losartan-potassium and Diabetes-Mellitus--Type-1

Diabetic retinopathy (DR) is characterized by ischemia, hypoxia, and angiogenesis. Erythropoietin (EPO), an angiogenic hormone, is upregulated in DR, and the association of EPO genetic variants with DR is still uncertain, as conflicting results have been reported. Therefore, we performed a case-control study followed by a meta-analysis to investigate whether the rs1617640, rs507392, and rs551238 polymorphisms in EPO gene are associated with DR.. The case-control study included 1042 Southern Brazilians with type 2 diabetes (488 without DR and 554 with DR). Eligible studies for the meta-analysis were searched from electronic databases up to June 1, 2021. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for five genetic inheritance models.. The minor alleles of the EPO polymorphisms had nearly the same frequency in all groups of patients (35%), and no association was detected with DR in the case-control study. The meta-analysis included 14 independent sets of cases and controls with 9117 subjects for the rs1617640 polymorphism and nine independent sets with more than 5000 subjects for the rs507392 and rs551238 polymorphisms. The G allele of the rs1617640 polymorphism was suggestively associated with DR under the dominant (OR = 0.82, 95% CI: 0.68-0.98), heterozygous additive (OR = 0.82, 95% CI: 0.69-0.97), and overdominant (OR = 0.88, 95% CI: 0.79-0.97) models. In the subgroup analyses, the G allele was also suggestively associated with proliferative DR (PDR), non-proliferative DR (NPDR), and DR (PDR + NPDR) among patients with type 1 diabetes (T1DM) or non-Asian ancestry. After considering the Bonferroni correction for multiple comparisons, the G allele remained associated with NPDR and DR in T1DM. Regarding the rs507392 and rs551238 polymorphisms, no association was found between these variants and DR.. Our findings provide additional support to EPO as a susceptibility gene for DR, with the rs1617640 polymorphism deserving further investigation.

Topics: Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide

We investigated the association of signals from previous GWAS and candidate gene meta-analyses for diabetic retinopathy (DR) or nephropathy (DN), as well as an EPO variant in meta-analyses of severe (SDR) and mild diabetic retinopathy (MDR). Meta-analyses of SDR (≥severe non-proliferative diabetic retinopathy (NPDR) or history of panretinal photocoagulation) and MDR (≥mild NPDR), defined based on seven-field stereoscopic fundus photographs, were performed in two well-characterized type 1 diabetes (T1D) cohorts: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC, n = 1,304) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR, n = 603). Among 34 previous signals for DR, after controlling for multiple testing, no association was replicated in our meta-analyses. rs1571942 and rs12219125 at PLXDC2 locus showed nominally significant (<0.05) association with SDR in the same direction as previous report, as did rs1801282 in PPARG gene with MDR. Among 55 loci previously associated with DN, three showed suggestive associations with SDR in our study without maintaining significance after correction for multiple testing. Of particular interest, rs1617640 (EPO) was not significantly associated with DR status, combined SDR-DN phenotype, time to SDR or time to DN (all P > 0.05). Lack of replication of previous DR hits and EPO despite reasonable statistical power implies that many of these may be false positives. Consistent with pleiotropy, we provide suggestive collective evidence for association between DR and variants previously associated with DN without reaching statistical significance at any single locus.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Erythropoietin; Female; Genetic Loci; Humans; Male; Polymorphism, Genetic; Receptors, Cell Surface

We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Topics: Adaptor Proteins, Signal Transducing; Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Finland; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Ireland; Kidney Failure, Chronic; Phenotype; Promoter Regions, Genetic; United States; White People

Anaemia is a common complication of chronic kidney disease (CKD). It is often more severe and occurs at an earlier stage in patients with diabetic nephropathy than in patients with CKD of other causes. This anaemia results from erythropoietin deficiency, which seems to develop in patients with type 1 diabetes even at relatively "normal" levels of serum creatinine. Early erythropoietin- deficiency anaemia occurs in both type 1 and type 2 diabetes, although the prevalence may be higher in type 1 diabetes. However, numerically most patients with erythropoietin-deficiency anaemia have type 2 diabetes as it is a much more common disease. There is also a greater prevalence in women than men but this is not related to iron stores. In addition, erythropoietin-deficiency anaemia is associated with the presence of autonomic neuropathy in patients with diabetes. Small studies have suggested that recombinant human erythropoietin (rhEPO; epoetin) treatment is effective in correcting erythropoietin-deficiency anaemia in patients with diabetes. Additionally, rhEPO therapy improves quality of life and well-being in these patients. Studies also suggest that treatment with rhEPO to restore a normal haematocrit ameliorates orthostatic hypotension. Given the high cardiovascular risk in patients with diabetic nephropathy, it is important to determine in prospective clinical trials whether early anaemia correction can also improve cardiovascular outcomes.

Topics: Anemia; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins

Anaemia occurs earlier and is more severe in diabetic patients with end-stage renal disease (ESRD) than in non-diabetic ESRD patients controlled for the same level of renal function. In contrast to non-diabetic patients, diabetic ESRD patients demonstrate an impaired physiological response to anaemia; endogenous serum erythropoietin levels are low in relation to the level of anaemia. The reasons for the anaemia are probably a combination of tubulointerstitial damage and autonomic neuropathy. The use of angiotensin-converting enzyme inhibitors, which has been reported to be associated with an inhibition of erythropoiesis, does not seem to have a clinically significant effect on haemoglobin levels. In order to address all the independent risk factors in diabetic ESRD, optimal management of these patients should involve interdisciplinary care (diabetologist and nephrologist) and consideration of correction of anaemia.

Topics: Anemia; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic

The demonstration of the existence of tissue-specific adult stem cells has had a great impact on our understanding of stem cell biology and its application in clinical medicine. Their existence has revolutionized the implications for the treatment of many degenerative diseases characterized by either the loss or malfunction of discrete cell types. However, successful exploitation of this opportunity requires that we have sufficient know-how of stem cell manipulation. Because stem cells are the founders of virtually all tissues during embryonic development, we believe that understanding the cellular and molecular mechanisms of embryogenesis and organogenesis will ultimately serve as a platform to identify factors and conditions that regulate stem cell behavior. Discovery of stem cell regulatory factors will create potential pharmaceutical opportunities for treatment of degenerative diseases, as well as providing critical knowledge of the processes by which stem cells can be expanded in vitro, differentiated, and matured into desired functional cells for implantation into humans. A well-characterized example of this is the hematopoietic system where the discovery of erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF), which regulate hematopoietic progenitor cell behavior, have provided significant clinical success in disease treatment as well as providing important insights into hematopoiesis. In contrast, little is known about the identity of pancreatic stem cells, the focus of this review. Recent reports of the potential existence of pancreatic stem cells and their utility in rescuing the diabetic state now raise the same possibilities of generating insulin-producing beta cells as well as other cell types of the pancreatic islet from a stem cell. In this review, we will focus on the potential of these new developments and how our understanding of pancreas development can help design strategies and approaches by which a cell replacement therapy can be implemented for the treatment of insulin-dependent diabetes which is manifested by the loss of beta cells in the pancreas.

Topics: Animals; Cell Differentiation; Diabetes Mellitus, Type 1; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cells; Humans; Islets of Langerhans; Islets of Langerhans Transplantation; Pancreas; Stem Cells

The incidence of severe hypoglycemia in type 1 diabetes has not decreased over the past decades. New treatment modalities minimizing the risk of hypoglycemic episodes and attenuating hypoglycemic cognitive dysfunction are needed. We studied if treatment with the neuroprotective hormone erythropoietin (EPO) enhances cognitive function during hypoglycemia.. Eleven patients with type 1 diabetes, hypoglycemia unawareness and recurrent severe hypoglycemia completed the study. In a double-blind, randomized, balanced, cross-over study using clamped hypoglycemia they were treated with 40,000 IU of EPO or placebo administered intravenously six days before the two experiments. Cognitive function (primary endpoint), hypoglycemic symptoms, and counter-regulatory hormonal response were recorded.. Compared with placebo, EPO treatment was associated with a significant reduction in errors in the most complex reaction time task (-4.7 (-8.1 to -1.3), p = 0.01) and a less reaction time prolongation (-66 (-117 to -16) msec, p = 0.02). EPO treatment did not change performance in other measures of cognition. Hypoglycemic symptoms, EEG-changes, and counter-regulatory hormone concentrations did not differ between EPO and placebo treatment.. In patients with type 1 diabetes and hypoglycemia unawareness, treatment with EPO is associated with a beneficial effect on cognitive function in a complex reaction time task assessing sustained attention/working memory. Hypoglycemic symptoms and hormonal responses were not changed by EPO treatment.. ClinicalTrials.gov NCT00615368.

