losartan-potassium and Diabetes-Mellitus--Type-2

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

Diabetes is one of the leading causes of chronic kidney disease (CKD), and multiple underlying mechanisms involved in pathogenesis of diabetic nephropathy (DN) have been described. Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden, considering that about 40% of type 2 diabetes patients will develop nephropathy. In the past years, some research found that hypoxia response and hypoxia-inducible factors (HIFs) play critical roles in the pathogenesis of DN. Hypoxia-inducible factors (HIFs) HIF-1, HIF-2, and HIF-3 are the main mediators of metabolic responses to the state of hypoxia, which seems to be the one of the earliest events in the occurrence and progression of diabetic kidney disease (DKD). The abnormal activity of HIFs seems to be of crucial importance in the pathogenesis of diseases, including nephropathies. Studies using transcriptome analysis confirmed by metabolome analysis revealed that HIF stabilizers (HIF-prolyl hydroxylase inhibitors) are novel therapeutic agents used to treat anemia in CKD patients that not only increase endogenous erythropoietin production, but also could act by counteracting the metabolic alterations in incipient diabetic kidney disease and relieve oxidative stress in the renal tissue. In this review, we present the newest data regarding hypoxia response and HIF involvement in the pathogenesis of diabetic nephropathy and new therapeutic insights, starting from improving kidney oxygen homeostasis.

Topics: Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Humans; Hypoxia; Oxygen; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values.. The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

Topics: Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Tubules; Renal Reabsorption; Renin-Angiotensin System; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Topics: Adenosine Triphosphate; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Progression; Diuresis; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Glucose; Heart; Heart Failure; Hematocrit; Hemoglobins; Humans; Kidney; Kidney Tubules, Proximal; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Potassium-Exchanging ATPase; Sympathetic Nervous System

Topics: Acetamides; Aged; Anemia, Refractory; Anemia, Sideroblastic; Anti-Bacterial Agents; Arthroplasty; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Combined Modality Therapy; Comorbidity; Diabetes Mellitus, Type 2; Diagnosis, Differential; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Obesity, Morbid; Oxazolidinones; Polypharmacy; Postoperative Complications; Prosthesis-Related Infections; Reoperation

The triad of diabetes mellitus, anemia, and chronic kidney disease (CKD) define a group of patients at high risk for death and cardiovascular complications. The approval of epoetin alfa in 1989 transformed the treatment of anemia in patients with CKD. However, evidence has emerged from randomized controlled trials that correcting anemia with erythropoiesis-stimulating agents in CKD patients is associated with increased risk. Most recently, the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) study of anemic type 2 diabetic patients with CKD reported that treatment with darbepoetin conferred no benefit in mortality or in attenuating cardiovascular or renal events. Instead, there was a twofold higher rate of stroke and thromboembolic complications and a higher rate of cancer deaths in patients randomized to treatment with darbepoetin. Furthermore, there was an inconsistent and modest improvement in health-related quality of life. TREAT raises questions about whether anemia in type 2 diabetic patients should be treated and under what circumstances.

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins

Both chronic kidney disease (CKD) and type II diabetes mellitus (DM) are increasing in frequency among Western populations and both are potent risk factors for the development of anaemia. The presence of CKD and diabetes together represent the most important aetiopathogenic combination for the development of anaemia. New evidence has highlighted some of the underlying mechanisms which make diabetic patients more susceptible to dyserythropoiesis, particularly once they have developed concomitant CKD. In addition, recent publications from large-scale epidemiological studies have highlighted the impact of anaemia on diabetic patients. The purpose of this review was to focus on the pathophysiology and impact of anaemia in DM.

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Quality of Life

The number of diabetic patients with renal disease increased significantly in the last years worldwide. Anemia is an important and frequent component of diabetic nephropathy that may begin early in the course of the chronic renal disease of diabetics, and is more severe in diabetic patients with renal disease than in non - diabetic renal patients controlled for the same level of renal function. The reason for the anemia is decreased erythropoietin level caused by diminished production and, in a lesser degree, by increased excretion of erythropoietin in the urine. There is a close connection between diabetic nephropathy, anemia and cardiovascular complications. On the basis of small studies correction of anemia may decrease the progression of diabetic nephropathy and cardiovascular complications. However, the result of ongoing large randomised controlled studies are required to get "evidence-based" data to prove that correction of anemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, and on progression of diabetic nephropathy.

Topics: Anemia, Hypochromic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Time Factors

The combination of diabetes and chronic kidney disease is associated with increased mortality and reduced quality of life. Recent studies have shown that, in general, late referral of patients to the renal unit increases mortality, and that patients with diabetes who are referred late have a particularly poor prognosis. Several co-morbid conditions have been shown to contribute to poor patient outcomes, including both cardiovascular disease and anaemia. In patients with diabetic nephropathy, anaemia is more severe and is seen earlier than in patients with non-diabetic renal disease. Although the treatment of anaemia with recombinant human erythropoietin (rhEPO; epoetin) is well established, the only data currently available concerning the effects of early intervention in patients with diabetic nephropathy are from small-scale studies. Therefore, two large-scale studies have been designed to provide information on the efficacy of epoetin treatment and on how current management strategies might be improved. The Anaemia CORrection in Diabetes (ACORD) study will provide information on the potential cardiac benefits of early anaemia management in patients with early, type 2 diabetic nephropathy. The Individualised Risk-profiling In DIabEtes Mellitus (IRIDIEM) study will provide evidence-based guidance in risk factor management, by assessing the efficacy of individualized interventions.

Topics: Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Referral and Consultation; Survival Rate

The rising incidence of type 2 diabetes mellitus and of its complications will make it the most important health care challenge in the first quarter of the 21st Century. Diabetic nephropathy left unchecked will overwhelm the renal resources. Simple methods (proper diet and exercise, prevention of obesity) are successful in preventing type 2 diabetes in the great majority of the persons at risk. In patients with established type 2 diabetes, nephropathy can be prevented or greatly delayed by strict metabolic control, strict control of blood pressure using angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the first line of drugs, tight control of serum lipids using statins as indicated, low protein diet, avoidance of smoking and other nephrotoxic influences, prevention of abnormalities in calcium/phosphorus metabolism, and prevention of renal anemia by the early use of erythropoietin. Current research offers the promise of definitive prevention of both type 2 diabetes and diabetic nephropathy.

Topics: Albuminuria; Anemia; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Erythropoietin; Glomerular Filtration Rate; Humans; Hypertension; Mitochondria

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Failure, Chronic

Insulin resistance is a characteristic feature of uremia. As long as the hyperinsulinemia adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the beta cell compensatory response declines, and relative, or absolute, insulin deficiency develops. At this point glucose intolerance and eventually frank type 2 diabetes occur. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Several studies have confirmed that hemodialysis (HD) treatment significantly improves insulin resistance. Both CAPD and CCPD are shown to improve insulin resistance in uremic patients. Comparing the effect of PD and HD treatment, it was found that the CCPD group has significantly higher insulin sensitivity than the HD group with the CAPD group similar to HD. Treatment of calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia. Treatment with recombinant human erythropoietin (EPO) is an efficient way to increase hematocrit, to reverse cardiovascular problems and to improve insulin sensitivity. Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia and glucose intolerance in uremic patients. Thiazolidinediones (TZDs), the new insulin-sensitizing drugs, provide the proof that pharmacologic treatment of insulin resistance can be of enormous clinical benefit. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Hyperparathyroidism; Hypoglycemic Agents; Insulin Resistance; Phosphoric Diester Hydrolases; Pyrophosphatases; Recombinant Proteins; Renal Dialysis; Thiazoles; Thiazolidinediones; Uremia

Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion.. Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation.. Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation.. Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Humans; Hypoglycemic Agents; Kidney; Middle Aged; Perfusion; Treatment Outcome

Im Rahmen der vorliegenden Studie sollte der Einfluss des Weichteilschadens auf das klinische Ergebnis nach offener Ellenbogenluxation untersucht werden.. Von Oktober 2008 bis August 2015 wurden insgesamt 230 Patienten mit Ellenbogenluxation behandelt. Diese retrospektive Studie umfasst 21 Fälle von offenen Ellenbogenluxationen. Das Durchschnittsalter der Patienten betrug 49 Jahre alt (20–83 Jahre), 6 Patienten waren weiblich (29%), 15 männlich (71%). Das Bewegungsausmaß des verletzten und unverletzten Ellenbogens wurde erhoben und das funktionelle Ergebnis u. a. mittels Mayo Elbow Performance Score (MEPS), Mayo Wrist Score (MWS) und dem Disability of Arm, Shoulder and Hand (DASH) Score erfasst. Zusätzlich wurden Komplikationen und Revisionsoperationen aufgezeichnet. Der Einfluss des Weichteilschadens (I°/II° offen vs. III° offen) und des Luxationstyps (einfach vs. komplex) auf das klinische Ergebnis wurde analysiert.. Offene Ellenbogenluxationen können mit einem zufriedenstellenden klinischen Ergebnis einhergehen. Insbesondere komplexe offene Ellenbogenluxationen sind jedoch sehr komplikationsbehaftet, wobei neurovaskuläre Komplikationen am häufigsten auftreten.. The current high rate of multidrug-resistant gram-negative bacteria infections among hospitalised patients with cUTIs in the studied area is alarming. Our predictive model could be useful to avoid inappropriate antibiotic treatment and implement antibiotic stewardship policies that enhance the use of carbapenem-sparing regimens in patients at low risk of multidrug-resistance.. The results indicated differential patterns of Inhibition of Return between the High and Low shape/weight based self-worth groups. The High group displayed increased inhibition of return for the shape/weight stimuli relative to control stimuli, while the Low group displayed reduced inhibition of return for the shape/weight stimuli compared to control stimuli. The ED group displayed a similar pattern of results to the High group, but this did not reach significance.. The current findings indicate that young women without an eating disorder who base their self-worth on shape/weight display a pattern of avoidance of shape/weight stimuli that is in direct contrast to those at low risk of developing eating disorders. The possible implications of these specific patterns of inhibition of return across those at varying levels of risk for an eating disorder are discussed along with their implications for intervention approaches.. These results indicated that Sr. An unusually high HbA

