The impact of age on endothelial dysfunction measured by peripheral arterial tonometry in a healthy population-based cohort - the Malmö offspring study.

BACKGROUND/AIMS: The reactive hyperaemia index (RHI) assesses endothelial function, with a proposed cut-off of <1.67 for prevalent endothelial dysfunction (ED). However, uncertainties remain about whether this cut-off is age-dependent and applicable in healthy individuals. We aimed to explore ED in relation to age within a large population-based cohort of young to middle-aged, healthy individuals. METHODS: Within the Malmö Offspring Study, a total of 1812 subjects (50.9% women, mean age 48 ± 11 years) were included. Post-occlusion/pre-occlusion ratio of the pulsatile signal amplitudes in the non-dominant upper arm was used to calculate RHI by EndoPat®. ED was defined as RHI < 1.67. Multivariable regression models were used to explore associations between ED and age. RESULTS: Prevalent ED was found in 534 (29.5%) participants. In subjects aged ≤30 years, ED was present in 47.4% compared to 27.6% in subjects ≥30 years (p < 0.001). In multivariable logistic regression analyses, ED was associated with younger age (p < 0.001), higher BMI (p < 0.001) and current smoking (p < 0.001). No sex differences were observed. CONCLUSION: In a large healthy population, RHI < 1.67, an early marker of endothelial dysfunction, was more prevalent in younger individuals, implying that RHI might not be a suitable measure of endothelial function in individuals under 30 years of age. Our findings suggest that low RHI in young, healthy individuals may not necessarily indicate true ED but rather an artefact of the limited ability of young and healthy arteries to dilate post-occlusion. Therefore, the term "pseudo-ED" may be applicable to young individuals with low RHI values.

What is the context?The endothelium is a thin layer of cells that lines the inside of blood vessels, and its proper function is crucial for the maintenance of vascular health. Endothelial dysfunction (ED) is an early marker of cardiovascular disease and is characterised by impaired dilation of blood vessels, which can lead to reduced blood flow and increased risk of heart attacks and strokes. The reactive hyperaemia index (RHI) is a widely used non-invasive test that measures endothelial function by evaluating the dilation of blood vessels in response to temporary occlusion.What is new?This study aimed to investigate the relationship between age and ED in a large population-based cohort of young to middle-aged healthy individuals. The results showed that prevalent ED was more common in younger individuals, with 47.4% of participants aged ≤30 years having ED, compared to 27.6% in those ≥30 years. The study also found that ED was associated with higher BMI and current smoking, but no sex differences were observed.What is the impact?The findings suggest that the proposed RHI cut-off of <1.67 for prevalent ED may not be applicable to individuals under the age of 30, as young and healthy arteries may have limited ability to dilate post-occlusion, resulting in low RHI values that do not necessarily indicate true ED. Therefore, the term "pseudo-ED" may be more appropriate for young individuals with low RHI values.

Proteomic and Metabolomic Characterization of Metabolically Healthy Obesity: A Descriptive Study from a Swedish Cohort.

Method: Associations between different biomarkers (proteomics, lipidomics, and metabolomics) coupled to either MHO or metabolically unhealthy obese (MUO) individuals were analyzed through principal component analysis (PCA). Subjects were identified from a subsample of 416 obese individuals, selected from the Malmö Diet and Cancer study-Cardiovascular arm (MDCS-CV, n = 3,443). They were further divided into MHO (n = 143) and MUO (n = 273) defined by a history of hospitalization, or not, at baseline inclusion, and nonobese subjects (NOC, n = 3,027). Two distinctive principle components (PL2, PP5) were discovered with a significant difference and thus further investigated through their main loadings. Results: MHO individuals had a more metabolically favorable lipid and glucose profile than MUO subjects, that is, lower levels of traditional blood glucose and triglycerides, as well as a trend of lower metabolically unfavorable lipid biomarkers. PL2 (lipidomics, p=0.02) showed stronger associations of triacylglycerides with MUO, whereas phospholipids correlated with MHO. PP5 (proteomics, p=0.01) included interleukin-1 receptor antagonist (IL-1ra) and leptin with positive relations to MUO and galanin that correlated positively to MHO. The group differences in metabolite profiles were to a large extent explained by factors included in the metabolic syndrome. Conclusion: Compared to MUO individuals, corresponding MHO individuals present with a more favorable lipid metabolic profile, accompanied by a downregulation of potentially harmful proteomic biomarkers. This unique and extensive biomarker profiling presents novel data on potentially differentiating traits between these two obese phenotypes.

Antibodies against phosphorylcholine in hospitalized versus non-hospitalized obese subjects.

Obesity associates with reduced life expectancy, type 2 diabetes, hypertension and cardiovascular disease, and is characterized by chronic inflammation. Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein, dead cells and some microorganisms. Antibodies against PC (anti-PC) have anti-inflammatory properties. Here, we explored the role of anti-PC in hospitalized versus non-hospitalized obese. One-hundred-and-twenty-eight obese (BMI ≥ 30 kg/m2) individuals (59.8 (± 5.5) years, 53.9% women) from the Malmö Diet and Cancer Cardiovascular Cohort were examined and IgM, IgG1 and IgG2 anti-PC were analyzed by ELISA. Individuals with at least one recorded history of hospitalization prior to study baseline were considered hospitalized obese (HO). Associations between IgM, IgG1 and IgG2 anti-PC and HO (n = 32)/non-hospitalized obese (NHO) (n = 96), but also with metabolic syndrome and diabetes were analysed using logistic regressions. Both IgM and IgG1 anti-PC were inversely associated with HO, also after controlling for age and sex. When further adjusted for waist circumference, systolic blood pressure, glucose levels and smoking status, only IgG1 anti-PC remained significantly associated with HO. In multivariate models, each 1 standard deviation of increment in anti-PC IgG1 levels was inversely associated with prevalence of HO (odds ratio 0.57; CI 95% 0.33-0.98; p = 0.044). IgG2 anti-PC did not show any associations with HO. Low levels of IgM and IgG1 anti-PC are associated with higher risk of being a HO individual independent of sex and age, IgG1 anti-PC also independently of diabetes and metabolic syndrome. The anti-inflammatory properties of these antibodies may be related to inflammation in obesity and its complications.

Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population-based study.

AIM: The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. METHODS: Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. RESULTS: Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found. CONCLUSIONS: Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.

Increased blood cadmium levels were not associated with increased fracture risk but with increased total mortality in women: the Malmö Diet and Cancer Study.

This study aimed to investigate if high levels of blood cadmium at baseline were associated with increased fracture risk during follow-up in middle-aged women. No increased fracture risk was observed during follow-up, but women with higher levels of cadmium had an increased overall mortality. INTRODUCTION: Exposure to high levels of cadmium has been associated with an increased fracture risk. The aim was to investigate a perceived association between low levels of blood cadmium (B-Cd) at baseline and risk of first incident fracture. METHODS: From the population-based Malmö Diet and Cancer Study Cardiovascular cohort, 2920 middle-aged women with available background questionnaire and B-Cd measurements were included. Women were divided into quartiles (Q) according to their cadmium levels (Cd-Q1 <0.18 µg/L, Cd-Q2 0.18-0.28 µg/L, Cd-Q3 0.28-0.51 µg/L, and Cd-Q4 >0.51 µg/L). National registries were analysed for prospective risk of fractures or death. Associations between B-Cd and fracture risk were assessed by survival analysis (Cox regression analysis). RESULTS: In total, 998 first incident fractures occurred in women during a follow-up lasting 20.2 years (median) (12.5-21.2 years) (25th-75th percentile). Women in Cd-Q4 were more often current smokers than in Cd-Q1 78.4 vs. 3.3% (p < 0.001) and the number of cigarettes smoked per day correlated with B-Cd (r = 0.49; p < 0.001). The risk of fracture was not associated with baseline B-Cd in adjusted models. The hazard ratio (HR) Cd-Q4 vs. Cd-Q1 was 1.06 (95% confidence interval (CI) 0.89-1.27). In the multivariate Cox regression, independent variables for increased fracture risk were history of gastric ulcer and increasing age, whereas increasing body mass index (BMI) lowered fracture risk. Overall mortality was significantly higher for women with high B-Cd, HR 2.06 (95% CI 1.57-2.69). CONCLUSIONS: Higher blood levels of cadmium did not increase fracture risk in middle-aged women but reduced overall survival.