Topics: Adult; Aged; Blood Glucose; Cognition; Cross-Over Studies; Diabetes Mellitus, Type 1; Electroencephalography; Electrophysiological Phenomena; Erythropoietin; Female; Glucose Clamp Technique; Hematologic Tests; Hormones; Humans; Male; Middle Aged; Monitoring, Physiologic

Topics: Adult; Anemia; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Erythropoietin; Female; Follow-Up Studies; Humans; Hypotension, Orthostatic; Middle Aged; Recombinant Proteins; Time Factors

To identify and treat a unique form of anemia in patients with long-term IDDM.. Patients with IDDM, unexplained symptomatic anemia, and serum creatinine levels of < 177 mumol/l (2.0 mg/dl) were treated with epoetin alfa (Procrit, Ortho Biotech, Raritan, NJ), 50 U/kg three times weekly, subcutaneously, to reach a target hematocrit of 38-40%. Baseline serum erythropoietin titers were measured before drug therapy.. Six patients were treated with epoetin alfa. Median age of the group was 74 years, with IDDM being diagnosed for a median of > 20 years. All patients had symptoms of anemia with a median hematocrit of 28.9% (range 27-31). Compared with iron deficiency control patients, the group had a limited erythropoietin (EPO) response to the degree of anemia. All patients showed increases in hematocrit, median peak of 40.9%, with median time-to-peak response of 12 weeks. Baseline symptoms of anemia resolved in all patients. No adverse effects were noted during the treatment period.. There is a unique form of anemia in patients with long-term IDDM and clinically normal renal function who respond to low-dose epoetin alfa therapy. The rapid response to therapy and depressed baseline erythropoietin titers suggest the anemia is due to a lack of endogenous EPO release.

Topics: Aged; Aged, 80 and over; Anemia; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Glycated Hemoglobin; Hematinics; Hematocrit; Humans; Male; Middle Aged; Potassium; Recombinant Proteins; Treatment Outcome

To explore the possible pathogenetic role of erythropoietin (EPO) in the anaemia associated with cyclosporin (Cs) in newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM).. A multicentre randomized placebo controlled prospective trial of Cs immunosuppression for 12 months in IDDM patients.. Patients were recruited from the out-patient clinics of diabetes centres in Europe and Canada.. Patients 9-35 years old with a clinical diagnosis of ketonuric IDDM entering less than 6 weeks after diagnosis. 188 patients were originally recruited; 105 patients completed the investigation, 52 patients being treated with Cs, and 53 patients receiving placebo.. Random allocation to receive either Cs or placebo. The initial dose of Cs was 10 mg kg-1 BW day-1. Therapy was maintained for 12 months.. B-Haemoglobin, s-creatinine, and s-EPO concentrations were monitored before, during and after therapy with either Cs or placebo.. Blood-haemoglobin (Hgb) fell from 8.5 +/- 0.8 to a nadir of 7.8 +/- 0.9 mmol l-1 at 6 months (P < 0.0001) in IDDM patients treated with Cs but not in the placebo patients (8.5 +/- 0.8 to 8.8 +/- 0.9 mmol l-1, NS). The mean serum EPO levels remained unaltered throughout the 6-month period of Cs and placebo therapy. No significant differences in serum EPO levels between Cs and placebo-treated diabetic patients were found after 6 months of treatment.. The light anaemia associated with Cs therapy in IDDM patients is not related to an insufficient production of EPO, but is caused by other, as yet unknown mechanisms, unrelated to the nephrotoxic action of this drug.

Topics: Adolescent; Adult; Anemia; Autoimmune Diseases; Child; Cyclosporine; Diabetes Mellitus, Type 1; Double-Blind Method; Erythropoietin; Follow-Up Studies; Humans; Prospective Studies; Time Factors

Erythropoietin (EPO) is known to stimulate erythropoiesis after binding with its specific receptor. In clinics, EPO is widely used in hemodialyzed patients with diabetes. However, changes in the expression of the erythropoietin receptor (EPOR) under diabetic conditions are still unclear. Therefore, we investigated EPOR expression both in vivo and in vitro. Streptozotocin-induced type 1-like diabetic rats (STZ rats) were used to evaluate the blood glucose-lowering effects of EPO. The expression and activity of the transducer and activator of transcription 3 (STAT3), the potential signaling molecule, was investigated in cultured rat skeletal myoblast (L6) cells incubated in high-glucose (HG) medium to mimic the in vivo changes. The EPO-induced reduction in hyperglycemia was more pronounced in diabetic rats. The increased EPOR expression in the soleus muscle of diabetic rats was reversed by the reduction in hyperglycemia. Glucose uptake was also increased in high-glucose (HG)-treated L6 cells. Western blotting results indicated that the EPO-induced hyperglycemic activity was enhanced mainly through an increase in EPOR expression. Increased EPOR expression was associated with the enhanced nuclear expression of STAT3 in HG-exposed L6 cells. In addition, treatment with siRNA specific to STAT3 reversed the increased expression of EPOR observed in these cells. Treatment with Stattic at a dose sufficient to inhibit STAT3 reduced the expression level of EPOR in STZ rats. In conclusion, the increased expression of EPOR by hyperglycemia is mainly associated with an augmented expression of nuclear STAT3, which was identified both in vivo and in vitro in the present study.

Topics: Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Erythropoiesis; Erythropoietin; Hyperglycemia; Male; Rats; Rats, Wistar; Receptors, Erythropoietin; Streptozocin

We have previously reported that the topical application of erythropoietin (EPO) to cutaneous wounds in rats and mice with experimentally induced diabetes accelerates their healing by stimulating angiogenesis, reepithelialization, and collagen deposition, and by suppressing the inflammatory response and apoptosis. Aquaporins (AQPs) are integral membrane proteins whose function is to regulate intracellular fluid hemostasis by enabling the transport of water and glycerol. AQP3 is the AQP that is expressed in the skin where it facilitates cell migration and proliferation and re-epithelialization during wound healing. In this report, we provide the results of an investigation that examined the contribution of AQP3 to the mechanism of EPO action on the healing of burn wounds in the skin of pigs with experimentally induced type 1 diabetes. We found that topical EPO treatment of the burns accelerated their healing through an AQP3-dependent mechanism that activates angiogenesis, triggers collagen and hyaluronic acid synthesis and the formation of the extracellular matrix (ECM), and stimulates reepithelialization by keratinocytes. We also found that incorporating fibronectin, a crucial constituent of the ECM, into the topical EPO-containing gel, can potentiate the accelerating action of EPO on the healing of the burn injury.

