Low-grade inflammation in persons with recently diagnosed type 2 diabetes: The role of abdominal adiposity and putative mediators.

AIMS: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities. MATERIALS AND METHODS: We measured waist circumference, clinical characteristics, and inflammatory markers i.e. tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), in >9000 persons with recently diagnosed T2D. We applied multiple mediation analysis using structural equation modelling, with adjustment for age and sex. RESULTS: Waist circumference as a proxy for abdominal adiposity was positively associated with all inflammatory markers. Hence, a one-standard deviation (SD) increase in waist circumference (SD = 15 cm) was associated with a 22%, 35%, and 46% SD increase in TNF-α (SD = 1.5 pg/mL), IL-6 (SD = 4.4 pg/mL), and hsCRP (SD = 6.9 mg/L), respectively. The level of hyperinsulinaemia assessed by fasting C-peptide was quantitatively the most important mediator, accounting for 9%-25% of the association between abdominal adiposity and low-grade inflammation, followed by low physical activity (5%-7%) and high triglyceride levels (2%-6%). Although mediation of adiposity-induced inflammation by greater comorbidity and higher glycated haemoglobin levels reached statistical significance, their impact was minor (1%-2%). CONCLUSIONS: In persons with recently diagnosed T2D, there was a clear association between abdominal adiposity and low-grade inflammation. A considerable part (20%-40%) of this association was mediated by other factors, with hyperinsulinaemia as a potentially important driver of adiposity-induced inflammation in T2D.

Triglyceride-glucose index improves risk prediction beyond traditional risk factors and hypertension mediated organ damage in healthy adults.

BACKGROUND AND AIMS: Triglyceride-glucose (TyG) index, a surrogate measure of insulin resistance, is associated with hypertension mediated organ damage (HMOD) and cardiovascular disease. This study investigated the association between TyG index and major adverse cardiovascular events (MACE) and its interaction with traditional risk factors and HMOD. METHODS AND RESULTS: Healthy subjects recruited from the general population were thoroughly examined and followed for MACE using nation-wide registries. Cox proportional hazard models were used to calculate the association between TyG index and MACE occurrence. Models were adjusted for Systematic Coronary Risk Evaluation (SCORE) risk factors, pulse wave velocity, left ventricular mass index, carotid atherosclerotic plaque status, and microalbuminuria. Continuous net reclassification and Harrell's Concordance index (C-index) were used to assess the added prognostic value of TyG index. During a follow-up period of mean 15.4 ± 4.7 years, MACE were observed in 332 (17%) of 1970 included participants. TyG index was associated with MACE; HR = 1.44 [95%CI:1.30-1.59] per standard deviation. After adjustment for traditional cardiovascular (CV) risk factors, HR was 1.16 [95%CI:1.03-1.31]. The association between TyG index and MACE remained significant after further adjustment for each HMOD component. However, this finding was evident only in subjects aged 41 or 51 years (HR = 1.39; 95%CI:1.15-1.69). Including TyG index in a risk model based on traditional CV risk factors improved C-index with 0.005 (P = 0.042). CONCLUSION: In this population-based study of healthy middle-aged subjects, TyG index was associated with MACE independently of traditional CV risk factors and HMOD. TyG index may have a potential role in future risk prediction systems.

Sex- and age-related differences in the predictive capability of circulating biomarkers: from the MONICA 10 cohort.