Insulin resistance and ß-cell function in smokers: results from the EGIR-RISC European multicentre study.

AIMS: Tobacco smoking is known to increase the long-term risk of developing Type 2 diabetes mellitus, but the mechanisms involved are poorly understood. This observational, cross-sectional study aims to compare measures of insulin sensitivity and ß-cell function in current, ex- and never-smokers. METHODS: The study population included 1246 people without diabetes (mean age 44 years, 55% women) from the EGIR-RISC population, a large European multicentre cohort. Insulin sensitivity was measured using a hyperinsulinaemic, euglycaemic clamp and the homeostatic model assessment - insulin resistance (HOMA-IR) index. Two ß-cell function parameters were derived from measures during an oral glucose tolerance test: the early insulin response index and ß-cell glucose sensitivity. Additionally, the areas under the curve during the oral glucose tolerance test were calculated for glucose, insulin and C-peptide. RESULTS: According to smoking habits, there were differences in insulin sensitivity, which was lower in women who smoked, and in ß-cell glucose sensitivity, which was lower in men who smoked, but these associations lost significance after adjustment. However, after adjustment, the areas under the glucose and the C-peptide curves during the oral glucose tolerance test were significantly higher in men who smoked. CONCLUSIONS: Smoking habits were not independently associated with insulin sensitivity or ß-cell function in a healthy middle-aged European population. Health-selection bias, methodological shortcomings or a true lack of causal links between smoking and impaired insulin sensitivity/secretion are possible explanations. The mechanisms behind the observed increased glucose and C-peptide areas under the curve during the oral glucose tolerance test in male smokers need to be further evaluated.

Inverse relationship between a genetic risk score of 31 BMI loci and weight change before and after reaching middle age.

BACKGROUND/OBJECTIVE: Genome-wide-association studies have identified numerous body mass index (BMI)-associated variants, but it is unclear how these relate to weight gain in adults at different ages. METHODS: We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight change (AWC) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; s.d.: 8 y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73 y; s.d.: 6 y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER (Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk) participants (mean: 45 y; s.d.: 7 y) with 10 y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses. RESULTS: In MDCS, the GRS was associated with increased AWC (ß: 0.003; s.e: 0.01; P: 7 × 10(-8)) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWC (ß: -0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20 y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWC and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWC (ß: -0.005; s.e.m. 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele. CONCLUSIONS: Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.

Risk factors for the progression of carotid intima-media thickness over a 16-year follow-up period: the Malmö Diet and Cancer Study.