Topics: Administration, Topical; Angiogenesis Inducing Agents; Animals; Aquaporin 3; Burns; Collagen; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Erythropoietin; Extracellular Matrix; Fibronectins; Hyaluronic Acid; Keratinocytes; Neovascularization, Physiologic; Re-Epithelialization; Skin; Swine; Wound Healing

Erythropoietin (EPO) is widely used in diabetic patients receiving hemodialysis. The role of EPO in glucose homeostasis remains unclear. Therefore, we investigated the effect of EPO on hyperglycemia in rats with type 1-like diabetes.. Rats with streptozotocin-induced type 1-like diabetes (STZ rats) were used to estimate the blood glucose-lowering effects of EPO, and changes in the expression levels of glucose transporter 4 (GLUT4) and the hepatic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were identified by Western blot analysis.. EPO attenuated the hyperglycemia in the STZ rats in a dose-dependent manner without altering the hematopoietic parameters, including the hematocrit and number of red blood cells. The involvement of the EPO receptor (EPOR) was identified using EPOR-specific antibodies. In addition, injection of EPO enhanced the glucose utilization, which was assessed using an intravenous glucose tolerance test in rats. However, blood insulin was not changed by EPO in this assay, showing the insulinotropic action of EPO. Moreover, EPO treatment increased the insulin sensitivity. Western blots indicated that the phosphorylation of AMP-activated protein kinase was enhanced by EPO to support the signaling caused by EPOR activation. Furthermore, the decrease in the GLUT4 level in skeletal muscle was reversed by EPO, and the increase in the PEPCK expression in liver was reduced by EPO, as shown in STZ rats.. Taken together, the results show that EPO injection may reduce hyperglycemia in diabetic rats through activation of EPO receptors. Therefore, EPO is useful for managing diabetic disorders, particularly hyperglycemia-associated changes. In addition, EPO receptor will be a good target for the development of antihyperglycemic agent(s) in the future.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Erythropoietin; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Rats; Rats, Wistar; Streptozocin

To investigate the intravitreal levels of potent vasoactive, angiogenic and extracellular matrix remodelling factors in the diabetic patients with simvastatin treatment.. This is an institutional, prospective, observational case-control study. Type-1 and type-2 diabetic patients on lipophilic simvastatin (N = 14) compared with patients without statin medication (N = 50). Vitreous samples were subjected to protein measurements of angiopoietin (Ang)-1 and Ang-2, erythropoietin (EPO), transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) by ELISA and matrix metalloproteinase (MMP)-2 and MMP-9 by gelatin zymography.. Intravitreal levels of Ang-2 (p = 0.029), VEGF (p = 0.001) and proMMP-9 (p = 0.015) were lower in simvastatin-treated than in non-statin-treated controls. In diabetics with macular oedema (DME), intravitreal Ang-2 (p = 0.006) and VEGF (p = 0.002) levels were lower in simvastatin-treated patients compared with non-statin-treated controls. In those patients with proliferative diabetic retinopathy (PDR), intravitreal Ang-2 (p = 0.002), TGF-β1 (p = 0.037), VEGF (p = 0.001) and pro- and totalMMP-9 (p = 0.004 and p = 0.007) levels were lower when receiving simvastatin medication.. In diabetic patients with DME or PDR, the intravitreal levels of permeability and proangiogenic factors Ang-2 and VEGF were lower in simvastatin-treated than in those without statin medication. Moreover, the levels of MMP-9 and TGF-β1, factors involved in the breakdown of basement membrane and fibroproliferation, were lower in patients with PDR having simvastatin medication. When acetylsalicylic acid was combined with simvastatin treatment, the intraocular levels of Ang-2 and VEGF were significantly lower than in diabetics treated with simvastatin alone. These data provide a novel insight into the potential protective mechanisms underlying simvastatin medication in patients with diabetic retinopathy complications.

Topics: Adult; Aged; Angiopoietin-2; Biomarkers; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Hypolipidemic Agents; Macular Edema; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Prospective Studies; Simvastatin; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Vitrectomy; Vitreous Body

Small-diameter nerve fibers, which subserve nociception, can be affected early in peripheral neuropathies, although their injury may not be detectable by routine neurophysiologic tests. On the other hand, skin biopsy has proved to be a reliable tool to examine nonmyelinated nerve fibers, as assessed by the quantification of intra-epidermal nerve fiber (IENF) density not only along with the degenerative process but, noteworthy, IENF density could be very helpful in evaluating drug efficacy such as erythropoietin (EPO) treatment.

Topics: Animals; Diabetes Mellitus, Type 1; Erythropoietin; Male; Nerve Fibers; Nociception; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley

Angiogenesis in diabetic retinopathy (DR) is a multifactorial process regulated by hypoxia-induced growth factors and inflammatory cytokines. In addition to the angiogenic switch, the proteolytic processing and altered synthesis of the extracellular matrix are critical steps in this disease. This study was performed to evaluate the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9), angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF), erythropoietin (EPO) and transforming growth factor-β1 (totalTGFβ1) in the vitreous of diabetic eyes undergoing vitrectomy compared with control eyes operated because of macular hole or pucker.. Prospective consecutive controlled observational study performed in the unit of vitreoretinal surgery in Finland during the years 2006-2008. Vitreous samples were collected before the start of the conventional 3-ppp vitrectomy. Vitreous MMP-2 and MMP-9, Ang-1 and Ang-2, VEGF, EPO and TGFβ1 concentrations were measured from 69 patients with Type 1 or 2 diabetes and 40 controls.. Comparison of eyes with DR with controls revealed that the mean vitreous concentrations of proMMP-2 (p = 0.0015), totalMMP-2 (p = 0.0011), proMMP-9 (p = 0.00001), totalMMP-9 (p < 0.00001), Ang-2 (p < 0.00001), VEGF (p < 0.00001), EPO (p < 0.00001) and totalTGFβ1 (p = 0.000026) were significantly higher in the former group. A multivariate logistic regression analysis suggested intravitreal Ang-2 concentration being the key marker of PDR (p = 0.00025) (OR = 1507.9).. The main new finding is that the intravitreal concentrations of Ang-2 correlated significantly with MMP-9, VEGF, EPO and TGFβ1 levels in diabetic eyes undergoing vitrectomy. Thus, these factors could promote retinal angiogenesis synergistically.

Topics: Aged; Angiopoietin-1; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Prospective Studies; Retinal Neovascularization; Retinal Perforations; Tomography, Optical Coherence; Transforming Growth Factor beta1; Up-Regulation; Vascular Endothelial Growth Factor A; Vesicular Transport Proteins; Vitrectomy; Vitreous Body

In spite of improvement in obstetrical care, pregnancy in women with type 1 diabetes mellitus is associated with increased perinatal morbidity and mortality. Hyperglycemia during pregnancy causes excessive fetal growth and chronic fetal hypoxia as reflected in increased erythropoietin (EPO) levels in amniotic fluid (AF).. We hypothesized that the degree of fetal hypoxia would correlate with fetal oxidative and nitrosative stress as evidenced ty the concentration of specific biomarkers in AF.. 19 pregnant women with type 1 or insulin-treated gestational diabetes mellitus were studied. AF samples were collected and processed for EPO, meta-tyrosine, nitro-tyrosine and 8-hydroxy-2-deoxiguanosine by chemiluminescent immunoassay and high-performance liquid chromatography coupled to tandem mass spectrometry methods, respectively.. The mean (SD) of the last HbA1c concentration before delivery was 7.7% (1.1). Median gestational age was 258 days (range 231-268). Birth weight was 3,868 ± 695 g with a z-score >2 SD in 47% of the cases. A significant correlation was found between the concentrations of AF EPO and meta-tyrosine/phenylalanine ratio (p < 0.001), nitro-tyrosine (p < 0.01) and 8-oxo-dG/2dG ratio (p < 0.001).. We confirmed that fetuses of type 1 diabetes or insulin-treated gestational diabetes pregnancies experience chronic hypoxia as reflected by increased EPO concentrations in AF near term. Moreover, EPO levels significantly correlated with the concentration of oxidative and nitrosative stress biomarkers in AF. This pro-oxidant status may predispose newborn infants to poor postnatal adaptation and early neonatal complications.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Amniocentesis; Amniotic Fluid; Biomarkers; Birth Weight; Chromatography, High Pressure Liquid; Chronic Disease; Deoxyguanosine; Diabetes Mellitus, Type 1; Diabetes, Gestational; Erythropoietin; Female; Fetal Hypoxia; Gestational Age; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoassay; Infant, Newborn; Insulin; Male; Nitrosation; Oxidative Stress; Pilot Projects; Pregnancy; Pregnancy in Diabetics; Tandem Mass Spectrometry; Tyrosine; Young Adult

