adrenomedullin and Diabetic-Retinopathy

Diabetic retinopathy (DR) is the main cause of working-age adult-onset blindness. The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR. Therefore, new pharmacological treatments for these early stages of the disease are required. In order to develop therapeutic strategies for early stages of DR new diagnostic tools are urgently needed. In this regard, circulating biomarkers could be useful to detect early disease, to identify those diabetic patients most prone to progressive worsening who ought to be followed up more often and who could obtain the most benefit from these therapies, and to monitor the effectiveness of new drugs for DR before more advanced DR stages have been reached. Research of biomarkers for DR has been mainly based on the pathogenic mechanism involved in the development of DR (i.e., AGEs, oxidative stress, endothelial dysfunction, inflammation, and proangiogenic factors). This review focuses on circulating biomarkers at both early and advanced stages that could be relevant for the prediction or detection of DR.

Topics: Adrenomedullin; Arginine; Autoantibodies; Basement Membrane; Biomarkers; C-Reactive Protein; Collagen Type IV; Diabetic Retinopathy; E-Selectin; Endothelial Progenitor Cells; Extracellular Matrix; Glycation End Products, Advanced; Homocysteine; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Laminin; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; MicroRNAs; Retinol-Binding Proteins, Plasma; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.

Topics: Adrenomedullin; Animals; Capillary Permeability; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Electric Impedance; Endothelial Cells; Intravitreal Injections; Male; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Retinitis; Vascular Endothelial Growth Factor A; Vasodilator Agents

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 study objective was to assess chosen biochemical parameters of blood and bioelectric function of the retina in patients with T1DM. The study group consisted of 41 patients with T1DM with no signs of diabetic retinopathy. The control group included 21 pediatric patients. We performed (1) S-cone ERG testing with retina response stimulation in both eyes at the luminance of 0.1, 0.2, and 0.5 (cd × s/m(2)) with the 440 nm blue flash and light application of the amber background (300 ph cd/m(2), 495 nm wavelength), (2) anthropometric measurements, (3) biochemical investigations: IL-17, VEGF, and ADM by the ELISA method. A comparison of the ERG results with biochemical investigations indicates a likely correlation between the worsening of retinal bioelectric function and VEGF levels growing with diabetes duration. We showed a negative correlation between ADM and HbA1c and described possible causes of ADM reduction observed in subgroup I. We demonstrated the presence of bioelectric retinal dysfunction already before the diagnosis of diabetic retinopathy, which provides new possibilities in the diagnosis of preclinical chronic complications of diabetes. The changes observed in the levels of IL-17, ADM, and VEGF suggest their involvement in the diabetic pathogenesis of eye diseases.

Topics: Adolescent; Adrenomedullin; Child; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Electroretinography; Humans; Interleukin-17; Regression Analysis; Retinal Cone Photoreceptor Cells; Vascular Endothelial Growth Factor A

To measure adrenomedullin (ADM) levels in the blood, vitreous fluid and fibrous membrane in patients with proliferative diabetic retinopathy (PDR) and study its changes in different pathological conditions.. We used radioimmunoassay technique to determine immunoreactive- adrenomedullin (IR-ADM) concentrations in the plasma, vitreous samples and fibrous membrane obtained from 9 control subjects with idiopathic macular hole and 23 patients with PDR undergoing vitrectomy.. IR-ADM levels in the plasma, vitreous samples and fibrous membrane tissues (16.1 ± 2.91fmol/ml, 9.80 ± 2.51fmol/ml and 34.8 ± 5.22fmol/mg) were all significantly elevated in patients with PDR compared with control subjects (11.6 ± 2.38 fmol/ml, 5.8 ± 1.64 fmol/ml and 22.4 ± 1.72 fmol/mg). The levels of ADM in vitreous were also significantly higher in PDR patients with diabetic macular edema (DME) (11.2 ± 2.36 fmol/ml) than those of patients without DME (8.0 ± 1.11 fmol/ml) and controls (5.8 ± 1.64 fmol/ml).. These findings suggest that ADM may be produced locally in the eyes and may correlate with the severity and proliferative reactions of diabetic retinopathy.

