Reports estimate that there are over 17 million individuals with diagnosed Type 2 Diabetes (T2DM) in the US, and an additional ~ 6 million undiagnosed individuals unaware of having (or at risk of having) T2DM. This number of afflicted individuals is expected to double in the US in the next 40 years. Current costs for diabetes in the US are estimated at $174 billion (~$1 of every $10 health care dollars), with cardiovascular disease (CVD) - the major cause of morbidity and mortality for individuals with diabetes - being the largest contributor to direct and indirect costs. Currently, there are two common biomarkers used in the detection and monitoring of T2DM: blood glucose and glucose modified hemoglobin. In preliminary studies, we have built upon these current diagnostic tests by viewing subtle, dynamic changes in the proteome of patients with T2DM and CVD. Briefly, molecular differences were observed in a number of plasma proteins, which during univariate analysis resulted in good separation between healthy and T2DM cohorts. In subsequent treatments, data were grouped into panels and correlated to a three-dimensional view of glycation vs. oxidative-stress vs. perturbations in the insulin-signaling pathway. Scatter plots revealed subtypes in the T2DM population exhibiting differential glycation/oxidative stress/signaling relationships, in particular low glycation, but high oxidative stress - a sub-clinical driver of CVD. These studies lead to creating a multidimensional view of the T2DM/CVD continuum aligned with the pathobiologies of the diseases. Here, we will continue our investigations using >700 patients in total, across a continuum of healthy - to - pre-T2DM - to - T2DM - to negative CVD outcome. We will follow a systematic biomarker development pathway to: (Specific Aim 1) identify additional candidate biomarkers for detection and monitoring T2DM and CVD;(Specific Aim 2), verify the utility of the candidate biomarkers using larger populations;which provides the knowledge to (Specific Aim 3) design and implement 2nd-generation assays that group the T2DM and CVD comorbidity protein biomarkers into multiplexed assays. The overall goal of this proposed research is to produce verified protein biomarkers along with accompanying assays and methods of data evaluation that will result in the improved monitoring and treatment of type 2 diabetes mellitus and cardiovascular disease comorbidities.

Public Health Relevance

Diabetes affects ~ 10% of the people in the US, and in conjunction with comorbidities represent a significant financial drain on the US economy. New markers and assays are needed to assist in the early detection of diabetes, for monitoring the effects of treatment, and as indicators of the transition of diabetes into negative outcomes such as cardiovascular disease. Technologies developed by the principal investigator allow for high throughput identification and development of multiple T2DM and comorbidity biomarkers that will quickly reach the clinical phase and result in faster and more accurate identification of the disease state, ultimately decreasing impact of diabetes and its comorbidities on the US economy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK082542-05
Application #
8640929
Study Section
Enabling Bioanalytical and Biophysical Technologies Study Section (EBT)
Program Officer
Sechi, Salvatore
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$523,481
Indirect Cost
$128,664
Name
Arizona State University-Tempe Campus
Department
Miscellaneous
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Yassine, Hussein N; Trenchevska, Olgica; Dong, Zhiwei et al. (2016) The association of plasma cystatin C proteoforms with diabetic chronic kidney disease. Proteome Sci 14:7
Trenchevska, Olgica; Yassine, Hussein N; Borges, Chad R et al. (2016) Development of quantitative mass spectrometric immunoassay for serum amyloid A. Biomarkers :1-9
Azizkhanian, Ida; Trenchevska, Olgica; Bashawri, Yara et al. (2016) Posttranslational modifications of apolipoprotein A-II proteoforms in type 2 diabetes. J Clin Lipidol 10:808-15
Trenchevska, Olgica; Nelson, Randall W; Nedelkov, Dobrin (2016) Mass spectrometric immunoassays for discovery, screening and quantification of clinically relevant proteoforms. Bioanalysis 8:1623-1633
Koska, Juraj; Yassine, Hussein; Trenchevska, Olgica et al. (2016) Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes. J Lipid Res 57:894-905
Yassine, Hussein N; Trenchevska, Olgica; He, Huijuan et al. (2015) Serum amyloid a truncations in type 2 diabetes mellitus. PLoS One 10:e0115320
Yassine, Hussein N; Trenchevska, Olgica; Ramrakhiani, Ambika et al. (2015) The Association of Human Apolipoprotein C-III Sialylation Proteoforms with Plasma Triglycerides. PLoS One 10:e0144138
Rehder, Douglas S; Gundberg, Caren M; Booth, Sarah L et al. (2015) Gamma-carboxylation and fragmentation of osteocalcin in human serum defined by mass spectrometry. Mol Cell Proteomics 14:1546-55
Manard, Benjamin T; Jones, Sarah M H; Marcus, R Kenneth (2015) Capillary-channeled polymer (C-CP) fibers for the rapid extraction of proteins from urine matrices prior to detection with MALDI-MS. Proteomics Clin Appl 9:522-30
Trenchevska, Olgica; Sherma, Nisha D; Oran, Paul E et al. (2015) Quantitative mass spectrometric immunoassay for the chemokine RANTES and its variants. J Proteomics 116:15-23

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