The Akita mouse is a robust model of diabetic autonomic neuropathy which develops severe diabetes following beta cell death, which occurs reproducibly at 3-4 weeks of age, and maintains the diabetic state without therapy for as long as 11 additional months. Neuritic dystrophy and neuronopathy involving prevertebral sympathetic superior mesenteric and celiac ganglia begin to develop within the first two months of onset of diabetes and are progressive with time. We have examined the effect of insulin implants resulting in normoglycemia and injections of ARA290, a small erythropoietin peptide which has no effect on glycemic parameters, on the reversal of established neuritic dystrophy and neuronopathy. We have found that 4 weeks of insulin therapy beginning at 2 months of diabetes resulted in normalization of blood glucose, body weight and HbA1c. Insulin therapy successfully reversed established neuritic dystrophy and neuronopathy to control levels. Numbers of sympathetic neurons were not significantly changed in either 3 month diabetic or insulin-treated Akita mice. Treatment with ARA290 for 7 weeks beginning at 4 months of diabetes did not result in altered metabolic severity of diabetes as measured by blood glucose, body weight or HbA1c levels. ARA290 treatment was able to decrease neuritic dystrophy by 55-74% compared to untreated diabetics or in comparison to a separate group of diabetic animals representing the 4 month treatment onset point. Surprisingly, there was no effect of ARA290 on ganglionic neuron number or ongoing neuronopathy (pale/degenerating neurons) in diabetic Akita mice during this time period. The development of neuroprotective EPO-like peptides may provide a possible future therapy for this debilitating complication of diabetes; however, it appears that discrete elements may be differentially targeted by the diabetic state and may require selective therapy.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Disease Models, Animal; Erythropoietin; Ganglia, Sympathetic; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron; Nerve Degeneration; Neurites; Peptides

To determine whether sequence variation in the erythropoietin gene (EPO) is associated with the development of diabetic retinopathy (DR).. This was a multicenter study based on 518 subjects with long-standing diabetes mellitus (DM), 173 with type 1 DM (T1DM) and 345 with type 2 DM (T2DM). Study groups consisted of 233 control subjects with no DR, 155 subjects with nonproliferative DR, 126 with proliferative DR, and 90 with clinically significant macular edema. Subjects with end-stage renal disease were excluded. DNA extracted from blood of each subject was genotyped for 3 EPO single-nucleotide polymorphisms (SNPs).. All 3 SNPs in EPO were associated with overall DR status in the combined T1DM and T2DM and T2DM alone groups (CC genotype of rs507392, P < .008; GG genotype of rs1617640, P < .008; and CC genotype of rs551238, P < .008) in the multivariate analysis. The GCC haplotype was also associated with overall DR status in the combined DM and T2DM alone groups (P = .008) by multivariate analysis. All SNPs and the GCC haplotype were also associated with proliferative DR and clinically significant macular edema in the combined DM and T2DM alone groups. No associations were found with T1DM alone.. Sequence variation in EPO is associated with the risk of DR independent of duration of DM, degree of glycemic control, and nephropathy.. Identifying EPO genetic markers for high risk of developing DR could lead to the possibility of developing novel treatments or preventive therapies.

Topics: Adult; Blood Pressure; Body Mass Index; Cholesterol; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Female; Genotype; Glycated Hemoglobin; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors

Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe hypoglycaemia in a cohort of patients with type 1 diabetes.. Prospective observational follow-up study.. Totally 219 patients with type 1 diabetes (41% females, age 46+/-13 years (mean+/-s.d.), duration of diabetes 21+/-12 years, and HbAlc 8.5+/-1.1%) were followed in a 1-year observational study. Plasma EPO and serum VEGF levels were measured at baseline with ELISA. Events of severe hypoglycaemia defined by third party assistance were recorded and validated in telephone interviews within 24 h.. Totally 235 episodes of severe hypoglycaemia (1.1 episodes per patient-year) were reported by 82 patients (37%). At baseline, plasma EPO was 8.6 (3.1-34.3) U/l (median (range)), and serum VEGF was 52.2 (6.6-337) pg/ml. The levels of EPO and VEGF were not associated with frequency of severe and mild hypoglycaemia. The levels of EPO were not associated with age, sex, duration of diabetes, body mass index, HbAlc, C-peptide level or hypoglycaemia awareness status. The levels of VEGF were positively associated with age and female sex.. Although several studies suggest that VEGF and EPO may affect brain function during hypoglycaemia, this study does not support random VEGF or EPO levels to determine future risk of severe hypoglycaemia in people with type 1 diabetes.

Topics: Adult; Age Factors; Biomarkers; Diabetes Mellitus, Type 1; Erythropoietin; Female; Follow-Up Studies; Humans; Hypoglycemia; Male; Middle Aged; Prospective Studies; Risk Factors; Severity of Illness Index; Sex Factors; Vascular Endothelial Growth Factor A

A common feature among all forms of diabetes mellitus is a functional β-cell mass insufficient to maintain euglycemia; therefore, the promotion of β-cell growth and survival is a fundamental goal for diabetes prevention and treatment. Evidence has suggested that erythropoietin (EPO) exerts cytoprotective effects on nonerythroid cells. However, the influence of EPO on pancreatic β cells and diabetes has not been evaluated to date. In this study, we report that recombinant human EPO treatment can protect against diabetes development in streptozotocin-induced and db/db mouse models of type 1 and type 2 diabetes, respectively. EPO exerts antiapoptotic, proliferative, antiinflammatory, and angiogenic effects within the islets. Using β-cell-specific EPO receptor and JAK2 knockout mice, we show that these effects of EPO result from direct biological effects on β cells and that JAK2 is an essential intracellular mediator. Thus, promotion of EPO signaling in β cells may be a novel therapeutic strategy for diabetes prevention and treatment.

Topics: Animals; Apoptosis; Blood Glucose; Blotting, Western; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Erythropoietin; Female; Gene Expression Regulation; Humans; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Janus Kinase 2; Ki-67 Antigen; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Erythropoietin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction

Preservation of cognitive function during hypoglycaemic episodes is crucial for patients with insulin-treated diabetes to avoid severe hypoglycaemic events. Erythropoietin has neuroprotective potential. However, the role of erythropoietin during hypoglycaemia is unclear. The aim of the study was to explore plasma erythropoietin response to hypoglycaemia and the relationship to basal renin-angiotensin system (RAS) activity and cognitive function.. We performed a single-blinded, controlled, cross-over study with induced hypoglycaemia or maintained glycaemic level. Nine patients with type 1 diabetes with high and nine with low activity in RAS were studied. Hypoglycaemia was induced using a standardized insulin-infusion.. Overall, erythropoietin concentrations increased during hypoglycaemia. In the high RAS group erythropoietin rose 29% (p=0.032) whereas no significant response was observed in the low RAS group (7% increment; p=0.43). Independently, both hypoglycaemia and high RAS activity were associated with higher levels of erythropoietin (p=0.02 and 0.04, respectively). Low plasma erythropoietin at baseline was associated with poorer cognitive performance during hypoglycaemia.. Hypoglycaemia triggers a rise in plasma erythropoietin in patients with type 1 diabetes. The response is influenced by basal RAS activity. Erythropoietin may carry a neuroprotective potential during hypoglycaemia.

Topics: Adult; Blood Glucose; C-Peptide; Cognition; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 1; Erythropoietin; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Renin-Angiotensin System; Single-Blind Method

To investigate the relationship between Erythropoietin (EPO) and 1,25-dihydroxyvitamin D levels, and tubular damage in patients with diabetes mellitus (DM) without persistent microalbuminuria.. We measured serum EPO and 1,25-dihydroxyvitamin D levels and tubular injury markers such as urinary N-acetyl-beta-d-glucosaminidase (NAG) and retinol binding protein (RBP) levels in 41 non-diabetic controls, 40 patients with Type 1 and 40 with Type 2 DM.. Median serum EPO levels were lower in Type 1 (2.57 mIU/ml: p<0.001) and Type 2 DM (5.69 mIU/ml: p=0.044) than in controls (8.76 mIU/ml), though haemoglobin levels did not differ. Median 1,25-dihydroxyvitamin D levels were lower in Type 1 (41.0 pmol/l: p=0.001) and Type 2 DM (41.8 pmol/l: p=0.035) than in controls (56.1 pmol/l), though serum creatinine, calcium, phosphate and PTH levels did not differ. Median RBP excretion was higher in Type 2 DM (0.35 mg/l vs. 0.23 mg/l: p=0.013) than in controls. Median NAG excretion was higher in Type 1 DM (1,079 micromol/h vs.1,030 micromol/h: p=0.048) compared to controls.. Tubulo-interstitial damage with low levels of EPO and 1,25-dihydroxyvitamin D occurs early in Type 1 and Type 2 DM before persistent microalbuminuria.

