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YKL-40 and low grade inflammation in diabetes and cardiovascular disease


Camilla Noelle Rathcke


The present PhD thesis describes the investigation of YKL-40 as a low grade inflammatory markerin innate immunity with respect to diabetes and cardiovascular disease. Substantial evidencepresents YKL-40 as an inflammatory marker involved in innate immunity and vascularinflammation. In this thesis, it is hypothesized, that the normal maturation and differentiation ofmonocytes to macrophages are accompanied by a basal YKL-40 secretion which can be influencedby inflammatory as well as anti-inflammatory substances. Furthermore, elevated YKL-40 levels areexpected both in patients with type 1 and type 2 diabetes and an association with albuminuriaexplained as progression of vascular damage in the kidneys is expected since it is hypothesized, thatYKL-40 is a marker of early stages of the atherosclerotic process. Finally, YKL-40 is expected tobe a predictor of cardiovascular morbidity and mortality.YKL-40 is investigated in four different settings: i) in an in vitro setting of monocyte-tomacrophagedifferentiation where the basal YKL-40 secretion is examined under differentinflammatory and anti-inflammatory influences; ii) in two different clinical settings of patients withuncomplicated type 2 diabetes and patients with type 1 diabetes with increasing levels ofalbuminuria, respectively; and iii) in an epidemiological study of a population-based sample of thenormal elderly population investigating YKL-40 with respect to cardiovascular morbidity and mortality.The thesis documents, that the basal YKL-40 secretion by monocytes increases during thematuration and differentiation to macrophages and in glucose-enriched cultures, and this secretionis tripled over a 2 weeks period. It is documented, that YKL-40 is elevated in type 2 diabetespatients and is positively correlated with insulin resistance and the diabetic lipid profile, but are notcorrelated with parameters of the glycemic profile. YKL-40 is also elevated in type 1 diabetespatients and is independently associated with increasing levels of albuminuria. Furthermore,increasing YKL-40 levels seem to be an independent predictor of overall and cardiovascularmortality in elderly individuals without known diabetes or cardiovascular disease. In general,increasing YKL-40 levels of 50-120 ng/ml are seen with increasing diabetic and cardiovascularmorbidity and none or only weak intercorrelations are found between YKL-40 and otherinflammatory and cardiovascular markers.The thesis concludes, that YKL-40 seems to play a role in early inflammatory and vascularprocesses e.g. insulin resistance, endothelial dysfunction and atherosclerosis, that not immediateunveil or present with clinical symptoms neither in “healthy and normal” individuals nor in patients with diabetes but eventually can result in micro- and macrovascular late diabetic complications andmanifest cardiovascular disease.