Aims
The glycolysis‐derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that ...methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6‐year follow‐up in 1481 people with screen‐detected Type 2 diabetes, as part of the Danish arm of the ADDITION‐Europe trial (ADDITION‐DK).
Methods
Biobank serum samples collected at ADDITION‐DK baseline (2001–2006) and follow‐up (2009–2010) were used in the current analysis of methylglyoxal. We assessed cross‐sectional baseline and longitudinal associations between methylglyoxal and urinary albumin‐to‐creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR.
Results
Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow‐up was inversely associated with change in eGFR (–1.6 ml/min/1.73 m2 per doubling in methylglyoxal change), in models adjusted for age, sex, HbA1c, systolic blood pressure, anti‐hypertensive treatment, LDL‐cholesterol, lipid‐lowering treatment, C‐reactive protein and smoking.
Conclusions
In a population of people with screen‐detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6‐year change in methylglyoxal was inversely associated with 6‐year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy.
What's new?
In this study, the glucose‐derived metabolite methylglyoxal was found to be associated with changes in kidney function.
This is one of the largest studies with methylglyoxal data (n ˜ 1400) obtained within a clinical setting (well‐characterized population of people with screen‐detected Type 2 diabetes mellitus).
Measurements of serum methylglyoxal were performed in samples from two time points (6 years of follow‐up).
The findings lend support to existing research implicating methylglyoxal in microvascular diabetes complications.
Periodontitis is a common finding among people with diabetes mellitus (DM) and has been cited as a DM complication. Whether and how periodontitis relates to other diabetes-related complications has ...yet to be explored. This study aims to examine the clustering of periodontitis with other diabetes-related complications and explore pathways linking diabetes-related complications with common risk factors. Using data from participants with DM across 3 cycles of the National Health and Nutrition Examination Survey (NHANES) (n = 2,429), we modeled direct and indirect pathways from risk factors to diabetes-related complications, a latent construct comprising periodontitis, cardiovascular diseases, proteinuria, and hypertension. Covariates included age, sex, socioeconomic status (SES), smoking, physical activity, healthy diet, alcohol consumption, hemoglobin A1c (HbA1c), dyslipidemia, and body mass index (BMI). Sensitivity analyses were performed considering participants with overweight/obesity and restricting the sample to individuals without DM. Periodontitis clustered with other diabetes complications, forming a latent construct dubbed diabetes-related complications. In NHANES III, higher HbA1c levels and BMI, older age, healthy diet, and regular physical activity were directly associated with the latent variable diabetes-related complications. In addition, a healthy diet and BMI had a total effect on diabetes-related complications. Although sex, smoking, dyslipidemia, and SES demonstrated no direct effect on diabetes-related complications in NHANES III, a direct effect was observed using NHANES 2011–2014 cycles. Sensitivity analysis considering participants with overweight/obesity and without DM showed consistent results. Periodontal tissue breakdown seems to co-occur with multiple diabetes-related complications and may therefore serve as a valuable screening tool for other well-known diabetes-related complications.
Aims
To present the longer‐term impact of multifactorial treatment of type 2 diabetes on self‐reported health status, diabetes‐specific quality of life, and diabetes treatment satisfaction at 10‐year ...follow up of the ADDITION‐Europe trial.
Methods
The ADDITION‐Europe trial enrolled 3057 individuals with screen‐detected type 2 diabetes from four centres Denmark, the UK (Cambridge and Leicester) and the Netherlands, between 2001 and 2006. Participants were randomized at general practice level to intensive treatment or to routine care . The trial ended in 2009 and a 10‐year follow‐up was performed at the end of 2014. We measured self‐reported health status (36‐item Short‐Form Health Survey and EQ‐5D), diabetes‐specific quality of life (Audit of Diabetes‐Dependent Quality of Life questionnaire), and diabetes treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire) at different time points during the study period. A mixed‐effects model was applied to estimate the effect of intensive treatment (intention‐to‐treat analyses) on patient‐reported outcome measures for each centre. Centre‐specific estimates were pooled using a fixed effects meta‐analysis.
Results
There was no difference in patient‐reported outcome measures between the routine care and intensive treatment arms in this 10‐year follow‐up study EQ‐5D: –0.01 (95% CI –0.03, 0.01); Physical Composite Score (36‐item Short‐Form Health Survey): –0.27 (95% CI –1.11, 0.57), Audit of Diabetes‐Dependent Quality of Life questionnaire: –0.01 (95% CI –0.11, 0.10); and Diabetes Treatment Satisfaction Questionnaire: –0.20 (95% CI –0.70, 0.29).
