Arterial stiffness and subclinical atherosclerosis in the coronary arteries at different stages of dysglycaemia.

AIM: Our aim was to investigate in a large population-based cohort study whether increased arterial stiffness and subclinical atherosclerosis in the coronary arteries differ at different stages of dysglycaemia. METHODS: Data were obtained from SCAPIS, a population-based cohort of participants 50-64 years. The study population of 9379 participants was categorised according to glycaemic status: normoglycaemic, pre-diabetes (fasting glucose: 6.1-6.9 mmol/L and/or HbA1c 6%-6.4%) and diabetes. Pulse wave velocity (PWV) was measured by the SphygmoCor XCEL system and arterial stiffness was defined by PWV ≥10 m/s. Coronary artery calcium score (CACS) was assessed by coronary computed tomography and coronary artery calcification was defined by CACS ≥100. RESULTS: We identified 1964 (21%) participants with dysglycaemia, out of which 742 (7.9%) had diabetes mellitus. PWV ≥10 m/s was present in 808 (11%), 191 (16%), 200 (27%) and CACS ≥100 in 801 (11%), 190 (16%), 191 (28%) participants with normoglycaemia, pre-diabetes and diabetes, respectively, all, p < 0.001. The overlap between PWV ≥10 m/s and CACS ≥100 within each glycaemic category was 188 (2.5%), 44 (3.6%) and 77 (10) respectively. There was an association between glycaemic status and increased PWV in the fully adjusted models, but not for glycaemic status and CACS ≥100, where there was no difference for pre-diabetes compared to normoglycaemia, OR 1.2 (95% CI 0.98-1.4). In the total study population, there was an association between HbA1c and PWV after adjustment, p < 0.001. CONCLUSIONS: Our results show that increased arterial stiffness and subclinical coronary artery atherosclerosis are present in the early stages of dysglycaemia, but the overlap between markers of major subclinical vascular damage was small in all glycaemic categories. This could be explained by different pathways in the pathogenesis of arterial stiffness or atherosclerosis in the coronary arteries.

Plasma prostasin: a novel risk marker for incidence of diabetes and cancer mortality.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of cancer. Prostasin is an epithelial sodium channel stimulator that has been associated with suppression of tumours, glucose metabolism and hyperglycaemia-associated tumour pathology. However, the association between prostasin, diabetes and cancer mortality has not been well investigated in humans. We aim to investigate the associations between plasma prostasin and diabetes, and to explore whether prostasin has an effect on cancer mortality risk in individuals with hyperglycaemia. METHODS: Plasma prostasin was measured using samples from the Malmö Diet and Cancer Study Cardiovascular Cohort, and statistical analysis was performed from both sex-specific quartiles and per 1 SD. The cross-sectional association between plasma prostasin and diabetes was first studied in 4658 participants (age 57.5 ± 5.9 years, 39.9% men). After excluding 361 with prevalent diabetes, the associations of prostasin with incident diabetes and cancer mortality risk were assessed using Cox regression analysis. The interactions between prostasin and blood glucose levels as well as other covariates were tested. RESULTS: The adjusted OR for prevalent diabetes in the 4th vs 1st quartile of prostasin concentrations was 1.95 (95% CI 1.39, 2.76) (p for trend <0.0001). During mean follow-up periods of 21.9 ± 7.0 and 23.5 ± 6.1 years, respectively, 702 participants developed diabetes and 651 died from cancer. Prostasin was significantly associated with the incidence of diabetes. The adjusted HR for diabetes in the 4th vs 1st quartile of prostasin concentrations was 1.76 (95% CI 1.41, 2.19) (p for trend <0.0001). Prostasin was also associated with cancer mortality There was a significant interaction between prostasin and fasting blood glucose for cancer mortality risk (p for interaction =0.022), with a stronger association observed in individuals with impaired fasting blood glucose levels at baseline (HR per 1 SD change 1.52; 95% CI 1.07, 2.16; p=0.019). CONCLUSIONS/INTERPRETATION: Plasma prostasin levels are positively associated with diabetes risk and with cancer mortality risk, especially in individuals with high blood glucose levels, which may shed new light on the relationship between diabetes and cancer.

Association of arterial stiffness with coronary artery calcium score in the general-population: the Swedish CArdioPulmonary bioImage study.