Topics: Activities of Daily Living; Acute Disease; Adalimumab; Adaptation, Physiological; Adenosine Triphosphate; Adipose Tissue; Administration, Intravaginal; Adolescent; Adsorption; Adult; Adverse Childhood Experiences; Age Distribution; Age Factors; Aged; Aged, 80 and over; Air Pollution, Indoor; Aldehyde Oxidase; Alginates; Alloys; alpha-Globins; Aluminum Hydroxide; Alveolar Bone Loss; Anaerobiosis; Anesthesia, General; Anesthetics; Animals; Anovulation; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Bacillus cereus; Bacterial Typing Techniques; Bacteroidetes; Base Composition; Biocompatible Materials; Biofilms; Biological Availability; Biological Transport; Biosensing Techniques; Bipolar Disorder; Blood Glucose; Body Mass Index; Bone Regeneration; Boranes; Brachial Artery; Butyric Acid; Candida albicans; Carbon; Carcinoembryonic Antigen; Cell Differentiation; Cell Line, Tumor; Cell Respiration; Cell Survival; Cells, Cultured; Cerebrovascular Circulation; Charcoal; Child; Child Health; China; Chloride Channels; Chlorides; CHO Cells; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromium; Chronic Disease; Chronic Periodontitis; Circular Dichroism; Cities; Cohort Studies; Comamonadaceae; Comorbidity; Coronary Artery Disease; Corrosion; Cricetinae; Cricetulus; Cross Infection; Cross-Sectional Studies; Crowding; Culture Media; Cytokines; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes, Gestational; Diarylheptanoids; Diclofenac; Disability Evaluation; Diterpene Alkaloids; DNA; DNA Mutational Analysis; DNA, Bacterial; Drug Liberation; Drug Resistance, Multiple, Bacterial; Electrochemical Techniques; Electrodes; Electrolytes; Endothelium, Vascular; Enterococcus faecalis; Epithelial Cell Adhesion Molecule; Epithelial Cells; Erbium; Erythropoietin; Ethanol; Ethylenediamines; Fast Foods; Fatty Acids; Female; Fermentation; Ferric Compounds; Fibroblasts; Flavobacteriaceae; Fluorides; Fluorodeoxyglucose F18; Food Microbiology; Formaldehyde; Furaldehyde; Gamma Cameras; Gene Expression; Geologic Sediments; Glucose Tolerance Test; Glycated Hemoglobin; Glycolipids; Glycosylation; Gracilaria; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Guanine; Health Surveys; HeLa Cells; Hemoglobins, Abnormal; Hexosamines; High Fructose Corn Syrup; High-Intensity Interval Training; Hip Fractures; Hippocampus; HLA-B27 Antigen; Hospitalization; Housing; Humans; Hydrogen-Ion Concentration; Hydrolysis; Hydroxides; Hypercapnia; Hypertension; Hypocreales; Hypromellose Derivatives; Image Processing, Computer-Assisted; Incidence; Indole Alkaloids; Indonesia; Inflammation Mediators; Infrared Rays; Insulin Resistance; Intercalating Agents; Ion Transport; Ionophores; Japan; Kinetics; Kluyveromyces; Letrozole; Linear Models; Lipopolysaccharides; Liposomes; Liver; Lung Diseases; Magnesium Hydroxide; Magnetic Resonance Spectroscopy; Male; Membrane Glycoproteins; Membrane Transport Proteins; Mice, Inbred BALB C; Microbial Sensitivity Tests; Microbial Viability; Microscopy, Electron, Transmission; Middle Aged; Mitochondria; Mitochondria, Muscle; Molecular Docking Simulation; Molecular Structure; Muscle, Skeletal; Mutant Proteins; Mutation; Mutation, Missense; Nanocomposites; Nanoparticles; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Nucleic Acid Hybridization; Obesity; Occupational Exposure; Oceans and Seas; Odds Ratio; Organometallic Compounds; Osteogenesis; Ovulation Induction; Oxidation-Reduction; Particle Size; Periodontal Ligament; Permeability; Phaseolus; Phenotype; Philippines; Phosphatidylethanolamines; Phospholipids; Photochemical Processes; Phylogeny; Pichia; Pigmentation; Plant Extracts; Polycystic Ovary Syndrome; Polysaccharides; Postprandial Period; Pregnancy; Pregnancy Rate; Prevalence; Product Surveillance, Postmarketing; Progesterone; Progestins; Protein Engineering; Pseudomonas aeruginosa; Psoriasis; Public Facilities; Rats; Rats, Wistar; Receptors, Thyrotropin; Recombinant Proteins; Reproducibility of Results; Republic of Korea; Retrospective Studies; Rhodobacteraceae; Risk; Risk Assessment; Risk Factors; RNA, Ribosomal, 16S; ROC Curve; Saccharomyces cerevisiae; Salinity; Saliva; Seawater; Seaweed; Sensitivity and Specificity; Sequence Analysis, DNA; Sex Factors; Silver Compounds; Smokers; Social Class; Socioeconomic Factors; Soil Microbiology; Solubility; Soy Foods; Spectrometry, Mass, Electrospray Ionization; Spondylitis, Ankylosing; Staphylococcus aureus; Static Electricity; Steroids; Strontium; Sucrose; Surface Properties; Survival Rate; Sweden; Swine; Synapses; Synchrotrons; Tandem Mass Spectrometry; Tannins; Tea; Temperature; Terpenes; Thalidomide; Thermodynamics; Thiadiazoles; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy; Time Factors; Tissue Distribution; Titanium; Toilet Facilities; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ubiquinone; Urinary Tract Infections; Vaginal Creams, Foams, and Jellies; Venezuela; Vitamin K 2; Waist Circumference; Waste Disposal, Fluid; Wastewater; Water Microbiology; Water Pollutants, Chemical; Whole Body Imaging; X-Ray Diffraction; Young Adult; Ytterbium; Yttrium; Yttrium Radioisotopes; Zinc Compounds

It is unknown whether early intervention with low-dose erythropoiesis-stimulating agents (ESAs) in non-anaemic patients delays progression of chronic kidney disease (CKD).. In a single-blind, 24-month trial, adults with estimated glomerular filtration rate (eGFR) 30–59 mL/min/1.73 m2 and either Type 2 diabetes mellitus or previous kidney transplantation were randomized to low-dose continuous erythropoiesis receptor activator (CERA; monthly dose 30–75 µg; n = 115) or placebo (n = 120). The primary endpoint was the annual change in eGFR (abbreviated Modification of Diet in Renal Disease formula).. Mean (standard deviation) eGFR was 40.7 (9.8) mL/min/1.73 m2 versus 39.8 (9.2) mL/min/1.73 m2 at baseline for CERA and placebo, respectively, and 39.0 (11.6) g/dL versus 39.7 (10.6) g/dL at the final visit. The median (interquartile range) annual reduction in eGFR was 0.5 (−2.2, 3.8) mL/min/1.73 m2 with CERA versus 0.4 (−2.0, 3.2) mL/min/1.73 m2 with placebo (P = 0.657). No significant difference in the annual change in eGFR was observed between treatment groups in the subpopulations with Type 2 diabetes or kidney transplant. Adverse events with a suspected relation to study drug occurred in 22.0% and 16.2% of patients randomized to CERA or placebo, respectively, and adverse events led to study drug discontinuation in 11.0% and 8.5% of patients.. Patients with moderate CKD and Type 2 diabetes or previous kidney transplantation showed stable renal function that was unaffected by administration of low-dose ESA. In addition, there was no clinically meaningful effect of 2-year low-dose ESA treatment on albuminuria, an important surrogate marker of kidney injury.

Topics: Anemia; Diabetes Mellitus, Type 2; Disease Progression; Erythropoiesis; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Male; Middle Aged; Renal Insufficiency, Chronic; Single-Blind Method

As the syndrome of hypogonadotropic hypogonadism (HH) is associated with anaemia and the administration of testosterone restores haematocrit to normal, we investigated the potential underlying mechanisms.. Randomized, double-blind, placebo-controlled trial.. We measured basal serum concentrations of erythropoietin, iron, iron binding capacity, transferrin (saturated and unsaturated), ferritin and hepcidin and the expression of ferroportin and transferrin receptor (TR) in peripheral blood mononuclear cells (MNC) of 94 men with type 2 diabetes. Forty-four men had HH (defined as subnormal free testosterone along with low or normal LH concentrations) while 50 were eugonadal. Men with HH were randomized to testosterone or placebo treatment every 2 weeks for 15 weeks. Blood samples were collected at baseline, 3 and 15 weeks after starting treatment. Twenty men in testosterone group and 14 men in placebo group completed the study.. Haematocrit levels were lower in men with HH (41·1 ± 3·9% vs 43·8 ± 3·4%, P = 0·001). There were no differences in plasma concentrations of hepcidin, ferritin, erythropoietin, transferrin or iron, or in the expression of ferroportin or TR in MNC among HH and eugonadal men. Haematocrit increased to 45·3 ± 4·5%, hepcidin decreased by 28 ± 7% and erythropoietin increased by 21 ± 7% after testosterone therapy (P < 0·05). There was no significant change in ferritin concentrations, but transferrin concentration increased while transferrin saturation and iron concentrations decreased (P < 0·05). Ferroportin and TR mRNA expression in MNC increased by 70 ± 13% and 43 ± 10%, respectively (P < 0·01), after testosterone therapy.. The increase in haematocrit following testosterone therapy is associated with an increase in erythropoietin, the suppression of hepcidin, and an increase in the expression of ferroportin and TR.

Topics: Adult; Aged; Cation Transport Proteins; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Ferritins; Hematocrit; Hepcidins; Humans; Hypogonadism; Iron; Leukocytes, Mononuclear; Male; Middle Aged; Receptors, Transferrin; Testosterone

Although erythropoietin ameliorates experimental type 2 diabetes with neuropathy, serious side effects limit its potential clinical use. ARA 290, a nonhematopoietic peptide designed from the structure of erythropoietin, interacts selectively with the innate repair receptor that mediates tissue protection. ARA 290 has shown efficacy in preclinical and clinical studies of metabolic control and neuropathy. To evaluate the potential activity of ARA 290 in type 2 diabetes and painful neuropathy, subjects were enrolled in this phase 2 study. ARA 290 (4 mg) or placebo were self-administered subcutaneously daily for 28 d and the subjects followed for an additional month without further treatment. No potential safety issues were identified. Subjects receiving ARA 290 exhibited an improvement in hemoglobin A(1c) (Hb A(1c)) and lipid profiles throughout the 56 d observation period. Neuropathic symptoms as assessed by the PainDetect questionnaire improved significantly in the ARA 290 group. Mean corneal nerve fiber density (CNFD) was reduced significantly compared with normal controls and subjects with a mean CNFD >1 standard deviation from normal showed a significant increase in CNFD compared with no change in the placebo group. These observations suggest that ARA 290 may benefit both metabolic control and neuropathy in subjects with type 2 diabetes and deserves continued clinical evaluation.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Erythropoietin; Female; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Oligopeptides

The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD.. TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m(2)), and anemia (hemoglobin level ≤11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes.. Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics.. Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors.

Topics: Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Ethnicity; Follow-Up Studies; Global Health; Glomerular Filtration Rate; Hematinics; Humans; Incidence; Kidney Failure, Chronic; Prognosis; Prospective Studies; Racial Groups; Survival Rate; Time Factors

Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients.. A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers.. In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance.. Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies.. The study was registered at the German medical authority (BfArM; registration number 401 3206). The sponsor protocol ID and clinical trial unique identified number was CT-981-423-239. The results of the study are published and available at http://www.ncbi.nlm.nih.gov/pubmed/16034009.

Topics: Age Factors; Aged; Diabetes Mellitus, Type 2; Drug Resistance; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Renal Dialysis; Sex Factors

Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents.. Prospective clinical trial cohort.. 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL.. Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL.. 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level.. Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD.. In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.

Topics: Aged; Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic

This study aims to examine predictors of cardiovascular mortality and morbidity in patients with chronic kidney disease (CKD). Individuals with the triad of diabetes, CKD, and anemia represent a significant proportion of patients with cardiovascular disease and are at particularly high risk for adverse outcomes.. Using Cox proportional hazards models, we identified independent predictors of the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for myocardial ischemia, or heart failure (HF) in 3,847 patients in the TREAT, 961 (25%) of whom experienced this outcome. The predictors (ranked by χ(2) value) were prior HF (hazard ratio [HR] 1.74, 95% CI 1.51-2.01), age (HR 1.03, 95% CI 1.02-1.04 per year), log urine protein/creatinine ratio (HR 1.19, 95% CI 1.13-1.26 per log unit ), C-reactive protein ≥6.6 mg/L (HR 1.44, 95% CI 1.23-1.69, compared with C-reactive protein ≤3.0 mg/L), and abnormal electrocardiogram (HR 1.42, 95% CI 1.21-1.66 ), all P < .0001. Addition of cardiac-derived biomarkers (subset of first 1,000 patients enrolled) significantly enhanced risk estimation, with N-terminal pro B-type natriuretic peptide becoming the highest ranked predictor of outcome (HR 1.30, 95% CI 1.15-1.46 per log unit, P < .001) and troponin T providing additional predictive information. These biomarkers improved risk classification in 17.8% (9.4%-26.2%) of patients.. In patients with diabetes, CKD, and anemia, cardiovascular risk is most strongly predicted by age, history of HF, C-reactive protein, urinary protein/creatinine ratio, abnormal electrocardiogram, and 2 specific cardiac biomarkers, serum N-terminal pro B-type natriuretic peptide and troponin T, which are elevated in many. These findings suggest ways to improve cardiovascular risk stratification of patients with predialysis CKD, support the concept of cardiorenal syndrome, and may help target therapy.

