Study On The Effects And Underlying Mechanisms In The Regulation Between ADMA And Insulin Sensitivity

With the development of economy and the improvement of people's living standard in China,the incidence of diabetes has increased significantly.According to the data from the International Diabetes Federation(International Diabetes Federation,IDF),the global number of adult patients with Diabetes has reached 415 million in 2015,the Diabetes in China accounts for about a third of them.At present,it is well known that insulin resistance is an important characteristic of type 2 diabetes,which is regulated by both environmental and genetic factors.And the mechanisms underlying needs to be further studied.It is important to reveal the molecular mechanisms involved in insulin resistance with type 2diabetes.And looking for valuable biomarkers for the early diagnosis of type 2 diabetes is helpful for the development of targeted drugs.Unsymmetrical dimethyl arginine(Asymmetric Dimethylarginine,ADMA)is a non-selective inhibitors of NO synthetase involved in inflammation and oxidative stress,as well as the occurrence of a variety of diseases such as cardiovascular disease,tumor development.ADMA induced dysfunction of endothelial cells resulting in decreased insulin sensitivity.Research based on small sample clinical diabetes showed that the serum ADMA levels were significantly increased in patients with diabetes,and was positively correlated with HOMA-IR.And the serum ADMA level was independent factor associated with diabetes.Other research has shown that metformin can reverse the liver damage caused by ADMA.All these studies indicated that ADMA is a potential independent predictor of insulin resistance in the early period of type 2 diabetes.The molecular mechanisms underlying metformin relating to ADMA remains to be further evaluated.In order to reveal the role of the serum ADMA in type 2 diabetes and mechanisms underlying the regulation of insulin sensitivity,we performed the clinical study with the large sample with type 2 diabetes to access the role of serume ADMA as type 2 diabetes early prediction of molecular markers.And primary hepatocytes were used to investigate the molecular mechanisms involved in ADMA regulating insulin sensitivity.In this thesis,according to the diagnosis of WHO 1990,we selected different glucose metabolism patients and divided them into three groups:58 patients with normal glucose tolerance(NGT),69 patients with impaired glucose tolerance(IGT),68 patients with type2 diabetes.In type 2 diabetes group,we divide two sub groups:obese group(BMI?28kg/)and non-obese group BMI<28 kg/m~2.We found that:(1)serum ADMA levels are significantly increased IGT and diatetic patients,especial in diabetic patients with obesity.(2)The serum ADMA levels are closely correlated to HOMA-IR,and Logistic regression analysis indicated that ADMA is the independent factors associated with diabetes with obesity.So,serum HOMA level can serve as biomarker of early warning for diabetes with obesity.Using primary hepatocytes,we illustrated that:(1)ADMA inhibits insulin sensitivity in primary hepatocytes reling on MAPK pathways,which are associated with the expression of inflammatory factors.It is possiblely that ADMA inhibits insulin sensitivity by promoting inflammatory response;(2)we use metformin to treat primary hepatocytes and found that metformin can reverse ADMA-induced insulin resistance.In summary,this topic illustrated that the elevated ADMA is closely related to the occurrence of diabetes in obesity.Further study indicated that ADMA promotes the inflammation levels partially by regulating the MAPK signaling pathways resulting in decreased insulin sensitivity.The study put a new insight on ADMA in regulating insulin sensitivity.And higher levels of ADMA play a warning signs for obesity to provent the occurrence of diabetes.Our results have important theoretical significance and potential clinical application value.