OBJECTIVE: To evaluate the progression of carotid intima-media thickness (IMT) in the common carotid artery (CCA) and the bifurcation over a mean follow-up of 16 years in relation to cardiovascular risk factors. METHODS: The study population included 3426 middle-aged Swedish men and women participating in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the cardiovascular cohort of the Malmö Diet and Cancer Study (MDCS). RESULTS: There were differences in risk factor patterns in arterial segments in that diabetes and male sex were associated with the progression of IMT in the bifurcation, but not in the CCA, and high-density lipoprotein cholesterol (HDL) was associated with the progression of IMT in the CCA, but not in the bifurcation. Favourable changes in systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL) and HDL during follow-up decreased the IMT progression rate in the CCA. There was a cumulative relationship between traditional cardiovascular risk factors (i.e., regular smoking, LDL/HDL-ratio ≥ 3, hypertension) and IMT progression rates. The odds ratio (OR) of high IMT CCA progression rate (>75th percentile) was 1.0 (reference), 1.4 (95% CI: 1.1, 1.7), 1.7 (95% CI: 1.3, 2.2) and 2.1 (95% CI: 1.4, 3.1), respectively, for individuals with none, one, two, and three risk factors. CONCLUSION: There were differences in the associations between risk factors and progression rate in different arterial segments. Favourable changes in SBP and lipids during the follow-up period were associated with reduced IMT progression rates in the CCA.

Consumption of fatty foods and incident type 2 diabetes in populations from eight European countries.

BACKGROUND/OBJECTIVES: Diets high in saturated and trans fat and low in unsaturated fat may increase type 2 diabetes (T2D) risk, but studies on foods high in fat per unit weight are sparse. We assessed whether the intake of vegetable oil, butter, margarine, nuts and seeds and cakes and cookies is related to incident T2D. SUBJECTS/METHODS: A case-cohort study was conducted, nested within eight countries of the European Prospective Investigation into Cancer (EPIC), with 12,403 incident T2D cases and a subcohort of 16,835 people, identified from a cohort of 340,234 people. Diet was assessed at baseline (1991-1999) by country-specific questionnaires. Country-specific hazard ratios (HRs) across four categories of fatty foods (nonconsumers and tertiles among consumers) were combined with random-effects meta-analysis. RESULTS: After adjustment not including body mass index (BMI), nonconsumers of butter, nuts and seeds and cakes and cookies were at higher T2D risk compared with the middle tertile of consumption. Among consumers, cakes and cookies were inversely related to T2D (HRs across increasing tertiles 1.14, 1.00 and 0.92, respectively; P-trend <0.0001). All these associations attenuated upon adjustment for BMI, except the higher risk of nonconsumers of cakes and cookies (HR 1.57). Higher consumption of margarine became positively associated after BMI adjustment (HRs across increasing consumption tertiles: 0.93, 1.00 and 1.12; P-trend 0.03). Within consumers, vegetable oil, butter and nuts and seeds were unrelated to T2D. CONCLUSIONS: Fatty foods were generally not associated with T2D, apart from weak positive association for margarine. The higher risk among nonconsumers of cakes and cookies needs further explanation.

Red cell distribution width, haemoglobin A1c and incidence of diabetes mellitus.

OBJECTIVE: Hyperglycaemia has multiple effects on the red blood cell (RBC), including glycation of haemoglobin, reduced deformability and reduced lifespan. Red cell distribution width (RDW) is a measure of the heterogeneity of erythrocyte volumes. The aim of this study was to explore the relationships between RDW and glucose, haemoglobin A1c (HbA1c) and incidence of diabetes mellitus (DM). DESIGN, SETTING AND SUBJECTS: RDW and mean corpuscular volume were measured in 26 709 non-diabetic participants (aged 45-73 years) from the population-based Malmö Diet and Cancer cohort. HbA1c and fasting venous blood glucose levels were measured in 4845 subjects. MAIN OUTCOME MEASURE: Incidence of DM (n = 2944) over 14 years of follow-up was studied by linkage with national and local DM registers. RESULTS: Individuals with low RDW had significantly higher risk of developing DM [adjusted hazard ratio (HR) 1.48, 95% confidence interval (CI) 1.29-1.70, for 1st vs. 4th quartile], especially in subjects with impaired fasting glucose (n = 416) (HR 2.15, 95% CI 1.12-4.14). Low RDW was also associated with significantly higher waist circumference and glucose, insulin and triglyceride concentrations. By contrast, RDW was significantly and positively associated with HbA1c, corresponding an increase in HbA1c of 0.10% per 1 SD increase in RDW. CONCLUSION: Low RDW is associated with increased incidence of DM independently of other risk factors. We propose that low RDW could be a surrogate marker of reduced RBC survival, with lower HbA1c due to shorter duration of glucose exposure. RDW is a biomarker that could improve risk assessment for individuals at risk of developing DM.