Topics: Aged; Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Prognosis

More strokes were observed in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) among patients assigned to darbepoetin alfa. We sought to identify baseline characteristics and postrandomization factors that might explain this association.. A multivariate logistic regression model was used to identify baseline predictors of stroke in 4038 patients with diabetes mellitus, chronic kidney disease, and anemia randomized to receive darbepoetin alfa or placebo. To determine whether postrandomization blood pressure, hemoglobin level, platelet count, or treatment dose were responsible for the increased risk related to darbepoetin alfa, we performed a nested case-control analysis (1:10 matching) identifying nonstroke controls with propensity matching. The risk of stroke was doubled with darbepoetin alfa. Overall, 154 patients had a stroke, 101/2012 (5.0%) in the darbepoetin alfa arm and 53/2026 (2.6%) in the placebo arm (hazard ratio 1.9; 95% confidence interval, 1.4-2.7). Independent predictors of stroke included assignment to darbepoetin alfa (odds ratio 2.1; 95% confidence interval, 1.5-2.9), history of stroke (odds ratio 2.0; 95% confidence interval, 1.4-2.9), more proteinuria, and known cardiovascular disease. In patients assigned to darbepoetin alfa, postrandomization systolic and diastolic blood pressure, hemoglobin level, platelet count, and darbepoetin alfa dose did not differ between those with and without stroke. Additional sensitivity analyses using maximal values, latest values, or changes over varying periods of exposure yielded similar results.. The 2-fold increase in stroke with darbepoetin alfa in TREAT could not be attributed to any baseline characteristic or to postrandomization blood pressure, hemoglobin, platelet count, or dose of treatment. These readily identifiable factors could not be used to mitigate the risk of darbepoetin alfa-related stroke.. http://www.clinicaltrials.gov. Unique identifier: NCT00093015.

Topics: Aged; Anemia; Case-Control Studies; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Incidence; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Risk Reduction Behavior; Stroke; Treatment Outcome

We aimed to assess the effect of long-term pioglitazone treatment on erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis.. We conducted a prospective, open-label, parallel-group, controlled study of 63 type 2 diabetic hemodialysis patients who were randomly assigned to two groups: pioglitazone group (P-group; 15-30 mg/day pioglitazone plus conventional oral hypoglycemic agents) and control group (C-group; conventional oral hypoglycemic agents alone). We determined the efficacy of pioglitazone by monitoring anemia, glycemic control, insulin resistance, and levels of inflammatory cytokines and high-molecular-weight (HMW) adiponectin for 96 weeks.. Pioglitazone effectively reduced erythropoietin dose and maintained the target hemoglobin levels by improving insulin resistance up to the end of the study. In the P-group, hemoglobin A(1c), glycated albumin, and triglycerides significantly decreased compared with the C-group. There was a significant reduction in homeostasis model assessment for insulin resistance and the level of high-sensitivity C-reactive protein, and a significant increase in HMW adiponectin level in the P-group; these changes were significantly different compared with values for the C-group. No serious adverse effects such as hypoglycemia, liver impairment, or heart failure were observed in any of the patients.. Pioglitazone treatment resulted in better glycemic control, improved lipid levels, an increase in insulin sensitivity and adiponectin levels, and a decrease in inflammatory markers, thus improving the risk factors of cardiovascular disease. Erythropoietin responsiveness improved with a reduction in erythropoietin dose and may be associated with the improvement in insulin resistance due to long-term pioglitazone treatment.

Topics: Adiponectin; Adult; Aged; Anemia; Blood Pressure; C-Reactive Protein; Calcitriol; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Male; Middle Aged; Pioglitazone; Prospective Studies; Recombinant Proteins; Renal Dialysis; Thiazolidinediones

Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response.. We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug.. Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78).. A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)

Topics: Aged; Anemia; Cardiovascular Diseases; Chi-Square Distribution; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Proportional Hazards Models; Risk; Stroke

Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes.. Randomized trial.. 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin < or = 11 g/dL) from 24 countries.. Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo.. TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point.. With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia.

Topics: Aged; Anemia; Cardiovascular Diseases; Cohort Studies; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Proteinuria; Risk Factors; Treatment Outcome

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Topics: Aged; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Renal Insufficiency, Chronic; Stroke

Anaemia in diabetes mellitus (DM) and/or chronic renal failure (CRF) may be caused by a decreased production of erythropoietin (EPO), EPO resistance, and by the lysis of the young circulating red blood cells (neocytolysis) induced by subclinical inflammation and low EPO level. Aims of this study were to detect EPO resistance in patients with DM and/or CRF and to prove, that acetylsalicylic acid (ASA) is able to improve the haemopoietic status by decreasing neocytolysis.. In a cross-sectional study, three groups of selected patients (patients with DM; patients with DM+CRF; patients with CRF without DM, n=15 each) and a group of controls (non-diabetic, nonazotemic subjects, n = 10) were compared. In the intervention part of the study, the effect of a single dose of 1 gram ASA on neocytolysis was investigated in a subgroup of these patients.. Despite the similar EPO level (p = 1.000), all three patient groups had lower haemoglobin and haematocrit than control persons (p < 0.05 in all cases). Patients with DM+CRF had lower haemoglobin than patients with DM or CRF alone (p < 0.05). Single dose of ASA induced a fast increase in serum EPO level, a concomitant rise of the Rtc number and rate, red blood cell count, haematocrit and haemoglobin p < 0.01 for each). These changes were accompanied by a marked decrease in serum lactate dehydrogenase activity (p < 0.01).. DM and CRF may induce erythropoietin resistance. In these patients, ASA treatment increases serum EPO level. The higher EPO level and the anti-inflammatory effect of ASA may decrease neocytolysis.

Topics: Aged; Anemia; Aspirin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hemolysis; Humans; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Middle Aged

A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5-11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications.. Epo, s.c., was given every 1-3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8 + 8.2 months.. With the Epo-Fe treatment the Hb increased from 10.41 +/- 1.0 to 13.1 +/- 1.3 g% in diabetics and from 10.5 +/- 1.0 to 12.9 +/- 1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of approximately 1 ml/min/month before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IU/week/kg body weight, was similar in the two groups.. The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.

Topics: Aged; Anemia; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Recombinant Proteins; Treatment Outcome

Type 2 diabetes mellitus (T2DM) is strongly associated with an increased risk of developing cognitive dysfunction. Numerous studies have indicated that erythropoietin (EPO) has neurotrophic effects. Ferroptosis has been reported to be associated with diabetic cognitive dysfunction. However, the impact of EPO on T2DM-associated cognitive dysfunction and its protective mechanism remain unclear. To evaluate the effects of EPO on diabetes-associated cognitive dysfunction, we constructed a T2DM mouse model and found that EPO not only decreased fasting blood glucose but also ameliorated hippocampal damage in the brain. The Morris water maze test indicated that EPO improved cognitive impairments in diabetic mice. Moreover, a ferroptosis inhibitor improved cognitive dysfunction in mice with T2DM in vivo. Furthermore, a ferroptosis inhibitor, but not other cell death inhibitors, mostly rescued high-glucose damaged PC12 cell viability. EPO had a similar effect as the ferroptosis inhibitor, which increased cell viability in the presence of a ferroptosis inducer. In addition, EPO reduced lipid peroxidation, iron levels, and regulated ferroptosis-related expression of proteins in vivo and in vitro. These findings indicate that EPO ameliorates T2DM-associated cognitive dysfunction, which might be related to decreasing iron overload and inhibiting ferroptosis.

Topics: Animals; Cognitive Dysfunction; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Ferroptosis; Iron Overload; Mice

To determine the correlation of serum erythropoietin concentration with diabetic retinopathy in patients with type 2 diabetes mellitus.. Cross-sectional study. Place and Duration of the Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from July to December 2021.. A total of 180 individuals were enrolled in the study and placed in 2 groups as group 1 have 90 cases of type 2 diabetes mellitus and group 2 having 90 age-matched healthy controls. Group 1 was further subclassified into proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR) subgroups by an expert ophthalmologist. Serum erythropoietin, creatinine, blood HbA1c, and haemoglobin were analysed. Correlation between stages of proliferation and serum erythropoietin, creatinine, blood HbA1c, and haemoglobin were analysed. An independent-sample student t-test was applied to compare mean Serum erythropoietin between PDR and NPDR groups. Pearson's correlation was applied among disease severity, and type of retinopathy. A p-value of ≤0.05 was considered significant.. The average age of participants in groups 1 and 2 was 45.88±8.6 and 56.6±10.23 years, respectively. More males (n=60, 66.7%) were noted in cases compared to controls (n=42, 46.7%). serum erythropoietin concentration observed in cases (8.4±1.87 IU/L) was higher than controls (6.50±0.9). The mean serum erythropoietin concentration in PDR (9.35±1.74 IU/L) was significantly greater than that in NPDR (7.3±1.38 IU/L, p <0.001). The serum concentration of erythropoietin in group 1 increased linearly with the severity of the disease (r=0.103).. Serum erythropoietin concentrations increased in uncontrolled type 2 diabetics more so in proliferative retinopathy cases, and increased with disease severity.. Erythropoietin, Diabetic retinopathy, Proliferative diabetic retinopathy.

Topics: Adult; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Glycated Hemoglobin; Humans; Male; Middle Aged

Topics: Asian People; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide; Transcription Factor 7-Like 2 Protein

The aim of this study was to investigate the relationship between erythropoietin rs1617640 polymorphism and proliferative diabetic retinopathy (PDR) in Slovenian subjects with type 2 diabetes mellitus. The second aim was to find whether erythropoietin expression in fibrovascular membranes varies among individuals carrying different genotypes of the rs1617640.. This was a retrospective cross-sectional study based on 797 unrelated Slovenian (Caucasian) participants with type 2 diabetes mellitus. The study group consisted of 217 cases with PDR and 580 controls without clinical signs of diabetic retinopathy. Each subject was genotyped for rs1617640 polymorphism. Fibrovascular membranes from 27 subjects who underwent vitreoretinal surgery were analysed with immunohistochemistry. We searched for expression of erythropoietin, its cognate receptor and for a pan-endothelial marker CD-34.. Our results show that subjects carrying a minor GG genotype had significantly higher risk for PDR in both unadjusted (p = 0.02) and adjusted (p = 0.04) recessive genetic models. Subjects with the GG genotype had a 1.6-fold increased risk of developing PDR compared to subjects carrying the major T allele. In fibrovascular membranes from subjects with PDR, the mean number of cells expressing EPO was significantly higher in G allele carriers compared to the homozygotes for the common T allele.. In Slovenian subjects with type 2 diabetes mellitus, a significant increased risk of PDR was found in GG carriers of the erythropoietin gene rs1617640 polymorphism.