Topics: Adult; Albuminuria; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Glycated Hemoglobin; Humans; Kidney Tubules; Male; Middle Aged; Reference Values; Vitamin D; Young Adult

Diabetic patients with nephropathy show a decline of hemoglobin even at a moderate degree of kidney dysfunction which may impair cardiovascular prognosis. As main reason a disturbed synthesis of erythropoietin (EPO) has been suggested, the pathogenesis, however, is unclear. The clinical significance of metabolic control for the hemoglobin and EPO levels was investigated.. The following parameters were determined in 185 type 1 diabetic patients: hemoglobin, HbA1c, calculated creatinine clearance, urinary albumin/creatinine ratio, lipids, high-sensitive C-reactive protein (hsCRP). Serum concentration of EPO was determined in 56 consecutive patients with renal dysfunction.. Hemoglobin concentration decreased with declining renal function. Patients were stratified according to median HbA1c level (7.4%) in those with better (HbA1c < 7.4%) and worse metabolic control (HbA1c > 7.4%). In patients with kidney dysfunction, the group with better metabolic control showed higher hemoglobin concentrations than the group with worse metabolic control: 13.6 versus 12.6 g/dl at creatinine clearance < 60 ml/min (p = 0.02). Linear regression analysis revealed metabolic control aside from kidney function, gender, hsCRP and use of ACE inhibitiors as a significant influencing factor of hemoglobin concentration. In patients with renal dysfunction, EPO levels were higher in the group with better than worse metabolic control (13.0 vs. 9.8 U/l).. The decline of hemoglobin in diabetic patients with renal dysfunction is mitigated in case of good metabolic control, possibly due to higher EPO concentrations. The results emphasize the clinical significance of a good metabolic control in diabetic patients with nephropathy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Regression Analysis; Triglycerides

To determine the effects of maternal diabetes on fetal iron status using serum transferrin receptors (STfR) and their ratio to ferritin (TfR-F index) in cord blood.. Iron, ferritin, erythropoietin, STfR and haemoglobin concentration were measured and TfR-F index calculated in 97 maternal/cord blood pairs. Forty-nine women had type 1 diabetes (diagnosed before pregnancy) and these were compared with forty-eight non- diabetic controls. The women with type 1 diabetes were recruited consecutively from attendance at the joint antenatal endocrine clinic while the control group of women was recruited from consecutive attendance at the remaining antenatal clinics.. The infants of the diabetic women had significantly lower levels of ferritin (47 vs 169 mug/l; p<0.01) and higher STfR (17.4 vs 12.9 mg/l; p<0.01) and TfR-F index (10.4 vs 5.8; p<0.01) than controls. They were also significantly more acidotic at birth (7.25 vs 7.30; p<0.01), were born at an earlier gestation (36.7 vs 39.7 weeks; p<0.01) and had higher z Scores for weight (0.53 vs 0.02; p = 0.016).. Maternal diabetes causes depletion of fetal iron stores and is associated with higher fetal iron demands as indicated by higher STfR level and TfR-F index in cord blood.

Topics: Birth Weight; Diabetes Mellitus, Type 1; Erythropoietin; Female; Ferritins; Fetal Blood; Humans; Hydrogen-Ion Concentration; Infant, Newborn; Iron; Maternal-Fetal Exchange; Pregnancy; Pregnancy in Diabetics; Receptors, Transferrin

The present study investigated the relationship between hemoglobin (Hb) levels and autonomic failure using a sensitive marker, coefficient of variation of R-R intervals in electrocardiogram (CVR-R) in order to clarify a cause of normocytic normochromic anemia in type 1 diabetic patients without overt nephropathy. We recruited 46 patients with type 1 diabetes and measured creatinine clearance (Ccr), HbA1c, albuminuria, Hb levels and CVR-R of all patients. In addition, the status of diabetic retinopathy and neuropathy were also evaluated. Serum erythropoietin (EPO), Fe, total iron binding capacity, lactate dehydrogenase, total bilirubin levels and number of reticulocytes and mean corpuscular volume were also measured to distinguish types of anemia. To survey the statistical correlation existing between Hb and body mass index (BMI), Ccr, HbA1c, albuminuria or retinopathy, multiple regression analysis was performed. Serum EPO, Fe, TIBC, LDH and TB levels and number of reticulocytes and MCV were within normal limits. Multiple regression analysis disclosed that HbA1c, nephropathy evaluated by albuminuria and Ccr, and retinopathy has no concern with Hb level. There is only significant relationship between Hb levels and CVR-R. Similar results were obtained even if we analyzed a group of male and female separately. We conclude that CVR-R has the strong relationship on anemia without overt nephropathy in type 1 diabetes, indicating that autonomic failure contributes on the progression of anemia via a poor response of EPO to anemia.

Topics: Adult; Aged; Albuminuria; Anemia; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electrocardiography; Erythropoietin; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Sensitivity and Specificity

Maternal diabetes increases the risk of intrauterine hypoxia. Inflammation may play a role in the pathogenesis of hypoxia-related neonatal complications. We studied correlations between levels of cord serum C-reactive protein (CRP), measured by a highly sensitive immunofluorometric assay, and indices of fetal hypoxia in diabetic pregnancies. Cord serum CRP correlated positively with amniotic fluid erythropoietin and umbilical artery pCO2. A negative correlation existed between cord serum CRP and umbilical artery pH and pO2. Amniotic fluid erythropoietin showed an independent effect on cord serum CRP in multiple regression analysis. These data suggest that the fetus responds to hypoxia by an inflammatory reaction.

Topics: Adult; Amniotic Fluid; Body Mass Index; C-Reactive Protein; Carbon Dioxide; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Fluoroimmunoassay; Humans; Hydrogen-Ion Concentration; Inflammation; Oxygen; Pregnancy; Pregnancy in Diabetics; Regression Analysis; Umbilical Arteries

Coincidental with the pandemic growth of diabetes as the prime cause of end-stage renal disease (ESRD), blindness attributable to diabetic retinopathy has become a major concern for all those involved in the care of diabetic ESRD patients. Vision loss is linked to progression of proliferative retinopathy and macular edema.. Extracted from a study of azotemic anemic pre-ESRD patients treated with erythropoietin, a cohort of five diabetic subjects was reassessed in terms of stability of renal function, changes in blood rheology, and course of diabetic eye disease.. All subjects reported subjective improvement in well-being, including enhanced effort tolerance following an increase in hematocrit from a baseline level of to 29.6 +/- 2.0% to a level of 39.5 +/- 2.4% after one year of treatment with erythropoietin (P = <0.0005). Neither hypertension nor deterioration of renal function was noted in any subject. Three patients with macular edema evinced substantive improvement-based stable vision and documented resolution noted in flourescein angiography.. Erythropoietin treatment of anemic azotemic diabetic patients is well tolerated. In a small observational retrospective study of three patients with macular edema, retention of vision and resolution of exudates was noted.

Topics: Anemia; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Female; Humans; Middle Aged; Papilledema; Uremia

We evaluated the concentrations of vascular endothelial growth factor (VEGF) and angiogenin in the umbilical cord blood from 14 fetuses with erythroblastosis or alloimmune thrombocytopenia and at birth from 28 preterm fetuses, from 42 healthy term fetuses, and from 24 term fetuses born to mothers with insulin-treated diabetes. A correlation appeared between VEGF and angiogenin levels (r = 0.44, p = 0.038). The gestational age correlated with both VEGF (r = 0.38, p = 0.0008) and angiogenin levels (r = 0.80, p = 0.0001). The concentration of VEGF was lower in fetuses born to mothers with insulin-treated diabetes than in the healthy term fetuses (p = 0.0028), but this difference was absent for angiogenin (p > 0.05). In conclusion, in umbilical cord plasma, a developmental increase was evident in concentrations of VEGF and angiogenin during the last trimester of gestation. That the umbilical cord VEGF level was lower in term fetuses born to mothers with diabetes than in term fetuses of healthy mothers may be associated with an aberrant fetal vascular development in diabetic pregnancies.