OBJECTIVES: The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and soluble urokinase plasminogen activator receptor (suPAR) differed in their ability to predict cardiovascular outcomes beyond traditional risk factors in younger and older men and women without known cardiovascular disease. Design. Prospective population-based cohort study of 1951 individuals from the MONItoring of trends and determinants in Cardiovascular disease (MONICA) study, examined 1993-1994. Participants were stratified into four groups based on sex and age. Subjects aged 41 or 51 years were classified as younger; those aged 61 or 71 years were classified as older. The principal endpoint was death from cardiovascular causes. Predictive capabilities of biomarkers were tested using Cox proportional-hazards regression, Harrell's concordance-index, net reclassification improvement, and classification and regression tree (CART) analysis. Results. Median follow-up was 18.5 years, during which 19/597 younger men, 100/380 older men, 12/607 younger women, and 46/367 older women had died from a cardiovascular cause. NT-proBNP was independently associated with death from cardiovascular causes among all participants (p ≤ .02) except younger women (p = .70), whereas hs-CRP was associated with this endpoint in men (p ≤ .007), and suPAR in older men only (p < .001). None of the biomarkers improved discrimination ability beyond traditional risk factors (p ≥ .07). However, NT-proBNP enhanced reclassification in men and older women. CART-analysis showed that NT-proBNP was generally of greater value among men, and suPAR among women. Conclusions. Hs-CRP, NT-proBNP, and suPAR displayed different associations with cardiovascular death among apparently healthy younger and older men and women.

Association between antecedent blood pressure, hypertension-mediated organ damage and cardiovascular outcome.

Purpose: The objective of this study was to test if combining antecedent systolic blood pressure (SBP) with traditional risk factors and hypertension-mediated organ damage (HMOD) improves risk stratification for subsequent cardiovascular disease.Materials and methods: 1910 subjects participated in this study. Antecedent SBP was defined as the average of measurements obtained in 1982 and in 1987. Current SBP was obtained in 1993. HMOD were examined in 1993. HMOD was defined as either atherosclerotic plaque(s), increased pulse wave velocity, increased urine albumin creatinine ratio (above the 90th percentile) or left ventricular hypertrophy. Major adverse cardiovascular events (MACE) including myocardial infarction, cerebrovascular disease, heart failure and arrhythmia were obtained from national registries.Results: Subjects were divided into two age categories: a middle-aged group (aged 41 or 51) and an older group (aged 61 or 71). From 1993 to 2010, 425 events were observed. In multivariable analysis with both current and antecedent SBP adjusted for traditional risk factors, current SBP was associated with each measure of HMOD whilst antecedent SBP was not significantly associated with urine albumin creatinine ratio in the older group, LVMI in the middle-aged group, or the presence of plaque in any of the age groups (all p > 0.15). When current and antecedent SBP were evaluated together, current SBP was not associated with MACE in the middle-aged subgroup [HR = 1.09 (0.96-1.22), p = 0.18] but remained associated with MACE in the older subgroup [HR = 1.21 (1.10-1.34), p < 0.01]. Contrariwise, antecedent SBP was only associated with MACE in the middle-aged subgroup [HR = 1.24 (1.04-1.48), p = 0.02]. Adding antecedent SBP to traditional risk factors did not improve the predictive accuracy of the survival model.Conclusion: In healthy non-medicated middle-aged subjects, antecedent SBP is associated with cardiovascular outcome independently of current BP, traditional risk factors and HMOD. However, improvement in risk stratification seems to be limited.

Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool.

BACKGROUND: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. METHODS: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. RESULTS: Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105 cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92 cm) and 17.5% had CVD (P = 0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112 cm), and 25.5% had CVD (P < 0.0001 vs classical diabetes). CONCLUSIONS: Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis.

Lifestyle and clinical factors associated with elevated C-reactive protein among newly diagnosed Type 2 diabetes mellitus patients: a cross-sectional study from the nationwide DD2 cohort.