Topics: Adult; Aged; Alleles; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; DNA; Erythropoietin; Female; Follow-Up Studies; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Incidence; Male; Middle Aged; Polymorphism, Single Nucleotide; Retrospective Studies; Slovenia; Time Factors; Young Adult

Our aim in this study was to determine the association of erythropoietin (EPO) gene polymorphisms with diabetic retinopathy in patients with type 2 diabetes from northern India.. In this case-control study, we recruited 614 participants, consisting of 302 diabetic retinopathy cases and 312 individuals with confirmed type 2 diabetes without retinopathy as controls. EPO polymorphism analysis was performed in all participants using polymerase chain reaction and direct DNA sequence analysis.. The genotype distribution and allele frequency of the c.246+265G>A (rs507392) polymorphism differed significantly (p<0.05) between the retinopathy and control groups. For the -1306C>A (rs1617640) polymorphism, genotype distribution among the 2 groups analyzed differed significantly (p=0.047), but the distribution of allele frequency was not found to be statistically significant (p=0.07). For the c.∗772G>T (rs551238) variant, genotype distribution did not differ significantly when comparing the 2 groups (p=0.062), but allele frequency distribution did differ significantly (p=0.045). For the polymorphisms analyzed, namely rs507392 and rs1617640, a statistically significant association with retinopathy was observed (dominant model: adjusted odds ratio [OR], 2.23; 95% confidence interval [CI], 1.36 to 3.35; p<0.01; codominant model: adjusted OR, 1.45; 95% CI, 1.00 to 2.09; p=0.048). However, no significant association between c.∗772G>T (rs551238) polymorphism and diabetic retinopathy was found.. Our findings show 2 polymorphisms (c.246+265G>A [rs507392] and -1306C>A [rs1617640]) in EPO to be risk factors for type 2 diabetic retinopathy in a northern Indian cohort. To our knowledge, this is the first report from India to demonstrate an association between EPO gene polymorphisms and retinopathy.

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Genotype; Humans; India; Polymorphism, Single Nucleotide

This study was designed to investigate the mechanism of Dapagliflozin (Dapa) cardioprotection against diabetic cardiomyopathy (DCM). Structural and functional changes in the heart as well as decrease of erythropoietin (EPO) levels were reported in DCM. EPO simultaneously activates three pathways: the Janus-activated kinase-signal transducer and activator of transcription (JAK2/STAT5), phosphatidylinositol-3-kinase-Akt (PI3K/Akt), and extracellular signal-related kinase (ERK/MAPK) cascades, that result in proliferation and differentiation of cardiac cells.. DCM was induced by a high fat diet for 10 weeks followed by administration of streptozotocin. After confirmation of diabetes, rats were divided randomly to 5 groups: Group 1; normal control group, Group 2; untreated diabetic group and Groups (3-5); diabetic groups received Dapa daily (0.75 mg, 1.5 or 3 mg/Kg, p.o) respectively for a month. At the end of the experiment, full anaesthesia was induced in all rats using ether inhalation and ECG was recorded. Blood samples were collected then rats were sacrificed and their heart were dissected out and processed for biochemical and histopathological studies. Untreated diabetic rats showed abnormal ECG pattern, elevation of serum cardiac enzymes, decrease EPO levels, downregulation of P-Akt, P-JAK2 and pMAPK pathways, abnormal histological structure of the heart and increase immunostaining intensity of P53 and TNF α in the cardiomyocytes. Dapa in a dose dependent manner attenuated the alterations in the previously mentioned parameters.. The cardioprotective effect of Dapa could be mediated by increasing EPO levels and activation of P-Akt, P-JAK2 and pMAPK signalling cascades which in turn decrease apoptosis.

Topics: Animals; Benzhydryl Compounds; Cardiotonic Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Electrocardiography; Erythropoietin; Glucosides; Male; MAP Kinase Signaling System; Myocardium; Rats, Wistar; Streptozocin

Topics: Benzhydryl Compounds; Coronary Artery Disease; Diabetes Mellitus, Type 2; Erythrocyte Count; Erythrocytes; Erythropoietin; Ferritins; Glucosides; Hematocrit; Humans; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

In the setting of type-2 diabetes, there are declines of structural stability and functionality of blood capillaries and red blood cells (RBCs), increasing the risk for microcirculatory disturbances. Correcting hyperglycemia is not entirely effective at reestablishing normal cellular metabolism and function. Therefore, identification of pathological changes occurring before the development of overt hyperglycemia may lead to novel therapeutic targets for reducing the risk of microvascular dysfunction. Here we determine whether RBC-capillary interactions are altered by prediabetic hypersecretion of amylin, an amyloid forming hormone co-synthesized with insulin, and is reversed by endothelial cell-secreted epoxyeicosatrienoic acids. In patients, we found amylin deposition in RBCs in association with type-2 diabetes, heart failure, cancer and stroke. Amylin-coated RBCs have altered shape and reduced functional (non-glycated) hemoglobin. Amylin-coated RBCs administered intravenously in control rats upregulated erythropoietin and renal arginase expression and activity. We also found that diabetic rats expressing amyloid-forming human amylin in the pancreas (the HIP rat model) have increased tissue levels of hypoxia-inducible transcription factors, compared to diabetic rats that express non-amyloid forming rat amylin (the UCD rat model). Upregulation of erythropoietin correlated with lower hematocrit in the HIP model indicating pathologic erythropoiesis. In the HIP model, pharmacological upregulation of endogenous epoxyeicosatrienoic acids protected the renal microvasculature against amylin deposition and also reduced renal accumulation of HIFs. Thus, prediabetes induces dysregulation of amylin homeostasis and promotes amylin deposition in RBCs and the microvasculature altering RBC-capillary interaction leading to activation of hypoxia signaling pathways and pathologic erythropoiesis. Hence, dysregulation of amylin homeostasis could be a therapeutic target for ameliorating diabetic vascular complications.

Topics: Adult; Amyloid; Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Eicosanoids; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Humans; Islet Amyloid Polypeptide; Kidney; Male; Microcirculation; Microvessels; Middle Aged; Rats; Retrospective Studies

Erythropoietin (EPO) is one of the systemic angiogenic factors, and its role in ocular angiogenesis and in diabetic retinopathy (DR) is not yet fully understood. The latest research data reveal a possible correlation of higher erythropoietin concentrations in the blood and in the eye with the development of more advanced stages of DR. The main aim of this work was to examine the possible influence of serum concentrations of erythropoietin on the development of diabetic retinopathy in patients with diabetes mellitus type 2.. The research involved 90 patients examined at the University Eye Clinic of the Clinical Center of Vojvodina, Novi Sad, Serbia. The first group comprised 60 patients with diabetes mellitus lasting for 10 years or more, with diabetic retinopathy. The second, control group consisted of 30 healthy individuals. In the first group of 60 patients with diabetes, 30 of them had non-proliferative diabetic retinopathy (NPDR), and 30 had proliferative diabetic retinopathy (PDR). Laboratory EPO serum levels were determined, and they were correlated to the stage of DR. Concentration of EPO was assessed by ELISA method.. The highest average concentration of EPO in serum (9.95 mIU/ml) was determined in the group of people with diabetes with PDR. The lowest average concentration of EPO in the serum (6.90 mIU/ml) was found in the control group. The average concentration of EPO in serum in the group of patients with diabetes with NPDR was 7.00 mIU/ml. The EPO concentration in serum was elevated in the group of PDR, and it was directly proportional to the level of the clinical stadium of PDR, being significantly higher in the moderate and severe subgroup of PDR comparing to the control healthy subjects, NPDR and mild PDR (p = 0.007).. Significantly elevated serum concentration of EPO in the advanced stages of DR, and positive correlation between EPO serum concentration and clinical stages of PDR, suggest that erythropoietin represents an important growth factor from blood, which plays a significant role in retinal ischemia and angiogenesis in diabetic retinopathy, especially in the proliferative stage of this disease.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Female; Glycated Hemoglobin; Humans; Intraocular Pressure; Male; Middle Aged; Visual Acuity

Anemia is common in patients with type 2 diabetes. This aims at determining long-term effects of nitrate administration on diabetes-induced anemia in obese type 2 diabetic rats.. Male Wistar rats were divided into 4 groups: Control, control + nitrate, diabetes, and diabetes + nitrate. Type 2 diabetes was induced using high-fat diet followed by injection of streptozotocin (30 mg/kg). Sodium nitrate (100 mg/L in drinking water) was administered for six months. After overnight fasting, levels of glucose and erythropoietin (EPO) and complete blood cell count (CBC) were measured at month 0, month 3, and month 6. At month 6, serum iron, and testosterone as well as EPO protein levels and hypoxia-inducible factor-1 (HIF-1) mRNA levels in kidney and liver were measured.. Nitrate administration decreased serum glucose in diabetic rats by 10% and 15% at months 3 and 6, respectively. Nitrate restored decreased red blood cells count, hemoglobin concentration, and hematocrit to control levels in diabetic rats; in addition, nitrate restored decreased serum, kidney, and liver EPO levels to near normal values. Nitrate also increased HIF-1 mRNA levels in both kidney and liver of diabetic rats. Diabetic rats had lower serum testosterone (37%) and iron (20%) and nitrate restored these parameters to near normal values.. Long-term and low dose of nitrate had beneficial effects against anemia in obese type 2 diabetic rats; these effects were associated with increased EPO and HIF-1 levels in kidney and liver as well as increased circulating EPO, testosterone, and iron.

Topics: Administration, Oral; Anemia; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Erythrocyte Count; Erythropoietin; Ferritins; Hematocrit; Hemoglobins; Homeostasis; Hypoxia-Inducible Factor 1; Iron; Male; Nitrates; Rats, Wistar; RNA, Messenger; Streptozocin; Testosterone

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate < 0.1) associated with mortality. Haplotype multivariate analysis revealed that patients carrying the G-C-C haplotype have an increased probability of survival, while an opposite effect was observed among subjects carrying the T-T-A haplotype. Our findings provide evidence that the EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Erythropoietin; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Italy; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Proportional Hazards Models; Risk Factors

Adult human kidneys produce erythropoietin (EPO), which regulates red blood cell formation; however, whether EPO also functions directly on kidney development and controls diabetic kidney disease remains unknown. Here we analyzed the role of EPO in kidney development and under hyperglycemic conditions in zebrafish and in humans.. Diabetic patients and respective controls were enrolled in two cohorts. Serum EPO level and urine protein change upon human EPO administration were then analyzed. Transient knockdown and permanent knockout of EPO and EPOR in renal TG(WT1B:EGFP) zebrafish were established using the morpholino technology and CRISPR/Cas9 technology. Zebrafish embryos were phenotypically analyzed using fluorescence microscopy, and functional assays were carried out with the help of TexasRed labeled 70 kDa Dextran. Apoptosis was determined using the TUNEL assay and Annexin V staining, and caspase inhibitor zVADfmk was used for rescue experiments.. In type 2 diabetic patients, serum EPO level decreased with the duration of diabetes, which was linked to reduced kidney function. Human recombinant EPO supplementation ameliorated proteinuria in diabetic nephropathy patients. In zebrafish, loss-of-function studies for EPO and EPOR, showed morphological and functional alterations within the pronephros, adversely affecting pronephric structure, leading to slit diaphragm dysfunction by increasing apoptosis within the pronephros. Induction of hyperglycemia in zebrafish embryos induced pronephros alterations which were further worsened upon silencing of EPO expression.. EPO was identified as a direct renal protective factor, promoting renal embryonic development and protecting kidneys from hyperglycemia induced nephropathy.