Topics: Adrenomedullin; Adult; Aged; Biomarkers; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Prognosis; Radioimmunoassay; Retrospective Studies; Severity of Illness Index; Vitreous Body

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

Altered activity of retinal endothelin-1 (ET-1) and nitric oxide may play a causal role in the hemodynamic and histopathological changes of diabetic retinopathy. This study evaluated the therapeutic potential of long-term selective blockade of the ET-1(A) receptor (ETRA) to prevent the development of retinopathy in a genetic mouse model of nonobese type 1 diabetes (NOD). Mice with NOD that received subcutaneous implantation of insulin pellets and wild-type control mice were treated for 4 months with the selective ETRA antagonist LU208075 (30 mg/kg/day) via drinking water. At the end of the study, blood glucose levels were evaluated, and animals were anesthetized and perfused intracardially with FITC-labeled dextran. Retinas were removed and either fixed in formalin for confocal microscope evaluation of retinal vascular filling or transferred to RNALater for quantitative reverse transcriptase-polymerase chain reaction to evaluate expression of NOS-3, NOS-1, ET-1, ETRA, ETRB, and the angiogenic factor adrenomedullin. Compared with wild-type controls, expression of ET-1, ETRA, ETRB, and adrenomedullin in mice with NOD were markedly upregulated in the retinas of nontreated mice (cycle time values relative to GAPDH [deltaCt], 14.8 vs. 13.7, 18.57 vs. 17.5, 10.76 vs. 9.9, and 11.7 vs. 9.1, respectively). Mean integral fluorescence intensity (MIFI) of retinal vascular filling was reduced from normal values of 24 to 12.5 in nontreated animals. LU208075 treatment normalized the upregulated expression of ET-1 and adrenomedullin, as well as the deficit in MIFI, but did not affect the increased ETRA and ETRB expression or the elevated plasma glucose levels found in nontreated animals. NOS isoform expression was essentially unchanged. ETRA antagonists may provide a novel therapeutic strategy to slow or prevent progression of retinal microvascular damage and proliferation in patients for whom there is clear evidence of activation of the ET-1 system.

Topics: Adrenomedullin; Animals; Blood Glucose; Diabetic Retinopathy; Endothelin A Receptor Antagonists; Endothelin-1; Female; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Mice; Mice, Inbred NOD; Peptides; Phenylpropionates; Pyridazines; Time Factors; Vasodilator Agents

To explore the possible involvement of adrenomedullin (AM)in the pathophysiology of diabetic retinopathy, we employed streptozotocin (STZ)-induced diabetic rats to study the alteration of the AM expression in the retinal pigment epithelium (RPE) cells of diabetic and normal rats by immunohistochemistry. The weight, blood sugar and urine sugar were also measured before and after model induction in both groups. The data of weight, blood sugar and urine sugar indicated no significant difference between the two groups before animal model induction. Four weeks after the induction of diabetes,the differences between the control and the diabetic group in weight,blood sugar and urine sugar were distinct (P<0.01). When compared with the normal retina, a significant increase of AM expression was observed in the diabetic rat' RPE cells,as shown by increased optical density and immunohistochemistry positive cell number(P<0.01). Our study provides experimental evidence that up-regulation of AM expression in retina of streptozotocin-induced diabetic rats under hyperglycemia condition. Adrenomedullin may play a role in the pathophysiology of diabetic retinopathy.

Topics: Adrenomedullin; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Female; Immunohistochemistry; Rats; Rats, Sprague-Dawley; Retinal Pigment Epithelium; Streptozocin

To evaluate the role of various vasoactive hormones in the evolution of diabetic retinopathy during pregnancy and postpartum.. Retinopathy was graded from fundus photographs of 45 pregnant women with type 1 diabetes and seven pregnant women without diabetes in a prospective study. Markers of renin-angiotensin-system (RAS), plasma renin activity (PRA), angiotensin II (AngII), aldosterone, natriuretic peptides (ANP, BNP, CNP) and adreonomedullin (AM) were measured during the first and third trimesters and at 3 months postpartum. The women with diabetes were grouped by progression of retinopathy during pregnancy and postpartum.. Levels of PRA (p = 0.001) and ANP (p = 0.03) were significantly lower in diabetes than in non-diabetes subjects throughout pregnancy and postpartum. No significant differences appeared in levels of AngII, aldosterone, AM, BNP or CNP between the two groups. In multivariate logistic regression analyses with retinopathy progression by the third trimester as the dependent variable, only duration of diabetes qualified in the model (p = 0.027, R = 0.227, Exp(B) = 1.28).. Diabetic pregnancy is associated with lower levels of PRA and ANP compared to non-diabetic pregnancy. Lowered RAS activity may contribute to the hyperdynamic blood flow and progression of DR during diabetic pregnancy. Within the power of this study no clear associations between the vasoactive hormones and progression of retinopathy could be detected.

