Pang, Terence Tat Lun (2011)
Ph.D. thesis, University of Birmingham.
Type 1 diabetes (T1D) is characterised by pancreatic cell autoimmunity and inflammation, resulting in cell islet destruction and insulin deficiency. Prospective studies from different continents have shown that insulin resistance is independently associated with risk for the development of T1D. We wanted to investigate the role of adiponectin in mediating this link. Adiponectin is a circulating adipokine whose anti-inflammatory and insulin sensitising actions appear to be mediated via two related receptors, AdipoR1 and AdipoR2. We began by characterising adiponectin receptor expression on PBMC by flow cytometry. We showed that monocytes express both receptors abundantly, that this expression correlates with insulin sensitivity in both health and diabetes. Furthermore, expression can be increased with lifestyle intervention. Adiponectin receptor expression on monocytes is reduced in T1D, and we demonstrate this leads to an apparent resistance in the ability of adiponectin to inhibit the stimulatory capacity of antigen presenting cells (APC). Specifically, we show that adiponectin inhibits the stimulatory capacity of APCs through down-regulation of CD86 expression, and that this effect is decreased in T1D. In this way, the release from the regulatory effects of adiponectin is one potential mechanism by which immune tolerance is lost in T1D.
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