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 i

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 i

Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study

The immune response involved in each phase of type 2 diabetes (T2D) development might be different. We aimed to identify novel inflammatory markers that predict progression from normoglycemia to pre-diabetes, incident T2D and insulin therapy. We used plasma levels of 26 inflammatory markers in 971 subjects from the Rotterdam Study. Among them 17 are novel and 9 previously studied. Cox regression models were built to perform survival analysis. Main Outcome Measures: During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012) 139 cases of pre-diabetes, 110 cases of T2D and 26 cases of insulin initiation were identified. In age and sex adjusted Cox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH (1.24), IL18 (1.22) and CRP (1.32) were associated with incident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE (1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27), IL1ra (1.24) and CRP (1.64) were associated with incident T2D. In multivariate models, IL13 (0.77), EN-RAGE (1.23) and CRP (1.26) remained associated with pre-diabetes. IL13 (0.67), IL17 (0.76) and CRP (1.32) remained associated with T2D. IL13 (0.55) was the only marker associated with initiation of insulin therapy in diabetics. Various inflammatory markers are associated with progression from normoglycemia to pre-diabetes (IL13, EN-RAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE is a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start

Novel metabolic indices and incident type 2 diabetes among women and men: the Rotterdam Study

Aims/hypothesis: Both visceral and truncal fat have been associated with metabolic disturbances. We aimed to investigate the associations of several novel metabolic indices, combining anthropo

Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes

CONTEXT: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. OBJECTIVE: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). DESIGN: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. MAIN OUTCOME MEASURES: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. RESULTS: In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. CONCLUSIONS: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation

Plasma Metabolomics Identifies Markers of Impaired Renal Function:A Meta-analysis of 3089 Persons with Type 2 Diabetes

CONTEXT: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. OBJECTIVE: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). DESIGN: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. MAIN OUTCOME MEASURES: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. RESULTS: In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. CONCLUSIONS: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation

Blood Metabolomic Measures Associate With Present and Future Glycemic Control in Type 2 Diabetes

Objective: We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy. Methods: A total of 162 metabolomic measures were analyzed using a nuclear magnetic resonance-based method in people with T2D from four cohort studies (n = 2641) and one replication cohort (n = 395). Linear and logistic regression analyses with adjustment for potential confounders, followed by meta-analyses, were performed to analyze associations with hemoglobin A1c levels, six glucose-lowering drug categories, and insulin initiation during a 7-year follow-up period (n = 698). Results: After Bonferroni correction, 26 measures were associated with insufficient glycemic control (HbA1c >53 mmol/mol). The strongest association was with glutamine (OR, 0.66; 95% CI, 0.61 to 0.73; P = 7.6 × 10-19). In addition, compared with treatment-naive patients, 31 metabolomic measures were associated with glucose-lowering drug use (representing various metabolite categories; P ≤ 3.1 × 10-4 for all). In drug-stratified analyses, associations with insufficient glycemic control were only mildly affected by different glucose-lowering drugs. Five of the 26 metabolomic measures (apolipoprotein A1 and medium high-density lipoprotein subclasses) were also associated with insulin initiation during follow-up in both discovery and replication. The strongest association was observed for medium high-density lipoprotein cholesteryl ester (OR, 0.54; 95% CI, 0.42 to 0.71; P = 4.5 × 10-6). Conclusion: Blood metabolomic measures were associated with present and future glycemic control and might thus provide relevant cues to identify those at increased risk of treatment failure

Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study

The immune response involved in each phase of type 2 diabetes (T2D) development might be different. We aimed to identify novel inflammatory markers that predict progression from normoglycemia to pre-diabetes, incident T2D and insulin therapy. We used plasma levels of 26 inflammatory markers in 971 subjects from the Rotterdam Study. Among them 17 are novel and 9 previously studied. Cox regression models were built to perform survival analysis. Main Outcome Measures: During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012) 139 cases of pre-diabetes, 110 cases of T2D and 26 cases of insulin initiation were identified. In age and sex adjusted Cox models, IL13 (HR = 0.78), EN-RAGE (1.30), CFH (1.24), IL18 (1.22) and CRP (1.32) were associated with incident pre-diabetes. IL13 (0.62), IL17 (0.75), EN-RAGE (1.25), complement 3 (1.44), IL18 (1.35), TNFRII (1.27), IL1ra (1.24) and CRP (1.64) were associated with incident T2D. In multivariate models, IL13 (0.77), EN-RAGE (1.23) and CRP (1.26) remained associated with pre-diabetes. IL13 (0.67), IL17 (0.76) and CRP (1.32) remained associated with T2D. IL13 (0.55) was the only marker associated with initiation of insulin therapy in diabetics. Various inflammatory markers are associated with progression from normoglycemia to pre-diabetes (IL13, EN-RAGE, CRP), T2D (IL13, IL17, CRP) or insulin therapy start (IL13). Among them, EN-RAGE is a novel inflammatory marker for pre-diabetes, IL17 for incident T2D and IL13 for pre-diabetes, incident T2D and insulin therapy start. Electronic supplementary material The online version of this article (doi:10.1007/s10654-017-0236-0) contains supplementary material, which is available to authorized users