The goal of this proposal is to validate glycated CD59 in human blood (GCD59) as a screening test to identify individuals with pre-diabetes, and an early bio-marker of diabetes complications focusing on diabetic neuropathy. This proposal is highly translational and addresses major Public Health priorities because 1) diabetes affects H 25 million Americans, 2) diabetes complications are a major cause of morbidity and mortality in the U.S., and 3) treatment of these complications costs a staggering 245 billion dollars/year (expected to rise to >300 billion by 2034). HbA1c, the clinical gold standard for management of patients with diabetes, does not identify individuals at higher risk of developing some complications and is not sensitive enough to clearly discriminate individuals with pre-diabetes. Chronic hyperglycemia is ultimately responsible for the complications of human diabetes but the cellular and molecular mechanism(s) by which hyperglycemia causes tissue damage are still poorly understood. 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 GCD59 in blood and tissues. Specifically, we have demonstrated that 1) GCD59 is present in target organs of diabetic complications, and 2) GCD59 can be readily measured in normal plasma or serum. Furthermore, our preliminary data show that GCD59 is a) significantly increased in the blood of individuals with diabetes or pre-diabetes as well as in pregnant women with gestational diabetes mellitus, b) is a strong and independent predictor of glucose tolerance determined by standard 2hr oral glucose tolerance test, and c) seems to respond faster than HbA1c to changes in glycemic load within an individual All necessary tools and expertise to accomplish our aims are available in the laboratory of the applicant and expert collaborators, including monoclonal antibodies specific for GCD59 and assay calibrators, access to large and diverse population of individuals with and without diabetes, and diagnostic tools, equipment and expertise necessary to conduct all studies proposed in the application. Successful accomplishment of our aims would represent a major advancement in diagnosis, treatment and prevention of the devastating complications of glucose dysmetabolism and diabetes, and should help lower the extremely high costs derived from diabetes and its complications.
This highly translational proposal (a) has as a main goal the validation of glycated CD59 (the glucose inactivated form of the key complement regulatory protein known as CD59) in human blood (GCD59), as 1) a screening tool for Impaired Glucose Tolerance (IGT); and 2) a biomarker and predictor of vascular diabetic complications, (b) addresses major Public Health priorities, and (c) is based on a robust hypothesis, extensive preliminary data and availability of all assays/reagents needed. The relevance of the proposed studies is highlighted by the following facts 1) diabetes mellitus affects H25 million Americans, and diabetic micro- and macro-vascular complications are a major cause of morbidity and mortality in the U.S., 2) diabetic neuropathy, retinopathy, nephropathy and cardiovascular disease are respectively the leading cause of end-stage renal failure and renal transplants, blindness and nerve damage in adults, and of the much higher risk of myocardial infarction, stroke, and non-traumatic limb amputation in diabetics, 3) treatment of diabetic complications costs a staggering 245 billion dollars/year, and is expected to rise to >300 billion by 2034.
|Liu, Fengming; Sahoo, Rupam; Ge, Xiaowen et al. (2017) Deficiency of the complement regulatory protein CD59 accelerates the development of diabetes-induced atherosclerosis in mice. J Diabetes Complications 31:311-317|
|Ghosh, Pamela; Luque-Fernandez, Miguel A; Vaidya, Anand et al. (2017) Plasma Glycated CD59, a Novel Biomarker for Detection of Pregnancy-Induced Glucose Intolerance. Diabetes Care 40:981-984|
|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|
|Denoyelle, Séverine; Chen, Ting; Yang, Hongwei et al. (2013) Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2·GTP·Met-tRNAiMet ternary complex inhibitors. Eur J Med Chem 69:537-53|