Topics: Aged; Animals; Apoptosis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged; Proteinuria; Recombinant Proteins; Zebrafish

Erythropoietin (EPO) can reduce insulin resistance (IR) in adipocytes; however, it is unknown whether EPO can decrease IR in skeletal muscle. Here we investigated whether EPO could reduce IR in type 2 diabetic mouse skeletal muscle and its possible signaling mechanisms of action. Twelve-week-old

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Erythropoietin; Insulin Resistance; Mice; Muscle, Skeletal; Phosphatidylinositol 3-Kinases; Phosphorylation; Receptors, Erythropoietin; Signal Transduction

Physical inactivity and a low maximal aerobic capacity (VO

Topics: Blood Volume; Cardiac Output; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Erythrocytes; Erythropoietin; Exercise; Hematocrit; Hemoglobins; Humans; Hypoxia; Muscle, Skeletal; Oxygen; Oxygen Consumption

Anemia is defined as a reduction in the hemoglobin concentration of blood, which consequently reduces the oxygen-carrying capacity of red blood cells such that they are unable to meet the body's physiological needs. Several reports have indicated that anemia mostly occurs in patients with diabetes with renal insufficiency while limited studies have reported the incidence of anemia in people with diabetes prior to evidence of renal impairment. Other studies have also identified anemia as a risk factor for the need for renal replacement therapy in diabetes. Understanding the pathogenesis of anemia associated with diabetes may lead to the development of interventions to optimize outcomes in these patients. The aim of this study was therefore to determine the prevalence of anemia among patients with type 2 diabetes.. A total of 100 (50 with type 2 diabetes and 50 controls) participants were recruited for our study. Participants' blood samples were analyzed for fasting blood glucose, full blood count and renal function tests among others. The prevalence of anemia was then determined statistically.. A high incidence of anemia was observed in the cases. Of the patients with diabetes, 84.8% had a hemoglobin concentration that was significantly less (males 11.16±1.83 and females 10.41±1.49) than the controls (males 14.25±1.78 and females 12.53±1.14). Renal insufficiency determined by serum creatinine level of >1.5 mg/dL, estimated glomerular filtration rate <60 ml/minute/1.73 m2, and erythropoietin levels was also observed to be high in the cases (54.0%; with mean creatinine concentration of 3.43±1.73 and erythropoietin 6.35±1.28 mIU/mL). A significantly increased fasting blood glucose, urea, sodium, potassium, and calcium ions were observed in the cases (7.99±1.30, 5.19±1.99, 140.90±6.98, 4.86±0.53 and 1.47±0.31 respectively) as compared to the controls (4.66±0.54, 3.56±2.11, 135.51±6.84, 4.40±0.58 and 1.28±0.26 respectively). Finally, a significant association between hemoglobin concentration and fasting blood glucose was also observed in the cases.. The findings suggest that a high incidence of anemia is likely to occur in patients with poorly controlled diabetes and in patients with diabetes and renal insufficiency.

Topics: Adult; Aged; Anemia; Blood Glucose; Calcium; Case-Control Studies; Creatinine; Diabetes Mellitus, Type 2; Erythropoietin; Female; Ghana; Hemoglobins; Humans; Male; Middle Aged; Potassium; Prevalence; Renal Insufficiency; Sodium; Urea

The aim of the present study was to assess the role of a concomitant type 2 diabetes as a potentially negative factor in the management of low-risk myelodysplastic syndrome (MDS) patients treated with high-dose (40,000 UI s.c. 2 times/week) recombinant human erythropoietin (EPO) alpha (rHuEPO alpha).. One hundred and forty patients (M/F 69/71, median age 76, interquartile range [IR] 68-81) were included in the analysis: 27/140 (19.2%) had a concomitant type 2 diabetes.. No difference was reported between patients with and without diabetes as to the grade of anemia, the EPO endogenous levels and the need for transfusional requirement at baseline. Erythroid response was achieved in 79/140 patients (56.4%): factors associated with response were lower EPO levels (P < 0.0001), higher baseline Hb levels (P < 0.0001) and transfusion independence (P < 0.0001). Diabetes was not predictive of response: 17/27 (62.9%) patients with diabetes were responsive to high-dose EPO compared with 62/113 (54.8%) patients without diabetes (P = 0.446). This was confirmed in multivariate analysis, controlling for the effects of Hb levels, transfusion-dependence and serum EPO levels. No difference was observed in relapse rate, response duration and OS between patients with and without diabetes.. Concomitant type 2 diabetes was not a major concern in the management of MDS patients.

Topics: Aged; Diabetes Mellitus, Type 2; Erythropoietin; Female; Humans; Male; Myelodysplastic Syndromes

Anemia is prevalent but under-recognized in patients with diabetes mellitus (DM). Genetic variants in angiotensin-converting enzyme (ACE), tumor necrosis factor-alpha (TNF-α) and erythropoietin (EPO) have been associated with diabetic nephropathy. In the present study, we investigated the associations between anemia and polymorphisms in EPO promoter (rs1617640), TNF-α G-308A and ACE Insertion/Deletion in Chinese patients with type 2 diabetes.. Polymorphisms in ACE, TNF-α and EPO were genotyped in 1142 patients. Anemia was defined as hemoglobin (Hb) levels below 12 g/dL for women and 13 g/dL for men.. 286 (25%) patients had anemia. Patients with anemia were older, had longer duration of diabetes, worse renal function and more albuminuria. ACE Insertion/Deletion and TNF-a G-308A were not associated with anemia. The frequencies of EPO polymorphism (rs1617640) were significantly different between anemic and nonanemic patients. Patients with TT genotype had higher prevalence of anemia than those with TG and GG. Regression analysis identified EPO SNP, duration of DM, serum albumin, albuminuria and renal function independently associated with anemia. After adjusting for multiple variables, TT and TG genotypes were associated with 3-5-fold increased risk for anemia compared to GG.. The EPO genotype in Chinese patients with type 2 diabetes is associated with anemia and may help to identify those at risk. Further evaluation of its effect on clinical outcomes in prospective studies may be useful to predict the outcomes of erythropoiesis stimulating therapy, and to individualize anemia management.

Topics: Aged; Anemia; Diabetes Mellitus, Type 2; DNA; Erythropoietin; Female; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Promoter Regions, Genetic; Prospective Studies; Real-Time Polymerase Chain Reaction; Tumor Necrosis Factor-alpha

This study was performed to investigate the correlation of erythropoietin gene polymorphisms with diabetic retinopathy (DR) in a Chinese cohort with type 2 diabetes mellitus (T2DM).. Case-control study held in Qilu hospital of Shandong University, China.. 792 T2DM individuals were involved, classified as groups DR (n = 448) and non-DR (NDR; n = 344). The DR group was subdivided into groups proliferative DR (PDR; n = 220) and non-PDR (NPDR; n = 228).. Three single-nucleotide polymorphisms, rs1617640, rs507392 and rs551238, in the erythropoietin gene were genotyped. Odds ratios (ORs) for the effects of erythropoietin gene polymorphisms on DR risk.. The genotype CC frequency in rs507392 was significantly lower in DR group (additive: OR, 0.45; 95% confidence interval [CI], 0.23-0.89; P = 0.027; recessive: OR, 0.44; 95%CI, 0.23-0.86; P = 0.012) or PDR group (additive OR, 0.18; 95%CI, 0.05-0.63; P = 0.002; recessive OR, 0.19; 95%CI, 0.06-0.66; P = 0.003) than in NDR group. The genotype CC frequency in rs551238 was significantly lower in DR group (additive OR, 0.42; 95%CI, 0.21-0.38; P = 0.016; recessive OR, 0.40; 95%CI, 0.20-0.79; P = 0.010) or PDR group (additive OR, 0.18; 95%CI, 0.05-0.62; P = 0.002; recessive OR, 0.18; 95%CI, 0.05-0.61; P = 0.002). No significant differences were detected in the distributions of rs1617640 genotype or all polymorphisms' alleles between groups NDR and DR, PDR or NPDR. Haplotype analyses did not provide any evidence for the correlation between the three polymorphisms and DR.. Our data suggest that rs507392 and rs551238 in the erythropoietin gene probably act to lessen the risk for DR and PDR in the Chinese T2DM cohort.

Topics: Aged; Asian People; Blood Glucose; Case-Control Studies; China; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Female; Gene Frequency; Genotype; Genotyping Techniques; Glycated Hemoglobin; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide

Erythropoietin (EPO), a key hormone involved in red blood cell formation has been recently acknowledged for its pleiotropic actions and protective role in ageing and various pathological conditions concurrent with oxidative stress, vascular diseases and metabolic abnormalities such as diabetes mellitus. The aim of the study was to evaluate the relationship between circulating erythropoietin levels and oxidative stress biomarkers, in elderly with type 2 diabetes (T2DM). The study was carried out in 67 subjects with T2DM (69 ± 5 years; n = 37) without anemia, and aged-matched controls (70 ± 6 years; n = 30). EPO serum levels, erythrocyte susceptibility to lipid peroxidation (ESP) and total antioxidant capacity (TAC) were evaluated. Lower EPO levels (p < 0.01) and higher ESP values (p < 0.001) were found in T2DM group, compared to healthy subjects. EPO levels showed significant negative associations with ESP, both in T2DM subjects (r = -0.565; p < 0.001) and in all study population (r = -0,600; p < 0,001; n = 67). In conclusion, we provide new data regarding the cytoprotective effect of EPO exerted at systemic level on erythrocyte membrane, in the particular state of impaired glucose metabolism associated with oxidative stress, in the elderly.

Topics: Aged; Anemia; Diabetes Mellitus, Type 2; Erythrocytes; Erythropoietin; Female; Glucose; Humans; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress

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

Chronic kidney disease (CKD) patients on dialysis regularly receive erythropoiesis stimulating agent (ESA) for treating renal anaemia during their dialysis unlike those who are not on dialysis. In such patients, the longer acting ESA can be helpful in reducing their frequent visits to the health care facilities and improving their compliance. This study was aimed to examine the efficacy and safety of continuous erythropoietin receptor activator (CERA), a long acting ESA in treating renal anaemia in patients with diabetic CKD not on dialysis.. In this prospective, open-labelled, pilot clinical study, 35 adult type 2 diabetes patients with nephropathy and renal anaemia, who were not on dialysis nor receiving treatment with ESA were administered CERA subcutaneously once in two weeks for a period of 24 weeks. The primary efficacy end point was to evaluate the Hb response (Hb rise of ≥1 g/dl above the baseline or Hb level ≥11 g/dl) during the study period.. All patients showed Hb rise ≥1 g/dl during the study period and 80 per cent patients could achieve Hb value ≥11 g/dl. The maximum median Hb rise of 1.2 g/dl occurred in the initial 6 weeks after starting the treatment. The mean creatinine clearance (CrCl) improved by 2.8 ml/min, with mean Hb rise of 2.6 g/dl from the baseline after administration of CERA. Worsening of blood pressure (BP) control (42.9%) was the most common adverse event.. CERA once in two weeks was found to be efficacious in correcting anaemia in the ESA-naïve patients with diabetic nephropathy who are not on dialysis. However, regular monitoring of blood pressure is required while on treatment with CERA.

Topics: Adult; Anemia; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

This study compared systemic and intraocular concentrations of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) in patients with type 2 diabetes (T2D) and proliferative diabetic retinopathy (PDR) with levels in patients without diabetes, and looked for possible correlations between the concentrations found and other variables analyzed.. Concentrations of EPO and VEGF were measured in the aqueous and vitreous humours and serum of patients undergoing vitrectomy for PDR (33 patients) or for macular holes or puckers (20 control patients). EPO was assayed by radioimmunoassay, with a lower limit of detection (LOD) of 1.0 mIU/mL. VEGF was assayed using enzyme-linked immunosorbent assay (ELISA), with a lower LOD of 10.0 pg/mL.. EPO concentrations in serum did not differ significantly between the two groups, whereas EPO in vitreous and aqueous were higher in diabetic than in non-diabetic patients. VEGF in serum was lower in diabetic patients than in non-diabetics; conversely, VEGF concentrations in vitreous were significantly higher in diabetic patients. A direct correlation was found between vitreous and aqueous EPO concentrations, and between vitreous EPO and blood glucose concentrations. A significant, negative correlation between vitreous EPO concentration and age was also recorded.. High EPO concentrations in the vitreous of patients with PDR and its correlation with blood glucose suggest that EPO could play a role in the pathogenesis of PDR. All possible factors affecting serum and ocular concentrations of EPO and VEGF should be determined to identify compounds able to prevent and control this serious microvascular complication of diabetes.