Dietary vitamin D intake and risk of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition: the EPIC-InterAct study.

BACKGROUND/OBJECTIVES: Prospective cohort studies have indicated that serum vitamin D levels are inversely related to risk of type 2 diabetes. However, such studies cannot determine the source of vitamin D. Therefore, we examined the association of dietary vitamin D intake with incident type 2 diabetes within the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study in a heterogeneous European population including eight countries with large geographical variation. SUBJECTS/METHODS: Using a case-cohort design, 11,245 incident cases of type 2 diabetes and a representative subcohort (N=15,798) were included in the analyses. Hazard ratios (HR) and 95% confidence intervals (CIs) for type 2 diabetes were calculated using a Prentice-weighted Cox regression adjusted for potential confounders. Twenty-four-hour diet-recall data from a subsample (N=2347) were used to calibrate habitual intake data derived from dietary questionnaires. RESULTS: Median follow-up time was 10.8 years. Dietary vitamin D intake was not significantly associated with the risk of type 2 diabetes. HR and 95% CIs for the highest compared to the lowest quintile of uncalibrated vitamin D intake was 1.09 (0.97-1.22) (Ptrend=0.17). No associations were observed in a sex-specific analysis. The overall pooled effect (HR (95% CI)) using the continuous calibrated variable was 1.00 (0.97-1.03) per increase of 1 µg/day dietary vitamin D. CONCLUSIONS: This observational study does not support an association between higher dietary vitamin D intake and type 2 diabetes incidence. This result has to be interpreted in light of the limited contribution of dietary vitamin D on the overall vitamin D status of a person.

Changes in body mass index following newly diagnosed type 2 diabetes and risk of cardiovascular mortality: a cohort study of 8486 primary-care patients.

AIMS: Elevated body mass index (BMI) is associated with an increased risk of type 2 diabetes and cardiovascular disease (CVD). This study explored the association between BMI changes in the first 18 months of newly diagnosed type 2 diabetes and the risk of long-term CVD mortality. METHODS: A total of 8486 patients with newly diagnosed type 2 diabetes and no previous history of CVD or cancer were identified from 84 primary-care centres in Sweden. During the first year after diagnosis, patients were grouped according to BMI change: 'Increase', or ≥+1 BMI unit; 'unchanged', or between +1 and-1 BMI unit; and 'decrease', or ≤-1 BMI unit. Associations between BMI change and CVD mortality, defined as death from stroke, myocardial infarction or sudden death, were estimated using adjusted Cox proportional hazards models (NCT 01121315). RESULTS: Baseline mean age was 60.0 years and mean BMI was 30.2kg/m(2). Patients were followed for up to 9 years (median: 4.6 years). During the first 18 months, 53.4% had no change in their BMI, while 32.2% decreased and 14.4% increased. Compared with patients with unchanged BMI, those with an increased BMI had higher risks of CVD mortality (hazard ratio: 1.63, 95% CI: 1.11-2.39) and all-cause mortality (1.33, 1.01-1.76). BMI decreases had no association with these risks compared with unchanged BMI: 1.06 (0.76-1.48) and 1.06 (0.85-1.33), respectively. CONCLUSION: Increased BMI within the first 18 months of type 2 diabetes diagnosis was associated with an increased long-term risk of CVD mortality. However, BMI decrease did not lower the long-term risk of mortality.

Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study.

AIMS/HYPOTHESIS: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption. RESULTS: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants. CONCLUSIONS/INTERPRETATION: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

Copeptin, a marker of vasopressin, in abdominal obesity, diabetes and microalbuminuria: the prospective Malmö Diet and Cancer Study cardiovascular cohort.