Topics: Diabetes Mellitus, Type 1; Embryonic and Fetal Development; Erythroblastosis, Fetal; Erythropoietin; Female; Fetal Blood; Gestational Age; Humans; Insulin; Isoantibodies; Male; Pregnancy; Pregnancy in Diabetics; Ribonuclease, Pancreatic; Thrombocytopenia; Vascular Endothelial Growth Factor A

Patients with the acute porphyrias may develop renal failure and autonomic dysfunction. Renal damage and sympathetic failure may both cause erythropoietin (EPO) deficiency. In this study, we have investigated serum erythropoietin levels and autonomic function in patients with acute porphyria in clinical remission.. Serum erythropoietin levels and the corresponding haemoglobin (Hb) were assayed in 31 patients with acute porphyria and were compared to 15 type 1 diabetic patients with autonomic neuropathy, 23 patients with iron-deficiency anaemia and 18 healthy individuals.. 9 out of 31 porphyric patients showed a normochromic normocytic anaemia with normal ferritin levels. Three patients had borderline-raised serum creatinine levels, and one of them was anaemic. Autonomic function was investigated in seven patients, six of them being anaemic, and the results were normal. Patients with iron-deficiency anaemia showed the expected increase in serum erythropoietin levels in response to a decreasing haemoglobin (r=-0.86, p<0.001). Patients with porphyria had inappropriately low serum erythropoietin levels for the degree of anaemia compared to iron-deficiency patients (p<0.001) although there was still a significant increase in serum erythropoietin with decreasing haemoglobin levels (r=-0.46, p=0.01). In contrast, diabetic autonomic neuropathy patients demonstrated a significant decrease in serum erythropoietin with decreasing Hb levels (r=+0.53, p=0.05).. Patients with acute porphyria may have inappropriately low levels of EPO. In contrast to the diabetic patients, this does not appear to be due to autonomic neuropathy but it may reflect mild renal tubular impairment.

Topics: Adult; Anemia, Iron-Deficiency; Creatinine; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged; Porphyria, Acute Intermittent; Reference Values

An erythropoietin (EPO)-deficient anaemia is recognized in Type 1 diabetic patients with early nephropathy and symptomatic autonomic neuropathy (DN). The aim of this study was to determine whether the EPO response to hypoxia was deficient in order to clarify the mechanisms involved in this process.. Five Type 1 diabetic patients DN (age 39 (28-48) years (mean (range))) with EPO-deficient anaemia (haemoglobin, Hb 10.6 (9.5-12.0) g/dl, EPO 5.0 (3.2-6.5) IU/l) and early diabetic nephropathy (persistent proteinuria 1161.6 (130-2835) mg/day, serum creatinine 97.6 (63-123) micromol/l)) were compared with nine normal subjects (age 31 (24-39) years, Hb 13.4 (11.8-15.7) g/dl, EPO 7.6 (5.6-10.3) IU/l) and four patients with non-diabetic advanced chronic renal failure RF (proteinuria 2157.5 (571-4578) mg/day, serum creatinine 490.2 (406-659) micromol/l, Hb 10.3 (9.0-11.3) g/dl, EPO 4.6 (2.9-8.5) IU/l). The subjects were exposed to 6 h of hypoxia (inspired oxygen 11.6-12.6%) by breathing a gas mixture via a hood. Hourly serum EPO levels were measured.. All groups showed a rise in EPO production after 2 h. The diabetic DN group achieved a similar maximal response to the normal subjects at 6 h (EPO 17.3 +/-5.4 vs. 17.8 +/-7.9 IU/l). The renal failure patients mounted an EPO response to hypoxia but at lower EPO levels.. Although the DN patients have inappropriately low EPO levels for the severity of their anaemia, they can mount an appropriate EPO response to moderate hypoxia. The mechanism underlying the EPO-deficient anaemia present in some diabetic patients remains unclear.

Topics: Adult; Anemia; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Female; Humans; Hypoxia; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria

Retroviral vectors encoding glucose-responsive promoters driving furin expression may provide an amplified, glucose-regulated secretion of insulin. We constructed LhI*TFSN virus to encode a glucose-regulatable transforming growth factor alpha promoter controlling furin expression with a viral LTR promoter driving constitutive expression of furin-cleavable human proinsulin. Autologous BB rat vascular smooth muscle cells transduced with LhI*TFSN virus and cultured in 1.7 and 16.7 mM glucose secreted 50.7 +/- 3.2 and 136.0 +/- 11.0 microU (mean +/- SD) of insulin per 10(6) cells per day, respectively. After the onset of diabetes spontaneously diabetic congenic DR lyp/lyp BB rats received stomach implants containing 2 x 10(6) LhI*TFSN-transduced primary rat vascular smooth muscle cells. In eight treated rats there was a major reduction in insulin requirement to as low as 25% of pretreatment level for up to 3 months and one rat became insulin free without hypoglycemia. Intraperitoneal glucose tolerance tests (IPGTTs) in diabetic rats receiving control implants did not show the characteristic decline in blood glucose of normal rats after glucose administration. In contrast, diabetic rats receiving LhI*TFSN-transduced cells showed significant clearances of blood glucose. These data suggest clinically significant levels of glucose-regulated insulin delivery from implanted vascular smooth muscle cells transduced with LhI*TFSN vector.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 1; Erythropoietin; Furin; Glucose; Glucose Tolerance Test; Humans; Insulin; Male; Muscle, Smooth, Vascular; Promoter Regions, Genetic; Rats; Rats, Inbred BB; RNA, Messenger; Subtilisins; Transduction, Genetic; Transforming Growth Factor alpha; Weight Gain

The normochromic normocytic anemia of erythropoietin (EPO) deficiency is recognized in advanced renal failure but not in early renal disease. The aim of this study was to determine whether anemia with EPO deficiency is found in type 1 diabetic patients with diabetic nephropathy in the absence of advanced renal failure and to compare them with patients with nondiabetic renal disease of similar severity.. A total of 27 type 1 diabetic patients with diabetic nephropathy (DN), defined as having persistent proteinuria (mean 1,086 mg/day [CI 120-5,1901), a serum creatinine < or = 180 micromol/l, and retinopathy, were compared with 26 nondiabetic patients with glomerulonephritis (GN) and persistent proteinuria (1,874 mg/day [349-5,005]). The Hb concentration, red cell indexes, and serum EPO levels were measured, and other causes for the anemia were excluded. The EPO values were compared with a normal reference range obtained from nondiabetic patients with a microcytic anemia. The DN patients were tested for signs of diabetic peripheral and autonomic neuropathy.. We found that 13 of the 27 DN patients were anemic (Hb 10.6 +/- 0.9 g/dl) in marked contrast to none of the GN patients (Hb 13.7 +/- 1.4 g/dl, P < 0.005). In the DN group, serum EPO concentrations failed to increase in response to anemia compared with the response seen in patients with microcytic anemia. Thus, the anemia of the DN group was associated with EPO deficiency. The anemic DN patients showed evidence of more severe proteinuria and diabetic neuropathy than the nonanemic DN patients.. Anemia associated with EPO deficiency can occur early in DN before the onset of advanced renal failure, but does not normally occur in nondiabetic renal disease of similar severity. The pathogenesis requires elucidation.

Topics: Adult; Anemia; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Female; Heart Rate; Hemoglobins; Humans; Male; Middle Aged; Proteinuria; Reference Values; Reproducibility of Results

We report the case of a 52-year-old woman with long-term type 1 diabetes mellitus, complicated with proliferative retinopathy, autonomic neuropathy and microalbuminuria and moderate renal failure. A normochromic, normocytic are generative anaemia had been diagnosed for three years. Clinical and biological investigations for the aetiology of anaemia remained normal or negative. Anaemia was associated with a concentration of erythropoietin (EPO) in the normal range, but inappropriately low regarding anaemia. Treatment with recombinant EPO induced a rapid increase in haemoglobin level and improved the patient's quality of life. The role of diabetic neuropathy in the genesis of anaemia, in conjunction with a modest renal impairment is discussed.

