Cardiovascular hormones in the development of type 2 diabetes

Type 2 diabetes and cardiovascular disease (CVD) commonly coexist. Both conditions share many overlapping risk factors, which suggests a shared pathological ground. It is widely known that several hormones regulating cardiovascular function, such as B-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP), endothelin-1 (ET-1), adrenomedullin (ADM), and arginine vasopressin (AVP) are implicated in the development of CVD. Less recognised is the fact that these hormones also have metabolic actions. For example, BNP, ANP and ADM were shown to ameliorate insulin resistance, while ET-1 and AVP could promote insulin resistance and glucose intolerance. Using data from several population-based studies, this doctoral thesis examined the hypothesis that cardiovascular hormones could be implicated in the development of type 2 diabetes. The specific research questions were addressed in three papers constituting the basis of this doctoral thesis. The first paper assessed whether the cardiovascular hormones ANP, ET-1, ADM, and AVP, were associated with impaired glucose metabolism. We found that elevated circulating concentrations of ANP were associated with a lower incidence of type 2 diabetes, while elevated circulating concentrations of AVP were associated with a higher incident prediabetes and type 2 diabetes. We also observed that the elevated circulating concentrations of ET-1 and ADM were associated with an increase in insulin-related traits. In the second paper, we investigated whether the natriuretic peptides BNP and ANP could lower the risk of type 2 diabetes and specifically assessed whether the link between both natriuretic peptides and risk of type 2 diabetes could be modified by the presence of CVD. Our results demonstrate that higher concentrations of BNP and ANP were associated with a lower incidence of type 2 diabetes. Here, using a large sample size, we were able to expand the current knowledge by showing that the inverse association with incident type 2 diabetes for BNP was modified by the presence of CVD, while similar differences were not seen for ANP. Analyses using genetic data further suggest that associations of higher concentrations of both BNP and ANP with a lower incidence of type 2 diabetes could probably be causal. Expanding the results from the first paper, in the third paper we further examined whether ET-1 and ADM could increase the risk of type 2 diabetes. We observed that elevated concentrations of ET-1 and ADM were associated with a higher incidence of type 2 diabetes, but analyses using genetic data suggest a probable causal link for ET-1 only. Furthermore, the findings of this paper provided new evidence that the positive association between ADM and incident type 2 diabetes was more apparent in obese than in non-obese individuals. In summary, this thesis highlights the importance of cardiovascular hormones beyond CVD. The findings suggest that several cardiovascular hormones play important roles in the development of type 2 diabetes and raise the possibility that targeting these cardiovascular hormones might be effective in preventing and managing not only CVD but also type 2 diabetes

Association of C-terminal pro-endothelin-1 with mortality in the population-based KORA F4 study

Introduction: Endothelin-1 and its prohormone C-terminal pro-endothelin-1 (CT-proET-1) have been linked to metabolic alterations, inflammatory responses and cardiovascular events in selected study populations. We analyzed the association of CT-proET-1 with cardiovascular events and mortality, carotid intima-media-thickness as surrogate for early atherosclerotic lesions, biomarkers of subclinical inflammation and adipokines in a population-based study. Methods: The cross-sectional and prospective analyses used data from the KORA F4 study with a median follow-up time of 9.1 (8.8-9.4) years. Data on CT-proET-1 and mortality were available for 1554 participants, data on the other outcomes in subgroups (n = 596-1554). The associations were estimated using multivariable linear regression and Cox proportional hazard models adjusted for sex, age, body mass index, estimated glomerular filtration rate, arterial hypertension, diabetes, low-density and high-density lipoprotein cholesterol, current and former smoking and physical activity. The Bonferroni method was used to correct for multiple testing. Results: In the fully adjusted model, CT-proET-1 was associated with cardiovascular (hazard ratio (HR) per standard deviation increase: 1.66; 95% confidence interval (CI): 1.10-2.51; p = 0.017) and all-cause mortality (HR: 2.03; 95% CI 1.55-2.67; p < 0.001), but not with cardiovascular events, and was inversely associated with the intima-media thickness (β: -0.09 ± 0.03; p = 0.001). CT-proET-1 was positively associated with five out of ten biomarkers of subclinical inflammation and with two out of five adipokines after correction for multiple testing. After inclusion of biomarkers of subclinical inflammation in the Cox proportional hazard model, the association of CT-proET-1 with all-cause mortality persisted (p < 0.001). Conclusion: These results emphasize the complexity of endothelin-1 actions and/or indicator functions of CT-proET-1. CT-proET-1 is a risk marker for all-cause mortality, which is likely independent of vascular endothelin-1 actions, cardiovascular disease and inflammation

Association of circulating MR-proADM with all-cause and cardiovascular mortality in the general population: results from the KORA F4 cohort study

BACKGROUND AND AIM: Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. METHODS: Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8–9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603–1551). RESULTS: MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72–3.26) and 2.31 (1.67–3.20)) and cardiovascular mortality (4.28 (2.19–8.39) and 4.44 (2.25–8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. CONCLUSIONS: We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality

Pengaruh Fraksi Etanol Kelopak Bunga Hibiscus sabdariffa Linn terhadap Lisis Sel Staphylococcus aureus Diamati dengan Scanning Electron Microscope (SEM)

Telah dilakukan uji untuk mengetahui pengaruh fraksi etanol kelopak bunga Hibiscus sabdariffa Linn. terhadap kemungkinan terjadinya lisis sel bakteri Staphylococcus aureus. Fraksi etanol kelopak bunga Hibiscus sabdariffa Linn. diperoleh dari proses ekstraksi dan fraksinasi dengan metode maserasi kinetik secara berturut-turut dengan pelarut n-heksan, diklorometana, dan etanol. Fraksi etanol yang diperoleh ditentukan konsentrasi bunuh minimumnya terhadap bakteri Staphylococcus aureus dengan metode dilusi dan dilanjutkan dengan uji lisis sel bakteri Staphylococcus aureus, diamati dengan scanning electron microscope (SEM). Sebagai kontrol positif digunakan amoksisilin Na. Hasil penelitian menunjukkan bahwa konsentrasi bunuh minimum fraksi etanol kelopak bunga Hibiscus sabdariffa Linn. terhadap Staphylococcus aureus sebesar 15.000 bpj dan tidak menyebabkan terjadinya lisis sel bakteri Staphylococcus aureus

Associations of cardiac stress biomarkers with incident type 2 diabetes and changes in glucose metabolism: KORA F4/FF4 study

Background High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism. Methods We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates. Results During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors. Conclusions High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism

Natriuretic Peptides and Risk of Type 2 Diabetes: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium

OBJECTIVE Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD. RESEARCH DESIGN AND METHODS Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models. RESULTS Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236). CONCLUSIONS NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms