Abstract P433: Associations of CD4+ T Lymphocyte Subpopulations with Insulin Levels and Type 2 Diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Background: Chronic inflammation is a characteristic feature of insulin resistance (IR) and type 2 diabetes (T2D). Elevated circulating levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), are predictive of disease onset suggesting contributions of adaptive immune responses in the etiology of T2D. Therefore, we hypothesized that increased populations of CD4 + effector/memory (EM) and T helper 1 (Th1) cells, and decreased populations of CD4 + naive cells, would be associated with high insulin levels and an increased risk of T2D. Methods: T cell subpopulations were measured in peripheral blood by flow cytometry, using CD4 + CD45RO + , CD4 + CD45RA + , CD4 + IFN-γ + , and CD4 + IL4 + as markers for EM, naive, Th1, and Th2 cells, respectively. Data for each subpopulation were reported as a percent of total CD4 + cells. Associations were explored with components of the metabolic syndrome, insulin measures, and type 2 diabetes in a random subset ( n =917) of the Multi-Ethnic Study of Atherosclerosis (MESA). T2D was defined by fasting glucose ≥126 mg/dL or use of glucose-lowering medications ( n =151). All variables were measured at Exam 4 (2005-2007), except for insulin which was measured at Exam 5 (2010-2012), and inflammatory biomarkers measured at Exam 1 (2000-2002). Results: Naive cells were inversely, and EM, and Th1 cells positively associated with insulin levels in minimally adjusted (age, gender, race/ethnicity) linear regression analyses that modeled insulin as the dependent variable. No significant associations were observed with Th2 cells. After further adjustment for the metabolic- and cardiovascular disease (CVD)-related variables, waist circumference, systolic blood pressure (BP), use of anti-hypertensive medication, smoking status, total- and HDL-cholesterol, use of lipid lowering medication, and IL-6, the association of insulin with Th1 cells, but not naive or EM cells, remained significant [β= 6.4 mU/L (± 1.69 mU/L) per standard deviation (SD) increase in Th1 cells (8.3%); p=0.0002]. Adjusting for body mass index (BMI) in place of waist circumference did not alter interpretation of the results. In standardized logistic regression models including cell subpopulations and metabolic- and CVD-related variables (as above) as the independent variables, naive cells were inversely associated with prevalent T2D [odds ratio (95% confidence interval)=0.78 (0.61-0.99)]. Conclusion: Increased populations of Th1 cells and decreased populations of CD4 + naive cells are associated with insulin levels and T2D, respectively, independent of measures of adiposity. These cross-sectional findings suggest that excess immune activation and Th1 bias, as reflected by these differences, may contribute to the etiology of IR and T2D.