BACKGROUND: We aimed to examine the prevalence of and modifiable factors associated with elevated C-reactive Protein (CRP), a marker of inflammation, in men and women with newly diagnosed Type 2 Diabetes mellitus (DM) in a population-based setting. METHODS: CRP was measured in 1,037 patients (57% male) with newly diagnosed Type 2 DM included in the prospective nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. We assessed the prevalence of elevated CRP and calculated relative risks (RR) examining the association of CRP with lifestyle and clinical factors by Poisson regression, stratified by gender. We used linear regression to examine the association of CRP with other biomarkers. RESULTS: The median CRP value was 2.1 mg/L (interquartile range, 1.0 - 4.8 mg/L). In total, 405 out of the 1,037 Type 2 DM patients (40%) had elevated CRP levels (>3.0 mg/L). More women (46%) than men (34%) had elevated CRP. Among women, a lower risk of elevated CRP was observed in patients receiving statins (adjusted RR (aRR) 0.7 (95% confidence interval (CI) 0.6-0.9)), whereas a higher risk was seen in patients with central obesity (aRR 2.3 (95% CI 1.0-5.3)). For men, CRP was primarily elevated among patients with no regular physical activity (aRR 1.5 (95% CI 1.1-1.9)), previous cardiovascular disease (aRR1.5 (95% CI 1.2-1.9) and other comorbidity. For both genders, elevated CRP was 1.4-fold increased in those with weight gain >30 kg since age 20 years. Sensitivity analyses showed consistent results with the full analysis. The linear regression analysis conveyed an association between high CRP and increased fasting blood glucose. CONCLUSIONS: Among newly diagnosed Type 2 DM patients, 40% had elevated CRP levels. Important modifiable risk factors for elevated CRP may vary by gender, and include low physical activity for men and central obesity and absence of statin use for women.

Risk of Diabetic Retinopathy According to Subtype of Type 2 Diabetes.

Type 2 diabetes is a heterogeneous disease that can be subdivided on the basis of ß-cell function and insulin sensitivity. We investigated the presence, incidence, and progression of diabetic retinopathy (DR) according to subtypes of type 2 diabetes. In a national cohort, we identified three subtypes of type 2 diabetes: classical, hyperinsulinemic, and insulinopenic type 2 diabetes, based on HOMA2 measurements. From the Danish Registry of Diabetic Retinopathy we extracted information on level of DR. We used several national health registries to link information on comorbidity, medications, and laboratory tests. We found individuals with hyperinsulinemic type 2 diabetes were less likely to have DR at entry date compared with those with classical type 2 diabetes, whereas individuals with insulinopenic type 2 diabetes were more likely to have DR. In multivariable Cox regression analysis, individuals with hyperinsulinemic type 2 diabetes had a decreased risk of both incidence and progression of DR compared to those with classical type 2 diabetes. We did not find any clear difference in risk of incident or progression of DR in individuals with insulinopenic compared to classical type 2 diabetes. These findings indicate that subcategorization of type 2 diabetes is important in evaluating the risk of DR.

Low Bone Turnover Associates With Lower Insulin Sensitivity in Newly Diagnosed Drug-Naïve Persons With Type 2 Diabetes.

CONTEXT: Bone turnover markers (BTMs) are lower in type 2 diabetes mellitus (T2D). The relationships between bone turnover, ß-cell function, and insulin sensitivity in T2D are uncertain. OBJECTIVE: To investigate if fasting levels of BTMs in persons with T2D are associated with ß-cell function or insulin sensitivity. METHODS: We defined three T2D phenotypes, the insulinopenic (low ß-cell function, high insulin sensitivity), the classical (low ß-cell function, low insulin sensitivity), and the hyperinsulinemic (high ß-cell function, low insulin sensitivity) phenotypes, in the Danish Centre for Strategic Research T2D cohort using the homeostatic model assessment. We selected age- and gender-matched subgroups to represent the three T2D phenotypes, yielding 326 glucose-lowering treatment-naïve persons with T2D. Median values of BTMs between the three T2D phenotypes were compared. Regression models were applied to assess the association between BTMs, ß-cell function, and insulin sensitivity adjusted for potential confounders. RESULTS: Median serum levels of procollagen type I N-terminal propeptide, C-terminal telopeptide of type I collagen, and osteocalcin were higher in the insulinopenic phenotype (52.3 µg/L, IQR 41.6, 63.3; 259.4 ng/L, IQR 163.4, 347.7; and 18.0 µg/L, IQR 14.4, 25.2, respectively) compared with the classical (41.4, IQR 31.0, 51.4; 150.4 IQR 103.5, 265.1; 13.1, IQR 10.0, 17.6, respectively) and the hyperinsulinemic (43.7, IQR 32.3, 57.3; 163.3, IQR 98.9, 273.1; 15.7 IQR 10.2, 20.8, respectively) phenotypes (all P < .01). These differences persisted after adjustment for age, sex, waist to hip ratio, or fasting plasma glucose (P < .01). CONCLUSION: BTMs are lower in newly diagnosed persons with T2D characterized by low insulin sensitivity.

