adrenomedullin and Diabetes-Mellitus

Adrenomedullin (AM) is a 52-amino acid peptide with a pluripotential activity. AM is expressed in many tissues throughout the body, and plays a critical role in several diseases such as cancer, diabetes, cardiovascular and renal disorders, among others. While AM is a protective agent against cardiovascular disorders, it behaves as a stimulating factor in other pathologies such as cancer and diabetes. Therefore, AM is a new and promising target for the development of molecules which, through their ability to regulate AM levels, could be used in the treatment of these pathologies.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus; Drug Design; Humans; Molecular Sequence Data; Neoplasms; Peptides; Sequence Alignment

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Coronary Disease; Diabetes Mellitus; Humans; Hypertension; Liver Failure; Mice; Natriuretic Peptide, Brain; Oxidative Stress; Peptides; Rats

Adrenomedullin (AM) is a peptide that possesses potentially beneficial properties. Since the initial discovery of the peptide by Kitamura et al. in 1993, the literature has been awash with reports describing its novel mechanisms of action and huge potential as a therapeutic target. Strong evidence now exists that AM is able to act as an autocrine, paracrine, or endocrine mediator in a number of biologically significant functions, including the endothelial regulation of blood pressure, protection against organ damage in sepsis or hypoxia, and the control of blood volume through the regulation of thirst. Its early promise as a potential mediator/modulator of disease was not, however, entirely as a result of the discovery of physiological functions but due more to the observation of increasing levels measured in plasma in direct correlation with disease progression. In health, AM circulates at low picomolar concentrations in plasma in 2 forms, a mature 52-amino acid peptide and an immature 53-amino acid peptide. Plasma levels of AM have now been shown to be increased in a number of pathological states, including congestive heart failure, sepsis, essential hypertension, acute myocardial infarction, and renal impairment. These earliest associations have been further supplemented with evidence of a role for AM in other pathologies including, most intriguingly, cancer. In this review, we offer a timely review of our current knowledge on AM and give a detailed account of the putative role of AM in those clinical areas in which the best therapeutic opportunities might exist.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Humans; Inflammation; Kidney Diseases; Neoplasms; Neovascularization, Pathologic; Peptides; Sepsis

Adrenomedullin (AM) is a recently discovered potent vasodilatory peptide, originally isolated in extracts of human pheochromocytoma, with activities including maintenance of cardiovascular and renal homeostasis through vasodilatation, diuresis and natriuresis. Human AM consists of 52 amino acids with a 6-member ring structure linked by a disulfide bond and amidated COOH terminal, which belongs to calcitonin gene-related peptide (CGRP) and amylin. The main sites of AM production are the lungs, vascular tissues (both endothelial and smooth muscle cells), heart, kidney, adrenal glands, pancreatic islets, placenta, anterior pituitary gland and gastrointestinal neuroendocrine system. Intravenous injection of AM increases blood flow predominantly in the tissues with the highest AM expression, suggesting that AM functions primarily as a paracrine/autocrine hormone, but it is also important as circulating hormone. The objective of this review is to analyze the evidence that AM may play a role in some endocrine disorders.

Topics: Adrenal Insufficiency; Adrenocorticotropic Hormone; Adrenomedullin; Amino Acid Sequence; Cushing Syndrome; Diabetes Mellitus; Endocrine System Diseases; Female; Humans; Hyperaldosteronism; Hyperparathyroidism; Hyperthyroidism; Insulinoma; Male; Menstrual Cycle; Molecular Sequence Data; Molecular Structure; Paraneoplastic Endocrine Syndromes; Peptides; Pheochromocytoma; Pregnancy

Topics: Adrenomedullin; Animals; Diabetes Mellitus; Endothelins; Gastrointestinal Hormones; Humans; Motilin; Neuropeptides; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide

Adrenomedullin (AM) is a recently discovered regulatory peptide involved in many functions including vasodilatation, electrolyte balance, neurotransmission, growth, and hormone secretion regulation, among others. This 52-amino acid peptide is expressed by specific cell types in many organs throughout the body. A complex receptor system has been described for AM; it requires at least the presence of a seven-transmembrane-domain G-protein-coupled receptor, a single-transmembrane-domain receptor activity modifying protein, and a receptor component protein needed to establish the connection with the downstream signal transduction pathway, which usually involves cyclicAMP. In addition, a serum-binding protein regulates the biological actions of AM, frequently by increasing AM functional attributes. Changes in levels of circulating AM correlate with several critical diseases, including cardiovascular and renal disorders, sepsis, cancer, and diabetes. Whether AM is a causal agent, a protective reaction, or just a marker for these diseases is currently under investigation. New technologies seeking to elevate and/or reduce AM levels are being investigated as potential therapeutic avenues.