Topics: Aged; Aqueous Humor; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Female; Humans; Linear Models; Male; Middle Aged; Vascular Endothelial Growth Factor A; Vitreous Body

The purpose of this study was to evaluate whether any stage of diabetic retinopathy (DR) is associated with levels of plasma erythropoietin and other plasma parameters.. It was examined a representative sample of 180 type 2 diabetes patients aged 40 to 79 years. Ophthalmic examination including a funduscopic examination, performed by an experienced ophthalmologist and the retinal finding were classified according to the grading system for diabetic retinopathy of ETDRS (Early Treatment Diabetic Retinopathy Study). It was measured the levels of plasma erythropoietin, cholesterol, triglyceride, apolipoproteins A and B, C-reactive protein, fasting blood glucose and hemoglobin A1C (HbA1C) in 88 DR patients and 92 controls without DR. Risk factors correlated with DR were compared between groups.. The study group of 180 patients included 72 males and 108 females. The mean age of the patients with and without DR was 57.36 ± 8.87 years and 55.33 ± 8.28 years, respectively. Of the 88 patients with DR, only 9 (10%) had proliferative DR and the rest suffered from non-proliferative DR. The mean plasma levels of erythropoietin in proliferative DR group showed a significant difference in comparison to other groups. The mean plasma levels of cholesterol, triglyceride, apolipoproteins A and B, C-reactive protein, and fasting blood glucose were not significantly different in the three groups except for HbA1C. The absolute relative risk (ARR) also showed that erythropoietin was an increasing risk for proliferative DR (ARR, 1.17; 95% confidence interval, 1.060 to 1.420; odds ratio,1.060).. Of the factors studied, erythropoietin level showed significant increase in proliferative DR group. The stepwise raised in mean plasma erythropoietin level which demonstrates significant correlation with proliferative DR versus remaining two groups, will be an indication of its role in proliferative DR.

Topics: Adult; Aged; Blood Glucose; Cholesterol; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Fluorescein Angiography; Glycated Hemoglobin; Humans; Male; Middle Aged; Risk Factors

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Erythropoietin; Female; Humans; Microvessels; Radiography; Vascular Endothelial Growth Factor A

Type 2 diabetes is characterised by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Since erythropoietin-producing hepatoma (Eph)-ephrin bidirectional signalling fine-tunes GSIS from pancreatic beta cells, we investigated Eph receptor tyrosine kinases (RTK) as potential drug targets for selectively increasing GSIS.. Insulin secretion assays were carried out using mouse and human pancreatic islets as well as mouse insulinoma (MIN6) cells in the presence or absence of two Eph RTK inhibitors. Furthermore, the most potent inhibitor was injected into mice to evaluate its effects on glucose tolerance and plasma insulin levels.. We showed that the Eph RTK inhibitors selectively increased GSIS from MIN6 cells as well as mouse and human islets. Our results also showed that the insulin secretory effects of these compounds required Eph-ephrin signalling. Finally, pharmacological inhibition of Eph receptor signalling improved glucose tolerance in mice.. We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance.

Topics: Animals; Benzamides; Cell Line; Cell Survival; Diabetes Mellitus, Type 2; Erythropoietin; Glucose; Humans; Imatinib Mesylate; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Magnetic Resonance Spectroscopy; Mice; Mice, Transgenic; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Receptor, EphA5; Receptors, Eph Family

The significance of glycated albumin (GA) compared with casual plasma glucose (PG) and glycated hemoglobin (HbA1c) was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. In HD patients with diabetes (n = 25), the mean PG, GA and HbA1c levels were 192.9 + 23 mg/dL, 278.8 + 43 μmol/L and 5.9 + 0.5%, respectively, which were higher by 43.9%, 67.04% and 18%, respectively, compared with HD patients without diabetes (n = 25). HbA1c levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the three parameters in patients who had diabetes without renal dysfunction (n = 25). A significant negative correlation was found between GA and serum albumin (r = 0.21, P <0.05) in HD patients with diabetes, whereas HbA1c correlated positively and negatively with hemoglobin (r = 0.11, P <0.01) and weekly dose of erythropoietin injection (r = -0.19, P < 0.01), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA1c levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartiles by GA level led to better glycemic control in a significantly higher proportion of HD patients with diabetes than those assessed by HA1c. Multiple regression analysis demonstrated that hemoglobin in addition to PG emerged as an independent factor associated with HbA1c in HD patients with diabetes, while PG, body mass index and albumin were an independent factor associated with GA.. it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA1c in these patients might lead to likely underestimation as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

Topics: Adult; Anemia; Biomarkers; Blood Glucose; Chi-Square Distribution; Diabetes Mellitus, Type 2; Egypt; Erythropoietin; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hematinics; Humans; Hypoglycemic Agents; Kidney; Logistic Models; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Renal Dialysis; Renal Insufficiency, Chronic; Reproducibility of Results; Serum Albumin; Time Factors

HbA(1c) values are unreliable in patients with diabetes who have chronic kidney disease who receive iron and/or erythropoiesis stimulating agents. The study aimed to evaluate the utility of the complementary glycaemic markers glycated albumin, fructosamine and 1,5 anhydroglucitol in this group of patients.. A prospective study of patients with Type 2 diabetes and chronic kidney disease stage IIIB/IV undergoing intravenous iron or erythropoiesis-stimulating agent therapy. Glycaemic control was monitored using HbA(1c), seven-point daily glucose thrice weekly, continuous glucose monitoring, glycated albumin, fructosamine and 1,5 anhydroglucitol.. Fifteen patients [9 men; median age 72 years (interquartile range 68-74), follow-up period (16.4 ± 3.7 weeks)] received parenteral iron; 15 patients [11 men; 70 years (interquartile range 62-75), (17.3 ± 3.3 weeks)] received erythropoiesis-stimulating agent. HbA(1c) fell following treatment with both iron [57 mmol/mol (7.4%) to 53 mmol/mol (7.0%), P < 0.001] and erythropoiesis-stimulating agent [56 mmol/mol (7.3%) to 49 mmol/mol (6.6%), P = 0.01] despite mean blood glucose remaining unchanged (iron: 9.55 to 9.71 mmol/l, P = 0.07; erythropoiesis-stimulating agent: 8.72 to 8.78 mmol/l, P = 0.89). Unlike HbA1c , the glycated albumin, fructosamine and 1,5 anhydroglucitol levels did not change following iron [glycated albumin (16.8 to 16.3%, P = 0.10); fructosamine (259.5 to 256 μmol/l, P = 0.89); 1,5 anhydroglucitol (54.2 to 50.9 μmol/l, P = 0.89)] or erythropoiesis-stimulating agent [glycated albumin (17.9 to 17.5%, P = 0.29), fructosamine (324.3 to 306.0 μmol/l, P = 0.52), 1,5 anhydroglucitol (58.2 to 46.7 μmol/l, P = 0.35)]. Despite this, HbA(1c) was consistently the marker most closely related to mean blood glucose before and after each treatment (R range 0.7-0.88).. These data indicate that HbA(1c) was statistically most closely related to mean blood glucose, but clinical trends in glycaemia in patients undergoing iron or erythropoiesis-stimulating agent therapy are likely best assessed by including one of these additional glycaemic markers.

Topics: Administration, Intravenous; Aged; Biomarkers; Blood Glucose; Delivery of Health Care; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Fructosamine; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hematinics; Humans; Iron; Male; Monitoring, Physiologic; Prospective Studies; Recombinant Proteins; Renal Insufficiency, Chronic; Serum Albumin; Severity of Illness Index; Time Factors; Treatment Outcome

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

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Renal Insufficiency, Chronic

This study assessed the added effect of 6 months of erythropoietin (EPO) administration in patients suffering from diabetic neuropathy with mild to moderate chronic kidney disease (CKD) managed with gabapentin. Twenty diabetic patients with mild to moderate CKD were included; 12 in gabapentin and 8 in EPO+gabapentin group. The subjects underwent nerve conduction studies (NCS) at the initiation of the investigation and after 6-month treatment. NCS were made in deep and superficial peroneal, tibial, and sural nerves. After 6 months, in both the groups, proximal motor latency (PML) nonsignificantly improved in deep peroneal and tibial nerves; conversely, dorsal motor latency (DML) got slightly impaired in these two nerves. A nonsignificant disruption and improvement was observed in deep peroneal and tibial motor nerve conduction velocity (MNCV), respectively, in gabapentin group. Although the F-wave of tibial and deep peroneal nerves remained stable in gabapentin group, a nonsignificant improvement was observed in EPO+gabapentin group. H-reflex of tibial nerve and all the evaluated parameters of sural and superficial peroneal nerves remained constant in all patients. Thus, it can be concluded that 6-month administration of EPO+gabapentin, or gabapentin alone in mild to moderate CKD patients with diabetic neuropathy could not improve nerve performance.

Topics: Aged; Aged, 80 and over; Amines; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Drug Therapy, Combination; Erythropoietin; Excitatory Amino Acid Antagonists; Female; Gabapentin; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Neural Conduction; Neurologic Examination; Peripheral Nervous System Diseases; Peroneal Nerve; Recombinant Proteins; Renal Insufficiency; Sural Nerve; Surveys and Questionnaires; Tibial Nerve

Topics: Anemia; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glycated Hemoglobin; Hepatitis C; Humans; Insulin Glargine; Insulin, Long-Acting; Interferon-alpha; Metformin; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin

To compare quality-of-care indicators for management of patients with chronic kidney disease (CKD) and type 2 diabetes among the James Bay Cree of Northern Quebec with those among residents of Montreal, Que.. A cross-sectional survey using medical records from patients seen between 2002 and 2008.. Predialysis clinics of the McGill University Health Centre in Montreal.. Thirty Cree and 51 nonaboriginal patients older than 18 years of age with type 2 diabetes mellitus and estimated glomerular filtration rates of less than 60 mL/min/1.73 m2.. Rates of anemia, iron deficiency, obesity, and renoprotective medication use among aboriginal and nonaboriginal patients.. Overall, the Cree patients were younger (59 vs 68 years of age, P < .0035) and weighed more (101 vs 77 kg,P < .001). The 2 groups were prescribed medication to control blood pressure, lipids, and phosphate levels at similar rates, but the Cree patients were more likely to receive renoprotective agents (87% vs 65%, P = .04). Despite similar rates of erythropoietin supplementation, the Cree patients were at greater risk of anemia, with an adjusted risk ratio of 2.80 (95% CI 1.01 to 7.87).. Cree patients with CKD were younger, weighed more, and were more likely to receive renoprotective agents. With the exception of the management of anemia, quality of CKD care was similar between the 2 groups.Anemia education for family physicians and continuous monitoring of quality indicators must be implemented in northern Quebec.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Female; Health Care Surveys; Healthcare Disparities; Hematinics; Humans; Indians, North American; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Quality Indicators, Health Care; Quebec; Renal Insufficiency, Chronic

Anemia is common in diabetes. The role of hepcidin in diabetic anemia is unknown.. To assess the relationship between serum hepcidin and anemia in diabetic patients without renal failure.. We prospectively studied 86 consecutive type II diabetic patients--39 with anemia (cases) and 47 without anemia (controls). Patients with renal failure, iron and vitamin B12 deficiency and chronic inflammatory diseases were excluded.. Univariate analyses showed that patients with anemia were older and had longer duration of diabetes compared to patients without anemia (P < 0.051). The median hepcidin level was 15 ng/mL (2-140 ng/ml) in patients with anemia compared to 14 ng/mL (2-128 ng/ml) in patients without anemia (P = 0.386]) Serum erythropoietin and creatinine levels were higher in patients with anemia compared to patients without anemia (P < 0.05). Patients with anemia had tower HbA1c levels (P = 0.035), and greater usage of anti-diabetic drugs; metformin 73% versus 46.8% (P = 0.016), and sulfonylurea 47.2% versus 19.1% (P = 0.006). After adjusting for age, the two groups still differed in duration of diabetes (P = 0.043), erythropoietin (P = 0.007) creatinine (P < 0.001), and usage of metformin, sulfonylurea and insulin (P < 0.05).. Subjects with diabetic anemia have Longer diabetes duration than subjects with diabetes without anemia. Based on the results of this small study, hepcidin was not associated with diabetic anemia.

