adrenomedullin and Diabetes-Mellitus--Type-2

Pancreatic cancer is a leading cause of cancer-related death. Its diagnosis is often delayed and patients are frequently found to have unresectable disease. Patients diagnosed with new-onset diabetes have an 8-fold risk of harboring pancreatic cancer. Adrenomedullin has been claimed to mediate diabetes in pancreatic cancer. New screening tools are needed to develop an early diagnosis protocol.. Patients aged 45-75 years within 2 years of first fulfilling the ADA criteria for diabetes will be prospectively enrolled in this study. Sepsis, renal failure, microangiopathy, pregnancy, acute heart failure and previous malignancies will be considered as exclusion criteria.. 440 patients diagnosed with new-onset diabetes will be enrolled and divided into 2 groups: one with high adrenomedullin levels and one with low adrenomedullin levels. Patients will undergo 3 years' follow-up to detect pancreatic cancer development.. Identifying a marker for pancreatic cancer among high-risk patients such as new-onset diabetics might lead to the identification of a subpopulation needing to be screened in order to enable early diagnosis and treatment of a highly lethal tumor.. This trial was registered at ClinicalTrials.gov on May 25, 2015 under registration number NCT02456051.

Topics: Adrenomedullin; Age of Onset; Aged; Diabetes Mellitus, Type 2; Early Diagnosis; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms

Topics: Adrenomedullin; Aged; Albuminuria; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycopeptides; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Peptide Fragments; Protein Precursors; Receptors, Urokinase Plasminogen Activator; Risk Factors; Tumor Necrosis Factor-alpha

Vascular calcification (VC) is regarded as an independent risk factor for cardiovascular events in type 2 diabetic patients. Glucose transporter 1 (GLUT1) involves VC. Intermedin/Adrenomedullin-2 (IMD/ADM2) is a cardiovascular protective peptide that can inhibit multiple disease-associated VC. However, the role and mechanism of IMD in diabetic VC remain unclear. Here, we investigated whether IMD inhibits diabetic VC by inhibiting GLUT1.. These findings revealed that IMD exerted its anti-calcification effect by inhibiting GLUT1, providing a novel therapeutic target for diabetic VC.

Topics: Adrenomedullin; Animals; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Fructose; Glucose Transporter Type 1; Glycation End Products, Advanced; Humans; Mice; Myocytes, Smooth Muscle; Peptide Hormones; Rats; Signal Transduction; Vascular Calcification

Patients with diabetes have an increased risk for lower-limb amputation (LLA), but biomarkers to assess risk of LLA are lacking. Adrenomedullin (ADM) is a vasodilator peptide that also plays a role in fluid and electrolyte homeostasis in the kidney, increasing natriuresis and diuresis. ADM was shown to be associated with cardiovascular and renal events in diabetes, but it was not investigated in terms of LLA risk. We investigated the hypothesis that ADM is associated with LLA in people with type 2 diabetes.. We studied 4,375 participants in the DIABHYCAR and SURDIAGENE cohorts (men, 68%; mean 66 years of age; mean duration of diabetes 12 years; and median follow-up 5.3 years). Plasma midregional proadrenomedullin (MR-proADM; a surrogate for ADM) was measured by immunofluorescence. Five single nucleotide polymorphisms (SNPs) in the ADM gene region were genotyped.. LLA requirement during follow-up by increasing tertiles of plasma MR-proADM distribution was 1.0% (tertile 1 [T1]), 2.3% (T2), and 4.4% (T3) (P < 0.0001). In Cox multivariate analysis, the adjusted hazard ratio (95% CI) for LLA was 4.40 (2.30-8.88) (P < 0.0001) for T3 versus T1. Moreover, MR-proADM significantly improved indices for risk stratification of LLA. Four SNPs were associated with plasma MR-proADM concentration at baseline and with LLA during follow-up. Alleles associated with higher MR-proADM were associated with increased LLA risk.. We observed associations of plasma MR-proADM with LLA and of ADM SNPs with plasma MR-proADM and with LLA in people with type 2 diabetes. This pattern of Mendelian randomization supports the causality of the association of ADM with LLA.

Topics: Adrenomedullin; Alleles; Amputation, Surgical; Biomarkers; Child; Diabetes Mellitus, Type 2; Humans; Male; Prognosis