BACKGROUND: High plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin pro-hormone, has been associated with the metabolic syndrome (MetS), diabetes mellitus (DM) development and nephropathy. Here we tested whether elevated copeptin level is associated with later development of the MetS, its individual components and microalbuminuria. METHODS: We analysed copeptin at baseline (1991-1994) in the population-based Malmö Diet and Cancer Study cardiovasular cohort and re-examined 2064 subjects 15.8 years later (mean age 72.8 years, 59% women) with oral glucose tolerance test and measurement of MetS and its individual components. RESULTS: After age and sex adjustment, increasing quartiles of copeptin at baseline (the lowest quartile as reference) were associated with MetS (P for trend=0.008), incident abdominal obesity (P for trend=0.002), DM (P for trend=0.001) and microalbuminuria (P for trend=0.002). After additional adjustment for all the MetS components at baseline, increasing copeptin quartiles predicted incident abdominal obesity (odds ratios 1.55, 1.30 and 1.59; P for trend=0.04), DM (odds ratios 1.18, 1.32 and 1.46; P for trend=0.04) and microalbuminuria (odds ratios 1.05, 1.08 and 1.65; P for trend=0.02) but not MetS (P for trend=0.19) at the reexamination. Further, the relationship between copeptin and microalbuminuria was independent of baseline C-reactive protein, incident DM and incident hypertension. CONCLUSION: Copeptin independently predicts DM and abdominal obesity but not the cluster of MetS. Apart from predicting DM and abdominal obesity, elevated copeptin signals increased risk of microalbuminuria. Interestingly, the association between copeptin and later microalbuminuria was independent of both prevalent and incident DM and hypertension. Our findings suggest a relationship between a dysregulated vasopressin system and cardiometabolic risk, which could have implications for risk assessment and novel preventive treatments.

Blood cell telomere length among patients with an isolated popliteal artery aneurysm and those with multiple aneurysm disease.

OBJECTIVES: Short relative telomere length (RTL) is associated with vascular ageing, inflammation and cardiovascular risk factors. Previous studies have reported an association between abdominal aortic aneurysm and short RTL. The presence of atherosclerosis among patients with aneurysm disease may, however, be a confounder. The aim was to explore the associations between short RTL and aneurysm disease, by comparing patients with isolated popliteal artery aneurysms with those having multiple aneurysms. DESIGN AND PATIENTS: DNA was retrieved from 183 patients with popliteal artery aneurysm (PAA). They were all examined with ultrasound at the time of blood-sampling, and had a total of 423 aneurysms (range 1-7, mean 2.3/patient). METHODS: TL was measured with Real-Time PCR, RTL was calculated by comparing with three reference populations. RESULTS: Patients with bilateral PAAs had a mean RTL of 0.985 vs. 1.038 with unilateral PAAs (P = 0.326). Patients with abdominal aortic aneurysm had RTL 1.035, vs. 0.999 without (P = 0.513). No difference was seen with or without femoral or iliac aneurysms. Fifty-six patients with isolated PAA at surgery and at re-examination had RTL 0.974, vs. 1.033 who had >1 aneurysm (P = 0.308). RTL was not associated with the number of aneurysms at re-examination (P = 0.727, one-way ANOVA). There was a trend towards shorter RTL among active smokers (0.93 vs. 1.04, P = 0.066). CONCLUSIONS: No association between short RTL and multiple aneurysm disease was found. The previously reported association between AAA and short RTL may be secondary to cardiovascular risk factors, rather than by aneurysm disease.

Risk factors for cardiovascular disease and future osteoarthritis-related arthroplasty: a population-based cohort study in men and women from Malmö, Sweden.