Conclusions
Intensive, multifactorial treatment of individuals with screen‐detected type 2 diabetes did not affect self‐reported health status, diabetes‐specific quality of life, or diabetes treatment satisfaction at 10‐year follow‐up compared to routine care.
What's new?
The burden of diabetes and its treatment may cause psychosocial stress.
Good metabolic control improves psychosocial well‐being.
Identifying people early in the disease course through screening and introducing long‐term intensive treatment does not cause psychosocial harm.
Clinicians and public health systems implementing early detection and intensive treatment protocols for type 2 diabetes do not need to worry that these may have a long‐term adverse impact on peoples’ psychosocial well‐being.
Persons with severe mental illness (SMI) have excess mortality, which may partly be explained by their high prevalence of diabetes.
We compared the overall and cause-specific mortality in persons ...with SMI and diabetes with that of the general Danish population between 1997 and 2009 by linking data from Danish national registries.
The cohort counted 4 734 703 persons, and during follow-up 651 080 persons died of whom 1083 persons had SMI and diabetes. Compared with the background population, the overall mortality rate ratios (MRRs) for persons with SMI and diabetes were 4.14 95% confidence interval (CI) 3.81-4.51 for men and 3.13 (95% CI 2.88-3.40) for women. The cause-specific MRRs for persons with SMI and diabetes were lowest for malignant neoplasms (women: MRR = 1.98, 95% CI 1.64-2.39; men: MRR = 2.08, 95% CI 1.69-2.56) and highest for unnatural causes of death (women: MRR = 12.31, 95% CI 6.80-22.28; men: MRR = 7.89, 95% CI 5.51-11.29). The cumulative risks of death within 7 years of diabetes diagnosis for persons with SMI and diabetes were 15.0% (95% CI 12.4-17.6%) for those younger than 50 years, 30.7% (95% CI 27.8-33.4%) for those aged 50-69 years, and 63.8% (95% CI 58.9-68.2%) for those aged 70 years or older. Among persons suffering from both diseases, 33.4% of natural deaths were attributed to diabetes and 14% of natural deaths were attributed to the interaction between diabetes and SMI.
Long-term mortality is high for persons with SMI and diabetes. This calls for effective intervention from a coordinated and collaborating healthcare system.
Aims/hypothesis Recent genome-wide association studies have suggested that a polymorphism in GCKR, the gene encoding the glucokinase regulatory protein, is involved in triacylglycerol regulation. Our ...aim was to examine in large-scale studies the common GCKR rs780094 polymorphism in relation to metabolic traits (mainly fasting hypertriacylglycerolaemia) and traits related to pancreatic beta cell function. Methods The polymorphism was genotyped in 16,853 Danes using Taqman allelic discrimination. Association was analysed in case-control studies and quantitative trait analyses. We also analysed the possible interactive effect between the GCK -30G>A polymorphism and the GCKR rs780094 variant on metabolic traits. Results The minor GCKR A-allele of rs780094 is associated with an increased level of fasting serum triacylglycerol (p = 6 x 10-¹⁴), impaired fasting (p = 0.001) and OGTT-related insulin release (p = 3 x 10-⁶), reduced homeostasis model assessment of insulin resistance (p = 0.0004), WHO-defined dyslipidaemia (p = 6 x 10-⁹) and a modestly decreased risk of type 2 diabetes (p = 0.01). Significantly increased fasting serum insulin concentrations were demonstrated when analysing the GCK -30A and GCKR rs780094 G-alleles in an additive model. Conclusions/interpretation The GCKR rs780094 polymorphism, or another variant with which it is in tight linkage disequilibrium, is likely to increase glucokinase regulatory protein activity to induce improved glycaemic regulation at the expense of hypertriacylglycerolaemia as reflected in the present study of 16,853 Danes. We also suggest an additive effect of GCK and GCKR risk alleles on plasma glucose and serum insulin release.
To determine the risk of dementia in patients with type 1 or type 2 diabetes and in individuals with glycosylated haemoglobin, type A1C (HbA1c) of ⩾48 mmol/mol, which is the diagnostic limit for ...diabetes.
