The goal of this proposal is to assess glycated CD59 in human serum as a pathogenically relevant early bio-marker for screening of gestational diabetes mellitus (GDM). This proposal is highly translational and addresses major Public Health priorities because 1) diabetes affects H 25 million Americans, 2) and GDM is a major source of adverse pregnancy outcomes including macrosomia and pre-eclampsia. The proposed work opens the possibility of using glyCD59 as a biomarker for GDM, an innovative departure from the use of OGTT, a cumbersome, costly and time-consuming test with poor reproducibility and many times unwanted effects including nausea and vomiting. A simpler, easy to use, patient friendly marker that is also involved in the pathogenesis of diabetes and its complications may help fulfill an important clinical need in the widespread screening for GDM and prevention of associated adverse outcomes. The applicants have 1) discovered that human CD59 is inactivated by glycation, 2) provided evidence for a link between the complement system and the pathogenesis of the complications of diabetes, and 3) developed key reagents that allow quantification of glycated hCD59 in human fluids and tissues. Specifically, we have demonstrated that 1) glycated CD59 is present in target organs of diabetic complications, and 2) glyCD59 can be readily measured in normal urine and serum. Furthermore, our preliminary data show that glyCD59 is a) significantly increased (3-4 fold) in the serum of diabetic and pre-diabetics individuals, and b) seems to respond faster than HbA1c to changes in glycemic load within an individual All necessary tools and expertise to accomplish our aim are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for glycated CD59 and assay calibrators, access to large and diverse population of pregnant women undergoing pre-natal care at BWH, and diagnostic tools, equipment and expertise to necessary to conduct all studies proposed in the application. Successful accomplishment of our aims would represent a major advancement in screening and early diagnosis of GDM.
This highly translational proposal a) aims at establishing serum glycated CD59 as a novel biomarker of Gestational Diabetes Mellitus (GDM), b) is based on robust preliminary data and availability of all assays/reagents needed, and c) addresses major Public Health priorities. The importance of this goal is highlighted by the fact that 1) GDM occurs in 1 to 14% of all pregnancies, and is rising in the United States, 2) GDM is a major cause of adverse pregnancy outcomes including macrosomia, pre-eclampsia C-sections, hyperinsulinemia, 3) adverse outcomes can be prevented with adequate treatment, 4) screening for GDM with OGTT at 24-28th weeks is now the standard of care for most pregnant women seeking prenatal care in the United States, and 5) oral glucose tolerance test (OGTT), the current gold standard for GDM screening, is cumbersome, uncomfortable, at times causes nausea and vomiting and is not fully reproducible. Success will allow the use of a simpler, cheaper, more patient-friendly and accurate screening test for GDM.
|Ghosh, Pamela; Sahoo, Rupam; Vaidya, Anand et al. (2015) Role of complement and complement regulatory proteins in the complications of diabetes. Endocr Rev 36:272-88|