Topics: Adrenomedullin; Animals; Diabetes Mellitus; Disease Models, Animal; GTP-Binding Proteins; Humans; Neoplasms; Peptides; Receptors, Cell Surface; Signal Transduction; Viscera

Adrenomedullin (AM) is a novel 52-aminoacid-peptide hormone, originally isolated from human phaeocromocytoma. Adrenomedullin acts as a local autocrine and/or paracrine vasoactive hormone and has vasodilator and blood lowering properties, but its exact role is still uncertain. Adrenomedullin is considered to play an important endocrine role in various tissues maintaining the electrolyte and fluid homeostasis. Its normal plasma concentration is low. In hypertension, chronic renal failure and congestive heart failure its plasma concentration increases parallel to the seriousness of the disease. It is assumed that this peptide may be important under pathologic conditions compensating the effects of the vasoconstrictor molecules. Till now, investigations have proved that in diabetic angiopathies the levels and the production of vasoconstrictor factors and adrenomedullin were increased, while, those of other relaxing substances including nitrogenoxid were decreased. It is still uncertain whether increased release of adrenomedullin in diabetes is a compensatory mechanism or a coincidental event. Although, the precise role of adrenomedullin in the pathogenesis of diabetic complications is still to be elucidated, the elevated concentration of adrenomedullin in diabetes--which influences the vascular functions--let us speculate that there might be a certain interaction between adrenomedullin induction and vascular functions in diabetes. Thus, the induction of vascular adrenomedullin could be a new target of a therapeutic approach to the diabetic complications.

Topics: Adrenomedullin; Antihypertensive Agents; Calcitonin Gene-Related Peptide; Diabetes Mellitus; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Peptides; Tissue Distribution; Vasodilator Agents

Topics: Adrenomedullin; Atrial Natriuretic Factor; Autoantibodies; Biomarkers; Bone Diseases, Metabolic; Diabetes Mellitus; Heart Failure; Humans; Immunoglobulins, Thyroid-Stimulating; Molecular Diagnostic Techniques; Multiple Endocrine Neoplasia; Peptides; Receptors, Thyrotropin; Thyroid Diseases; Thyroxine; Triiodothyronine

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Biomarkers; Cholesterol; Cystatin C; Diabetes Mellitus; Female; Glycopeptides; Humans; Hypertension; Longitudinal Studies; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Peripheral Arterial Disease; Prospective Studies; Protein Precursors; Risk Factors; Sex Factors; Smoking; Sweden

Topics: Adrenomedullin; Diabetes Mellitus; Exosomes; Humans; Pancreatic Neoplasms

Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion.. We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown.. Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species.. Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.

Topics: Adrenomedullin; Blotting, Western; CA-19-9 Antigen; Diabetes Mellitus; Exosomes; Humans; Insulin-Secreting Cells; Microscopy, Confocal; Pancreatic Neoplasms; Paraneoplastic Syndromes; Real-Time Polymerase Chain Reaction

Diabetes mellitus (DM) is associated with an adverse outcome in heart failure (HF). Increased concentrations of midregional proadrenomedullin (MR-proADM) have been associated with DM and are predictors of mortality in HF patients. The aim of this study was to elucidate the impact of DM on MR-proADM concentrations and the prognostic value regarding all-cause mortality and hospitalization among HF patients.. We included 366 patients from an HF clinic; 69 (19%) had a history of DM and 40 (11%) had newly diagnosed DM (HbA1c ≥48 mmol/mol). The median MR-proADM concentration was unaffected by DM status (P = .20) but increased in HF patients with impaired renal function (P < .001). During a median follow-up of 55 months, 189 died, and 292 either died or were hospitalized. After adjustment for clinically relevant parameters, MR-proADM was associated with all-cause mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1-1.4; P = .01) and the combined end point of death and hospitalization (HR 1.2, 95% CI 1.1-1.4; P = .02) per 1 SD increment of ln-transformed variable. No interaction between DM and MR-proADM was found regarding mortality or hospitalization.. Diabetes status had no impact on MR-proADM concentrations or in the predictive ability of MR-proADM in HF patients.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Ambulatory Care; Biomarkers; Cohort Studies; Diabetes Mellitus; Female; Heart Failure; Humans; Male; Middle Aged; Prognosis; Protein Precursors

Diabetes may be a consequence of pancreatic cancer, preceding cancer diagnosis. The underlying mechanism is the release of exosomes delivering adrenomedullin to β cells, inducing endoplasmic reticulum stress and perturbations in the unfolded protein response, leading to β-cell dysfunction and death. This knowledge could lead to improved diagnostic strategies for pancreatic cancer.

