Sex difference in the incidence of microvascular complications in patients with type 2 diabetes mellitus: a prospective cohort study.

AIMS: Type 2 diabetes mellitus is a major cause of death and disability due to its long-term macro- and microvascular diseases. Although women with type 2 diabetes have more macrovascular diseases, it is unclear whether there are sex differences in the occurrence of microvascular disease. The aim of our study was to investigate sex differences in the incidence of microvascular complications in type 2 diabetes. METHODS: Analyses were performed in the DiaGene study, a prospective cohort study for complications of type 2 diabetes, collected in the city of Eindhoven, the Netherlands (n = 1886, mean follow-up time = 6.93 years). Cox proportional hazard models adjusted for risk factors for complications (age, smoking, hypertension, dyslipidemia, HbA1c and duration of type 2 diabetes) were used to analyze the incidence of microvascular complications in men and women. RESULTS: The incidence of microalbuminuria was significantly higher in men (HR microalbuminuria 1.64 [CI 1.21-2.24], p = 0.002). Additionally, men are more likely to develop two or three microvascular complications compared to women (OR 2.42 [CI 1.69-3.45], p < 0.001). CONCLUSIONS: This study shows that men with type 2 diabetes are more likely to develop microvascular complications, especially microalbuminuria. Furthermore, men seem to have a higher chance of developing multiple microvascular complications. Our results highlight that men and women may not benefit to a similar extent from current treatment approaches to prevent diabetes-related microvascular diseases.

Plasma protein N-glycan signatures of type 2 diabetes.

BACKGROUND: Little is known about enzymatic N-glycosylation in type 2 diabetes, a common posttranslational modification of proteins influencing their function and integrating genetic and environmental influences. We sought to gain insights into N-glycosylation to uncover yet unexplored pathophysiological mechanisms in type 2 diabetes. METHODS: Using a high-throughput MALDI-TOF mass spectrometry method, we measured N-glycans in plasma samples of the DiaGene case-control study (1583 cases and 728 controls). Associations were investigated with logistic regression and adjusted for age, sex, body mass index, high-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol, and smoking. Findings were replicated in a nested replication cohort of 232 cases and 108 controls. RESULTS: Eighteen glycosylation features were significantly associated with type 2 diabetes. Fucosylation and bisection of diantennary glycans were decreased in diabetes (odds ratio (OR) = 0.81, p = 1.26E-03, and OR = 0.87, p = 2.84E-02, respectively), whereas total and, specifically, alpha2,6-linked sialylation were increased (OR = 1.38, p = 9.92E-07, and OR = 1.40, p = 5.48E-07). Alpha2,3-linked sialylation of triantennary glycans was decreased (OR = 0.60, p = 6.38E-11). CONCLUSIONS: While some glycosylation changes were reflective of inflammation, such as increased alpha2,6-linked sialylation, our finding of decreased alpha2,3-linked sialylation in type 2 diabetes patients is contradictory to reports on acute and chronic inflammation. Thus, it might have previously unreported immunological implications in type 2 diabetes. GENERAL SIGNIFICANCE: This study provides new insights into N-glycosylation patterns in type 2 diabetes, which can fuel studies on causal mechanisms and consequences of this complex disease.

IgG glycan patterns are associated with type 2 diabetes in independent European populations.

BACKGROUND: Type 2 diabetes results from interplay between genetic and acquired factors. Glycans on proteins reflect genetic, metabolic and environmental factors. However, associations of IgG glycans with type 2 diabetes have not been described. We compared IgG N-glycan patterns in type 2 diabetes with healthy subjects. METHODS: In the DiaGene study, a population-based case-control study, (1886 cases and 854 controls) 58 IgG glycan traits were analyzed. Findings were replicated in the population-based CROATIA-Korcula-CROATIA-Vis-ORCADES studies (162 cases and 3162 controls), and meta-analyzed. AUCs of ROC-curves were calculated using 10-fold cross-validation for clinical characteristics, IgG glycans and their combination. RESULTS: After correction for extensive clinical covariates, 5 IgG glycans and 13 derived traits significantly associated with type 2 diabetes in meta-analysis (after Bonferroni correction). Adding IgG glycans to age and sex increased the AUC from 0.542 to 0.734. Adding them to the extensive model did not substantially improve the AUC. The AUC for IgG glycans alone was 0.729. CONCLUSIONS: Several IgG glycans and traits firmly associate with type 2 diabetes, reflecting a pro-inflammatory and biologically-aged state. IgG glycans showed limited improvement of AUCs. However, IgG glycans showed good prediction alone, indicating they may capture information of combined covariates. The associations found may yield insights in type 2 diabetes pathophysiology. GENERAL SIGNIFICANCE: This work shows that IgG glycomic changes have biomarker potential and may yield important insights into pathophysiology of complex public health diseases, illustrated here for the first time in type 2 diabetes.