Topics: Adult; Age Factors; Aged; Anemia; Antimicrobial Cationic Peptides; Creatinine; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hepcidins; Humans; Hypoglycemic Agents; Male; Middle Aged; Prospective Studies; Risk Factors; Time Factors

Our recent studies indicated that up-regulation of calcineurin activity and unfolded protein responses (UPRs) disrupt cytoprotective Akt- and ERK-signaling in OLETF, a model of obese type 2 diabetes (T2DM). To determine whether the mechanisms can be generalized, we used Goto-Kakizaki rats (GK), a model of non-obese T2DM, in this study. Infarct sizes after 20-min ischemia/2-h reperfusion were similar in GK and non-diabetic controls, Wistar rats (Wistar). However, erythropoietin (EPO) limited infarct size in Wistar (64.0±5.3% vs. 45.7±4.4%, p<0.05) but not in GK (56.2±2.2% vs. 52.6±2.3%). Levels of calcineurin activity and EPO-induced phosphorylation of Akt and ERK were similar in GK and Wistar, though cytosolic HSP70 level was 50% lower and mitochondrial HSP60 level was 60% higher in GK. EPO preserved mitochondrial calcium retention capacity (CRC), an index of the threshold for opening of the mitochondrial permeability transition pore (mPTP), after ischemia/reperfusion in Wistar but not in GK. Interaction of cyclophilin D (CypD) with mitochondrial inorganic phosphate carrier (PiC), which sensitizes the mPTP, was enhanced in GK. There was a negative exponential relationship between CypD-PiC interaction and CRC upon reperfusion, indicating that increase in CRC by reduction of CypD-PiC interaction is smaller when CypD-PiC interaction level is at a higher range. A chemical chaperone, 4-phenylbutyric acid, attenuated the changes in HSPs and CypD-PiC interaction and restored responses of CRC and infarct size to EPO in GK. These results suggest that cytoprotective regulation of the mPTP is impaired in GK by enhanced CypD-PiC interaction in which UPRs are involved.

Topics: Animals; Calcineurin; Calcium; Cardiotonic Agents; Cyclophilins; Diabetes Mellitus, Type 2; Disease Models, Animal; Erythropoietin; Heart; In Vitro Techniques; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Reperfusion Injury; Myocardium; Peptidyl-Prolyl Isomerase F; Rats; Rats, Wistar; Signal Transduction

Any condition that shortens erythrocyte lifespan or decreases mean erythrocyte age may falsely lower hemoglobin A1c (A1C) test results. Ribavirin (RBV) used for chronic hepatitis C virus (HCV) infection can cause reversible hemolytic anemia; erythropoietin (EPO) used for treatment-related anemia can stimulate the production of red blood cells. We reported a 55-year-old woman with diabetes who received peginterferon alfa plus RBV for HCV infection. Four weeks following HCV therapy, her Hb level declined from 13.3 g/dL to 11.3 g/dL with elevated lactate dehydrogenase and reduced haptoglobin, which confirmed hemolysis. As her Hb fell to a nadir of 8.5 g/dL at the eighth week, darbepoetin alfa was administered to treat anemia consecutively for 10 weeks. Two months later, the patient's A1C declined from 7.5% to an extremely low value of 4.0%, accompanied by a fasting glucose level of 116 mg/dL. During the preceding 3 months, there was no self-reported hypoglycemia or documented low blood glucose. About 3 months after HCV therapy was terminated, the A1C returned to 6.1% without medication adjustment. The concurrent use of RBV and EPO treatments can synergistically cause falsely low A1C values and may lead to inappropriate relaxation of glycemic control. During HCV treatment with RBV, A1C should not be used alone to guide diabetes therapy.

Topics: Diabetes Complications; Diabetes Mellitus, Type 2; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Female; Glycated Hemoglobin; Hepatitis C, Chronic; Humans; Middle Aged; Ribavirin

Insulin resistance is an independent predictor of cardiovascular mortality in hemodialysis (HD) patients. Inflammation plays an important role in insulin resistance, and adipocytokines, including tumor necrosis factor-alpha and leptin, can induce insulin resistance. However, data on insulin resistance and erythropoietin responsiveness in HD patients are lacking.. We conducted a prospective, observational cohort study to clarify the relationship between insulin resistance and erythropoietin responsiveness in HD patients. Insulin resistance as assessed by the homeostasis model assessment for insulin resistance (HOMA-IR), levels of adiponectin and inflammatory cytokines, required erythropoietin (EPO) dose, and other metabolic parameters were measured in patients with (n = 52) and without diabetes (n = 55) over the course of 12 months.. The diabetes group had significantly higher serum leptin, high-sensitivity C-reactive protein, and interleukin-6 concentrations but lower serum adiponectin concentration. Average hemoglobin (Hb) levels during the 12-month study period were significantly lower in the diabetes group than in the non-diabetes group, and a higher dose of EPO was required in the diabetes group. There was a significant negative correlation between adiponectin and HOMA-IR, a significant positive correlation between EPO dose and HOMA-IR, and a significant negative correlation between EPO dose and adiponectin in the two groups. Insulin resistance as established by HOMA-IR and adiponectin was associated with EPO responsiveness in HD patients. HOMA-IR, Hb, and adiponectin levels were found to be independent predictors of EPO dose in HD patients with diabetes.. Insulin resistance is associated with EPO responsiveness in HD patients. Patients in the diabetes group had a lower response to EPO than those in the non-diabetes group. For improvement in EPO response, insulin resistance may be a new target for treating HD patients.

Topics: Adiponectin; Aged; Anemia; Biomarkers; Cytokines; Diabetes Mellitus, Type 2; Erythropoiesis; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Inflammation Mediators; Insulin Resistance; Japan; Kidney Diseases; Linear Models; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Glycated Hemoglobin; Hematinics; Humans; Hyperglycemia; Kidney Failure, Chronic

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic

Topics: Anemia; C-Reactive Protein; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Risk

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Ferritins; Hematinics; Humans; Iron; Kidney Failure, Chronic; Risk

This study aimed to explore the relationship between recombinant human erythropoietin (EPO) responsiveness, insulin resistance, and malnutrition-inflammation-atherosclerosis (MIA) syndrome in hemodialysis patients.. This was an observational cohort study in hemodialysis patients. Adipokines, inflammatory cytokines, and required EPO dosage were measured in diabetes (DM; n=58) and non-diabetes (non-DM; n=58) groups over 48 weeks. Furthermore, the EPO responsiveness index (required EPO dosage divided by hemoglobin) was evaluated with or without MIA syndrome in both groups.. The DM group had significantly higher plasma leptin, interleukin-6 (IL-6), and high sensitivity C-reactive protein (hs-CRP) levels but lower plasma high molecular weight (HMW) adiponectin levels compared to the non-DM group. Although hemoglobin levels were not significantly different, required EPO dosage was significantly higher in the DM group than in the non-DM group, particularly in the presence of MIA syndrome. The DM group with MIA syndrome had significantly higher plasma leptin, IL-6, and hs-CRP levels but lower plasma HMW adiponectin levels compared to the non-DM group with MIA syndrome. There was also a significant association between EPO dosage and homeostasis model assessment for insulin resistance (HOMA-IR), hs-CRP, IL-6, tumor necrosis factor a, leptin, and HMW adiponectin levels in DM patients with MIA syndrome.. Diabetic hemodialysis patients with MIA syndrome have a lower response to EPO and a higher resistance to insulin. This fact may explain the poor outcome of these patients and demonstrate the importance of diagnosis and therapeutic management.

Topics: Aged; Analysis of Variance; Anemia; Atherosclerosis; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glycated Hemoglobin; Hematinics; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Japan; Kidney Failure, Chronic; Lipids; Male; Malnutrition; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Syndrome; Time Factors; Treatment Outcome

Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.

Topics: AC133 Antigen; Aged; Antigens, CD; Antigens, CD34; Biomarkers; Cell Proliferation; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelial Cells; Erythropoietin; Female; Glycoproteins; Hematinics; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Peptides; Philadelphia; Prospective Studies; Stem Cells; Time Factors; Treatment Outcome; Vasodilation

To investigate the possible involvement of erythr opoietin (EPO)/erythropoietin receptor (EPOR) system in neovascularization and vascular regeneration in diabetic retinopathy (DR).. EPOR positive circulating progenitor cells (CPCs: CD34(+)) and endothelial progenitor cells (EPCs: CD34(+)KDR(+)) were assessed by flow cytometry in type 2 diabetic patients with different stages of DR. The cohort consisted of age- and sex-matched control patients with out diabetes ( n=7),non-proliferative DR (NPDR, n=7),non-proliferative DR (PDR, n=8), and PDR complicated with diabetic nephr opathy (PDR-DN, n=7).. The numbers of EPOR(+) CPCs and EPOR(+) EPCs were reduced remarkably in NPDR compared with the control group (both Pü0.01), whereas rebounded in PDR and PDR-DN groups in varyingdegrees. Similar changes were observed in respect of the proportion of EPOR(+)CPCs in CPCs (NPDR vs. control, Pü0.01) and that of EPOR(+) EPCs in EPCs (NPDR vs. control, Pü0.05).. Exogenous EPO, mediated via the EPO/EPOR system of EPCs, may alleviate the impaired vascular regeneration in NPDR, whereas it might aggravate retinal neovascularization in PDR due to a rebound of EPOR(+)EPCs associated with ischemia.

Topics: Aged; Cell Count; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelium, Vascular; Erythropoietin; Female; Humans; Male; Middle Aged; Receptors, Erythropoietin; Stem Cells

Anemia and inflammation are prevalent in diabetic patients with chronic kidney disease (CKD). The role of endogenous erythropoietin (EPO) in the pathophysiology of anemia in chronic diseases and its relationship to clinical outcomes remain uncertain. In this cohort study, we aimed to identify factors associated with endogenous EPO levels and investigate their relation to all-cause mortality.. Between 2004 and 2005, 215 patients with type 2 diabetes were enrolled. Exclusion criteria included stage renal disease ESRD and any form of anemia therapy. The association of EPO levels with clinical and laboratory variables was investigated by linear regression modeling. Predictors of all-cause mortality were evaluated by Cox proportional hazards analyses.. Patients (median age, 67 years; 52% men; median duration of diabetes, 10 years; median estimated GFR, 49 ml/min per 1.73 m²) were followed for up to 7.0 years. Forty-one patients died. Elevated EPO levels were independently associated with elevated C-reactive protein, low ferritin, and hypertension, in a multivariate model that also included age, cardiovascular disease, kidney function, albumin, cholesterol, and hemoglobin. Higher EPO levels were independently predictive for mortality, as were age, low levels of albumin, and cardiovascular disease.. In diabetic patients with CKD, elevated endogenous EPO levels were predictive for mortality and were related mainly to markers of inflammation, independent of kidney function, and despite low hemoglobin levels. Understanding the phenomenon of EPO resistance and iron dysregulation caused by inflammation is crucial for effective and safe treatment of anemia in patients with CKD.