OBJECTIVES: Coronary artery calcium score (CACS) is a marker of subclinical atherosclerosis. However, there is little data related to the association between arterial stiffness and CACS in the general population. The aim of this study was to explore the association between carotid femoral-pulse wave velocity (c-f PWV), a widely accepted marker of arterial stiffness, and CACS. METHODS: Participants with complete measurements on c-f PWV, CACS and confounding variables from the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort were included in the final study population (n = 8725). CACS was divided into three categories (<10, >10 and ≤100, and >100) and multinomial logistic regression was performed to explore the association between these categories of CACS and quartiles of c-f PWV, and for per one standard deviation (SD) increment of c-f PWV. RESULTS: CACS ≤10, >10 and ≤100, and >100 were present in 69.3, 17.8 and 12.9% of the study population, respectively. The odds ratio (OR) for CACS >100 for the fourth quartile (Q4) of c-f PWV vs. Q1 (reference category) was 1.62 (95% confidence interval [CI] 1.25-2.12) after adjustments. One standard deviation increase in c-f PWV was independently associated with a higher odds of having a CACS category >100 (OR: 1.25, 95% CI 1.14-1.36) in the final multivariable model. CONCLUSION: c-f PWV is positively associated with increased risk of higher CACS, and can be valuable in identifying individuals at risk for sub-clinical atherosclerosis.http://links.lww.com/HJH/B863.

Triglyceride-glucose (TyG) index is a predictor of arterial stiffness, incidence of diabetes, cardiovascular disease, and all-cause and cardiovascular mortality: A longitudinal two-cohort analysis.

Background: Triglyceride-glucose (TyG) index is a useful low-cost marker of insulin resistance. We aimed to evaluate the association between TyG index and arterial stiffness, incidence of diabetes, adverse cardiovascular outcomes, and all-cause and cardiovascular mortality in two large prospective Swedish cohorts, the Malmö Diet and Cancer Study-Cardiovascular Cohort (MDCS-CV) and the Malmö Preventive Project (MPP). Methods: Association between baseline TyG index and arterial stiffness, measured by carotid femoral pulse wave velocity (c-f PWV), was assessed using linear regression and general linear models, adjusting for covariates. Cox proportional hazard regression was used to assess the association between TyG index and incidence of diabetes, coronary events (CE), stroke, atrial fibrillation (AF), heart failure, and all-cause and cardiovascular mortality. Results: After multivariable adjustment, baseline TyG index was significantly associated with increased arterial stiffness (ß for c-f PWV = 0.61, p = 0.018). Participants in the highest quartile of TyG index vs. lowest quartile had an increased incidence of diabetes (HR: 3.30, 95% CI: 2.47-4.41), CE (HR: 1.53, 95% CI: 1.41-1.68), stroke (HR: 1.30, 95% CI: 1.18-1.44), all-cause mortality (HR: 1.22, 95% CI: 1.16-1.28), and cardiovascular mortality (HR: 1.37, 95% CI: 1.26-1.49) after adjustment for covariates. Per unit increase in TyG index was associated with increased heart failure risk. No significant association was observed for incident AF. Conclusion: Elevated TyG index is positively associated with increased arterial stiffness and increased incidence of diabetes, CE, stroke, and all-cause and cardiovascular mortality. The results suggest that TyG index can potentially be useful in the identification of those at increased long-term risk of adverse health outcomes.

Comparison of risk factors for ischemic stroke and coronary events in a population-based cohort.

BACKGROUND: Although coronary events (CE) and ischemic stroke share many risk factors, there are also some important differences. The aim of this paper was to assess the association of risk factors in relation to incident CE and ischemic stroke and to evaluate the heterogeneity in patterns of risk factors between the two outcomes. METHOD: Traditional risk factors and inflammatory markers associated with coronary events and ischemic stroke were measured in the Malmö Diet and Cancer Cohort (MDCS, n = 26 519), where a total of 2270 incident ischemic stroke and 3087 incident CE occurred during a mean follow up time 19 ± 6 years, and in relation to inflammatory markers in the cardiovascular sub-cohort (MDC-CV, n = 4795). Cox regression analysis was used to obtain hazard ratios. A modified Lunn-McNeil competing risk analysis was conducted to assess the significance of any differences in risk profiles of these outcomes. RESULTS: Most cardiovascular risk factors were associated both with incident CE and ischemic stroke. However, current smoking, ApoB, low ApoA1, male sex and education level of ≤ 9 years of schooling were preferentially associated with CE compared to ischemic stroke. Conversely, age showed a stronger association with ischemic stroke than with CE. CONCLUSION: CE and ischemic stroke have broadly similar risk factors profiles. However, there are some important differential associations, as well as substantial differences in the magnitude of the association. These could reflect the distinct biology of atherogenesis in different vascular beds. The difference in the determinants highlights the importance of looking at CE and ischemic stroke, two manifestations of cardiovascular disease, separately.

Carotid-Femoral Pulse Transit Time Variability Predicted Mortality and Improved Risk Stratification in the Elderly.

[Figure: see text].

The association between carotid-femoral pulse-wave velocity and lung function in the Swedish CArdioPulmonary bioImage study (SCAPIS) cohort.

BACKGROUND: Arterial ageing is characterised by degradation of elastic fibres and increased stiffness of elastic arteries. Although low lung function and arterial stiffness are strongly related to age, the association between lung function and arterial ageing has not been widely explored. We used a large population-based study of 50-64 year olds to assess the association between lung function (measured by spirometry and CO diffusing capacity (DLCO)) and arterial stiffness (measured by carotid-femoral pulse-wave velocity (c-f PWV)). METHODS: Participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort with information on spirometry (n = 8941) and DLCO (n = 8616) were included. General linear models (lung function quartiles) and linear regression was used to determine the association between lung function and c-f PWV. RESULTS: FEV1 (L), FVC (L), DLCO (mmol/(min kPa)) and DLCO/VA (mmol/(min kPa L)) were significantly and inversely associated with c-f PWV after adjustments; mean PWV (m/s) in Q1 (highest lung function) vs Q4: FEV1; 8.45 vs 8.60, p-value 0.001; FVC; 8.45 vs 8.57, p-value 0.018; DLCO; 8.46 vs 8.60, p-value 0.002; and DLCO/VA; 8.47 vs 8.58, p-value 0.001. In sex-stratified analyses, significant findings were reflected for FEV1 and DLCO in men only. The results remained significant for DLCO in all never smokers and in all participants without COPD or airflow limitation on spirometry. CONCLUSIONS: A reduction in spirometry and DLCO is associated with elevated arterial stiffness in middle-aged men. A reduction in DLCO is associated with higher c-f PWV even in never smokers and in those without COPD or airflow limitation on spirometry.

Sex-Specific Associations of Circulating Uric Acid with Risk of Diabetes Incidence: A Population-Based Cohort Study from Sweden.

OBJECTIVE: To explore the longitudinal, as well as sex-specific, associations between circulating uric acid (UA) and diabetes incidence. METHODS: A cohort study of the Malmö Diet Cancer-cardiovascular Cohort (Malmö, Sweden) consisting of 3140 individuals without diabetes at baseline, was followed up until the end of 2018. Incident diabetes cases were identified by linking to local and national diabetes registers. Cox proportional hazard regression was used to assess plasma UA levels in relation to diabetes incidence with adjustment for established confounders. RESULTS: At baseline, with increasing levels of UA, subjects were more likely to be older and have significantly higher body mass index, waist circumference, triglycerides, C-reactive protein, fasting glucose and 2-h plasma glucose postoral glucose tolerance test, and lower levels of high-density lipoprotein. During a mean follow-up period of 8.09±2.24 years, 315 (10.0%) participants developed diabetes, and diabetes incidence rates were 7.89, 9.48 and 18.11 per 1000 person-years for subjects in the 1st, 2nd, and 3rd tertiles of UA, respectively (log-rank test: p<0.001). With adjustment for potential confounders, elevated UA levels were significantly associated with increased risks of diabetes incidence, with the adjusted hazard ratio (HR) (95% confidence interval) for per standard deviation increment of UA of 1.22 (1.08-1.39, p=0.002). Compared with the 1st tertile of UA, the 3rd tertile showed significantly increased risk of diabetes incidence with the adjusted HR of 1.74 (1.24-2.45, p=0.002), and there was a significant trend between increasing tertiles of UA and diabetes incidence (trend test: p<0.001). Stratified analyses showed that elevated circulating UA levels were independently associated with increased risks of diabetes incidence in men but not in women, although the interaction between sex and UA was not statistically significant. CONCLUSION: Elevated circulating UA was independently associated with increased risk of diabetes incidence, especially for men.

Difference in the risk profiles of carotid-femoral pulse wave velocity: results from two community-based studies in China and Sweden.