Associations between insulin-like growth factor binding protein-2 and insulin sensitivity, metformin, and mortality in persons with T2D.

AIMS: Serum insulin-like growth factor binding protein-2 (IGFBP-2) is low in persons with type 2 diabetes mellitus (T2D) and possibly regulated by metformin. Counter-intuitively, high IGFBP-2 associates with mortality. We investigated the association between IGFBP-2, metformin-treatment, and indices of insulin sensitivity, and assessed IGFBP-2 in relation to prior comorbidity and mortality during five-year follow-up. METHODS: The study included 859 treatment-naive and 558 metformin-treated persons enrolled in the Danish Centre for Strategic Research in T2D and followed for 4.9 (3.9-5.9) years through national health registries. All proteins were determined in serum collected at enrollment. RESULTS: Following adjustment for age, metformin-treated and treatment-naive persons has similar IGFBP-2 levels. Low IGFBP-2 level was associated with increased BMI, fasting glucose, and C-peptide. IGFBP-2 was higher in the 437 persons who had comorbidities at enrollment than in those with T2D only (343 (213;528) vs. 242 (169;378) ng/mL). During follow-up, 87 persons died, and IGFBP-2 predicted mortality with an unadjusted HR (95% CI) per doubling in IGFBP-2 concentration of 2.62 (2.04;3.37) and a HR of 2.21 (1.61;3.01) following full adjustment. CONCLUSIONS: In T2D, high IGFBP-2 associates with low glucose and insulin secretion, is unaffected by metformin treatment, and associates with risk of prior comorbidity and mortality.

Retinal microvascular markers in type 2 diabetes subphenotypes and latent autoimmune diabetes of adults.

PURPOSE: To estimate if newly diagnosed patients with different subphenotypes of type 2 diabetes (T2DM) or latent autoimmune diabetes of adults (LADA) differ with respect to subclinical retinal microvascular structure or diabetic retinopathy (DR). METHODS: This population-based, cross-sectional study of 340 patients (675 eyes) classified patients with recently diagnosed T2DM in different subphenotypes according to beta cell function and insulin sensitivity in to; classical (n = 218), hyperinsulinaemic (n = 86), insulinopenic (n = 20), or LADA (n = 16). Retinal 6-field images were graded according to the International Clinical DR Severity Scale by a retinal expert. Retinal microvascular structures were analysed in eyes by a semiautomatic software. RESULTS: Median age and duration of diabetes were 58.1 (49.9; 65.5) and 0.9 (0.5; 2.4) years, respectively, and 56.8% were male. In a multivariate linear mixed model regression analysis of eyes without DR (n = 570), there was no statistically significant difference in retinal venular or arteriolar width between subtypes and patients with classical T2DM. In addition, eyes from different subphenotypes did not differ according to vessel density, tortuosity or fractal dimension. In a multivariate logistic regression model adjusted for age, sex, HbA1c, diabetes duration, body mass index, mean arterial blood pressure and history of cardiovascular disease, there was a tendency towards persons with hyperinsulinaemic T2DM to be more likely to have DR (OR 1.97, 95% CI 0.95; 4.09) compared to classical T2DM. CONCLUSION: We found no difference in retinal microvascular structure in patients with newly diagnosed subtypes of T2DM. However, DR may be more prevalent in newly diagnosed patients with hyperinsulinaemic T2DM compared to individuals with classical T2DM.

