Inflammation in type 2 diabetes and the neuroendocrine role of IL-18

Abstract

Cardiovascular disease is one of the leading causes of morbidity and mortality in type 2 diabetes, and yet, recent randomised controlled trials investigating the effect of different regimens of blood glucose control failed to show any benefit of more intensive control on rates of cardiovascular mortality, and minimal benefit on levels of morbidity. This thesis examines the theoretical understanding of type 2 diabetes, including the historical process which led to the above trials being conducted. A review of the historical and modern evidence surrounding the role of chronic inflammation suggests that this may be a common pathogenic alteration in obesity, diabetes and cardiovascular disease which may contribute to the development of cardiovascular disease in persons with type 2 diabetes, and even the pathogenesis of type 2 diabetes itself. This thesis therefore investigates the role of inflammation in type 2 diabetes, by a two-pronged approach: one investigates the effects of a dietary intervention on levels of chronic inflammation in participants with type 2 diabetes in the Lifestyle Over and Above Drugs in Diabetes (LOADD) randomised controlled trial. In this trial, chronic inflammation is assessed by a range of inflammatory markers and adipokines including leptin, neopterin, tumor necrosis factor α and its soluble receptors, the interleukins 1, 6, 10, and 18, and interleukin 1 receptor antagonist. The dietary intervention group exhibited a significant reduction in circulating levels of interleukin-18 (IL-18) and neopterin relative to a 'care as usual' control group; reductions which further analyses suggest were unrelated to concomitant changes in adiposity or glycaemia. In the second branch of the thesis, the neuroendocrine effects of IL-18 are further investigated in rodents, as previous evidence has linked this cytokine with effects on appetite, body weight, and blood glucose control. Clear evidence of central production of IL-18 in the medial habenula is presented, with transport along fibres in the fasciculus retroflexus terminating in the interpeduncular nucleus (IPN). However, no evidence for a corresponding IPN focus of expression of the genes encoding the IL-18 receptor was found. In light of this discrepancy, further investigations were conducted to assess other potential receptors for central IL-18 action; bioinformatics approaches suggest that the interleukin-1 receptor accessory protein like (IL1RAPL) receptors may form alternative central receptors for IL-18, and immunohistochemistry experiments localize IL1RAPL1 in the interpeduncular nucleus. A model is thus proposed whereby habenula IL-18 expression may influence appetite via actions on IL1RAPL1 in the IPN. The thesis concludes with a discussion of the hypothesis of inflammation as a cause of diabetes and cardiovascular disease, and the potential for an improved understanding of the pathological processes involved in type 2 diabetes to produce greater improvements in clinical outcomes than has been attained thus far.