Topics: Albuminuria; Anemia; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electrocardiography; Erythropoietin; Female; Hemoglobins; Humans; Hypotension, Orthostatic; Kidney Failure, Chronic; Middle Aged; Quality of Life; Recombinant Proteins

Topics: Adult; Anemia; Diabetes Mellitus, Type 1; Erythropoietin; Female; Humans

Topics: Anemia; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Erythropoietin; Humans

The purpose of this study was to examine whether fetal leptin concentration correlates with severity of chronic or subchronic fetal hypoxia as indicated by increased fetal concentrations of erythropoietin in fetuses of mothers with Type I (insulin dependent) diabetes mellitus.. We measured leptin and erythropoietin concentrations in cord plasma and amniotic fluid with radioimmunoassay in 25 pregnancies (gestational age 37.2 +/- 1.0 weeks). Fetuses with amniotic fluid erythropoietin over 22.5 mU/ml were classified as hypoxic (n = 9) and those with amniotic fluid erythropoietin below 22.5 mU/ml (n = 16) as non-hypoxic.. The hypoxic fetuses had significantly higher cord leptin concentrations than non-hypoxic fetuses (median 36.8; range, 12.5-135.1 vs median 16.2; range, 3.7-52.2 micrograms/l), (p = 0.0066). Cord plasma leptin (n = 25) correlated directly with amniotic fluid erythropoietin (r = 0.727, p = 0.0001), with cord plasma erythropoietin (r = 0.644, p = 0.0005) and with the maternal last trimester HbA1C (r = 0.612, p = 0.0019) and negatively with cord artery pO2 (r = -0.440, p = 0.032), and pH (r = -0.414, p = 0.040).. Fetal leptin concentrations increased concomitantly with erythropoietin during chronic or subchronic hypoxia. This phenomenon could indicate a role for leptin in fetal adaptation to hypoxia.

Topics: Amniotic Fluid; Birth Weight; Body Constitution; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Hypoxia; Gestational Age; Glycated Hemoglobin; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Pregnancy in Diabetics; Reference Values; Regression Analysis

Topics: Adult; Anemia; Diabetes Mellitus, Type 1; Erythropoietin; Female; Humans; Male

The association of anemia and hyporeninemic hypoaldosteronism (HRHA) in type 1 diabetes has been described, and erythropoietin deficiency has been proposed as the cause. Subjects with type 1 diabetes with (n = 8) and without HRHA (n = 11) were studied, as were subjects taking angiotensin-converting enzyme inhibitors (ACEIs; n = 10). Renal function and sodium excretion were estimated with a 24-hour urine collection. Values for hemoglobin, hematocrit, serum erythropoietin, and red blood cell volume were determined. HRHA subjects were anemic (hemoglobin, 99 +/- 8 g/L ), and ACEI subjects had lower hemoglobin concentrations (120 +/- 4 g/L) compared with controls (134 +/- 3 g/L; P < 0.001 and P = 0.01, respectively). Also, the red cell mass in patients with HRHA was significantly less than that in controls (14.8 +/- 1.4 v 20.8 +/- 1.1 mL/kg; P = 0.004), indicating that the lower hemoglobin level in HRHA is not attributable to an expansion of extracellular volume. Erythropoietin levels in the HRHA (27% +/- 11% of predicted) and ACEI groups (43% +/- 9% of predicted) were low compared with controls (94% +/- 13% of predicted; P = 0.001 and P = 0.005, respectively). Renal function was greater than the levels at which anemia becomes a clinical feature in all groups, but creatinine clearance was less in the HRHA (63 +/- 12 mL/min/1.73 m2) and ACEI groups (76 +/- 11 mL/min/1.73 m2) compared with controls (123 +/- 9 mL/min/1.73 m2; P < 0.001 and P = 0.004, respectively). The fractional sodium reabsorption was decreased in HRHA (98.7% +/- 0.3%) and ACEI groups (98.7% +/- 0.3%) versus controls (99.4% +/- 0.1%; P = 0.007 and P = 0.01, respectively). Subjects with type 1 diabetes with HRHA had low hemoglobin concentrations that were caused, at least in part, by inappropriately low serum erythropoietin levels.

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Erythrocyte Volume; Erythropoietin; Female; Hematocrit; Humans; Hypoaldosteronism; Male; Renin; Renin-Angiotensin System

To discover whether Type 1 diabetic patients with autonomic neuropathy might be anaemic and erythropoietin (EPO)-depleted.. Fifteen Type 1 diabetic patients with serious complications (DM-COMP) were selected because of severe symptomatic autonomic neuropathy, including significant postural hypotension. All had proteinuria from nephropathy (three microalbuminuria and 12 macroalbuminuria), but a normal serum creatinine (< 122 micromol/l). They were compared to age and duration matched Type 1 diabetic controls without autonomic neuropathy (DM-controls) and non-diabetic patients with and without hypochromic, microcytic anaemia.. The DM-COMP patients were anaemic (mean haemoglobin (Hb) 11.1+/-1.2 g/dl), sometimes severely (minimum Hb 9.2 g/dl), compared to non-neuropathic DM-controls (Hb 13.7+/-0.7 g/dl; P < 0.001). Furthermore, EPO failed to increase in association with anaemia in the DM-COMP group compared to the progressive increase in the non-diabetic, anaemic patients (difference of regression lines P < 0.001), indicating EPO depletion in the anaemic, diabetic patients. There was no other demonstrable cause for the anaemia. Treatment with EPO in 5 DM-COMP patients led to a rapid increase in haemoglobin (range 1.7-5.0 g/dl) with improvement in wellbeing.. Some Type 1 diabetic patients with autonomic neuropathy present with an EPO-depleted anaemia, which responds to treatment with EPO. This observation supports the concept of autonomic neuropathy as a cause of anaemia with EPO depletion, although the role of established renal damage cannot be excluded.

Topics: Adult; Albuminuria; Anemia; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Female; Hemoglobins; Humans; Middle Aged; Proteinuria

The aim of the study was evaluation, whether cord blood insulin (Ic) and erythropoietin (EPO) levels differ in accordance with mode of delivery: cesarean section (CS) or vaginal delivery (VD).. The study was performed in the diabetic group consisted of 148 newborns of diabetic mothers (NDM)--90 of them with GDM and 58 with IDDM as well as in the control group consisted of 100 newborns born to healthy mothers. 52.0% of NDM and 38.0% control subjects were delivered by cesarean section. The most frequent reason for performing CS in the diabetic group was fetal distress before labor and in the control group--fetal distress during labor. Cord blood Ic and EPO levels were compared in accordance with type of delivery: CS or VD. Into statistical analysis Mann-Whitney test was used.. There were found that cord blood Ic and EPO levels in NDM born by CS are significantly higher than in those born by VD (Ic--38.2 +/- 41.5 versus 26.6 +/- 38.6 mIU/ml adequately and EPO--51.8 +/- 76.0 versus 26.8 +/- 29.9 mU/ml adequately). There were no such differences in the control group.. 1. Fetal hyperinsulinemia in perinatal period is often connected with occurrence of indications for performing cesarean section in pregnant women with diabetes mellitus. 2. Cesarean section in diabetic pregnant women is often connected with previous fetal hypoxia.

Topics: Adult; Cesarean Section; Delivery, Obstetric; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Humans; Pregnancy

Peripheral vascular disease is a serious and frequent problem in diabetic patients. Since the beginning of the widespread use of erythropoietin (EPO), we have noted an increase in peripheral vascular disease in diabetic patients receiving peritoneal dialysis and erythropoietin. This prompted us to study the effects of erythropoietin on peripheral vascular disease in patients receiving peritoneal dialysis. We retrospectively reviewed medical records of all diabetic patients in our program who received peritoneal dialysis from 1990 to 1996. Demographic and laboratory data as well as EPO use data were collected. Hospital days and occurrence of vascular events (defined as peripheral vascular surgery, amputation, or recommendation of vascular surgery or amputation by a vascular surgeon) were determined for diabetic patients receiving peritoneal dialysis. Comparisons were made between those who received EPO and those who did not received EPO, as well as comparing vascular events in 28 patients who received peritoneal dialysis before and after beginning EPO. Patients who received erythropoietin were found to have a significantly shorter time to a first vascular event, a greater number of vascular events, and more hospital days associated with vascular disease than diabetic patients who did not receive erythropoietin. With multivariate analysis, significant risk factors for the development of peripheral vascular disease in these patients were erythropoietin use, erythropoietin dose, and smoking. Twenty-eight patients who initially performed peritoneal dialysis without receiving EPO, and later received EPO, had a significant increase in vascular events, including amputations only while receiving EPO. We found the use of erythropoietin to be associated with peripheral vascular events in diabetic patients who receive peritoneal dialysis. Further investigation is warranted.