Endothelin-1 (ET-1) and adrenomedullin (ADM) are commonly known as vasoactive peptides that regulate vascular homeostasis. Less recognised is the fact that both peptides could affect glucose metabolism. Here, we investigated whether ET-1 and ADM, measured as C-terminal-proET-1 (CT-proET-1) and mid-regional-proADM (MR-proADM), respectively, were associated with incident type 2 diabetes.. Based on the population-based Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium data, we performed a prospective cohort study to examine associations of CT-proET-1 and MR-proADM with incident type 2 diabetes in 12,006 participants. During a median follow-up time of 13.8 years, 862 participants developed type 2 diabetes. The associations were examined in Cox proportional hazard models. Additionally, we performed two-sample Mendelian randomisation analyses using published data.. CT-proET-1 and MR-proADM were positively associated with incident type 2 diabetes. The multivariable hazard ratios (HRs) [95% confidence intervals (CI)] were 1.10 [1.03; 1.18], P = 0.008 per 1-SD increase of CT-proET-1 and 1.11 [1.02; 1.21], P = 0.016 per 1-SD increase of log MR-proADM, respectively. We observed a stronger association of MR-proADM with incident type 2 diabetes in obese than in non-obese individuals (P-interaction with BMI < 0.001). The HRs [95%CIs] were 1.19 [1.05; 1.34], P = 0.005 and 1.02 [0.90; 1.15], P = 0.741 in obese and non-obese individuals, respectively. Our Mendelian randomisation analyses yielded a significant association of CT-proET-1, but not of MR-proADM with type 2 diabetes risk.. Higher concentrations of CT-proET-1 and MR-proADM are associated with incident type 2 diabetes, but our Mendelian randomisation analysis suggests a probable causal link for CT-proET-1 only. The association of MR-proADM seems to be modified by body composition.

Topics: Adrenomedullin; Biomarkers; Diabetes Mellitus, Type 2; Endothelin-1; Heart Disease Risk Factors; Humans; Obesity; Peptide Fragments; Prospective Studies; Protein Precursors

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.. 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.. 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.. 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.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Germany; Glycopeptides; Heart Diseases; Humans; Incidence; Insulin Resistance; Male; Middle Aged; Peptide Fragments; Prediabetic State; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors; Time Factors

Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D.. We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6-17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP.. A total of 126 CV events occurred (median follow-up 4.8 [4.1-5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89-202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64-4.00] and 3.32 [1.64-6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32-56] pmol/l) did not have an increased risk (HR 2.18 [0.78-6.14]).. Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

Topics: Adrenomedullin; Aged; Biomarkers; Cardiovascular Diseases; Denmark; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Incidence; Male; Middle Aged; Peptide Fragments; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Assessment; Risk Factors; Stroke Volume; Up-Regulation; Ventricular Function, Left

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is the gold standard prognostic biomarker for diagnosis and occurrence of heart failure. Here, we compared its prognostic value for the occurrence of congestive heart failure with that of plasma mid-region pro-adrenomedullin (MR-proADM), a surrogate for adrenomedullin, a vasoactive peptide with vasodilator and natriuretic properties, in people with type 2 diabetes.. Plasma MR-proADM concentration was measured in baseline samples of a hospital-based cohort of consecutively recruited participants with type 2 diabetes. Our primary endpoint was heart failure requiring hospitalisation.. We included 1438 participants (age 65 ± 11 years; 604 women and 834 men). Hospitalisation for heart failure occurred during follow-up (median 64 months) in 206 participants; the incidence rate of heart failure was 2.5 (95% CI 2.2, 2.9) per 100 person-years. Plasma concentrations of MR-proADM and NT-proBNP were significantly associated with heart failure in a Cox multivariable analysis model when adjusted for age, diabetes duration, history of coronary heart disease, proteinuria and baseline eGFR (. MR-proADM is a prognostic biomarker for heart failure in people with type 2 diabetes but gives no significant complementary information on prediction of heart failure compared with NT-proBNP.

Topics: Adrenomedullin; Aged; Biomarkers; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neuropeptides; Peptide Fragments; Prognosis; Prospective Studies

We explored the prognostic value of three circulating candidate biomarkers-midregional-proadrenomedullin (MR-proADM), soluble tumor necrosis factor receptor 1 (sTNFR1), and N-terminal prohormone brain natriuretic peptide (NT-proBNP)-for change in renal function in patients with type 2 diabetes.. Outcomes were defined as renal function loss (RFL), ≥40% decline of estimated glomerular filtration rate (eGFR) from baseline, and rapid renal function decline (RRFD), absolute annual eGFR slope <-5 mL/min/year. We used a proportional hazard model for RFL and a logistic model for RRFD. Adjustments were performed for established risk factors (age, sex, diabetes duration, HbA. Among 1,135 participants (mean eGFR 76 mL/min, median uACR 2.6 mg/mmol, and median GFR slope -1.6 mL/min/year), RFL occurred in 397, RRFD developed in 233, and 292 died during follow-up. Each biomarker predicted RFL and RRFD. When combined, MR-proADM, sTNFR1, and NT-proBNP predicted RFL independently from the established risk factors (adjusted hazard ratio 1.59 [95% CI 1.34-1.89],. In addition to established risk factors, MR-proADM, sTNFR1, and NT-proBNP improve risk prediction of loss of renal function in patients with type 2 diabetes.

