The Role of Soluble CD163, a Marker of Adipose Tissue Macrophage Activation, in the Etiology of Type 2 Diabetes Mellitus

Obesity is the most well-established risk factor for type 2 diabetes mellitus (T2DM), although the underlying pathophysiological mechanisms have yet to be fully described. A growing body of evidence suggests that obesity directly induces chronic subclinical inflammation, which is strongly linked with T2DM risk. The discovery of increased macrophage infiltration in the adipose tissue of obese individuals has offered new insights into the potential importance of adipose tissue as a primary driver of chronic subclinical inflammation. To date, however, few studies have investigated the association of adipose tissue inflammation with the natural history of T2DM in humans. The purpose of this thesis was to examine the association of adipose tissue inflammation, assessed using the novel biomarker soluble CD163 (sCD163), with the longitudinal progression of disorders underlying T2DM, and to identify factors related to the development and progression of adipose tissue inflammation. We conducted a systematic review of the current evidence on the association of sCD163 with T2DM and its underlying disorders. Our analytical assessment used data from a longitudinal cohort of well-characterized adults at-risk for T2DM. Insulin sensitivity and beta-cell function indices were calculated using glucose and insulin measures obtained from 75g oral glucose tolerance tests collected at each clinic examination. sCD163 concentrations were evaluated using an enzyme-linked immunosorbent assay. Our systematic review identified sixteen studies, demonstrating a consistent relationship between elevated sCD163 concentrations and insulin resistance, beta-cell dysfunction, and T2DM. Results from our analytical assessments showed that (1) changes in sCD163 concentrations over 6-years were longitudinally associated with impaired insulin sensitivity and beta-cell dysfunction, and with incident dysglycemia; (2) adipose tissue insulin resistance was associated with worsening adipose tissue inflammation as measured by increases in sCD163 and decreases in adiponectin concentrations; and (3) poor diet quality was associated with longitudinal changes in sCD163. Our findings on the association of sCD163 with changes in underlying pathophysiological disorders of T2DM support the concept of adipose tissue macrophage activation as an early abnormality in T2DM. Furthermore, the associations of sCD163 with adipose tissue insulin resistance and diet suggest that this phenomenon is responsive to early modification, setting the stage for future studies.Ph.D