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

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 Malmo Diet and Cancer Study-Cardiovascular Cohort (MDCS-CV) and the Malmo 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 (beta 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

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

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. Graphical abstract: [Figure not available: see fulltext.

Data_Sheet_1_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.pdf

BackgroundTriglyceride-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).MethodsAssociation 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.ResultsAfter multivariable adjustment, baseline TyG index was significantly associated with increased arterial stiffness (β 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.ConclusionElevated 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.</p

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 &amp;lt; 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 &amp;lt;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.Funding Agencies|Swedish Heart and Lung Foundation [2016- 0315]; Knut and Alice Wallenberg Foundation [2014- 0047]; Swedish Research Council [822- 2013- 2000]; VINNOVA [2012- 04476]; University of Gothenburg and Sahlgrenska University Hospital; Stockholm County Council; Linkoeping University; Lund University; Skane University Hospital; Umea University; Uppsala University; Swedish Heart and Lung Foundation</p

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±5.58years) and incident CVD (i.e., coronary events, including fatal and nonfatal myocardial infarction, or stroke); mean follow-up 17.7±5.46years, 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

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

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 biolmage Study (SCAPIS) cohort were included in the final study population (n=8725). CACS was divided into three categories (&amp;lt;10, &amp;gt;10 and &amp;lt;= 100, and &amp;gt;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 &amp;lt;= 10, &amp;gt;10 and &amp;lt;= 100, and &amp;gt;100 were present in 69.3, 17.8 and 12.9% of the study population, respectively. The odds ratio (OR) for CACS &amp;gt;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 &amp;gt;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.Funding Agencies|Swedish Heart and Lung Foundation [2016-0315]; Knut and Alice Wallenberg Foundation [2014-0047]; Swedish Research Council [822-2013-2000]; VINNOVA (Swedens Innovation agency) [2012-04476]; University of Gothenburg; Swedish Heart Lung foundation; Sahlgrenska University Hospital; Karolinska Institutet; Stockholm county council; Linkoping University; University Hospital; Lund University; Skane University Hospital; Umea University; University Hospital, Uppsala University</p