adrenomedullin and Diabetes-Mellitus--Type-1

We investigated whether maternal and fetoplacental adrenomedullin, a newly discovered hypotensive peptide involved in the insulin regulatory system, is modified in diabetic pregnancy. We studied its correlation with pregnancy complications associated with this disease. Thirty-six pregnant women with diabetes (13 with type I and 23 with gestational diabetes mellitus) and in 40 uncomplicated pregnancies were included. 10 out of 36 diabetic pregnancies were complicated by gestational hypertension. In each woman, adrenomedullin concentration in maternal and fetal plasma and in amniotic fluid was assessed by specific radioimmunoassay. We found that overall mean amniotic fluid adrenomedullin concentration was higher (p < 0.05) in diabetic (14.7 +/- 1.6 fmol/ml) than in uncomplicated pregnancies (10.8 +/- 0.9 fmol/ml), whereas no differences were present in maternal and fetal plasma adrenomedullin levels between diabetic and uncomplicated pregnant women. High levels of amniotic fluid adrenomedullin were found in both type I and gestational diabetes mellitus pregnancies (13.7 +/- 1.4 and 15.6 +/- 2.2 fmol/ml, respectively). Diabetic pregnancies complicated by gestational hypertension showed lower (p < 0.05) amniotic fluid adrenomedullin concentrations than normotensive diabetic patients. These findings suggest that placental adrenomedullin production is upregulated in diabetic pregnancy, and it may be important to prevent excessive vasoconstriction of placental vessels.

Topics: Adrenomedullin; Adult; Amniotic Fluid; Diabetes Mellitus, Type 1; Diabetes, Gestational; Female; Fetal Blood; Gestational Age; Humans; Hypertension; Middle Aged; Peptides; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Radioimmunoassay

Both advanced glycation end products (AGEs) and AGE-mediated M1 macrophage polarization contribute to bone marrow mesenchymal stem cell (BMSC) dysfunction, leading to impaired bone regeneration in type 1 diabetes mellitus (T1DM). Adrenomedullin 2 (ADM2), an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family, exhibits various biological activities associated with the inhibition of inflammation and reduction of insulin resistance. However, the effects and underlying mechanisms of ADM2 in AGE-induced macrophage M1 polarization, BMSC dysfunction, and impaired bone regeneration remain poorly understood.. The polarization of bone marrow-derived macrophages was verified using flow cytometry analysis. Alkaline phosphatase (ALP) staining, ALP activity detection, and alizarin red staining were performed to assess the osteogenesis of BMSCs. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence staining were used to assess polarization markers, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and osteogenic markers. In vivo, a distraction osteogenesis (DO) rat model with T1DM was established, and tibia samples were collected at different time points for radiological, biomechanical, and histological analyses, to verify the effects of ADM2 on bone regeneration and M2 polarization under diabetic conditions.. ADM2 treatment reversed AGE-induced M1 macrophage polarization towards the M2 phenotype, which was partially achieved by the peroxisome proliferator-activated receptor γ (PPARγ)-mediated inhibition of NF-κB signaling. The PPARγ inhibitor GW9662 significantly attenuated the effects of ADM2. Besides, ADM2 treatment improved the AGE-impaired osteogenic potential of BMSCs in vitro. Furthermore, ADM2 accelerated bone regeneration, as revealed by improved radiological and histological manifestations and biomechanical parameters, accompanied by improved M2 macrophage polarization in diabetic DO rats, and these effects were partially blocked by GW9662 administration.. These results indicate that ADM2 enhances diabetic bone regeneration during DO, by attenuating AGE-induced imbalances in macrophage polarization, partly through PPARγ/NF-κB signaling, and improving AGE-impaired osteogenic differentiation of BMSCs simultaneously. These findings reveal that ADM2 may serve as a potential bioactive factor for promoting bone regeneration under diabetic conditions, and imply that management of inflammation and osteogenesis, in parallel, may present a promising therapeutic strategy for diabetic patients during DO treatment.

Topics: Adrenomedullin; Animals; Bone Regeneration; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Humans; Macrophages; Osteogenesis; Peptide Hormones; Rats

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 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

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

Since adrenomedullin (AM) elicits vasodilatation by binding to specific AM receptors consisted of calcitonin-receptor-like receptor (CRLR)/receptor-activity-modifying protein 2 (RAMP2) or CRLR/receptor-activity-modifying protein 3 (RAMP3) on endothelial cells and stimulating nitric oxide production, AM possibly involves in glomerular capillary dilatation in early phase of diabetic nephropathy.. Streptozotocin (STZ)-induced diabetic Sprague-Dawley rats at 4 weeks after the injection were employed for expression studies of AM, RAPM2, and RAMP3. The measurement of AM peptide levels in kidney tissue, plasma, and urine was performed. Human aortic endothelial cells (HAEC) were used to investigate functional link between glucose-induced AM production and nitric oxide release.. STZ rats showed glomerular hypertrophy and increased urinary NO2- and NO3- excretion. By Northern blot analyses, AM and RAPM2 mRNAs significantly increased in the kidneys of STZ rats, while RAMP3 mRNA was not altered. In STZ rats, AM peptide was actively secreted into urine (1280 +/- 360 fmol/day vs. control 110 +/- 36 fmol/day). AM peptide was mainly detected on cortical and medullary collecting duct cells in control rat kidneys and AM peptide and mRNA were up-regulated on afferent arterioles and glomeruli of STZ rats. RAMP2 expression was detected on afferent arterioles and not in glomeruli in control rats and it was up-regulated on glomerular endothelial cells in STZ rats. In HAEC culture, d-glucose stimulated AM and nitric oxide production and they were suppressed by addition of AM antisense oligodeoxynucleotides.. Up-regulated expression of AM and RAMP2 in afferent arterioles and glomeruli may be related to selective dilatation of glomerular capillary in acute phase of type 1 diabetes.

Topics: Adrenomedullin; Animals; Aorta; Blood Glucose; Blotting, Northern; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; DNA, Antisense; Endothelium, Vascular; Gene Expression; Humans; Hypertrophy; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Male; Membrane Proteins; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitrites; Peptides; Rats; Rats, Sprague-Dawley; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Protein 3; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Peptide; RNA, Messenger

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