OBJECTIVE: To investigate the hypothesis that cardiovascular risk factors increase the likelihood of future osteoarthritis (OA)-related arthroplasty in adult men and women. METHODS: Baseline cohort data on cardiovascular risk factors [age, socio-economic class, family history, obesity, smoking, glucose, cholesterol, blood pressure, and early cardiovascular disease (CVD) history] were linked to clinical registers of OA-related arthroplasty data. The study included 8749 women and 14 821 men with up to a 30-year follow-up. RESULTS: In women, higher cardiovascular risk groups were more likely to have an OA outcome compared to the lowest risk quartile group (trend p < 0.001). The estimates were as follows: second quartile risk: rate ratio (RR) 2.15, 95% confidence interval (CI) 1.6-2.9, third quartile risk: 3.32 (2.5-4.5); and highest risk quartile: 3.47 (2.6-4.7). In men, higher cardiovascular risk groups were also more likely to have an OA outcome compared to the lowest risk quartile group (trend p = 0.001). The estimates were as follows: second quartile risk: RR 1.44, 95% CI 1.1-1.9; third quartile risk: 1.38 (1.1-1.8); and highest risk quartile: 1.67 (1.3-2.2). CONCLUSIONS: Our large cohort study with up to a 30-year follow-up period provides evidence to support the hypothesis of shared risk factors in CVD and OA, and the findings suggest an alternative aetiological process in the pathogenesis of OA.

Diabetes, prediabetes and cancer mortality.

AIMS/HYPOTHESIS: We aimed to investigate the risk of cancer mortality in relation to the glucose tolerance status classified according to the 2 h OGTT. METHODS: Data from 17 European population-based or occupational cohorts involved in the DECODE study comprising 26,460 men and 18,195 women aged 25-90 years were collaboratively analysed. The cohorts were recruited between 1966 and 2004 and followed for 5.9 to 36.8 years. Cox proportional hazards analysis with adjustment for cohort, age, BMI, total cholesterol, blood pressure and smoking status was used to estimate HRs for cancer mortality. RESULTS: Compared with people in the normal glucose category, multivariable adjusted HRs (95% CI) for cancer mortality were 1.13 (1.00, 1.28), 1.27 (1.02, 1.57) and 1.71 (1.35, 2.17) in men with prediabetes, previously undiagnosed diabetes and known diabetes, respectively; in women they were 1.11 (0.94, 1.30), 1.31 (1.00, 1.70) and 1.43 (1.01, 2.02), respectively. Significant increases in deaths from cancer of the stomach, colon-rectum and liver in men with prediabetes and diabetes, and deaths from cancers of the liver and pancreas in women with diabetes were also observed. In individuals without known diabetes, the HR (95% CI) for cancer mortality corresponding to a one standard deviation increase in fasting plasma glucose was 1.06 (1.02, 1.09) and in 2 h plasma glucose was 1.07 (1.03, 1.11). CONCLUSIONS/INTERPRETATION: Diabetes and prediabetes were associated with an increased risk of cancer death, particularly death from liver cancer. Mortality from all cancers rose linearly with increasing glucose concentrations.

Total adiponectin does not predict cardiovascular events in middle-aged men in a prospective, long-term follow-up study.

AIM: Plasma total adiponectin is a marker of insulin resistance, but its role in predicting cardiovascular events is unclear. We aimed to investigate the role of adiponectin as a predictor of cardiovascular risk in middle-aged men, and to describe the association between adiponectin and glucose metabolism. METHODS: In this population-based prospective study of middle-aged men (n=3885), total adiponectin was analyzed. All individuals had undergone an oral glucose tolerance test (OGTTs), and the mean follow-up duration was 27 years. Regression analyses were carried out for indices of glucose metabolism in relation to quintiles (Q1-Q5) of total adiponectin levels. After stratification for smoking or not, the association between total adiponectin and the first incidence of fatal or non-fatal cardiovascular disease (CVD) was analyzed, using Cox's proportional-hazards regression model. RESULTS: In a separate multiple-regression analysis and after adjusting for possible confounders, the relationship between adiponectin levels and markers of glucose metabolism were found to be significant (P<0.05). However, adiponectin did not independently predict the risk of stroke, coronary events, or a combination of these two outcomes. CONCLUSION: Levels of total plasma adiponectin are not useful for predicting long-term cardiovascular events in middle-aged men, but are strongly associated with glucose metabolism and markers of insulin resistance.

