Apolipoprotein-CIII O-Glycosylation Is Associated with Micro- and Macrovascular Complications of Type 2 Diabetes.

Apolipoprotein-CIII (apo-CIII) inhibits the clearance of triglycerides from circulation and is associated with an increased risk of diabetes complications. It exists in four main proteoforms: O-glycosylated variants containing either zero, one, or two sialic acids and a non-glycosylated variant. O-glycosylation may affect the metabolic functions of apo-CIII. We investigated the associations of apo-CIII glycosylation in blood plasma, measured by mass spectrometry of the intact protein, and genetic variants with micro- and macrovascular complications (retinopathy, nephropathy, neuropathy, cardiovascular disease) of type 2 diabetes in a DiaGene study (n = 1571) and the Hoorn DCS cohort (n = 5409). Mono-sialylated apolipoprotein-CIII (apo-CIII1) was associated with a reduced risk of retinopathy (ß = -7.215, 95% CI -11.137 to -3.294) whereas disialylated apolipoprotein-CIII (apo-CIII2) was associated with an increased risk (ß = 5.309, 95% CI 2.279 to 8.339). A variant of the GALNT2-gene (rs4846913), previously linked to lower apo-CIII0a, was associated with a decreased prevalence of retinopathy (OR = 0.739, 95% CI 0.575 to 0.951). Higher apo-CIII1 levels were associated with neuropathy (ß = 7.706, 95% CI 2.317 to 13.095) and lower apo-CIII0a with macrovascular complications (ß = -9.195, 95% CI -15.847 to -2.543). In conclusion, apo-CIII glycosylation was associated with the prevalence of micro- and macrovascular complications of diabetes. Moreover, a variant in the GALNT2-gene was associated with apo-CIII glycosylation and retinopathy, suggesting a causal effect. The findings facilitate a molecular understanding of the pathophysiology of diabetes complications and warrant consideration of apo-CIII glycosylation as a potential target in the prevention of diabetes complications.

Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids.

Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII0a), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII0c, apo-CIII1 and apo-CIII2). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation. We conducted GWAS on the four apo-CIII proteoforms in the DiaGene study in people with and without type 2 diabetes (n = 2318). We investigated the relations of the identified genetic loci and apo-CIII glycosylation with lipids and type 2 diabetes. The associations of the genetic variants with lipids were replicated in the Diabetes Care System (n = 5409). Rs4846913-A, in the GALNT2-gene, was associated with decreased apo-CIII0a. This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII0a was associated with raised high-density lipoprotein-cholesterol and triglycerides. Rs67086575-G, located in the IFT172-gene, was associated with decreased apo-CIII2 and with hypertriglyceridemia. In line, apo-CIII2 was associated with low triglycerides. On a genome-wide scale, we confirmed that the GALNT2-gene plays a major role i O-glycosylation of apolipoprotein-CIII, with subsequent associations with lipid parameters. We newly identified the IFT172/NRBP1 region, in the literature previously associated with hypertriglyceridemia, as involved in apolipoprotein-CIII sialylation and hypertriglyceridemia. These results link genomics, glycosylation, and lipid metabolism, and represent a key step towards unravelling the importance of O-glycosylation in health and disease.

Once-Weekly Semaglutide Use in Type 2 Diabetes: Real-World Data from the SURE Netherlands Observational Study.

