Plasma Water T2 as a Biomarker for Early Insulin Resistance Syndrome

Insulin resistance is defined as a blunted response to insulin by tissues. It is thought to be the body's response to energy imbalance and is exacerbated by over-nutrition, physical inactivity, obesity and/or genetic factors. Early-stage insulin resistance does not occur in isolation, but is part of a broader syndrome that includes four main components: (1) compensatory hyperinsulinemia, (2) dyslipidemia, (3) subclinical inflammation with shifts in plasma protein levels, and (4) subclinical acid-base abnormalities. Individuals with insulin resistance are at higher risk for developing type 2 diabetes. Yet, insulin resistance is often undetected by the tests used to diagnose and screen for type 2 diabetes, namely fasting serum glucose and hemoglobin A1c. There is an unmet need for practical screening tools for early insulin resistance syndrome in order to preserve pancreatic function and prevent type 2 diabetes. Since water hydrogen bonds to virtually every protein and lipoprotein particle in the blood, we hypothesized that the mobility of water in plasma is sensitive to the subclinical shifts in proteins and lipoproteins that occur in early insulin resistance syndrome. Water mobility can be measured as plasma water T2 using a simple benchtop implementation of nuclear magnetic resonance. To test this hypothesis, we conducted an observational cross-sectional study of 51 asymptomatic, non-diabetic human subjects, ages 24-80, and quantified the association of plasma water T2 values with over 100 established metabolic biomarkers and diagnostic tests. Plasma water T2 exhibited bivariate correlations with markers of each of the four components of the insulin resistance syndrome. Multiple regression models revealed independent associations of plasma water T2 with fasting insulin levels, total serum protein concentration or viscosity, white blood cell or neutrophil count, and total cholesterol. Analysis using receiver operator characteristic curves demonstrated that plasma water T2 can diagnose insulin resistance (as defined by the McAuley Index) with a sensitivity of 86%. By comparison, the sensitivities of fasting glucose and hemoglobin A1c were 14 and 47%, respectively. This discovery provides a foundation for developing a new diagnostic test for early insulin resistance syndrome and a practical screening tool for the early identification of individuals at risk for type 2 diabetes.