Plasma markers of inflammation and incidence of hospitalisations for COPD: results from a population-based cohort study.

BACKGROUND: The relationship between plasma markers of inflammation and the incidence of chronic obstructive pulmonary disease (COPD) is still unclear. This population-based study explored whether raised levels of five inflammation-sensitive plasma proteins (ISPs) predicted hospital admissions for COPD during 25 years of follow-up. METHODS: Spirometric tests and measurements of five ISPs (fibrinogen, ceruloplasmin, alpha(1)-antitrypsin, haptoglobin, orosomucoid) were performed in 5247 apparently healthy men from the city of Malmö (mean age 46 years). The incidence of hospitalisations for COPD was studied in relation to the number of ISPs in the fourth quartile. RESULTS: During the follow-up period, 258 men were admitted to hospital with COPD, 211 of whom were smokers at baseline. The incidence of hospital admissions for COPD was significantly associated with the number of raised ISPs. Adjusted for risk factors, the hazards ratio (95% CI) was 1.00 (reference), 1.28 (0.9 to 1.9), 1.29 (0.8 to 2.0) and 2.30 (1.6 to 3.2), respectively, for men with 0, 1, 2 and >or=3 ISPs in the top quartile (p for trend <0.001). This relationship was consistent in men with high and low lung function at baseline. The relationship with the incidence of hospital admissions for COPD was largely the same for all individual ISPs. CONCLUSION: Raised plasma ISP levels are associated with an increased incidence of COPD requiring hospitalisation.

Risk of cardiovascular disease and mortality in overweight and obese patients with type 2 diabetes: an observational study in 13,087 patients.

AIMS/HYPOTHESIS: The aim of this study of type 2 diabetic patients in the Swedish National Diabetes Register was to study the associations of BMI, overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI >or= 30 kg/m(2)) with cardiovascular disease in type 2 diabetes, as these associations have not previously been clarified. METHODS: Patients aged 30-74 years with no previous CHD or stroke (N = 13,087) were followed for a mean of 5.6 years until 2003 for fatal or non-fatal CHD, stroke, cardiovascular disease (CHD or stroke) and total mortality. In total, 1,922 cardiovascular-disease events occurred, based on 64,864 person-years. RESULTS: The relative risks of CHD, stroke, cardiovascular disease and total mortality for a 5 unit increase in BMI at baseline were 15%, 11%, 13% and 27%, respectively, using Cox regression analysis, after adjusting for age, sex, diabetes duration, hypoglycaemic treatment and smoking (model 1), and were 9%, 4% (not significant), 7% and 20%, respectively, when adjusting also for HbA(1c), blood pressure, antihypertensive drugs, lipid-reducing drugs and microalbuminuria (model 2). Adjusted hazard ratios (model 1) for CHD, cardiovascular disease and total mortality with overweight were 1.27 (95% CI 1.09-1.48), 1.24 (1.09-1.41) and 1.16 (0.94-1.45), respectively, and 1.49 (1.27-1.76), 1.44 (1.26-1.64) and 1.71 (1.36-2.14) with obesity, as compared with normal weight. Significant hazard ratios were attenuated when adjusted according to model 2. For a 1 unit increase in BMI during follow-up, the relative risk of CHD (model 2) was 1.13 (1.04-1.23; p = 0.005). CONCLUSIONS/INTERPRETATION: Both overweight and obesity independently increased the risk of CHD and cardiovascular disease in patients with type 2 diabetes. The CHD risk was higher with increasing BMI than with stable or decreasing BMI during the study.