Carotid-femoral pulse wave velocity (cfPWV) and its risk factors may differ between various populations. Few studies have compared the risk profiles associated with cfPWV in different ethnic populations. The study population included 4321 subjects from Shanghai, China (n = 1272, age 75.0 ± 6.5 years, female 57.3%) and Malmö, Sweden (n = 3049, age 72.5 ± 5.5 years, female 60.4%). cfPWV was measured using the SphygmoCor device in both cohorts, with some difference in the determination of pulse transmission distance. The median cfPWV was 8.9 and 10.1 m/s (P < 0.001) respectively in the Chinese and Swedish subjects. cfPWV was associated (P < 0.05) with age, body mass index (BMI), mean arterial pressure (MAP), heart rate, fasting plasma glucose and serum triglycerides in both populations. The standardized effect size (m/s) associated with age (0.091 vs. 0.048, P < 0.001) and fasting plasma glucose (0.025 vs. 0.012, P = 0.046) was greater in the Swedish than Chinese subjects, whereas those with BMI (0.046 vs. 0.008, P < 0.001), MAP (0.079 vs. 0.067, P = 0.016), and heart rate (0.057 vs. 0.046, P = 0.036) were greater in Chinese. No difference was observed in those associated with serum triglycerides (P = 0.128). cfPWV was additionally associated with sex, serum total cholesterol, and on antihypertensive medication in the Swedish subjects, and with serum uric acid in the Chinese subjects (P ≤ 0.041). In conclusion, Chinese and Swedish subjects shared similar major risk factors of arterial stiffness, but with some differences in the strength of associations.

Circulating HER2/ErbB2 Levels Are Associated With Increased Incidence of Diabetes: A Population-Based Cohort Study.

OBJECTIVE: HER2/ErbB2 is a member of the epidermal growth factor receptor family. It is widely used as a tumor marker, but it also has recently been associated with insulin resistance. Both ErbB2 and diabetes have been associated with cancer; however, the relationship between ErbB2 and diabetes has not been well explored. The aim of this population-based cohort study was to assess the association between plasma ErbB2 and incidence of diabetes. RESEARCH DESIGN AND METHODS: The study population included participants from the Malmö Diet and Cancer-Cardiovascular Cohort (age range 46-68 years). After excluding participants with a history of diabetes and those missing data for ErbB2 and other covariates, the final study population consisted of 4,220 individuals. Incidence of diabetes was followed through linkages to local and national registers. Cox proportional hazards regression was used to assess the incidence of diabetes in relation to quartiles of ErbB2, adjusted for potential confounders. RESULTS: Plasma ErbB2 was significantly and positively associated with glucose, insulin, and HbA1c after being adjusted for potential confounding factors. During a mean ± SD follow-up period of 20.20 ± 5.90 years, 615 participants (14.6%) were diagnosed with new-onset diabetes. Individuals with high levels of ErbB2 had a significantly higher risk of diabetes than those with low levels of ErbB2. The multivariable-adjusted hazard ratio was 1.31 (95% CI 1.03-1.66; P < 0.05) for the highest versus the lowest quartile of ErbB2 and was 1.15 (95% CI 1.05-1.25; P < 0.05) per 1-SD increase in ErbB2. CONCLUSIONS: Elevated levels of ErbB2 are associated with increased incidence of diabetes.

Complement C3 and incident hospitalization due to chronic kidney disease: a population-based cohort study.

BACKGROUND: Circulating C3 has been associated with diabetes and hypertension, which are the leading causes of chronic kidney disease (CKD). C3 activation is considered to contribute to several renal diseases. Here we examined whether elevated C3 concentration is associated with hospitalization due to CKD in the general population, and whether this relationship is mediated by factors such as diabetes and hypertension. METHODS: Baseline plasma C3 was quantified in 4552 participants, without previous hospital admission due to CKD, from the Malmö Diet and Cancer cohort study. Incidence of first hospitalization due to CKD (main diagnosis) was investigated in relation to C3 levels using Cox proportional hazards regression models after a mean follow-up of 19.2 ± 4.16 years. Traditional risk factors of CKD including diabetes, blood pressure, C-reactive protein and baseline renal function were considered in adjustments and sensitivity analyses. RESULTS: During the follow-up period, 94 subjects were admitted to hospital due to CKD. After multivariate adjustment, the hazard ratios (95% confidence interval) for hospitalization from CKD across quartiles of C3 were 1.00 (reference), 1.68 (0.69, 4.13), 2.71 (1.15, 6.39), and 3.16 (1.36, 7.34) (p for trend = 0.003). Results were generally consistent across different sensitivity analyses. CONCLUSIONS: These findings indicate that C3 is associated with incidence of first hospitalization due to CKD in the general population. The observed relationship cannot be entirely attributed to hyperglycemia and hypertension.

Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer-Cardiovascular Cohort.

AIMS/HYPOTHESIS: Growth differentiation factor 15 (GDF-15) is an anti-inflammatory cytokine of the transforming growth factor-ß superfamily. Circulating levels of GDF-15 are associated with hyperglycaemia among people with obesity or diabetes, but longitudinal evidence on the association between GDF-15 levels and diabetes risk is scarce. Our aim was to explore whether circulating levels of GDF-15 at baseline are positively associated with future diabetes incidence in a middle-aged urban population. METHODS: Between 1991 and 1994, baseline fasting plasma GDF-15 levels were measured in 4360 individuals without diabetes (mean age 57.4 ± 5.96 years, 38.6% men) who were participants in the Malmö Diet and Cancer-Cardiovascular Cohort. After a follow-up of 19.0 ± 5.16 years (mean ± SD), Cox proportional hazards regression analysis was used for the study of the relationship between baseline GDF-15 and incident diabetes, with adjustment for established confounders. A sensitivity analysis included further adjustment for levels of C-reactive protein (CRP). RESULTS: During the follow-up period, 621 individuals developed diabetes. The multivariate-adjusted HR for diabetes incidence was 1.43 (95% CI 1.11, 1.83; p for trend = 0.007) for the fourth compared with the first quartile of GDF-15, and was 1.17 (95% CI 1.07, 1.28; p < 0.001) per SD increase of GDF-15. If participants were grouped according to baseline fasting glucose, the association between GDF-15 and diabetes risk was only evident in the group without impaired fasting glucose (n = 3973). The association tended to be less significant with increasing age: multivariate-adjusted HRs for diabetes per SD increase of GDF-15 were 1.24 (95% CI 1.08, 1.42), 1.19 (95% CI 1.00, 1.41) and 1.04 (95% CI 0.89, 1.23) for participants aged ≤55, 56-60 (>55 and ≤60) and >60 years, respectively. With adjustment for levels of CRP, the HR per SD increase of GDF-15 (1.21, 95% CI 1.09, 1.35) was significant (p = 0.015), but the HR for the fourth compared with the first quartile of GDF-15 was not significant (HR 1.30; 95% CI 1.01, 1.67; p for trend = 0.061). CONCLUSIONS/INTERPRETATION: GDF-15 may be useful for identification of people with a risk of incident diabetes, especially if those people are ≤60 years old.

FADD (Fas-Associated Protein With Death Domain), Caspase-3, and Caspase-8 and Incidence of Ischemic Stroke.

Background and Purpose- Apoptosis has been implicated in atherosclerosis and plaque rupture. This population-based study examined the relationship between 3 markers of apoptosis, that is, FADD (Fas-associated protein with death domain), caspase-3, and caspase-8, and incidence of ischemic stroke. Methods- The study population included 4356 participants from the MDCS (Malmö Diet and Cancer Study) cardiovascular cohort, without a history of stroke. Incidence of ischemic stroke was followed by linkages to local and national registers. Cox proportional hazards regression was used to assess the incidence of ischemic stroke in relation to quartiles of FADD, caspase-3, and caspase-8, adjusted for potential confounders. Results- During a mean follow-up period of 19.5±4.9 years, a total of 321 (7.4%) participants were diagnosed with incident ischemic stroke. Individuals with high levels of FADD and caspase-8 had a significantly increased risk of ischemic stroke, after adjustment for potential confounders. The multivariable-adjusted hazard ratios for Q4 versus Q1-Q3 of FADD and caspase-8 were 1.49 (95% CI, 1.18-1.87; P<0.01) and 1.77 (95% CI, 1.41-2.22; P<0.001), respectively. The hazard ratios per 1-SD increment of FADD and caspase-8 were 1.27 (95% CI, 1.14-1.41) and 1.31 (95% CI, 1.18-1.45), respectively. No association was observed for caspase-3 with ischemic stroke. Conclusions- Elevated levels of FADD and caspase-8, but not caspase-3, are associated with increased incidence of ischemic stroke.