Topics: Adrenomedullin; Diabetes Mellitus; Exosomes; Humans; Insulin-Secreting Cells; Pancreatic Neoplasms

Midregional pro-adrenomedullin (MR-proADM) and C-terminal pro-vasopressin (copeptin) are novel biomarkers providing prognostic information in various settings. We aimed to (1) assess the kinetics of MR-proADM and copeptin during cardiopulmonary exercise testing (CPET); (2) assess the relationship of MR-proADM and copeptin measured at rest with peak oxygen consumption (peak VO2) and other key CPET parameters; (3) compare this relationship to that of B-type natriuretic peptide (BNP).. In 162 patients undergoing symptom-limited CPET for evaluation of exercise intolerance, MR-proADM, copeptin, and BNP were measured at rest and peak exercise.. There was a significant rise in copeptin and BNP (p < 0.001) but not in MR-proADM (p = 0.60) from rest to peak exercise. MR-proADM (r = -0.57; p < 0.001) and BNP (r = -0.49; p < 0.001) but not copeptin were significantly and inversely related to peak VO2. MR-proADM was inversely correlated to the percentage of predicted heart rate achieved and peak oxygen pulse and directly related to the peak ventilation/carbon dioxide production relationship, the physiological dead space-to-tidal volume ratio, and the alveolo-arterial oxygen gradient (p ≤ 0.01 for all), and these associations were at least as strong as for BNP. In contrast, copeptin was not significantly related to any of these parameters (p > 0.05 for all).. In contrast to BNP and copeptin, MR-proADM is not immediately affected by a maximal exercise test. MR-proADM but not copeptin is at least as good an indicator of low peak VO2 and CPET parameters reflecting an impaired cardiac output reserve, ventilatory efficiency and diffusion capacity as BNP, and thereby a global cardiopulmonary stress marker.

Topics: Adrenomedullin; Aged; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Exercise; Exercise Tolerance; Female; Glycopeptides; Heart Rate; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen Consumption; Respiratory Tract Diseases; Tidal Volume

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

Glucose increases the expression of glycolytic enzymes and other hypoxia-response genes in pancreatic beta-cells. Here, we tested whether this effect results from the activation of Hypoxia-Inducible-factors (HIF) 1 and 2 in a hypoxia-dependent manner.. Isolated rat islets and insulin-secreting INS-1E cells were stimulated with nutrients at various pO₂ values or treated with the HIF activator CoCl₂. HIF-target gene mRNA levels and HIF subunit protein levels were measured by real-time RT-PCR, Western Blot and immunohistochemistry. The formation of pimonidazole-protein adducts was used as an indicator of hypoxia. In INS-1E and islet beta-cells, glucose concentration-dependently stimulated formation of pimonidazole-protein adducts, HIF1 and HIF2 nuclear expression and HIF-target gene mRNA levels to a lesser extent than CoCl₂ or a four-fold reduction in pO₂. Islets also showed signs of HIF activation in diabetic Lepr(db/db) but not non-diabetic Lepr(db/+) mice. In vitro, these glucose effects were reproduced by nutrient secretagogues that bypass glycolysis, and were inhibited by a three-fold increase in pO₂ or by inhibitors of Ca²⁺ influx and insulin secretion. In INS-1E cells, small interfering RNA-mediated knockdown of Hif1α and Hif2α, alone or in combination, indicated that the stimulation of glycolytic enzyme mRNA levels depended on both HIF isoforms while the vasodilating peptide adrenomedullin was a HIF2-specific target gene.. Glucose-induced O₂ consumption creates an intracellular hypoxia that activates HIF1 and HIF2 in rat beta-cells, and this glucose effect contributes, together with the activation of other transcription factors, to the glucose stimulation of expression of some glycolytic enzymes and other hypoxia response genes.

Topics: Adrenomedullin; Animals; Basic Helix-Loop-Helix Transcription Factors; Calcium; Cell Hypoxia; Diabetes Mellitus; Female; Gene Expression Regulation; Gene Knockdown Techniques; Glucose; Glycolysis; Hypoxia-Inducible Factor 1; Insulin; Insulin Secretion; Insulin-Secreting Cells; Kinetics; Male; Mice; Mitochondria; Oxygen; Rats; RNA, Messenger

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.

Topics: Acute Disease; Adrenomedullin; Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Clinical Trials as Topic; Diabetes Mellitus; Dyspnea; Female; Heart Failure; Humans; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Multivariate Analysis; Peptide Fragments; Prognosis; Protein Precursors; ROC Curve

Adrenomedullin (AM) is a regulatory peptide involved in several physiological processes. Among them, AM has been implicated in the regulation of growth, both with mitogenic and antiproliferative activities on normal cells. AM is widely expressed during embryogenesis and may have a significant role in the proliferation and differentiation processes associated with development. AM is also expressed by cancer cell lines and tumors and has been implicated in the growth of malignant cells. Some additional activities associated with AM (antiapoptotic capabilities, angiogenic potential, and upregulation in hypoxic conditions), together with its wide distribution in cancer, suggest that AM may be an important factor in carcinogenesis. Besides its implication in growth, embryogenesis and tumor biology, AM is also involved in pancreatic regulation and diabetes. AM regulates insulin secretion and is overexpressed in the plasma of diabetic patients. Several findings indicate that AM may participate in the pathogenesis and/or clinical complications of this disease.

Topics: Adrenomedullin; Animals; Cell Division; Complement Factor H; Diabetes Mellitus; Humans; Neoplasms; Pancreas; Peptides

Topics: Adrenomedullin; Adult; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Peptides; Reference Values

Topics: Adrenomedullin; Adult; Case-Control Studies; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Peptides; Radioimmunoassay