INTRODUCTION: SURE Netherlands (NCT03929679) evaluated the use of once-weekly (OW) semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), in routine clinical care for individuals with type 2 diabetes (T2D). METHODS: Adults (age ≥ 18 years) with T2D were enrolled into the single-arm study. The primary endpoint was change from baseline to end of study (EOS; approx. 30 weeks) in glycated haemoglobin (HbA1c). Secondary endpoints were change from baseline to EOS in body weight (BW) and waist circumference (WC). Proportions of participants achieving predefined HbA1c targets and weight-loss responses at EOS, safety, health-related quality of life (HRQoL) and treatment satisfaction were assessed. RESULTS: In total, 211 participants (mean age 60.5 years; diabetes duration 13.3 years) initiated semaglutide; most were receiving metformin (82.9%) and/or basal insulin (59.2%) at baseline, and 6.2% switched from another GLP-1RA. Mean baseline HbA1c, BW and WC were 8.6%, 105.2 kg and 118.8 cm. In the 186 (88.2%) participants receiving semaglutide at EOS, mean reduction in HbA1c with semaglutide was - 1.2%-points (95% [confidence interval] CI - 1.3; - 1.0; p < 0.0001), with 124 (70.5%), 95 (54.0%) and 65 (36.9%) participants achieving HbA1c targets of < 8.0%, < 7.5% and < 7.0%, respectively. Mean reduction in BW was - 7.8 kg [95% CI - 8.7; - 6.8; p < 0.0001], corresponding to relative reduction of - 7.5% [95% CI - 8.4; - 6.6; p < 0.0001]. Improvements in WC (- 8.8 cm [95% CI - 10.4; - 7.2; p < 0.0001]), HRQoL and treatment satisfaction were observed, including across most Short-Form 36 Health Survey domains. One serious adverse drug reaction (cholecystitis) was reported. Eight participants (all receiving concomitant insulin) experienced severe or documented hypoglycaemia. CONCLUSION: Individuals with T2D treated with OW semaglutide experienced significant and clinically relevant improvements in glycaemic control and BW from baseline. These results from a diverse real-world population in the Netherlands support the use of OW semaglutide in treating adults with T2D in routine clinical practice.

Plasma protein N-glycosylation is associated with cardiovascular disease, nephropathy, and retinopathy in type 2 diabetes.

INTRODUCTION: Although associations of total plasma N-glycome (TPNG) with type 2 diabetes have been reported, little is known on the role of TPNG in type 2 diabetes complications, a major cause of type 2 diabetes-related morbidity and mortality. Here, we assessed TPNG in relation to type 2 diabetes complications in subsamples of two Dutch cohorts using mass spectrometry (n=1815 in DiaGene and n=1518 in Hoorn Diabetes Care System). RESEARCH DESIGN AND METHODS: Blood plasma samples and technical replicates were pipetted into 96-well plates in a randomized manner. Peptide:N-glycosidase F (PNGase F) was used to release N-glycans, whereafter sialic acids were derivatized for stabilization and linkage differentiation. After total area normalization, 68 individual glycan compositions were quantified in total and were used to calculate 45 derived traits which reflect structural features of glycosylation. Associations of glycan features with prevalent and incident microvascular or macrovascular complications were tested in logistic and Cox regression in both independent cohorts and the results were meta-analyzed. RESULTS: Our results demonstrated similarities between incident and prevalent complications. The strongest association for prevalent cardiovascular disease was a high level of bisection on a group of diantennary glycans (A2FS0B; OR=1.38, p=1.34×10-11), while for prevalent nephropathy the increase in 2,6-sialylation on triantennary glycans was most pronounced (A3E; OR=1.28, p=9.70×10-6). Several other TPNG features, including fucosylation, galactosylation, and sialylation, firmly demonstrated associations with prevalent and incident complications of type 2 diabetes. CONCLUSIONS: These findings may provide a glance on how TPNG patterns change before complications emerge, paving the way for future studies on prediction biomarkers and potentially disease mechanisms.

Association Between Intraoperative Blood Glucose and Anastomotic Leakage in Colorectal Surgery.

BACKGROUND: Perioperative hyperglycemia is a known risk factor for postoperative complications after colorectal surgery. The aim of this study was to investigate whether intraoperative blood glucose values are associated with colorectal anastomotic leakage in diabetic and non-diabetic patients undergoing colorectal surgery. METHODS: This is an additional analysis of a previously published prospective, observational cohort study (the LekCheck study). Fourteen hospitals in Europe and Australia collected perioperative data. Consecutive adult patients undergoing colorectal surgery with primary anastomosis between 2016 and 2018 were included. From all patients, preoperative diabetic status was known and intraoperative blood glucose was determined just prior to the creation of the anastomosis. The primary outcome was the occurrence of anastomotic leakage within 30 days postoperatively. RESULTS: Of 1474 patients (mean age 68 years), 224 patients (15%) had diabetes mellitus, 737 patients (50%) had intraoperative hyperglycemia (≥126 mg/dL, ≥7.0 mmol/L), and 129 patients (8.8%) developed anastomotic leakage. Patients with intraoperative hyperglycemia had higher anastomotic leakage rates compared to patients with a normal blood glucose level (12% versus 5%, P<0.001). Anastomotic leakage rate did not significantly differ between diabetic and non-diabetic patients (12% versus 8%, P=0.058). Logistic regression analyses showed that higher blood glucose levels were associated with an increasing leakage risk in non-diabetic patients only. CONCLUSION: Incidence and severity of intraoperative hyperglycemia are associated with anastomotic leakage in non-diabetic patients. Whether hyperglycemia is an epiphenomenon, a marker for other risk factors or a potential modifiable risk factor per se for anastomotic leakage requires future research.

