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 #
5R01DK082542-03
Application #
8233490
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
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$586,372
Indirect Cost
$125,372
Name
Arizona State University-Tempe Campus
Department
Miscellaneous
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Borges, Chad R; Sherma, Nisha D (2014) Techniques for the analysis of cysteine sulfhydryls and oxidative protein folding. Antioxid Redox Signal 21:511-31
Borges, Chad R; Rehder, Douglas S; Jensen, Sally et al. (2014) Elevated plasma albumin and apolipoprotein A-I oxidation under suboptimal specimen storage conditions. Mol Cell Proteomics 13:1890-9
Oran, Paul E; Trenchevska, Olgica; Nedelkov, Dobrin et al. (2014) Parallel workflow for high-throughput (>1,000 samples/day) quantitative analysis of human insulin-like growth factor 1 using mass spectrometric immunoassay. PLoS One 9:e92801
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Sogawa, Kazuyuki; Noda, Kenta; Umemura, Hiroshi et al. (2013) Serum fibrinogen alpha C-chain 5.9 kDa fragment as a biomarker for early detection of hepatic fibrosis related to hepatitis C virus. Proteomics Clin Appl 7:424-31
Borges, Chad R; Rehder, Douglas S; Boffetta, Paolo (2013) Multiplexed surrogate analysis of glycotransferase activity in whole biospecimens. Anal Chem 85:2927-36
Borges, Chad R; Oran, Paul E; Buddi, Sai et al. (2011) Building multidimensional biomarker views of type 2 diabetes on the basis of protein microheterogeneity. Clin Chem 57:719-28
Kimzey, Michael J; Yassine, Hussein N; Riepel, Brent M et al. (2011) New site(s) of methylglyoxal-modified human serum albumin, identified by multiple reaction monitoring, alter warfarin binding and prostaglandin metabolism. Chem Biol Interact 192:122-8
Oran, Paul E; Jarvis, Jason W; Borges, Chad R et al. (2011) Mass spectrometric immunoassay of intact insulin and related variants for population proteomics studies. Proteomics Clin Appl 5:454-9
Weiss, Noah G; Jarvis, Jason W; Nelson, Randall W et al. (2011) Examining serum amyloid P component microheterogeneity using capillary isoelectric focusing and MALDI-MS. Proteomics 11:106-13

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