We included the following cohorts: all incident diabetes cases aged 15 or above registered in the National Diabetes Registry (NDR) from January 2000 through December 2012 (n = 148 036) and a reference population, adult participants from the Glostrup cohort (n = 16 801), the ADDITION Study (n = 26 586) and Copenhagen Aging and Midlife Biobank (CAMB) (n = 5408). Using these cohorts, we analysed if a diagnosis of type 1 or type 2 diabetes in the NDR or HbA1c level of ⩾ 6.5% (48 mmol/mol) in the cohorts increased risk of dementia in the Danish National Patient Registry or cognitive performance assessed by the Intelligenz-Struktur-Test 2000R (IST2000R).
A diagnosis of type 1 or type 2 diabetes in the NDR was associated with increased risk of dementia diagnosed both before or after age 65 as well as across different subtypes of dementia. Self-reported diabetes or high HbA1c levels were associated with lower cognitive performance (p = 0.004), while high HbA1c was associated with increased risk of dementia (HR 1.94 (1.10-3.44) in the Glostrup cohort but not in the ADDITION Study (HR 0.96 (0.57-1.61)).
Both type 1 and type 2 diabetes are associated with an increased risk of dementia, while the importance of screening-detected elevated HbA1c remains less clear.
Aims
Cardiovascular autonomic neuropathy and diabetic peripheral neuropathy are common diabetic complications and independent predictors of cardiovascular disease. The glucose metabolite ...methylglyoxal has been suggested to play a causal role in the pathogeneses of diabetic peripheral neuropathy and possibly diabetic cardiovascular autonomic neuropathy. The aim of this study was to investigate the cross‐sectional association between serum methylglyoxal and diabetic peripheral neuropathy and cardiovascular autonomic neuropathy in a subset of patients in the ADDITION‐Denmark study with short‐term screen‐detected Type 2 diabetes (duration ~ 5.8 years).
Methods
The patients were well controlled with regard to HbA1c, lipids and blood pressure. Cardiovascular autonomic neuropathy was assessed by measures of resting heart rate variability and cardiovascular autonomic reflex tests. Diabetic peripheral neuropathy was assessed by vibration detection threshold (n = 319), 10 g monofilament (n = 543) and the Michigan Neuropathy Screening Instrument questionnaire (n = 966). Painful diabetic neuropathy was assessed using the Brief Pain Inventory short form (n = 882).
Results
No associations between methylglyoxal and cardiovascular autonomic reflex tests or any measures of diabetic peripheral neuropathy or painful diabetic neuropathy were observed. However, a positive association between methylglyoxal and several heart rate variability indices was observed, although these associations were not statistically significant when corrected for multiple testing.
Conclusion
Serum methylglyoxal is not associated with cardiovascular autonomic neuropathy, diabetic peripheral neuropathy or painful diabetic neuropathy in this cohort of well‐treated patients with short‐term diabetes.
What's new?
This is the largest study on the association between methylglyoxal and diabetic peripheral neuropathy.
This is the first study investigating the association between methylglyoxal and neuropathy in patients with short‐term diabetes, allowing a study on the early stages of neuropathy.
Methylglyoxal was positively associated with parasympathetic heart rate variability indices before adjustment for multiple testing.
No associations between methylglyoxal and a diagnosis of diabetic cardiovascular autonomic neuropathy, objectively measured peripheral neuropathy or painful diabetic neuropathy assessed by questionnaire were found.
Methylglyoxal seems unsuitable as a marker of neuropathy in patients with short‐term Type 2 diabetes.
The results call for new studies that focus on the associations between methylglyoxal‐derived advanced glycation end products and diabetic neuropathy
Aims/hypothesis
There is limited evidence on how multifactorial treatment improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine ...clinical practice. Cardiac autonomic neuropathy (CAN) in people with diabetes indicates widespread damage to the autonomic nervous system, which may severely affect health and quality of life. We examined effects of early detection and subsequent intensive treatment of type 2 diabetes in primary care on the prevalence of CAN at the 6-year follow-up examination in a pragmatic cluster-randomised parallel group trial.
Methods
One hundred and ninety general practices were randomised to deliver either intensive multifactorial treatment (IT) or routine care (RC) as recommended by national guidelines to patients with type 2 diabetes, identified through a stepwise screening programme in the primary care setting. 1533 people (IT,
n
= 910; RC,
n
= 623) were identified and included. At the 6-year follow-up examination, measures of CAN were applied in an unselected subsample of 777 participants using heart rate variability analysis and standard tests of CAN.