Introduction of the DiaGene study: clinical characteristics, pathophysiology and determinants of vascular complications of type 2 diabetes.

BACKGROUND: Type 2 diabetes is a major healthcare problem. Glucose-, lipid-, and blood pressure-lowering strategies decrease the risk of micro- and macrovascular complications. However, a substantial residual risk remains. To unravel the etiology of type 2 diabetes and its complications, large-scale, well-phenotyped studies with prospective follow-up are needed. This is the goal of the DiaGene study. In this manuscript, we describe the design and baseline characteristics of the study. METHODS: The DiaGene study is a multi-centre, prospective, extensively phenotyped type 2 diabetes cohort study with concurrent inclusion of diabetes-free individuals at baseline as controls in the city of Eindhoven, The Netherlands. We collected anthropometry, laboratory measurements, DNA material, and detailed information on medication usage, family history, lifestyle and past medical history. Furthermore, we assessed the prevalence and incidence of retinopathy, nephropathy, neuropathy, and diabetic feet in cases. Using logistic regression models, we analyzed the association of 11 well known genetic risk variants with type 2 diabetes in our study. RESULTS: In total, 1886 patients with type 2 diabetes and 854 controls were included. Cases had worse anthropometric and metabolic profiles than controls. Patients in outpatient clinics had higher prevalence of macrovascular (41.9% vs. 34.8%; P = 0.002) and microvascular disease (63.8% vs. 20.7%) compared to patients from primary care. With the exception of the genetic variant in KCNJ11, all type 2 diabetes susceptibility variants had higher allele frequencies in subjects with type 2 diabetes than in controls. CONCLUSIONS: In our study population, considerable rates of macrovascular and microvascular complications are present despite treatment. These prevalence rates are comparable to other type 2 diabetes populations. While planning genomics, we describe that 11 well-known type 2 diabetes genetic risk variants (in TCF7L2, PPARG-P12A, KCNJ11, FTO, IGF2BP2, DUSP9, CENTD2, THADA, HHEX, CDKAL1, KCNQ1) showed similar associations compared to literature. This study is well-suited for multiple omics analyses to further elucidate disease pathophysiology. Our overall goal is to increase the understanding of the underlying mechanisms of type 2 diabetes and its complications for developing new prediction, prevention, and treatment strategies.

The anti-inflammatory function of high-density lipoprotein in type II diabetes: A systematic review.

BACKGROUND: Inflammation is a pathophysiological factor in diabetes and its cardiovascular complications. High-density lipoprotein (HDL) suppresses inflammation in healthy individuals. The relationship of HDL with diabetes and cardiovascular disease may be explained by HDL function rather than by HDL cholesterol level. In diabetes, HDL seems to become dysfunctional. OBJECTIVE: We performed a systematic review to answer the following research questions: Is the anti-inflammatory function of HDL diminished in individuals with diabetes and if so, what causes this? METHODS: We systematically searched Medline and Embase and included original research articles on the anti-inflammatory effects of HDL or HDL-based interventions in diabetes or diabetes models. We assessed the risk of bias of all included studies. RESULTS: Fourteen studies were included. These showed great heterogeneity in methodology, study populations, and diabetes models. Overall, HDL from subjects with type II diabetes displayed a reduced ability to suppress inflammatory processes and inflammation markers. However, the mechanisms and the in vivo effects remain largely unknown. No studies reported on HDL from individuals with other types of diabetes. In most studies, the risk of bias was high or could not be assessed. CONCLUSIONS: HDL isolated from individuals with type II diabetes showed a decreased ability to suppress inflammation. However, the direction of causality and the underlying mechanisms are unknown and should be investigated. For development of treatments directed at restoring HDL anti-inflammatory function in diabetes, a standardized method for assessing HDL anti-inflammatory function needs to be developed and in vivo biomarkers must be identified.