Study On The Steroid Hormones Profiling In Polycystic Ovary Syndrome And Mechanism Of Incretin Effect In Type 2 Diabetes Mellitus

The prevalence of metabolic disorders has been increasing rapidly worldwide.Polycystic ovary syndrome(PCOS)is a common endocrine disorder affecting reproductive women.Hyperandrogenism is considered as a cardinal element in the pathogenesis of PCOS,while insulin resistance and its accompanied obesity play both direct and indirect roles.It is urgent to identify the possible source of androgen excess and understand the underlying mechanism,therefore to choose the optimal treatment.The incidence of type 2 diabetes mellitus(T2DM)has increased dramatically and the incretin-based therapy has drawn great attention.The regulation of incretin hormones and the incretin-based therapy,as well as its underlying mechanism still need further exploration.In the present study,we performed studies on the two metabolic disorders including PCOS and T2DM,in order to explore the metabolic profiling of PCOS and mechanism of incretin effect in T2DM.The study included three parts:the first part is about the steroid hormones profiling in PCOS;The second part is to compare the postprandial glucose,insulin and incretin responses to different carbohydrate tolerance tests;The third part is to compare the effects of two DPP-4 inhibitors on β-cell Function using the two-step hyperglycemic clamp.The first study was a multi-center,cross-sectional and observational study.A total of 1044(including 350 lean,312 overweight and 382 obese)PCOS patients and 366(including 203 lean,32 overweight and 131 obese)control women without PCOS were enrolled in two clinical centers from January 2006 to October 2016.The present study illustrated a comprehensive profile of steroid hormones and related enzymes activity in PCOS patients with a large sample size using the liquid chromatography-tandem mass spectrometry(LCMS/MS)method.Differences between PCOS and controls,as well as between obese and non-obese PCOS patients were thoroughly explored,and gene polymorphisms analysis was further applied to explain the potential mechanism.In this study,we found that lean PCOS patients presented with the most discrepancies compared with its corresponding control,with increased levels of DHEAS,17-OHP5,17-OHP,and E,so was found when compared with obese PCOS patients.Besides,lean PCOS patients showed decreased enzymes activity of P450c21 compared with obese PCOS patients.Interestingly,we found higher frequencies of CYP21A2 c.552C>G(p.D184E)in lean PCOS compared with obese PCOS patients.These findings suggested that differences in the steroidogenic pathway were involved in obese and nonobese PCOS patients,and the adrenal androgen excess played an important role in the pathogenesis of PCOS,especially in those with lower BMI.Identifying the possible source of androgen excess would help to choose the optimal treatments in improving hyperandrogensim in PCOS.The second study was an open-label,randomized,two-way crossover clinical trial,in order to compare the different effects of two carbohydrates(75 g oral glucose,a monosaccharide and 100 g standard noodle,a polysaccharide,with 75 g carbohydrates equivalently)on postprandial glucose,insulin and incretin responses.240 participants were assigned to take two carbohydrates in a randomized order separated by a washout period of 5-7 days.53 subjects also attended a three-way crossover study,with steamed bread tolerance test included.The results indicated that compared with polysaccharide,monosaccharide would stimulate a more rapid and higher glycemic and insulin response.Oral glucose of liquid state would elicit a more potent release of active GLP-1.Besides,the postprandial response curve was attributed with a more-like pattern with OGTT compared with steamed bread test.These properties suggested that standard noodles could be regarded as an alternative to oral glucose and steamed bread in routine monitoring of glycemic control in Chinese person.The patent of standard noodles has been granted(No.201310282631.2).The third study was a randomized,open-label,three-way,cross-over trial to explore the effects of two dipeptidyl peptidases(DPP)-4 inhibitors(sitagliptin and saxagliptin)on βcell function and incretin effect in type 2 diabetic patients using the two-step hyperglycemic clamp method.13 new-onset type 2 diabetic patients received a single dose of sitagliptin(100 mg),saxagliptin(5 mg)or nothing(blank control)before undergoing a two-step hyperglycemic clamp test,in which oral glucose was consumed between the first and second hyperglycemic clamp periods and allowed a comprehensive evaluation of the incretin-based effects on insulin secretion.It was found that the difference between DPP-4 inhibitors and the blank control in two phases of insulin secretion during the two-step hyperglycemic clamp procedure was amplified after oral glucose consumption in type 2 diabetic patients.Both DPP-4 inhibitors angmented active GLP-1 secretion after oral consumption,and exhibited similar effects on β-cell function and incretin effect.Sitagliptin further increased the first-phase insulin secretion after oral glucose consumption.This finding also suggested that oral consumption was necessary for DPP-4 inhibitors to exert their maximum efficacy on β-cell function in patients with T2DM,which would contribute to lower incidence of hypoglycemia.In conclusion,the article mainly focused on the steroid hormones profiling in PCOS and the mechanism of incretin effect in T2DM,using the method of mutitle-omics consisiting of clinical phenotype,genetic typing and metabonomics,in order to attain the aim of personalized medicine and promote the application of precision medicine in the diagnosis and treatment of metabolic disorders.