Results
At the 6-year follow-up examination, the prevalence of early CAN was 15.1% in the RC group and 15.5% in the IT group, while manifest CAN was present in 7.1% and 7.3%, respectively. We found no statistically significant effect of intensive treatment on the prevalence of CAN compared with routine care.
Conclusions/interpretation
In the Danish arm of the ADDITION Study, signs of CAN were highly prevalent 6 years after a screening-based diagnosis of type 2 diabetes. Intensive multifactorial treatment did not significantly affect the prevalence of CAN compared with routine care. However, at follow-up the level of medication was also high in the RC group.
Diabet. Med. 28, 1416–1424 (2011)
Aims To describe and compare attendance rates and the proportions of people identified with Type 2 diabetes mellitus in people with previously unknown diabetes who ...participated in screening programmes undertaken in general practice in the UK, Denmark and the Netherlands as part of the ADDITION‐Europe study.
Methods In Cambridge, routine computer data searches were conducted to identify individuals aged 40–69 years at high risk of Type 2 diabetes using the Cambridge Diabetes Risk Score. In Denmark, the Danish Diabetes Risk Score was mailed to individuals aged 40–69 years, or completed by patients visiting their general practitice. In the Netherlands, the Hoorn Symptom Risk Questionnaire was mailed to individuals aged 50–69 years. In these three centres, high‐risk individuals were invited to attend subsequent steps in the screening programme, including random blood glucose, HbA1c, fasting blood glucose and/or oral glucose tolerance test. In Leicester, eligible people aged 40–69 years were invited directly for an oral glucose tolerance test. In all centres, Type 2 diabetes was defined according to World Health Organization 1999 diagnostic criteria.
Results Attendance rates ranged from 20.2% (oral glucose tolerance test in Leicester without pre‐stratification) to 95.1% (random blood glucose in opportunistic screening in Denmark in high‐risk people). The percentage of people with newly detected Type 2 diabetes from the target population ranged from 0.33% (Leicester) to 1.09% (the Netherlands).
Conclusions Screening for Type 2 diabetes was acceptable and feasible, but relatively few participants were diagnosed in all participating centres. Different strategies may be required to increase initial attendance and ensure completion of screening programmes.
Aims
To examine variation between general practices in the prescription of lipid‐lowering treatment to people with screen‐detected Type 2 diabetes, and associations with practice and participant ...characteristics and risk of cardiovascular events and all‐cause mortality.
Methods
Observational cohort analysis of data from 1533 people with screen‐detected Type 2 diabetes aged 40–69 years from the ADDITION‐Denmark study. One hundred and seventy‐four general practices were cluster randomized to receive: (1) routine diabetes care according to national guidelines (623 individuals), or (2) intensive multifactorial target‐driven management (910 individuals). Multivariable logistic regression was used to quantify the association between the proportion of individuals in each practice who redeemed prescriptions for lipid‐lowering medication in the two years following diabetes diagnosis and a composite cardiovascular disease (CVD) outcome, adjusting for age, sex, prevalent chronic disease, baseline CVD risk factors, smoking and lipid‐lowering medication, and follow‐up time.
Results
The proportion of individuals treated with lipid‐lowering medication varied widely between practices (0–100%). There were 118 CVD events over 9431 person‐years of follow‐up. For the whole trial cohort, the risk of CVD was significantly higher in practices in the lowest compared with the highest quartile for prescribing lipid‐lowering medication adjusted odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6–7.3. Similar trends were found for all‐cause mortality.
Conclusions
More frequent prescription of lipid‐lowering treatment was associated with a lower incidence of CVD and all‐cause mortality. Improved understanding of factors underlying practice variation in prescribing may enable more frequent use of lipid‐lowering treatment. The results highlight the benefits of intensive treatment of people with screen‐detected diabetes (Clinical Trials Registry No; NCT 00237549).
What's new
Despite the well‐established cardioprotective benefits of lipid‐lowering treatment in Type 2 diabetes, evidence suggests large variations in statin use in primary care.
Variation may be particularly high among people with screen‐detected diabetes because general practitioners (GPs) might be reluctant to prescribe cardioprotective drugs for asymptomatic patients.
There was wide variation in the prescription of lipid‐lowering treatment among people with screen‐detected diabetes in Danish primary care; more frequent prescription of lipid‐lowering treatment was associated with a lower incidence of cardiovascular disease and all‐cause mortality.
More work is needed to improve understanding of the factors underlying practice variation in prescribing in order to encourage GPs to offer lipid‐lowering treatment to this high‐risk group.
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