathway inhibits lipid production by regulating lipid metabolism-related genes FXR-SHP/SREBP-1c and FXR/PPARα,promotes fatty acid decomposition,lowers blood lipids and improves liver function,thereby alleviating hepatic insulin resistance.In diabetic retinal complications,especially in male diabetic patients,we found that the prevalence of DR increases with the increasing of serum LH.Regression analysis shows that LH is also an independent risk factor for male diabetic retinopathy.LH is likely to become a predictor of diabetic retinopathy and a new therapeutic target.ObjectiveType 2 diabetes is often associated with fatty liver disease.Accumulation of lipids in the liver is considered a risk factor for insulin resistance.Hepatocyte growth factor(HGF)is commonly used in the treatment of liver dysfunction,and previous studies have demonstrated that the HGF/c-met signaling pathway improves insulin resistance by inhibiting gluconeogenesis and lowering blood glucose levels by regulating key genes of glucose metabolism,such as PEPCK and G6 PASE.However,the effect and mechanism of HGF on lipid metabolism in liver are not completely clear.MethodBased on our previous studies,C57BL/6 mice and Hep G2 cells were induced to insulin resistance model mice and cell.We conduct QPCR and Western Blot to compare the m RNA and protein expression of SREBP1-c and its target genes FAS and PPAR-α in the liver before and after HGF treatment.We selected the upstream FXR nuclear receptor(farnesoid X receptor)of SREBP1-c/FAS and PPAR-α,compared FXR and its target gene SHP m RNA and protein levels before and after HGF treatment,to clarify the possible mechanism of HGF involved lipid metabolism in liver.ResultThe m RNA expression of SREBP1-c and its target gene FAS in the liver of mice after HGF treatment was significantly lower than that in the untreated group.Western Blot also confirmed the same trend that the protein levels of SREBP1-c and its target gene FAS,and the results were statistically significant.The expression of PPAR-α m RNA after HGF treatment was significantly higher than that in the untreated group.A similar trend was observed in Western Blot,and the results were statistically significant.In addition,our study also found that HGF can significantly increase the expression of FXR and SHP in m RNA and protein level in the liver.Our results indicate that HGF may regulate lipid production and promote fatty acid degradation by regulating the two axes of FXR-SHP/SREBP-1c-FAS and FXR/PPARα in the liver,thereby regulating hyperlipidemia and improving liver function so as to relieve the insulin resistance in the liver.ConclusionIt is suggested that HGF therapy can improve insulin resistance and steatosis in liver by regulating lipid metabolism.ObjectiveDiabetic retinopathy(DR)is a common microvascular complication of diabetes mellitus,which is the main cause of vision loss in middle-aged and elderly people.Previous studies have confirmed that many risk factors are associated with DR.Luteopoietin(LH)is found in human eyes,and its receptor(LHR)is also expressed in various organs,including retina.Therefore,this study is to investigate the relationship between luteinizing hormone(LH)and male diabetic retinopathy.MethodA total of 724 male patients with type 2 diabetes who were hospitalized from January 2016 to January 2018 were enrolled,and their clinical data were retrospectively analyzed.According the standard of the International Clinical Grading Criteria for Diabetic Retinopathy,724 patients were divided into diabetic retinopathy group(DR group)and non-diabetic retinopathy group(non-DR group)by ophthalmoscopy examination.In the stratified analysis,DR group were divided inti three groups,mild non-proliferative diabetic retinopathy(Mild NPDR)group,moderate non-proliferative diabetic retinopathy(Moderate NPDR)group,and severe non-proliferative diabetic retinopathy(VTDR)group.Additionally,LH was analyzed as a categorical variable divided into tertiles,we divided LH into three groups T1(Tertile 1),T2(Tertile 2)and T3(Tertile 3).The relationship between LH and DR in each group was analyzed by comparing the clinical data.ResultA total of 724 male patients with type 2 diabetes were enrolled in the study.The subjects were divided into DR group and non-DR group according to theliver by regulating lipid metabolism.ophthalmoscopy examination.The mean age of the DR group was 54.3±10.3 years,and the average age of the non-DR group was 51.3±11.7 years.Compared with the non-DR group,the DR group had higher LH levels(P<0.05).In the stratified analysis,we found that LH showed different degrees of decline in the Moderate NPDR group and the VTDR group,but no statistical difference was found.In the comparison of the tertile method,we found that with the increase of LH level,the prevalence of the DR showed an increasing trend(P<0.05).Further binary logistic regression analysis showed that LH is also an independent risk factor for diabetic retinopathy.ConclusionThis study demonstrates that elevated levels of LH in serum are significantly associated with the development and severity of male diabetic retinopathy,providing new therapeutic targets for male DR patients.