Novel Biomarkers for Metabolic Health




Mishra, Ina


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The worldwide diabetes pandemic continues to worsen, and there is an urgent need for improved prevention strategies. The metabolic abnormalities that precede type 2 diabetes include insulin resistance with compensatory hyperinsulinemia, dyslipidemia and subclinical inflammation. By the time glucose tolerance is impaired (prediabetes), a 50-70% decline in pancreatic insulin secretion has occurred. Therefore, it is imperative to identify metabolic abnormalities early in order to preserve pancreatic β-cell function and prevent diabetes. Insulin resistance is the hallmark early abnormality in the progression towards prediabetes and type 2 diabetes, but is difficult to measure. There is an unmet need for new screening tools for metabolic health. This dissertation describes the discovery and characterization of a new biomarker for early metabolic syndrome. This biomarker is based on the transverse relaxation time (T2) for water in human plasma and serum, measured using benchtop nuclear magnetic resonance relaxometry. Water T2 values were measured in an observational cross-sectional study of 72 human subjects without acute or chronic disease. Water T2 exhibited strong correlations with markers of insulin, lipids, inflammation, coagulation and electrolyte balance. After correcting for confounders, low water T2 values were independently and additively associated with hyperinsulinemia, dyslipidemia and subclinical inflammation. Using water T2, 16 individuals with early metabolic abnormalities (22% of the study population) were identified. Thirteen of the 16 did not meet the criteria for metabolic syndrome and would have been missed by conventional screening for diabetes risk. Similar results were obtained using plasma and serum biobanked at -80°C. However, water T2 from biobanked samples revealed a negative offset compared with fresh samples, and the cut points must be calibrated independently. The contributions of individual proteins to the lowering of water T2 were quantified by determining relaxivity values and effective relaxation rates. The largest contributions were made by apolipoprotein B, complement C3, haptoglobin, fibrinogen, α-1 acid glycoprotein and complement C4. Water T2 detects early abnormalities associated with metabolic syndrome, providing a global view of an individual's metabolic health. It shows promise as an early, global and practical screening tool for the identification of individuals at risk for type 2 diabetes and atherosclerosis.