Comparing the inflammatory profiles for incidence of diabetes mellitus and cardiovascular diseases: a prospective study exploring the 'common soil' hypothesis.

BACKGROUND: Chronic low-grade inflammation and associated insulin resistance and metabolic abnormalities have been proposed as 'common soil' for diabetes mellitus (DM) and cardiovascular disease (CVD). This paper aimed to investigate the inflammatory profiles of DM and CVD and to distinguish their shared and specific markers. METHODS: Based on the Malmö Diet and Cancer cohort, total and differential leukocyte counts were measured in 25,969 participants without previous DM or CVD and were studied in relation to incident DM (mean follow-up 17.4 ± 5.58 years) and incident CVD (i.e., coronary events, including fatal and nonfatal myocardial infarction, or stroke); mean follow-up 17.7 ± 5.46 years, using multivariable Cox regression models. Furthermore, plasma concentrations of another seven inflammatory markers were examined in relation to incident DM and incident CVD in a sub-cohort of 4658 participants. The associations of each inflammatory marker with incident DM versus incident CVD were compared using the Lunn-McNeil competing risks approach. In sensitivity analyses, those who developed both DM and CVD during follow-up were excluded. RESULTS: After adjustment for conventional risk factors, total and differential leukocyte counts, orosomucoid, and C-reactive protein were associated with an increased risk of both DM and CVD. Neutrophil to lymphocyte ratio, ceruloplasmin, alpha1-antitrypsin and soluble urokinase plasminogen activator receptor predicted increased risk of CVD but not DM, while haptoglobin and complement C3 showed the opposite pattern. In competing risks analyses, lymphocyte count and complement C3 had stronger associations with risk of DM than with risk of CVD (p for equal associations = 0.020 and 0.006). The reverse was true for neutrophil to lymphocyte ratio (p for equal associations = 0.025). Results were consistent in sensitivity analyses. CONCLUSIONS: The results indicated substantial similarities in the inflammatory profiles associated with DM and CVD. However, there are also significant differences. These findings may help discriminate between individuals at elevated risk of DM and those at elevated risk of CVD, which is a prerequisite for targeted therapies.

Complement C3 Associates With Incidence of Diabetes, but No Evidence of a Causal Relationship.

Purpose: This study explored whether complement factor 3 (C3) in plasma is associated with incidence of diabetes in a population-based cohort. We also identified genetic variants related to C3 and explored whether C3 and diabetes share common genetic determinants. Methods: C3 was analyzed in plasma from 4368 nondiabetic subjects, 46 to 68 years old, from the Malmö Diet and Cancer Study. Incidence of diabetes was studied in relationship to C3 levels during 17.7± 4.4 years of follow-up. Genotypes associated with C3 were identified in a genome-wide association study. Diabetes Genetics Replication and Meta-Analysis and the European Genetic Database were used for in silico look-up. Results: In all, 538 (12.3%) subjects developed diabetes during 18 years of follow-up. High C3 was significantly associated with incidence of diabetes after risk factor adjustments (hazard ratio comparing 4th vs 1st quartile, 1.54 (95% confidence interval, 1.13 to 2.09; P = 0.005). C3 was associated with polymorphisms at the complement factor H locus (P < 10-8). However, no relationship with diabetes was observed for this locus. Another eight loci were associated with C3 with P < 10-5. One of them, the glucose kinase regulatory protein (GCKR) locus, has been previously associated with diabetes. The relationship between C3 levels and the GCKR locus was replicated in the European Genetic Database cohort. Conclusions: Plasma concentration of C3 is a risk marker for incidence of diabetes. The results suggest that this association could, in part, be explained by pleiotropic effects related to the GCKR gene.

Arterial Stiffness and Incidence of Diabetes: A Population-Based Cohort Study.