Lifetime risk to progress from pre-diabetes to type 2 diabetes among women and men: comparison between American Diabetes Association and World Health Organization diagnostic criteria.

INTRODUCTION: Pre-diabetes, a status conferring high risk of overt diabetes, is defined differently by the American Diabetes Association (ADA) and the WHO. We investigated the impact of applying definitions of pre-diabetes on lifetime risk of diabetes in women and men from the general population. RESEARCH DESIGN AND METHODS: We used data from 8844 women without diabetes and men aged ≥45 years from the prospective population-based Rotterdam Study in the Netherlands. In both gender groups, we calculated pre-diabetes prevalence according to ADA and WHO criteria and estimated the 10-year and lifetime risk to progress to overt diabetes with adjustment for competing risk of death. RESULTS: Out of 8844 individuals, pre-diabetes was identified in 3492 individuals (prevalence 40%, 95% CI 38% to 41%) according to ADA and 1382 individuals (prevalence 16%, 95% CI 15% to 16%) according to WHO criteria. In both women and men and each age category, ADA prevalence estimates doubled WHO-defined pre-diabetes. For women and men aged 45 years having ADA-defined pre-diabetes, the 10-year risk of diabetes was 14.2% (95% CI 6.0% to 22.5%) and 9.2% (95% CI 3.4% to 15.0%) compared with 23.2% (95% CI 6.8% to 39.6%) and 24.6% (95% CI 8.4% to 40.8%) in women and men with WHO-defined pre-diabetes. At age 45 years, the remaining lifetime risk to progress to overt diabetes was 57.5% (95% CI 51.8% to 63.2%) vs 80.2% (95% CI 74.1% to 86.3%) in women and 46.1% (95% CI 40.8% to 51.4%) vs 68.4% (95% CI 58.3% to 78.5%) in men with pre-diabetes according to ADA and WHO definitions, respectively. CONCLUSION: Prevalence of pre-diabetes differed considerably in both women and men when applying ADA and WHO pre-diabetes definitions. Women with pre-diabetes had higher lifetime risk to progress to diabetes. The lifetime risk of diabetes was lower in women and men with ADA-defined pre-diabetes as compared with WHO. Improvement of pre-diabetes definition considering appropriate sex-specific and age-specific glycemic thresholds may lead to better identification of individuals at high risk of diabetes.

Metformin and statin use associate with plasma protein N-glycosylation in people with type 2 diabetes.

INTRODUCTION: Recent studies revealed N-glycosylation signatures of type 2 diabetes, inflammation and cardiovascular risk factors. Most people with diabetes use medication to reduce cardiovascular risk. The association of these medications with the plasma N-glycome is largely unknown. We investigated the associations of metformin, statin, ACE inhibitor/angiotensin II receptor blocker (ARB), sulfonylurea (SU) derivatives and insulin use with the total plasma N-glycome in type 2 diabetes. RESEARCH DESIGN AND METHODS: After enzymatic release from glycoproteins, N-glycans were measured by matrix-assisted laser desorption/ionization mass spectrometry in the DiaGene (n=1815) and Hoorn Diabetes Care System (n=1518) cohorts. Multiple linear regression was used to investigate associations with medication, adjusted for clinical characteristics. Results were meta-analyzed and corrected for multiple comparisons. RESULTS: Metformin and statins were associated with decreased fucosylation and increased galactosylation and sialylation in glycans unrelated to immunoglobulin G. Bisection was increased within diantennary fucosylated non-sialylated glycans, but decreased within diantennary fucosylated sialylated glycans. Only few glycans were associated with ACE inhibitor/ARBs, while none associated with insulin and SU derivative use. CONCLUSIONS: We conclude that metformin and statins associate with a total plasma N-glycome signature in type 2 diabetes. Further studies are needed to determine the causality of these relations, and future N-glycomic research should consider medication a potential confounder.