Topics: Adult; Aged; Amputation, Surgical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Ischemia; Kidney Failure, Chronic; Leg; Length of Stay; Male; Middle Aged; Myocardial Infarction; Peritoneal Dialysis; Recombinant Proteins; Retrospective Studies

Meticulous glucose control that begins long before conception is fundamental to protecting the fetus and mother. Maternal hypertension, retinopathy, renal disease, and neuropathy may lead to complications, but optimal education, care, and fetal monitoring can reduce the risks.

Topics: Adult; Algorithms; Antihypertensive Agents; Blood Glucose Self-Monitoring; Cesarean Section; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Female; Fetal Monitoring; Humans; Hypertension; Infant, Newborn; Insulin; Male; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy, High-Risk; Prenatal Care

In this study we determine the erythropoietin levels and hematocrit in 22 women with preterm labor, 21 with insulin-dependent diabetes, 22 with preeclampsia, and 20 with normal gestation. The erythropoietin level was higher in the preeclamptic group than in the diabetic group compared with the normal and premature groups. There were no hypoxic fetuses. From this study, we found that the mechanism of increased erythropoietin levels in neonates can be different from fetal hypoxia. Further studies are needed on this subject.

Topics: Adult; Birth Weight; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Humans; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Prospective Studies

Diabetic retinopathy improved in three patients with renal insufficiency after a rise in hematocrit induced by administration of recombinant erythropoietin. The change involved significant resorption of hard exudates in patients who were not eligible to receive laser treatment.. Three patients with diabetic nephropathy had the associated chronic anemia of renal insufficiency. In each patient, diabetic retinopathy with foveal/parafoveal hard exudates (but no clinically significant macular edema) was initially evaluated ophthalmoscopically. Fluorescein angiography demonstrated a low-grade diffuse leakage pattern. Treatment with subcutaneous recombinant erythropoietin (4000 IU twice weekly) was initiated within 1 to 3 months of initial evaluation. The resolution of hard exudates was observed on ophthalmoscopic examination and graded fundus photography (ETDRS seven standard field).. Within 6 months of initiation of erythropoietin treatment, a substantial reduction of exudate was observed in all three patients, the hematocrit having increased from a mean of 21% to a mean of 33% (a mean increase of 33% in each patient). Visual acuity improved in two patients and stabilized in the other. Follow-up fluorescein angiographic examination demonstrated no change in the leakage pattern.. Although no direct cause and effect relationship can be established, raising the red cell mass by treatment with recombinant erythropoietin may serve as adjunctive treatment of diabetic retinopathy in patients with diabetic renal insufficiency.

Topics: Absorption; Anemia; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Exudates and Transudates; Female; Fundus Oculi; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins

We have investigated the relationship between erythropoietin (Epo) and pH, PaO2 and haematocrit in 100 cord blood samples obtained at Caesarean section prior to labour. Of 82 term (> 37 weeks) infants, 64 were appropriately grown (10th-90th centiles), and their mean cord serum Epo and cord blood Epo was 23 +/- 8 mU/ml (mean +/- SD). Strong inverse correlations were found between cord serum Epo and cord blood pH (r = -0.74; p < 0.0001), and between cord serum Epo and cord blood PaO2 (r = -0.55; p < 0.0001), but not between cord serum Epo and cord haematocrit (r = 0.02; p < 0.9). For the 18 preterm babies (gestation 32.4 +/- 4.1 weeks, birth weight 1,820 +/- 476 g), the Epo level was 36 +/- 8 mU/ml, which was not significantly greater than for the term babies. Strong inverse correlations were again found between Epo and pH (r = -0.87; p < 0.0001) and Epo and PaO2 (r = -0.69; p < 0.002). Babies from complicated pregnancies (intra-uterine growth retardation, pre-eclampsia, antepartum haemorrhage, diabetes mellitus and fetal distress) tended to have higher Epo levels. Thirteen babies had Epo levels > 40 mU/ml, and 11 (85%) of these required neonatal intensive care. Cord serum Epo correlates better with oxygen tension and pH at birth than with fetal growth and haematocrit, which are measures of chronic stress to the fetus.

Topics: Cesarean Section; Cordocentesis; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Fetal Distress; Fetal Growth Retardation; Fetal Hypoxia; Hematocrit; Humans; Hydrogen-Ion Concentration; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Oxygen; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Uterine Hemorrhage

In the present study the antepartum relationship between maternal diabetic glucose control and fetal hypoxaemia was examined in 44 Type 1 (insulin-dependent) diabetic and 23 non-diabetic control pregnancies. Maternal HbA1C was used to assess maternal integrated blood glucose control while fetal metabolic control was evaluated by antepartum glucose, insulin, and C-peptide determinations in amniotic fluid at elective caesarean delivery. Fetal hypoxaemia was assessed indirectly by fetal umbilical vein plasma erythropoietin level at delivery. A prospectively developed statistical pathway model was used to examine the relationship of these variables. In applying forced stepwise multiple regression with this model, we observed in the diabetic subjects that mean maternal HbA1C during the last month of pregnancy correlated significantly with fetal umbilical venous erythropoietin at delivery (r = 0.57, p less than 0.001). Additional significant contributions to umbilical venous erythropoietin were found for amniotic fluid glucose and amniotic fluid insulin when these two independent variables were added in stepwise fashion (p less than 0.01). We conclude that in diabetic pregnancy, antepartum control of maternal hyperglycaemia is a significant factor associated with fetal hypoxaemia. We speculate that this effect is mediated through perturbations which accelerate fetal metabolism and which is expressed by amniotic fluid levels of glucose and insulin.

Topics: Amniotic Fluid; Biomarkers; Birth Weight; Blood Glucose; C-Peptide; Cesarean Section; Diabetes Mellitus, Type 1; Erythropoietin; Female; Fetal Blood; Glucose; Glycated Hemoglobin; Humans; Infant, Newborn; Insulin; Models, Biological; Pregnancy; Pregnancy in Diabetics; Prospective Studies; Reference Values; Regression Analysis; Umbilical Veins

Neonatal polycythemia is a well-established perinatal complication in infants of diabetic mothers (IDM). To investigate the regulation of erythropoiesis in these infants, we measured cord blood erythropoietin (EP) levels by a sensitive radioimmune assay and examined the growth of erythroid progenitor colonies in a series of IDM and control infants. Fifteen of 18 diabetic mothers were managed on a protocol emphasizing careful glycemic control throughout pregnancy; 10 had glycosolated hemoglobin values within the normal, nondiabetic range during the third trimester. Cord blood EP was elevated in one of 18 IDM and in two of 13 controls (p = NS). In IDM, cord blood EP values were higher in infants delivered following maternal labor and were inversely correlated with umbilical artery pH (r = -0.72; p = 0.006). Growth of burst forming units-erythroid was similar in IDM and controls in the presence of 0.1 to 2.0 U of exogenous EP per ml of methylcellulose medium. Individual infants tended to respond consistently over the entire range of EP doses tested. The number of burst forming units-erythroid observed did not correlate with cord blood EP, birth weight, or neonatal hematocrits. We conclude that: umbilical cord blood EP levels are generally normal in IDM delivered by mothers in whom good glycemic control is maintained throughout gestation, cord blood EP values are strongly influenced by perinatal events, and the response of erythroid progenitors to EP is intrinsically normal in IDM. These data suggest that polycythemia is an adaptive response in IDM and is not associated with a primary abnormality in erythropoiesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Cells, Cultured; Diabetes Mellitus, Type 1; Erythropoiesis; Erythropoietin; Female; Fetal Blood; Hematocrit; Humans; Infant, Newborn; Polycythemia; Pregnancy; Pregnancy in Diabetics; Radioimmunoassay; Stem Cells