OBJECTIVE: Diabetes is known to be associated with increased arterial stiffness. However, the temporal association between increased carotid-femoral pulse wave velocity (c-f PWV) and diabetes is unclear. The aim of this study is to explore the relationship between arterial stiffness, as determined by c-f PWV, and incidence of diabetes. RESEARCH DESIGN AND METHODS: The study population included participants from the Malmö Diet and Cancer cardiovascular cohort, using measurements from the 2007-2012 reexamination as baseline. Arterial stiffness was evaluated by measuring c-f PWV (SphygmoCor). After excluding participants with prevalent diabetes (according to measurements of fasting glucose, oral glucose tolerance tests, and physician's diagnoses), the final study population consisted of 2,450 individuals (mean age = 71.9 ± 5.6 years). Incidence of diabetes was followed by linkage to local and national diabetes registers. Cox proportional hazards regression was used to assess the incidence of diabetes in relation to the tertiles of c-f PWV, adjusted for potential confounders. RESULTS: During a mean follow-up of 4.43 ± 1.40 years, 68 (2.8%) participants developed diabetes. Crude incidence of diabetes (per 1,000 person-years) was 3.5, 5.7, and 9.5, respectively, for subjects in the first, second, and third tertiles of c-f PWV. After adjustment for potential confounders, the hazard ratio of diabetes was 1.00 (reference), 1.83 (95% CI 0.88-3.8), and 3.24 (95% CI 1.51-6.97), respectively, for the tertiles of c-f PWV (P for trend = 0.002). CONCLUSIONS: Increased c-f PWV is associated with increased incidence of diabetes, independent of other risk factors. These results suggest that increased arterial stiffness is an early risk marker for developing diabetes.

Acute phase proteins as prospective risk markers for arterial stiffness: The Malmö Diet and Cancer cohort.

BACKGROUND AND OBJECTIVES: Arterial stiffness plays a significant role in the development and progression of adverse cardiovascular events and all-cause mortality. This observational study aims to explore the relationship between six acute phase proteins namely, ceruloplasmin, alpha-1-antitrypsin, orosomucoid, haptoglobin, complement C3 and C-reactive protein (CRP), and carotid-femoral pulse wave velocity (c-f PWV) in a population-based cohort, and to also explore the effect of low-grade inflammation on the relationship between diabetes and c-f PWV. METHOD: The study consisted of participants from the Malmö Diet and Cancer study with data from baseline examinations (1991-1994) and follow-up examinations (2007-2012). Arterial stiffness was measured at follow-up by determining c-f PWV. After excluding participants with missing data, the total study population included 2338 subjects. General linear models were used to assess the relationship between baseline acute phase proteins and c-f PWV. RESULTS: After adjusting for traditional risk factors the participants in the 4th quartile vs 1st quartile of alpha-1-antitrypsin (geometric mean: 10.32 m/s vs 10.04 m/s) (p<0.05), C3 (10.35 m/s vs 10.06 m/s) (p<0.05) and CRP (10.37 m/s vs 9.96 m/s) (p<0.001) showed significant association with c-f PWV. Diabetes at follow-up was also associated with high c-f PWV, however, this relationship was independent of low grade inflammation. CONCLUSION: Alpha-1-antitrypsin, C3 and CRP are associated with arterial stiffness. The results indicate that low grade inflammation is associated with arterial stiffness in addition to established cardiovascular risk factors.

Acute-phase proteins and incidence of diabetes: a population-based cohort study.

AIMS: To examine the relationship between plasma levels of the acute-phase proteins ceruloplasmin, alpha-1-antitrypsin, orosomucoid, haptoglobin and C-reactive protein (CRP), and incidence of diabetes in the population-based Malmö Diet and Cancer Study-Cardiovascular Cohort (MDCS-CC). METHODS: The study population consists of 4246 participants (aged 46-67 years, 60.8 % women) with no previous history of diabetes. Participants were followed, and incidence of diabetes was assessed by linkage with national registers and a clinical re-examination of the cohort. Cox proportional hazard regression analysis was used to compare incidence of diabetes in relation to sex-specific quartiles of the acute-phase proteins. RESULTS: During a mean follow-up period of 15.6 ± 3.4 years, a total of 390 participants were diagnosed with diabetes. Orosomucoid, haptoglobin, and CRP showed a significant increased risk of diabetes after adjustment for potential confounders. However, further adjustments for fasting glucose at baseline resulted in significant association only for CRP. The multivariable-adjusted hazard ratios (HR: 4th vs. 1st quartile) were 1.18 (95 % CI: 0.83-1.67; p = 0.51), 1.19 (CI: 0.85-1.62; p = 0.10), and 1.40 (CI: 1.01-1.95; p = 0.046) for orosomucoid, haptoglobin, and CRP respectively. CONCLUSION: The study demonstrated that there are associations between orosomucoid, haptoglobin and CRP and the risk of incidence of diabetes. However, after additional adjustment for fasting glucose levels at baseline, the association stayed significant only for CRP.