Association of the IgG N-glycome with the course of kidney function in type 2 diabetes.

INTRODUCTION: Inflammatory processes are thought to be involved in kidney function decline in individuals with type 2 diabetes. Glycosylation of immunoglobulin G (IgG) is an important post-translation process affecting the inflammatory potential of IgG. We investigated the prospective relationship between IgG N-glycosylation patterns and kidney function in type 2 diabetes. RESEARCH DESIGN AND METHODS: In the DiaGene study, an all-lines-of-care case-control study (n=1886) with mean prospective follow-up of 7.0 years, the association between 58 IgG N-glycan profiles and estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) per year and during total follow-up was analyzed. Models were adjusted for clinical variables and multiple comparisons. RESULTS: Eleven traits were significantly associated with eGFR change per year. Bisecting GlcNAc in fucosylated and fucosylated disialylated structures and monosialylation of fucosylated digalactosylated structures were associated with a faster decrease of eGFR. Fucosylation of neutral and monogalactosylated structures was associated with less eGFR decline per year. No significant associations between IgG glycans and ACR were found. CONCLUSIONS: In type 2 diabetes, we found IgG N-glycosylation patterns associated with a faster decline of kidney function, reflecting a pro-inflammatory state of IgG. eGFR, but not ACR, was associated with IgG glycans, which suggests these associations may represent renal macroangiopathy rather than microvascular disease.

Lipoprotein(a) plasma levels are not associated with incident microvascular complications in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Microvascular disease in type 2 diabetes is a significant cause of end-stage renal disease, blindness and peripheral neuropathy. The strict control of known risk factors, e.g. lifestyle, hyperglycaemia, hypertension and dyslipidaemia, reduces the incidence of microvascular complications, but a residual risk remains. Lipoprotein (a) [Lp(a)] is a strong risk factor for macrovascular disease in the general population. We hypothesised that plasma Lp(a) levels and the LPA gene SNPs rs10455872 and rs3798220 are associated with the incident development of microvascular complications in type 2 diabetes. METHODS: Analyses were performed of data from the DiaGene study, a prospective study for complications of type 2 diabetes, collected in the city of Eindhoven, the Netherlands (n = 1886 individuals with type 2 diabetes, mean follow-up time = 6.97 years). To assess the relationship between plasma Lp(a) levels and the LPA SNPs with each newly developed microvascular complication (retinopathy n = 223, nephropathy n = 246, neuropathy n = 236), Cox proportional hazards models were applied and adjusted for risk factors for microvascular complications (age, sex, mean arterial pressure, non-HDL-cholesterol, HDL-cholesterol, BMI, duration of type 2 diabetes, HbA1c and smoking). RESULTS: No significant associations of Lp(a) plasma levels and the LPA SNPs rs10455872 and rs3798220 with prevalent or incident microvascular complications in type 2 diabetes were found. In line with previous observations the LPA SNPs rs10455872 and rs3798220 did influence the plasma Lp(a) levels. CONCLUSIONS/INTERPRETATION: Our data show no association between Lp(a) plasma levels and the LPA SNPs with known effect on Lp(a) plasma levels with the development of microvascular complications in type 2 diabetes. This indicates that Lp(a) does not play a major role in the development of microvascular complications. However, larger studies are needed to exclude minimal effects of Lp(a) on the development of microvascular complications.

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.

The effect of guideline revisions on vascular complications of type 2 diabetes.

