Adipokines, inflammation & adverse clinical outcomes in type 2 diabetes

Abstract

Type 2 diabetes (T2D) is associated with the development of multiple complications and increased mortality. Inflammation has been implicated in the pathogenesis of various diseases including cardiovascular diseases (CVD), kidney disease and cancer. As obesity is closely linked with T2D, and adipose tissue inflammation leading to dysregulated adipokine secretion and responses is present in obese individuals, I sought to investigate the role of adipokines in the adverse clinical outcomes in T2D patients. Among the 600 adipokines reported to date, adipocyte fatty acid-binding protein (AFABP) and fibroblast growth factor 21 (FGF21) are among the new comers. High circulating AFABP and FGF21 levels have been found to associate with obesity and incident diabetes, whereas adiponectin, an anti-inflammatory adipokine, is associated with a reduced risk of incident diabetes. However, controversial findings have been reported regarding the relationship between adiponectin and diabetic complications. This thesis is based on several prospective studies performed in the Hong Kong West Diabetes Registry cohort with exclusively T2D individuals. The first three studies demonstrated the prognostic importance of circulating AFABP level in predicting multiple mortality outcomes, renal function decline and hospitalization for heart failure (HF). These findings highlighted the multifarious role of AFABP as a pro-inflammatory adipokine in the pathogenesis of cardio-renal, infective and cancer complications in T2D. The next two studies evaluated the prospective associations of circulating FGF21 level with progressive cardio-renal diseases. High baseline serum FGF21 levels were independently associated with the development of renal progression and coronary heart disease, especially in patients with relatively preserved renal function and those without CVD at baseline, respectively. Hormone resistance with impaired downstream signaling has been observed in obesity and T2D, with insulin and leptin being the classical examples. Given the established beneficial metabolic effects of FGF21 and its analogues, my findings provide clinical support to the notion that FGF21 resistance is also present in this context, and may play a role in the pathogenesis of diabetic complications. The next study examined the association between circulating adiponectin level and cancer, and found that higher serum adiponectin level was paradoxically associated with incident cancers and cancer-related deaths. Together with previous reports on adiponectin resistance and paradox in CVD and nephropathy, this study showed that a higher adiponectin level is not always beneficial, but may indicate increased risks of developing adverse outcomes in T2D. The last study evaluated and compared the independent relationship of the three adipokines in the development of adverse cardio-renal and mortality outcomes in T2D. All three adipokines were independently associated with all-cause mortality in T2D, and serum AFABP and FGF21 were independently associated with HF hospitalization. Importantly, the combination of baseline serum AFABP and adiponectin levels enhanced the risk prediction of all-cause mortality and adverse renal outcomes by conventional risk factors, and was superior to the use of either adipokine alone. This series of studies illustrated, from a clinical perspective, the role of adipokines as a link between adipose tissue inflammation and diabetic complications, and their potentials as therapeutic targets to combat these adverse clinical outcomes in T2D.