Risk of severe COVID-19 infection in persons with diabetes during the first and second waves in Denmark: A nationwide cohort study.

Objective: Coronavirus disease-2019 (COVID-19) increases risk of hospitalization and death in diabetes and diabetes-related conditions. We examined the temporal trends in COVID-19-related hospitalization and mortality in the total Danish population by diabetes and diabetes-related conditions in the two first waves of COVID-19 in Denmark. Materials and methods: We identified all persons with diabetes in the whole Danish population using national registries. COVID-19-related risks of hospitalization and death were assessed using Cox regression analysis in wave 1 (1 March-31 August 2020) and wave 2 (1 September 2020-28 February 2021) of the pandemic for persons with (n=321,933) and without diabetes (n=5,479,755). Analyses were stratified according to status of hypertension, obesity, cardiovascular and microvascular disease. Results: The cumulative incidence of COVID-19 hospitalization increased from wave 1 to wave 2 in both persons without (from 4 to 10 in 10,000) and with diabetes (from 16 to 54 per 10,000). The relative risk of hospitalization, however, increased more in patients with diabetes compared to persons without (age-, sex- and co-morbidity-adjusted HR [aHR] 1.40 (95% CI 1.27, 1.55) versus 1.76 (1.65, 1.87), p<0.001 for interaction with wave). The mortality rate, according to the whole population, increased similarly in persons without and with diabetes from wave 1 to wave 2 (from 0.63 to 1.5 versus from 4.3 to 10 in 10,000; aHR 1.65; 1.34, 2.03 and 1.64; 1.43, 1.88). However, when mortality was restricted to the hospitalized population, the crude mortality fell from 26.8% to 19.6% in persons with diabetes, while only a minor decrease was seen in persons without diabetes (from 16.7% to 15.5%). Conclusion: The risk of COVID-19-related hospitalization increased more in persons with than without diabetes from wave 1 to wave 2 of the COVID-19 pandemic in the Danish population. However, mortality according to the whole population did not change, due to reduced mortality among hospitalized persons with diabetes.

Accelerometer-derived physical activity and sedentary behaviors in individuals with newly diagnosed type 2 diabetes: A cross-sectional study from the Danish nationwide DD2 cohort.

Introduction: Habitual physical activity behaviors of individuals with new-onset type 2 diabetes are largely unknown. We aimed to investigate accelerometer-derived physical activity behaviors in individuals with newly diagnosed type 2 diabetes. We also examined sociodemographic and health-related correlates of a high-risk physical activity profile. Methods: This cross-sectional study used data from 768 participants enrolled in an intervention study nested within the Danish Centre for Strategic Research in Type 2 diabetes (DD2) cohort. Physical activity was assessed by 24-h dual monitor accelerometry. Prevalence ratios of having a high-risk physical activity profile were estimated using Poisson regression adjusted for age and sex. Results: Study participants spent on average 9.7 (25th and 75th percentiles, 8.3; 11.1) hours/day sitting, walked for 1.1 (0.8; 1.6) hours/day and accumulated 4,000 (2,521; 5,864) steps/day. Still, 62% met the recommendations for physical activity. Characteristics associated with a high-risk physical activity profile (observed in 24.5% of participants) included older age, higher body mass index (BMI), unemployment, retirement, comorbidities, and current smoking. Hence, participants aged 60-69, 70-79 and 80+ years had prevalence ratios of 2.12 (95% CI 1.31; 3.42), 1.99 (1.18; 3.34) and 3.09 (1.42; 6.75) for a high-risk activity profile, respectively, versus participants <50 years. BMI values of 30-39 and 40+ were associated with 1.83 (1.06; 3.15) and 3.38 (1.88; 6.05) higher prevalence ratios compared to normal-weight. Unemployment or retirement was associated with 1.62 (1.09; 2.41) and 2.15 (1.37; 3.39) times higher prevalence ratios, compared to individuals in the working force. Having a Charlson Comorbidity Index score of 1-2 or 3+ was associated with 1.36 (1.03-1.79) and 1.90 (1.27-1.84) higher prevalence ratios, while current smoking was associated with a prevalence ratio of 1.72 (1.25; 2.35) compared to never smokers. Conclusion: This study shows that 62% of individuals with newly diagnosed type 2 diabetes met the recommendations for physical activity. Still, the majority of participants were also highly sedentary and accumulated very few daily steps, emphasizing the need for focusing on both increasing physical activity and reducing sedentary behaviors in the prevention of diabetes-related complications. Individuals with a high-risk physical activity profile were characterized by more obesity, socioeconomic inequalities, advanced age and comorbidities.Trial registration number: NCT02015130.

Type 2 diabetes classification: a data-driven cluster study of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort.

INTRODUCTION: A Swedish data-driven cluster study identified four distinct type 2 diabetes (T2D) clusters, based on age at diagnosis, body mass index (BMI), hemoglobin A1c (HbA1c) level, and homeostatic model assessment 2 (HOMA2) estimates of insulin resistance and beta-cell function. A Danish study proposed three T2D phenotypes (insulinopenic, hyperinsulinemic, and classical) based on HOMA2 measures only. We examined these two new T2D classifications using the Danish Centre for Strategic Research in Type 2 Diabetes cohort. RESEARCH DESIGN AND METHODS: In 3529 individuals, we first performed a k-means cluster analysis with a forced k-value of four to replicate the Swedish clusters: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild age-related (MARD), and mild obesity-related (MOD) diabetes. Next, we did an analysis open to alternative k-values (ie, data determined the optimal number of clusters). Finally, we compared the data-driven clusters with the three Danish phenotypes. RESULTS: Compared with the Swedish findings, the replicated Danish SIDD cluster included patients with lower mean HbA1c (86 mmol/mol vs 101 mmol/mol), and the Danish MOD cluster patients were less obese (mean BMI 32 kg/m2 vs 36 kg/m2). Our data-driven alternative k-value analysis suggested the optimal number of T2D clusters in our data to be three, rather than four. When comparing the four replicated Swedish clusters with the three proposed Danish phenotypes, 81%, 79%, and 69% of the SIDD, MOD, and MARD patients, respectively, fitted the classical T2D phenotype, whereas 70% of SIRD patients fitted the hyperinsulinemic phenotype. Among the three alternative data-driven clusters, 60% of patients in the most insulin-resistant cluster constituted 76% of patients with a hyperinsulinemic phenotype. CONCLUSION: Different HOMA2-based approaches did not classify patients with T2D in a consistent manner. The T2D classes characterized by high insulin resistance/hyperinsulinemia appeared most distinct.

Impact of age on the association between 24-h ambulatory blood pressure measurements and target organ damage.

OBJECTIVE: The aim of this study was to evaluate the impact of age on the associations between hemodynamic components derived from 24-h ambulatory blood pressure (24-h ABPM) and target organ damage, in apparently healthy, nonmedicated individuals. METHODS: Twenty-four-hour ABPM and target organ damage (left ventricular mass index, pulse wave velocity, urine albumin : creatinine ratio and carotid atherosclerotic plaques) were evaluated in 1408 individuals. Associations were examined in regression models, stratified for age [middle-aged (41 or 51 years) or elderly (61 or 71 years)], and adjusted for sex, smoking status, and total-cholesterol. RESULTS: In middle-aged individuals, an increase of 10 mmHg in 24-h SBP was independently associated with an increase of 3.8 (2.7-4.8) g/m in LVMI. The effect was nearly doubled in the elderly subgroup, where the same increase resulted in an increase in LVMI of 6.3 (5.0-7.6) g/m (P for interaction <0.01). An increase of 10 mmHg of 24-h SBP was associated with a 6.7% increase in pulse wave velocity in middle-aged individuals and with an 9.1% increase in elderly individuals (P for interaction <0.01). An independent association between 24-h ABPM and urine albumin : creatinine ratio was only observed in the elderly subgroup. Associations between the presence of atherosclerotic plaques and components from 24-h ABPM except 24-h DBP were not modified by age (all P for interaction >0.26). CONCLUSION: Age enhances the associations between hemodynamic components obtained from 24-h ABPM and measures of arterial stiffness, microvascular damage, and cardiac structure, but not atherosclerosis.