BACKGROUND: The aim of this study was to investigate the impact of implementation and revision of the 'Diabetes Mellitus type II' guideline by the Dutch College of General Practitioners (DCGP) on the prevalence and incidence of macrovascular and microvascular complications. METHODS: The DiaGene study is a case-control study (n = 1886 patients of type 2 diabetes) with extensive, retrospectively collected complication data, as well as prospective follow up of complications. The study incorporates all lines of diabetes care. Cases were divided into categories according to the date of onset of diabetes and publication dates of the DCGP. Logistic regression models were used to investigate the associations between guideline version and complications. To investigate a possible trend between guideline version and complications, the 'guideline category' was also used as a continuous variable. All models were adjusted for clinical covariables. RESULTS: The 1999 and 2006 guidelines versions were associated with significantly lower risk of retinopathy than the group that started without a guideline [OR 0.32 (95% CI 0.14-0.72, p = 0.006) and 0.31 (95% CI 0.11-0.91, p = 0.034), respectively]. A significant trend in reduction of peripheral artery disease (PAD) over the guideline versions was found, adjusted for age, sex and diabetes duration (odds ratio (OR) 0.70, 95% CI 0.51-0.97, p trend = 0.029) and for retinopathy in all models (OR = 0.52, 95% CI 0.37-0.73, p trend < 0.001). CONCLUSIONS: The introduction of the first diabetes guideline and subsequent revisions have reduced the risk of macrovascular and microvascular complications of type 2 diabetes, most strongly in diabetic retinopathy. This indicates that real-time diabetes care has improved over time.

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.

Strength training affects lower extremity gait kinematics, not kinetics, in people with diabetic polyneuropathy.

Increased forefoot loading in diabetic polyneuropathy plays an important role in the development of plantar foot ulcers and can originate from alterations in muscle strength, joint moments and gait pattern. The current study evaluated whether strength training can improve lower extremity joint moments and spatiotemporal gait characteristics in patients with diabetic polyneuropathy. An intervention group receiving strength training during 24 weeks and a control group receiving no intervention. Measurements were performed in both groups at t=0, t=12, t=24 and t=52 weeks at an individually preferred and standardized imposed gait velocity. The strength training did not affect the maximal amplitude of hip, knee and ankle joint moments, but did result in an increase in stance phase duration, stride time and stride length of approximately 5%, during the imposed gait velocity. In addition, both groups increased their preferred gait velocity over one year. Future longitudinal studies should further explore the possible effects of strength training on spatiotemporal gait characteristics. The current study provides valuable information on changes in gait velocities and the progressive lower extremity problems in patients with polyneuropathy.

Lower leg muscle strengthening does not redistribute plantar load in diabetic polyneuropathy: a randomised controlled trial.

BACKGROUND: Higher plantar pressures play an important role in the development of plantar foot ulceration in diabetic polyneuropathy and earlier studies suggest that higher pressures under the forefoot may be related to a decrease in lower leg muscle strength. Therefore, in this randomised controlled trial we evaluated whether lower-extremity strength training can reduce plantar pressures in diabetic polyneuropathy. METHODS: This study was embedded in an unblinded randomised controlled trial. Participants had diabetes and polyneuropathy and were randomly assigned to the intervention group (n = 48) receiving strength training during 24 weeks, or the control group (n = 46) receiving no intervention. Plantar pressures were measured in both groups at 0, 12, 24 and 52 weeks. A random intercept model was applied to evaluate the effects of the intervention on peak pressures and pressure-time-integrals, displacement of center-of-pressure and the forefoot to rearfoot pressure-time-integral-ratio. RESULTS: Plantar pressure patterns were not affected by the strength training. In both the intervention and control groups the peak pressure and the pressure-time-integral under the forefoot increased by 55.7 kPa (95% CI: 14.7, 96.8) and 2.0 kPa.s (95% CI: 0.9, 3.2) over 52 weeks, respectively. Both groups experienced a high number of drop-outs, mainly due to deterioration of health status and lower-extremity disabilities. CONCLUSIONS: Plantar pressures under the forefoot increase progressively over time in people with diabetic polyneuropathy, but in this study were not affected by strength training. Future intervention studies should take this increase of plantar pressure into account and alternative interventions should be developed to reduce the progressive lower extremity problems in these patients. TRIAL REGISTRATION: This study was embedded in a clinical trial with trial number NCT00759265.

Increased forefoot loading is associated with an increased plantar flexion moment.