Topics: Adrenomedullin; Aged; Albumins; Biomarkers; Body Mass Index; Creatinine; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; France; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Function Tests; Logistic Models; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prognosis; Proportional Hazards Models; Prospective Studies; Receptors, Tumor Necrosis Factor, Type I; Risk Factors

To assess vitreous and plasma changes of vascular endothelial growth factor A (VEGF-A), adrenomedullin (ADM) and endothelin-1 (ET-1) in proliferative diabetic retinopathy (PDR).. 9 patients with PDR in type 2 diabetes (T2DM) and 11 age-matched non-diabetic patients were enrolled. The levels of VEGF-A, ADM and ET-1 were measured using an enzyme (ELISA) and a radioimmunoassay (RIA) both in vitreous and plasma samples.. Vitreous ADM and VEGF-A levels were significantly higher in PDR patients (p=0.04 and p=0.02), whereas no differences were found in ET-1 levels (p=0.29). Plasma ADM levels were significantly higher in the PDR group (p<0.01), whereas no significant differences were found in the plasma ET-1 and VEGF-A levels (p=0.30 and p=0.37). The ADM vitreous/plasma ratio was significantly reduced in PDR group.. The role of ET-1 in advanced PDR is still controversial; it has been supposed a role limited to induce hypoxic state and promote angiogenesis in the early phases. Once the neo-angiogenic process starts, other mediators are mainly involved as VEGF and ADM. Our findings suggest that ADM is an important marker of advanced PDR as well as VEGF. Conversely, ET-1 is not significantly involved in the advanced stage of PDR.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Vascular Endothelial Growth Factor A; Vitreous Body

The exact mechanism of premature atherosclerosis in diabetes is still unclear. Inappropriate activation of the renin-aldosterone-angiotensin system may be an important risk factor for cardiovascular disease. We investigated whether renin and aldosterone are associated with vasoactive peptides midregional-pro atrial natriuretic peptide (MR-proANP) and midregional-pro adrenomedullin (MR-proADM), or with intima media thickness (IMT) as a marker for early atherosclerotic alterations in the general community and in subjects with type 2 diabetes.. In 1261 participants in the KORA F4 study, the associations of renin, aldosterone and aldosterone to renin ratio with MR-proANP, MR-proADM and IMT were assessed using linear regression models stratified for the presence of prediabetes and type 2 diabetes.. After adjustment for confounding factors, an inverse association of MR-proANP with renin (p = 0.002) and aldosterone (p = 0.021) and a direct association of MR-proADM with renin (p < 0.001) and aldosterone (p = 0.019) were seen in nondiabetic individuals. In diabetic subjects, there was no significant correlation of MR-proANP or MR-proADM with renin or aldosterone. Renin and aldosterone were not directly associated with IMT in non-diabetic subjects and the total cohort, whereas aldosterone was associated with IMT in diabetic participants (p = 0.005).. This study shows associations between renin, aldosterone and MR-proANP/MR-proADM plasma levels that are altered in type 2 diabetes. Plasma renin and aldosterone are not independent biomarkers for early atherosclerotic damages of the carotid arteries in the general community.

Topics: Adrenomedullin; Adult; Aged; Aldosterone; Anthropometry; Biomarkers; Carotid Arteries; Carotid Intima-Media Thickness; Cohort Studies; Diabetes Mellitus, Type 2; Disease Progression; Female; Glucose Tolerance Test; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Peptide Fragments; Prediabetic State; Protein Precursors; Renin; Risk Factors

Production of adrenomedullin (ADM), a vasodilator peptide, increases in response to ischemia and hypoxia in the vascular wall and the kidney. This may be an adaptive response providing protection against organ damage. We investigated the hypothesis that ADM has a nephroprotective effect in two prospective cohorts of patients with type 2 diabetes recruited in France. The highest tertile of plasma MR-proADM (a surrogate for ADM) concentration at baseline was associated with the risk of renal outcomes (doubling of plasma creatinine concentration and/or progression to end-stage renal disease) during follow-up in both cohorts. Four SNPs in the ADM gene region were associated with plasma MR-proADM concentration at baseline and with eGFR during follow-up in both cohorts. The alleles associated with lower eGFR were also associated with lower plasma MR-proADM level. In conclusion, plasma MR-proADM concentration was associated with renal outcome in patients with type 2 diabetes. Our data suggest that the ADM gene modulates the genetic susceptibility to nephropathy progression. Results are consistent with the hypothesis of a reactive rise of ADM in diabetic nephropathy, blunted in risk alleles carriers, and with a nephroprotective effect of ADM. A possible therapeutic effect of ADM receptor agonists in diabetic renal disease would be worth investigating.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Cohort Studies; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Genetic Predisposition to Disease; Genetic Variation; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peptide Fragments; Prospective Studies; Protein Precursors; Renal Insufficiency, Chronic

The midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patients with type 2 diabetes treated in primary care.. Patients with type 2 diabetes participating in the observational Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study were included. Cox regression analyses were used to assess the relation of baseline MR-proADM with new-onset albuminuria and CV and all-cause mortality. Risk prediction capabilities of MR-proADM for new-onset albuminuria and CV and all-cause mortality were assessed with Harrell's C and the integrated discrimination improvement.. In 1,243 patients (mean age 67 [±12] years), the median follow-up was 5.6 years (interquartile range 3.1-10.1); 388 (31%) patients died, with 168 (12%) CV deaths. Log2 MR-proADM was associated with CV (hazard ratio 1.96 [95% CI 1.27-3.01]) and all-cause mortality (1.78 [1.34-2.36]) after adjusting for age, sex, BMI, smoking, systolic blood pressure, cholesterol-to-HDL ratio, duration of diabetes, HbA1c, ACE inhibitor/angiotensin receptor blocker, history of CV diseases, log serum creatinine, and log albumin-to-creatinine ratio. MR-proADM slightly improved mortality risk prediction. The age- and sex-adjusted, but not multivariate-adjusted, MR-proADM levels were associated with new-onset albuminuria.. MR-proADM was associated with CV and all-cause mortality in patients with type 2 diabetes after a median follow-up of 5.6 years. There was no independent relationship with new-onset albuminuria. In the availability of an extensive set of risk factors, there was little added effect of MR-proADM in risk prediction of CV and all-cause mortality.

Topics: Adrenomedullin; Aged; Albuminuria; Biomarkers; Blood Pressure; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Netherlands; Peptide Fragments; Prognosis; Protein Precursors; Risk Factors

To evaluate the significance of plasma adrenomedullin and calcitonin gene-related peptide (CGRP) concentration in patients with Type 2 diabetes mellitus who are treated for hypertension and dyslipidemia.. Plasma adrenomedullin and CGRP concentration, transthoracal echocardiography and ABPM were evaluated in 82 patients with Type 2 diabetes mellitus and 41 control subjects with no previous cardiovascular disease. All the subjects had casual blood pressure ≤140/90 mmHg or received antihypertensive medication, were treated by statin if LDL cholesterol was≥3mmol/L, by fibrates if triacylglyceroles≥2 mmol/L.. The mean age was 61±6 in patients with diabetes mellitus and 61±5 years in control subjects (p=0.9). Plasma CGRP was 3.0±1.8 in patients with diabetes mellitus and 2.3±1.0 ng/ml in control subjects (p=0.09). Plasma adrenomedullin was 2.2±0.9 in patients with diabetes mellitus and 2.8±1.1 ng/ml in control subjects (p=0.01). In patients with diabetes mellitus mass index of the left ventricle was significantly higher and the parameters of diastolic function were more deteriorated. Plasma adrenomedullin and CGRP correlated significantly negatively with serum creatinine and positively with mean 24 hours arterial blood pressure in patients with diabetes mellitus but not in control subjects. Plasma adrenomedullin concentration in patients with diabetes mellitus treated for hypertension was significantly reduced.. Despite concentration plasma adrenomedullin and CGRP modulation by cardioprotective treatment both neuropeptides remained involved in regulation of hemodynamic and metabolic parameters in patients with Type 2 diabetes mellitus. The low plasma of adrenomedullin in patients with Type 2 diabetic may be marker of the efficient intervention on cardiovascular risk factors.

Topics: Adrenomedullin; Aged; Antihypertensive Agents; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Dyslipidemias; Female; Humans; Hypertension; Hypolipidemic Agents; Male; Middle Aged; Prognosis; Risk Factors

Progressive micro-vascular vaso-degeneration is the major factor in progression of diabetic complications. Adrenomedullin (AM) and basic-Fibroblast growth factor (b-FGF) are strongly correlated with angiogenesis in vascular diseases. This study aims to provide base line data regarding the vascular effects and correlation of AM, and b-FGF with the peripheral blood flow in diabetic patients with peripheral vascular disease (PVD), and their effect on endothelial dysfunction markers. Ninety age- and sex matched females were enrolled in the study: 30 were controls, 30 had diabetes without complications (group II) and 30 had diabetes with PVD (group III) diagnosed by ankle/ brachial index (A/BI). Plasma levels of AM, b-FGF, intercellular adhesion molecule -1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured by indirect enzyme immunoassay (ELISA).. There was a significant increase in plasma AM, VCAM-1and ICAM-1, while a significant decrease in plasma b-FGF in diabetic patients with PVD (p < 0.05). A positive correlation was observed between plasma AM, b-FGF and A/BI and a negative correlation with VCAM -1 and ICAM in diabetic PVD. AM was not a predictor, while b-FG, VCAM-1 and ICAM-1 could be predictors for peripheral blood flow in diabetic PVD.. This study elucidates for the first time that AM and b-FGF are correlated and have a direct impact on the peripheral blood flow, the rise of AM in diabetic PVD may be a consecutive and compensatory vasculo-protective effect as its angiogenic and anti-inflammatory properties act to relief the endothelial insult. Down expression of b-FGF may be a predisposing factor for micro-vascular derangement. It is not clear if the rise of AM and the decline of b- FGF levels may be consequences or predisposing factors for VCAM-1 and ICAM-1 elevation as these endothelial dysfunction biomarkers could reduce peripheral blood flow and vascular integrity. It is optimistic to believe that drug intervention through AM and b-FGF administration together with reversing the endothelial inflammatory process by targeting VCAM and ICAM could reduce the prevalence of diabetic vascular complications, reduce the risk of cerebrovascular and cardiovascular morbidity in diabetes through normalizing vascular endothelium function and peripheral blood flow.