Impact of Age and Target-Organ Damage on Prognostic Value of 24-Hour Ambulatory Blood Pressure.

Markers of target-organ damage and 24-hour ambulatory blood pressure (BP) measurement improve cardiovascular risk stratification. The prevalence of target-organ damage and raised BP increases with aging. The study aim was to evaluate the impact of age and target-organ damage on the prognostic value of ambulatory BP. Markers of target-organ damage and ambulatory BP were measured in 1408 healthy people aged 41 or 51 (middle-aged group), and 61 or 71 (older group) years. The primary outcome was cardiovascular events after 16 years of follow-up, with data obtained from national registries. The prognostic value of BP was evaluated with Cox regression models, adjusted for traditional risk factors and target-organ damage, including left ventricular mass, pulse wave velocity, carotid plaques, and urine albumin/creatinine ratio. A total of 323 events were observed. In comparison with traditional risk factors, adding systolic BP and presence of target-organ damage improved risk stratification by increasing concordance index from 0.711 to 0.728 (P=0.01). In middle-aged subjects with target-organ damage, increment in pulse pressure (hazard ratio, 1.70; 95% confidence interval, 1.31-2.21; P<0.01) and increment in average real variability (hazard ratio, 1.29; 95% confidence interval, 1.05-1.59; P=0.02) were associated with a greater risk of cardiovascular disease compared with subjects without target-organ damage: hazard ratio, 1.04 (95% confidence interval, 0.74-1.46; P=0.81); P for interaction, 0.02; and hazard ratio, 0.89 (95% confidence interval, 0.69-1.14; P=0.36); P for interaction, 0.01. Target-organ damage may be a marker of individual susceptibility to the harmful effects of pulse pressure and BP variability on the cardiovascular system in middle-aged individuals.

Surfactant protein d deficiency in mice is associated with hyperphagia, altered fat deposition, insulin resistance, and increased basal endotoxemia.

Pulmonary surfactant protein D (SP-D) is a host defence lectin of the innate immune system that enhances clearance of pathogens and modulates inflammatory responses. Recently it has been found that systemic SP-D is associated with metabolic disturbances and that SP-D deficient mice are mildly obese. However, the mechanism behind SP-D's role in energy metabolism is not known.Here we report that SP-D deficient mice had significantly higher ad libitum energy intake compared to wild-type mice and unchanged energy expenditure. This resulted in accumulation but also redistribution of fat tissue. Blood pressure was unchanged. The change in energy intake was unrelated to the basal levels of hypothalamic Pro-opiomelanocortin (POMC) and Agouti-related peptide (AgRP) gene expression. Neither short time systemic, nor intracereberoventricular SP-D treatment altered the hypothalamic signalling or body weight accumulation.In ad libitum fed animals, serum leptin, insulin, and glucose were significantly increased in mice deficient in SP-D, and indicative of insulin resistance. However, restricted diets eliminated all metabolic differences except the distribution of body fat. SP-D deficiency was further associated with elevated levels of systemic bacterial lipopolysaccharide.In conclusion, our findings suggest that lack of SP-D mediates modulation of food intake not directly involving hypothalamic regulatory pathways. The resulting accumulation of adipose tissue was associated with insulin resistance. The data suggest SP-D as a regulator of energy intake and body composition and an inhibitor of metabolic endotoxemia. SP-D may play a causal role at the crossroads of inflammation, obesity, and insulin resistance.