The aim of this study was to identify the cascade of effects leading from alterations in force generation around the ankle joint to increased plantar pressures under the forefoot. Gait analysis including plantar pressure measurement was performed at an individually preferred and a standardized, imposed gait velocity in diabetic subjects with polyneuropathy (n=94), without polyneuropathy (n=39) and healthy elderly (n=19). The plantar flexion moment at 40% of the stance phase was negatively correlated with the displacement rate of center of pressure (r=-.749, p<.001 at the imposed, and r=-.693, p<.001 at the preferred gait velocity). Displacement rate of center of pressure was strongly correlated with forefoot loading (r=-.837, p<.001 at the imposed, and r=-.731, p<.001 at the preferred gait velocity). People with a relatively high plantar flexion moment at 40% of the stance phase, have a faster forward transfer of center of pressure and consequently higher loading of the forefoot. This indicates that interventions aimed at increasing the control of the roll-off of the foot may contribute to a better plantar pressure distribution.

Patients with chronic gastrointestinal ischemia have a higher cardiovascular disease risk and mortality.

OBJECTIVES: We determined the prevalence of classical risk factors for atherosclerosis and mortality risk in patients with CGI. METHODS: A case-control study was conducted. Patients referred with suspected CGI underwent a standard work-up including risk factors for atherosclerosis, radiological imaging of abdominal vessels and tonometry. Cases were patients with confirmed atherosclerotic CGI. Controls were healthy subjects previously not known with CGI. The mortality risk was calculated as standardized mortality ratio derived from observed mortality, and was estimated with ten-year risk of death using SCORE and PREDICT. RESULTS: Between 2006 and 2009, 195 patients were evaluated for suspected CGI. After a median follow-up of 19 months, atherosclerotic CGI was diagnosed in 68 patients. Controls consisted of 132 subjects. Female gender, diabetes, hypercholesterolemia, a personal and family history of cardiovascular disease (CVD), and current smoking are highly associated with CGI. After adjustment, female gender (OR 2.14 95% CI 1.05-4.36), diabetes (OR 5.59, 95% CI 1.95-16.01), current smoking (OR 5.78, 95% CI 2.27-14.72), and history of CVD (OR 21.61, 95% CI 8.40-55.55) remained significant. CGI patients >55 years had a higher median ten-year risk of death (15% vs. 5%, P = 0.001) compared to controls. During follow-up of 116 person-years, standardized mortality rate was higher in CGI patients (3.55; 95% CI 1.70-6.52). CONCLUSIONS: Patients with atherosclerotic CGI have an increased estimated CVD risk, and severe excess mortality. Secondary cardiovascular prevention therapy should be advocated in patients with CGI.

The Cockcroft-Gault: a better predictor of renal function in an overweight and obese diabetic population.

BACKGROUND: The performance of the Cockcroft-Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) formula, and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) was evaluated in body mass index (BMI) categories. MATERIAL AND METHODS: In this retrospective cohort study in diabetic patients, creatinine clearance was measured by collecting 24-hour urines. Renal function was estimated using the CG, MDRD, and CKD-EPI. The performance of the equations was evaluated using correlation, Krippendorff's coefficient, bias, precision, and accuracy. RESULTS: The bias of the MDRD and CKD-EPI increased from -13.9 ml/min/1.73 m(2) and -14.0 ml/min/1.73 m(2) (BMI < 25 kg/m(2)), respectively, to -31.7 ml/min/1.73 m(2) and -29.6 ml/min/1.73 m(2) (BMI > 30 kg/m(2)), respectively. Bias of the CG decreased from -13.4 ml/min (BMI < 25 kg/m(2)) to -3.2 ml/min (BMI > 30 kg/m(2)). With an accepted 30% dispersion, CG had the largest accuracy in the overweight and obese group (76.9 and 76.8%, respectively). The MDRD and CKD-EPI had an accuracy of 45.8 and 34.0% (overweight group), respectively,and 51.9 and 37.3% (obese group), respectively. CONCLUSIONS: All renal function prediction equations are biased when used in overweight or obese diabetic populations with preserved renal function. The CG provides the best estimate of kidney function. The limitations of renal function prediction equations should be kept in mind when making clinical decisions.