Topics: Adrenomedullin; Ankle Brachial Index; Arteries; Biomarkers; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factor 2; Humans; Intercellular Adhesion Molecule-1; Middle Aged; Peripheral Vascular Diseases; Regional Blood Flow; Saudi Arabia; Vascular Cell Adhesion Molecule-1

Adrenomedullin, an antimicrobial peptide, has biological applications in many tissues, but its main attribute is its ability to lower arterial pressure. The plasma adrenomedullin level is elevated in pathophysiological conditions such as arterial hypertension, acute coronary syndrome, renal diseases, diabetes mellitus and periodontal diseases. The aim of this study was to compare the amounts of adrenomedullin in the gingival crevicular fluid of periodontally healthy individuals, individuals with chronic periodontitis, periodontally healthy individuals with diabetes mellitus type 2 and individuals with chronic periodontitis and diabetes mellitus type 2.. Eighty-four individuals were included in this study: 21 periodontally healthy individuals; 21 individuals with chronic periodontitis; 21 periodontally healthy individuals with diabetes mellitus type 2; and 21 individuals with chronic periodontitis and diabetes mellitus type 2. An ELISA was performed to measure the adrenomedullin levels in gingival crevicular fluid.. Groups with diabetes mellitus type 2 (periodontally healthy individuals and individuals with chronic periodontitis) had significantly higher periodontal clinical indices than did nondiabetes mellitus groups (periodontally healthy individuals and individuals with chronic periodontitis). The group of individuals with chronic periodontitis and diabetes mellitus type 2 had a significantly higher total adrenomedullin level compared with the other groups. Also, a significantly higher total adrenomedullin level was found in diabetes mellitus type 2 groups (periodontally healthy individuals and individuals with chronic periodontitis) compared with nondiabetes mellitus groups (periodontally healthy individuals and individuals with chronic periodontitis).. An increased adrenomedullin level was found in individuals with chronic periodontitis and also in individuals with diabetes mellitus. It is thought that the effect of diabetes mellitus on the pathogenesis of chronic periodontitis could have been achieved through antimicrobial peptides such as adrenomedullin, or that increased adrenomedullin was released in individuals with diabetes mellitus in order to ensure no further periodontal tissue loss.

Topics: Adrenomedullin; Adult; Antimicrobial Cationic Peptides; Case-Control Studies; Chronic Periodontitis; Diabetes Mellitus, Type 2; Female; Gingival Crevicular Fluid; Humans; Male; Middle Aged; Statistics, Nonparametric

To examine concentrations of three cardiovascular propeptides in umbilical cord plasma of neonates born to mothers with Type 1, Type 2 and gestational diabetes. Measurement of cardiovascular markers in umbilical cord plasma may potentially help identify neonates at risk of postnatal complications. Neonates born to mothers with diabetes have an increased risk of neonatal morbidity and mortality, and measurement of these new biomarkers may potentially help identify neonates at risk of these complications.. Copeptin, midregional proadrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) were measured in cord plasma of neonates (n = 63) born to mothers with the three types of diabetes. Associations with maternal glycemic control, mode of delivery and neonatal metabolic acidosis were examined.. Umbilical cord plasma copeptin concentrations were lowest in neonates after elective cesarean sections (6.1 pmol/l; interquartile range [IQR]: 4.5-9.1) compared with emergency cesarean sections (156 pmol/l; IQR: 9.6-311; p = 0.019) and vaginal delivery (831 pmol/l; IQR: 107-2407; p < 0.0001). MR-proADM was also affected by mode of delivery; however, this seemed more likely to be caused by an inverse association with the acid-base balance. In this population, only MR-proANP plasma concentrations were related to type of diabetes. Neonates born to mothers with Type 1 diabetes had higher concentrations (median 260 pmol/l; IQR: 222-318) compared with Type 2 diabetes (175 pmol/l; IQR: 169-200; p = 0.003) and gestational diabetes (200 pmol/l; IQR: 149-276; p = 0.009).. Umbilical cord plasma copeptin and MR-proADM concentrations primarily reflect perinatal stress associated with mode of delivery and the degree of fetal acidosis, whereas MR-proANP concentrations are higher in neonates born to mothers with Type 1 diabetes.

Topics: Acidosis; Adrenomedullin; Adult; Atrial Natriuretic Factor; Biomarkers; Delivery, Obstetric; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fetal Blood; Glycopeptides; Humans; Infant, Newborn; Maternal-Fetal Relations; Pregnancy; Protein Precursors; Stress, Psychological

New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer.. Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls).. Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not.. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.

Topics: Adenocarcinoma; Adrenomedullin; Aged; Animals; Cell Line, Tumor; Cells, Cultured; Diabetes Mellitus, Type 2; Female; Glucose; Humans; In Vitro Techniques; Insulin; Insulin Resistance; Insulin-Secreting Cells; Male; Mice; Mice, Nude; Middle Aged; Models, Animal; Pancreas; Pancreatic Neoplasms; Rats; RNA, Small Interfering; Transplantation, Heterologous; Up-Regulation

To evaluate whether plasma adrenomedullin is involved in the previously reported significant inverse correlation between left ventricular (LV) end-diastolic pressure (peak velocity of early transmitral flow/peak velocity of early diastolic mitral annular motion ratio [E/E' ]) and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus, mild-to-moderate renal function impairment and LV relaxation impairment (E'≤7.1 cm/s).. Plasma adrenomedullin concentration, E/E' and eGFR were assessed in 82 patients with type 2 diabetes.. Plasma adrenomedullin concentration was positively correlated with eGFR in patients with or without LV relaxation impairment, and inversely correlated with E/E' in patients with LV relaxation impairment. Multivariate linear regression analysis supported a role for plasma adrenomedullin in the association between E/E' and eGFR.. These results support the hypothesis that adrenomedullin modulates the interaction between the heart and kidneys in early subclinical cardiorenal syndrome in patients with type 2 diabetes mellitus.

Topics: Adrenomedullin; Aged; Cardio-Renal Syndrome; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Ventricular Dysfunction, Left

Autonomic nervous system dysfunction is observed in Type 2 diabetes. As gestational diabetes is a potent risk factor of later Type 2 diabetes, we set out to determine whether autonomic nervous system imbalance could already be observed in women with this condition. Because activity of the sympathetic nervous system tends to be relatively stable in the nocturnal hours, we performed the study at night.. We studied 41 women with gestational diabetes, 22 healthy pregnant controls and 14 non-pregnant controls. We assayed plasma noradrenaline at 24.00, 04.00 and 07.00 h and performed an overnight Holter recording for heart rate variability analysis. In addition, we assayed plasma adrenomedullin, a cardiovascular protective hormone.. Compared with non-pregnant controls, plasma noradrenaline levels were increased at 04.00 and 07.00 h in the gestational diabetic (P = 0.003) and pregnant control (P = 0.002) groups, with no difference between them. Heart rate variability, very-low-frequency and low-frequency power were lower in pregnant groups compared to the non-pregnant controls. Heart rate variability remained unchanged between specified sampling times in the gestational diabetic group, in contrast to fluctuation seen in the control groups.. Gestational diabetes, compared with normal pregnancy, seems not to be a state of overall sympathetic nervous system activation. At the heart level, however, an inhibitory effect on autonomic nervous system modulation was seen. Plasma noradrenaline and heart rate variability correlated well, supporting the use of this function in future studies of overall sympathetic activity during pregnancy.

Topics: Adrenomedullin; Adult; Autonomic Nervous System; Blood Pressure; Catecholamines; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diabetic Angiopathies; Female; Heart Rate; Humans; Pregnancy

The increased cardiovascular risk in diabetes has been linked to endothelial and renal dysfunction. The aim of this study was to investigate the role of stable fragments of the precursors of adrenomedullin, endothelin-1, vasopressin, and atrial natriuretic peptide in progression of cardiovascular disease in patients with diabetes.. This was a prospective, observational study design with a composite end point (death or unexpected admission to hospital due to a cardiovascular event) on 781 patients with type 2 diabetes (54 events, median duration of observation 15 months). The four stable precursor peptides midregional adrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), COOH-terminal proendothelin-1 (CT-proET-1), and COOH-terminal provasopressin or copeptin (CT-proAVP) were determined at baseline, and their association to renal function and cardiovascular events was studied using stepwise linear and Cox logistic regression analysis and receiver operating characteristic analysis, respectively.. MR-proADM, CT-proET-1, CT-proAVP, and MR-proANP were all elevated in patients with future cardiovascular events and independently correlated to serum creatinine. MR-proADM and MR-proANP were significant predictors of a future cardiovascular event, with MR-proANP being the stronger (area under the curve 0.802 +/- 0.034, sensitivity 0.833, specificity 0.576, positive predictive value 0.132, and negative predictive value 0.978 with a cutoff value of 75 pmol/l).. The four serum markers of vasoactive and natriuretic peptides are related to both kidney function and cardiovascular events, thus linking two major complications of diabetes, diabetic nephropathy and cardiovascular disease.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Cardiovascular Diseases; Creatinine; Diabetes Mellitus, Type 2; Endothelin-1; Female; Glycopeptides; Humans; Kidney; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Protein Precursors

We investigated the effects of chronic simvastatin treatment on the impaired endothelium-dependent relaxation seen in aortas from type 2 diabetic mice. Starting at 8 weeks of diabetes, simvastatin (10 mg/kg per day) was administered to diabetic mice for 4 weeks. The significantly elevated systolic blood pressure in diabetic mice was normalized by simvastatin. Aortas from diabetic mice, but not those from simvastatin-treated diabetic mice, showed impaired endothelium-dependent relaxation in response to both clonidine and adrenomedullin. After preincubation with an Akt inhibitor, these relaxations were not significantly different among the three Akt inhibitor-treated groups (controls, diabetics, and simvastatin-treated diabetics). Although clonidine-induced NO(x)(-) (NO(2)(-) + NO(3)(-)) production was greatly attenuated in our diabetic model, it was normalized by simvastatin treatment. The expression levels of both total Akt protein and clonidine-induced Ser-473-phosphorylated Akt were significantly decreased in diabetic aortas, while chronic simvastatin administration improved these decreased levels. The expression level of clonidine-induced phosphorylated PTEN (phosphatase and tensin homolog deleted on chromosome ten) was significantly increased in diabetic aortas, but chronic simvastatin did not affect it. These results strongly suggest that simvastatin improves the endothelial dysfunction seen in type 2 diabetic mice via increases in Akt and Akt phosphorylation.

Topics: Adrenomedullin; Animals; Aorta; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Clonidine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Endothelium, Vascular; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin; Male; Mice; Mice, Inbred ICR; Nitrates; Nitrites; Nitroprusside; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Simvastatin; Vasodilation; Vasodilator Agents

Subjects with type 2 diabetes are at risk for vascular injury. Several vasoactive factors (e.g., angiotensin) have been implicated. We hypothesize that adrenomedullin, a novel vascoactive factor, is deranged in subjects with type 2 diabetes.. Using a new immunoluminometric method, plasma midregional proadrenomedullin (MR-proADM) was measured in four groups of Chinese subjects: healthy (n = 100, fasting plasma glucose [FPG] <5.6 mmol/l), impaired fasting glucose (IFG) (n = 60, FPG 5.6-6.9 mmol/l), and diabetic subjects with (n = 100) and without (n = 100) nephropathy. Resting forearm cutaneous microcirculatory perfusion (RCMP) was quantified in vivo using 2-dimensional laser Doppler flowmetry. We investigated the relationship between plasma MR-proADM concentrations, multiple metabolic factors, and vascular function.. We observed a stepwise increase in MR-proADM among the groups: healthy group mean +/- SD 0.27 +/- 0.09, IFG group 0.29 +/- 0.13, diabetic group 0.42 +/- 0.13, and diabetic nephropathy group 0.81 +/- 0.54 nmol/l (diabetic vs. healthy and IFG groups, P = 0.04; and diabetic nephropathy group vs. all, P < 0.01). Statistical adjustment for sex, age, BMI, and blood pressure did not affect the conclusions. Multiple linear regression analysis revealed that highly sensitive C-reactive protein (beta = 0.11; P = 0.01), insulin resistance index (beta = 0.20; P = 0.001), LDL cholesterol (beta = 0.31; P < 0.001), and adiponectin (beta = 0.33; P < 0.001) were significant predictors of plasma MR-proADM concentrations among nondiabetic individuals. Among subjects with diabetes, plasma MR-proADM concentrations correlated significantly with RCMP (r = 0.43, P = 0.002).. Plasma MR-proADM concentration was elevated in subjects with type 2 diabetes. This was further accentuated when nephropathy set in. MR-proADM was related to multiple metabolic factors and basal microcirculatory perfusion. Adrenomedullin might play a role in the pathogenesis of diabetic vasculopathy.

Topics: Adrenomedullin; Adult; Blood Pressure; Blood Vessels; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Female; Glucose Intolerance; Humans; Male; Middle Aged; Protein Precursors; Proteins; Reference Values

The aim of this study was to investigate whether adrenomedullin (AM) secretion is modified in type 2 diabetic patients with and without retinopathy.. The study was performed on 92 patients with type 2 diabetes, 65 of whom had uncomplicated diabetes, 27 had retinopathy, and 40 had mild to moderate hypertension. Patients with serum creatinine levels >1.2 mg/dL, were excluded. Circulating AM was assayed using a specific radioimmunoassay.. AM concentrations were significantly higher in type 2 diabetic patients (25+/-2.1 pg/mL) than in the 31 normal subjects (11+/-0.8 pg/mL) (P<0.001). Type 2 diabetic patients with retinopathy had significantly greater AM levels (30.8+/-3.4 pg/mL) than both controls (P<0.001) and type 2 diabetic patients without retinopathy (25.2+/-2 pg/mL same as previous value) (P<0.001). No statistical difference was found between diabetic patients with pre-proliferative retinopathy (27.3+/-4.7 pg/mL) and proliferative retinopathy (24+/-3.1 pg/mL) (P=0.543). In type 2 diabetic patients, a significant correlation between plasma AM levels and HbA1c values (r=0.467; P<0.01) was found.. Our findings indicate that circulating AM is increased in type 2 diabetic patients and that increase correlates with poor glucose metabolic control and presence of retinopathy.

Topics: Adrenomedullin; Aged; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Radioimmunoassay; Vasodilator Agents

Topics: Adrenomedullin; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Hypertension; Insulin; Male; Middle Aged; Oxidative Stress; Peptides

Adrenomedullin (AM) is a hypotensive peptide widely produced in the cardiovascular organs and tissues such as the heart, kidney, and the vascular cells. We have previously cloned and sequenced the genomic DNA encoding human AM gene, and determined that the gene is located in the short arm of chromosome 11. The 3'-end of the gene is flanked by the microsatellite marker of cytosine adenine (CA) repeats. In this study, we investigated the association between DNA variations in AM gene and the predisposition to develop nephropathy in type 2 diabetes mellitus.. Genomic DNA was obtained from the peripheral leukocytes of 233 normal healthy subjects (NH), 139 type 2 diabetic patients on hemodialysis (DM-HD), 106 control patients with type 2 diabetes without nephropathy (DM-C) and 318 hemodialysis patients due to chronic glomerulonephritis (CGN-HD). The genomic DNA was subject to polymerase chain reaction (PCR) using a fluorescence-labeled primer, and the number of CA repeats were determined by polyacrylamide gel electrophoresis (PAGE).. In our Japanese subjects, there existed four types of alleles with different CA-repeat number; 11, 13, 14, and 19. The frequencies of these alleles were 11: 27.7%, 13: 32.8%, 14: 35.6%, and 19: 3.9% in NH. These allele frequencies were not significantly different in DM-C and CGN-HD. However, DM-HD showed significantly different distribution of allele frequency from other groups (chi 2 = 18.9, P = 0.026). Namely, the frequency of 19-repeat allele in DM-HD was higher (9.0%) than NH, DM-C, and CGN-HD (P = 0.005, 0.041, and 0.004, respectively).. The microsatellite DNA polymorphism of AM gene may be associated with the genetic predisposition to develop nephropathy in Japanese patients with type 2 diabetes mellitus.

Topics: Adrenomedullin; Adult; Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Japan; Male; Microsatellite Repeats; Middle Aged; Peptides; Polymorphism, Genetic; Renal Insufficiency

To investigate the effect of acute hyperinsulinemia on the plasma levels of adrenomedullin (AM) in patients with type 2 diabetes mellitus.. We measured the plasma levels of AM in 18 patients with type 2 diabetes mellitus and in 19 normal subjects before and during a euglycemic hyperinsulinemic clamp study (the goal was for blood sugar levels of 5.24 mmol/l and insulin levels of 1200 pmol/l). Both plasma AM and serum insulin were measured by immunoradiometric assays.. Before the glucose clamp study there was no significant difference in the plasma levels of AM between patients with type 2 diabetes mellitus and normal subjects. During the glucose clamp study, the serum levels of insulin significantly increased (from 33.0+/-3.6 to 1344.6+/-67.8 pmol/ml, P<0.001), as did the plasma levels of AM (from 12.8+/-0.7 to 14.2+/-0.9 fmol/ml, P<0.03) only in patients with type 2 diabetes mellitus. There was a significant correlation between the change in circulating levels of insulin and AM (r=0.755, P<0.01).. Acute hyperinsulinemia induced a significant increase in the plasma levels of AM in patients with type 2 diabetes mellitus. Increased insulin may regulate circulating levels of AM in patients with type 2 diabetes mellitus.

Topics: Acute Disease; Adrenomedullin; Adult; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Peptides

Topics: Adrenomedullin; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Diabetic; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Peptides; Risk Factors

The study of two populations with a recent onset of type 2 diabetes showed that a subset of the patients had higher levels of adrenomedullin (AM) than the rest of the diabetics. In this subset, physiological elevations of AM might have triggered the disease in predisposed individuals. Diabetics showed higher levels of AM than healthy controls. In addition, glycemia was measured in diabetic rats after injection of saline, AM, or antiAM antibody. AM elevated glycemia, whereas the antibody reduced circulating glucose to normal. These results suggest that manipulation of AM levels could represent a new approach in the management of diabetes for the appropriate individuals.

Topics: Adolescent; Adrenomedullin; Adult; Animals; Antibodies; Blood Glucose; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetes, Gestational; Disease Models, Animal; Female; Humans; Male; Middle Aged; Peptides; Phenotype; Prediabetic State; Pregnancy; Rats; Rats, Inbred SHR

The present study was undertaken to determine plasma adrenomedullin levels in patients with non-insulin dependent diabetes mellitus (NIDDM) to elucidate the potential involvement in the pathogenesis of diabetic complications. The patients were 24 males and 21 females with ages of 55 +/- 2.1 years (mean +/- SEM). Plasma adrenomedullin levels were 5.94 +/- 0.44 pmol/l in patients with NIDDM, and were not affected by plasma glucose concentration. The plasma adrenomedullin increased dependent on the severity of diabetic nephropathy and retinopathy. Plasma levels of adrenomedullin positively correlated with various parameters, including serum creatinine levels, urinary excretion of protein, and systolic blood pressure. In contrast, there were negative correlations between the coefficient variation (CV) of RR intervals and plasma adrenomedullin, and between the conduction velocity of ulnar nerves and plasma adrenomedullin levels. These results indicate that the increase in plasma adrenomedullin was closely related to diabetic complications, which may be dependent on the development of microangiopathy.

Topics: Adrenomedullin; Albuminuria; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Proteinuria; Reference Values; Regression Analysis