Topics: Adrenomedullin; Adult; Aldosterone; Angiotensin II; Blood Flow Velocity; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Disease Progression; Female; Glycated Hemoglobin; Humans; Natriuretic Peptides; Peptides; Pregnancy; Pregnancy in Diabetics; Renin; Renin-Angiotensin System; Retinal Vessels; Vasoconstrictor Agents; Vasodilator Agents

To clarify possible involvement of adrenomedullin in the pathophysiology of inflammation of eyes, we measured immunoreactive-adrenomedullin concentrations in the aqueous humor and plasma obtained from 14 control subjects and 56 patients with uveitis or vitreoretinal disorders. Immunoreactive-adrenomedullin levels in the aqueous humor were significantly elevated in patients with active uveitis, proliferative vitreoretinopathy and proliferative diabetic retinopathy, as compared with control subjects. The plasma immunoreactive-adrenomedullin levels were not significantly correlated with the aqueous humor levels. These findings suggest that adrenomedullin produced locally in the eyes is involved in the pathophysiology of uveitis and some proliferative vitreoretinal disorders.

Topics: Adrenomedullin; Adult; Aged; Aqueous Humor; Calcitonin Gene-Related Peptide; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Peptides; Uveitis; Vitreoretinopathy, Proliferative

To explore the possible involvement of adrenomedullin in the pathophysiology of proliferative vitreoretinopathy.. The radioimmunoassay technique was used to determine immunoreactive adrenomedullin concentrations in the vitreous fluid from 41 eyes of 41 patients undergoing vitrectomy for a variety of retinal conditions, including proliferative vitreoretinopathy, proliferative diabetic retinopathy, age-related macular degeneration, and macular hole.. Immunoreactive adrenomedullin levels in the vitreous of patients with proliferative vitreoretinopathy were significantly higher than those of patients with proliferative diabetic retinopathy (P < .005), age-related macular degeneration (P < .001), and macular hole (P < .0001).. Adrenomedullin may be involved in the pathophysiology of proliferative vitreoretinopathy.

Topics: Adrenomedullin; Diabetic Retinopathy; Female; Humans; Macular Degeneration; Male; Middle Aged; Peptides; Radioimmunoassay; Retinal Perforations; Vasodilator Agents; Vitrectomy; Vitreoretinopathy, Proliferative; Vitreous Body

To assess the relationship between plasma adrenomedullin (AM) levels and the presence of microvascular complications in type 1 diabetic patients.. We measured plasma AM and cAMP levels in 103 type 1 diabetic patients (46 without complications, 24 with retinopathy only, 14 with microalbuminuria but normal kidney function, and 19 with renal insufficiency) and 41 matched healthy control subjects.. Patients with renal insufficiency had higher levels of AM and cAMP than all other groups. Patients with only retinopathy showed a trend to have higher levels than patients without complications. There were no differences among all other groups. There was a significant correlation between AM and cAMP in the total diabetic group (rs = 0.36, P < 0.001) but not in the control group. In multiple regression analysis, plasma AM demonstrated significant relationships with creatinine clearance (beta = -0.31, P = 0.004) and duration of the disease (beta = 0.28, P = 0.008).. Plasma AM and cAMP are increased in type 1 diabetic patients with renal insufficiency. Creatinine clearance (CrClc) and duration of the disease are related to plasma AM levels in these patients.

Topics: Adrenomedullin; Adult; Albuminuria; Biomarkers; Body Mass Index; Cholesterol; Creatinine; Cyclic AMP; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Peptides; Proteinuria; Regression Analysis; Smoking

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