Novel Risk Markers for Type 2 Diabetes : Inflammation, Body Fat and Sex Hormones

Background: Chronic low-grade inflammation, body fat composition and sex hormones are among the most important factors that enhance the risk of type 2 diabetes. The aim of this thesis was to further explore the role of pathways that link the above mentioned risk factors to type 2 diabetes development.
Methods: The studies in this thesis were performed in the Rotterdam Study, a prospective population-based cohort study.
Results: Chapter 2.1 studied the association of a set of inflammatory markers with progression from normoglycemia to pre-diabetes, type 2 DM and finally to insulin therapy. Our findings suggested that various inflammatory markers might be associated with progression from normoglycemia to pre-diabetes (IL13, ENRAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE was a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start. Chapter 2.2 investigated the role of dietary antioxidants and plasma oxidant-antioxidant status in low-grade chronic inflammation and adipocytokine levels. Our findings suggested that high overall dietary antioxidant capacity of diet and lower levels of UA were associated with lower levels of pro-inflammatory adipocytokines and higher levels of anti-inflammatory adipocytokines. In chapter 2.3, we aimed to investigate the association between serum uric acid and risk of prediabetes and type 2 diabetes mellitus. Our findings agreed with the notion that serum uric acid is more closely related to early-phase mechanisms in the development of type 2 diabetes mellitus than late-phase mechanisms. In chapter 3 we focused on the role of lipids and body fat in the risk for type 2 diabetes. Chapter 3.1 investigated the role of serum levels of various apolipoproteins on the risk for type 2 diabetes. We found that serum apoCIII levels as well as apoCIII-to-apoA1 ratio were independently associated with incident T2D. These associations were stronger than that of HDL-C levels with type 2 diabetes. Chapter 3.2 investigated the associations of several novel metabolic indices, combining anthropometric and lipid measures (VAI, LAP, TyG), and DXA measurements on body fat with incident type 2 diabetes among women and men from the large population-based Rotterdam Study. We found that among women, novel combined metabolic indices were stronger risk markers for T2D than the traditional anthropometric and laboratory measures and were comparable to DXA measures. Neither combined metabolic indices nor DXA measures were superior to traditional anthropometric and lipid measures in association with T2D among men. Chapter 3.3 studied the associations of epicardial fat volume with incident type 2 diabetes, coronary heart disease (myocardial infarction and cardiovascular mortality) as well as stroke. Our results suggested that increased amount of epicardial fat volume might be associated with excessive risk for T2D, CHD and stroke in the total population independent of traditional diabetes and cardiovascular risk factors. Chapter 4.1 assessed the associations between serum levels of dehydroepiandrosterone (DHEA) and its main derivatives: DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, with risk of type 2 diabetes. Our results suggested that DHEA might play a positive role in the pathogenesis of type 2 diabetes, which might have important implications for preventive interventions. Chapter 4.2 investigated the association between endogenous sex steroid levels and changes in body composition in postmenopausal women. Our findings supported the concept that changes in endogenous sex steroid levels are closely associated with changes in body composition in postmenopausal women.
Conclusions: In conclusion, the different risk markers for type 2 diabetes studied in this thesis give new insights regarding the disease pathophysiology and its course. Awaiting further research, these findings carry the potential to contribute to improvements in disease prevention, treatment and prognosis.