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.

A six-month low-carbohydrate diet high in fat does not adversely affect endothelial function or markers of low-grade inflammation in patients with type 2 diabetes: an open-label randomized controlled trial.

BACKGROUND: While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. METHODS: In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (< 20 E% carbohydrates, 50-60 E% fat) or a control diet (50-60 E% carbohydrates, 20-30 E% fat) for six months. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were assessed by ultrasound in the brachial artery together with plasma interleukin-6 (IL-6) and serum high-sensitivity C-reactive protein (hsCRP) in the participants at baseline (n = 70) and after six months (n = 64). RESULTS: The FMD and NID were unaltered in both groups after six months, and there were no between-group differences in change of either FMD (p = 0.34) or NID (p = 0.53) in response to the interventions. The circulating hsCRP and IL-6 levels decreased only in response to LCD (both p < 0.05). However, comparing changes over time with the control diet, the LCD did not reduce either IL-6 (p = 0.25) or hsCRP (p = 0.07) levels. The lack of changes in FMD and NID in response to LCD persisted after adjustment for cardiovascular risk factors. CONCLUSION: A LCD high in fat for six months does not adversely affect endothelial function or selected markers of low-grade inflammation, which suggests that this nutritional approach does not increase the risk of cardiovascular disease. Trial registration ClinicalTrials.gov (NCT03068078).

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.

Long-term weight loss in a 24-month primary care-anchored telehealth lifestyle coaching program: Randomized controlled trial.

Long-term weight loss can reduce the risk of type 2 diabetes for people living with obesity and reduce complications for patients diagnosed with type 2 diabetes. We investigated whether a telehealth lifestyle-coaching program (Liva) leads to long-term (24 months) weight loss compared to usual care. In a randomized controlled trial, n = 340 participants living with obesity with or without type 2 diabetes were enrolled and randomized via an automated computer algorithm to an intervention group (n = 200) or to a control group (n = 140). The telehealth lifestyle-coaching program comprised of an initial one-hour face-to-face motivational interview followed by asynchronous telehealth coaching. The behavioural change techniques used were enabled by individual live monitoring. The primary outcome was a change in body weight from baseline to 24 months. Data were assessed for n = 136 participants (40%), n = 81 from the intervention group and n = 55 from the control group, who completed the 24-month follow-up. After 24 months mean body weight and body mass index were reduced significantly for completers in both groups, but almost twice as much was registered for those in the intervention group which was not significant between groups -4.4 (CI -6.1; -2.8) kg versus -2.5 (CI -3.9; -1.1) kg, P = 0.101. Haemoglobin A1c was significantly reduced in the intervention group -3.1 (CI -5.0; -1.2) mmol/mol, but not in the control group -0.2 (CI -2.4; -2.0) mmol/mol without a significant between group difference (P = 0.223). Low completion was partly due to coronavirus disease 2019. Telehealth lifestyle coaching improve long-term weight loss (> 24 months) for obese people with and without type 2 diabetes compared to usual care.

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.