Topics: Aged; Analysis of Variance; Anemia; Biomarkers; C-Reactive Protein; Chronic Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Germany; Humans; Inflammation; Inflammation Mediators; Kaplan-Meier Estimate; Linear Models; Longitudinal Studies; Male; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Humans; Male; Renal Insufficiency, Chronic; Stroke

Sustained high glucose impairs bone metabolism in patients with type 2 diabetes mellitus (T2DM). In this study, the relationship between glycemic control and bone metabolism was examined in male hemodialysis (HD) patients with T2DM. To avoid the effect of menstruation and the menstrual cycle, obesity, and glycosuria-induced hypercalciuria on bone metabolism, male anuric nonobese HD patients with T2DM (n = 42) were enrolled. Calcaneus stiffness index (SI) was determined using ultrasound after HD session. Casual plasma glucose (PG), glycated hemoglobin (HbA(1c)), and glycated albumin (GA) were measured before the HD session. In simple regression analysis, log PG (r = -0.333, P < .05) and log GA (r = -0.350, P < .05), but not log HbA(1c) (r = -0.134, P = .3985), exhibited significant and negative correlations with calcaneus SI. In multiple regression analysis including log BMI, log cCa x Pi product, and log PG, log PG was associated significantly in a negative manner with calcaneus SI, in addition to log cCa x Pi product. When log PG was replaced with log GA or log HbA(1c), log GA, but not log HbA(1c), emerged as a significant factor associated. The mechanism as to why HbA(1c) failed to associate could be explained by its false reduction by erythropoietin injection. The present study supported the notion of GA as an appropriate indicator for glycemic control in HD patients with T2DM. Furthermore, it is suggested that poor glycemic control might be a significant factor toward decreasing calcaneus SI in T2DM HD patients.

Topics: Aged; Blood Glucose; Bone and Bones; Calcaneus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Glycated Hemoglobin; Glycoproteins; Humans; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Renal Dialysis; Serum Albumin; Ultrasonography

The diabetic heart is resistant to ischemic preconditioning because of diabetes-associated impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. The mechanism by which PI3K-Akt signaling is impaired by diabetes remains unclear.. Here, we examined the hypothesis that phosphorylation of Jak2 upstream of PI3K is impaired in diabetic hearts by an angiotensin II type 1 (AT1) receptor-mediated mechanism.. Infarct size (as percentage of risk area) after 20-minute ischemia/2-hour reperfusion was larger in a rat model of type 2 diabetes (Otsuka-Long-Evans-Tokushima fatty [OLETF] rat) than in its control (Long-Evans-Tokushima-Otsuka [LETO] rat) (60.4+/-1.6% versus 48.4+/-1.3%). Activation of Jak2-mediated signaling by erythropoietin or DADLE ([D-Ala2, D-Leu5]-enkephalin acetate), a delta-opioid receptor agonist, limited infarct size in LETO rats (27.7+/-3.4% and 24.8+/-5.0%) but not in OLETF rats (53.9+/-5.3% and 55.0+/-2.2%). Blockade of the AT1 receptor by valsartan or losartan for 2 weeks restored the myocardial response of OLETF rats to erythropoietin-induced infarct size limitation (39.4+/-4.9% and 31.2+/-7.5). In OLETF rats, erythropoietin failed to phosphorylate both Jak2 and Akt, and calcineurin activity was significantly higher than in LETO rats. Two-week treatment with valsartan normalized calcineurin activity in OLETF rats and restored the response of Jak2 to erythropoietin. This effect of AT1 receptor blockade was mimicked by inhibition of calcineurin by FK506.. These results suggest that the diabetic heart is refractory to protection by Jak2-activating ligands because of AT1 receptor-mediated upregulation of calcineurin activity.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Calcineurin; Diabetes Mellitus, Type 2; Enkephalin, Leucine-2-Alanine; Erythropoietin; Immunosuppressive Agents; Ischemic Preconditioning, Myocardial; Janus Kinase 2; Losartan; Male; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Inbred OLETF; Receptor, Angiotensin, Type 1; Receptors, Opioid, delta; Signal Transduction; Species Specificity; Tacrolimus; Tetrazoles; Up-Regulation; Valine; Valsartan

Anemia is a common but often overlooked complication of diabetes. We investigated the relationship between hemoglobin concentration and various factors as well as markers of subclinical atherosclerosis in men with type 2 diabetes mellitus. Hemoglobin concentration was measured in 319 men with type 2 diabetes mellitus. We evaluated the relationship between hemoglobin concentration and various factors including age, body mass index, and glycemic control, as well as between hemoglobin concentration and pulse wave velocity or ankle-brachial index (n = 209) and between hemoglobin concentration and carotid intima-media thickness or plaque score (n = 125). Mean hemoglobin concentration was 14.2 +/- 0.80 g/dL. Body mass index (r = 0.340, P < .0001) and estimated glomerular filtration rate (r = 0.219, P = .0011) were positively associated with hemoglobin concentration, whereas age (r = -0.388, P < .0001), glycated albumin (r = -0.148, P = .0121), serum creatinine concentration (r = -0.206, P = .0019), and log (urinary albumin excretion) (r = -0.188, P = .0010) were negatively associated with hemoglobin concentration. Multiple regression analysis identified age (beta = -0.222, P = .0019), body mass index (beta = 0.145, P = .0432), systolic blood pressure (beta = 0.214, P = .0015), total cholesterol concentration (beta = 0.170, P = .0077), and serum creatinine concentration (beta = -0.181, P = .0045) as independent determinants of hemoglobin concentration. No significant association was observed between hemoglobin concentration and serum erythropoietin concentration (r = -0.079, P = .2980). Negative correlations were found between hemoglobin concentration and pulse wave velocity (r = -0.289, P < .0001) and between hemoglobin concentration and plaque score (r = -0.275, P = .0024). In conclusion, hemoglobin concentration was associated with various factors; and decreased hemoglobin concentration was associated with subclinical markers of atherosclerosis in men with type 2 diabetes mellitus.

Topics: Age Factors; Aged; Ankle Brachial Index; Atherosclerosis; Blood Glucose; Blood Pressure; Body Mass Index; Carotid Arteries; Creatinine; Diabetes Mellitus, Type 2; Erythropoietin; Hemoglobins; Humans; Male; Middle Aged; Regression Analysis; Ultrasonography

This study investigated whether the antiinflammatory effect of statins improved erythropoietin responsiveness in hemodialysis patients. We also examined if Type 2 diabetes mellitus, which had been shown to increase erythropoietin resistance, affected this effect of statins.. 103 patients were included in the cross-sectional study. Patients were stratified into statin and non-statin groups, and subgrouped based on the presence of Type 2 diabetes mellitus. Demographic, laboratory and other relevant data were analyzed by independent sample t-tests. The outcome of interest was erythropoietin dose. Two-way analysis of variance was used to determine the interaction between the use of statins and the presence of Type 2 diabetes mellitus.. Of 103 patients, 34% were on statins and 38.8% were diabetic. The mean erythropoietin dose (units/kg per week) was significantly lower in the statin group (275.6 +/- 273.2, 449.5 +/- 555.9, p < 0.05). 20% of patients in the statin group required erythropoietin dose in excess of an epoetin equivalent of 500 units/kg per week, compared to 30.88% in the non-statin group. The mean C-reactive protein level (mg/l) was lower in the statin group, although there was no statistical significance (1.13 +/- 1.22, 1.77 +/- 2.43, p = 0.08). The two-way analysis of variance showed no interaction between the use of statins and the presence of Type 2 diabetes mellitus on erythropoietin dose.. Our study demonstrated that hemodialysis patients who were on statins had a significantly lower erythropoietin requirement. This association is possibly due to the pleiotropic effect of statins.

Topics: Adult; Aged; Analysis of Variance; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Interactions; Erythropoietin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Male; Medical Records; Middle Aged; Patient Selection; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

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

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Iron; Male; Neoplasms; Renal Insufficiency, Chronic; Stroke; Treatment Outcome

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Evidence-Based Medicine; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic; Safety

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Risk Factors

To examine the effect of intravenous iron and erythropoietin-stimulating agents (ESAs) on glycemic control and A1C of patients with diabetes and chronic kidney disease (CKD).. This was a prospective study of patients with type 2 diabetes and CKD stage IIIB or IV undergoing intravenous iron (group A) and/or ESA (group B). Full blood profiles were determined over the study period. Glycemic control was monitored using A1C, seven-point daily glucose three times weekly, and continuous glucose monitoring (CGM).. There were 15 patients in both group A and group B. Mean A1C (95% CI) values fell in both groups (7.40% [6.60-8.19] to 6.96% [6.27-7.25], P<0.01, with intravenous iron and 7.31% [6.42-8.54] to 6.63% [6.03-7.36], P=0.013, ESA). There was no change in mean blood glucose in group A (9.55 mmol/l [8.20-10.90] vs. 9.71 mmol/l [8.29-11.13], P=0.07) and in group B (8.72 mmol/l [7.31-10.12] vs. 8.78 mmol/l [7.47-9.99], P=0.61) over the study period. Hemoglobin and hematocrit values significantly increased following both treatments. There was no linear relationship found between the change in A1C values and the rise of hemoglobin following either treatment.. Both iron and ESA cause a significant fall in A1C values without a change to glycemic control in patients with diabetes and CKD. At the present time, regular capillary glucose measurements and the concurrent use of CGM remain the best alternative measurements of glycemic control in this patient group.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Glycated Hemoglobin; Humans; Iron; Renal Insufficiency, Chronic; Treatment Outcome

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

Anaemia is frequently found in patients with diabetes, in whom it is associated with increased morbidity and mortality. Low testosterone levels are also common in men with type 2 diabetes. We hypothesized that low testosterone levels are also associated with anaemia in men with type 2 diabetes, over the effects of chronic kidney disease.. Cross-sectional cohort study, performed in 2005 in a tertiary diabetes clinic. Patients 464 men with type 2 diabetes.. Anaemia (haemoglobin (Hb) < 13.7 g/dl in men aged < 60, or < 13.2 g/dl in men aged 60 and older).. About 24% of study participants had anaemia, which was associated with the presence and severity of chronic kidney disease, systemic inflammation, increased age, and reduced iron availability. In addition, testosterone levels were independently associated with reduced Hb levels, determining between 6 and 8% of the total variability in raw Hb levels in this population after adjusting for these other factors. Individuals with total testosterone level < 10 nmol/l (43% of the cohort) were more likely to have anaemia (adjusted odds ratio 1.7; 95% CI 1.1-2.8). Similarly, anaemia was twice as common in individuals with a calculated free testosterone of < 0.23 nmol/l (adjusted odds ratio 2.0, 95% CI 1.2-3.1).. These findings suggest that testosterone deficiency may contribute to the increased frequency of anaemia in men with type 2 diabetes. However, the appropriate clinical response to testosterone deficiency in anaemic patients remains to be established by prospective clinical trials.

Topics: Aged; Anemia; C-Reactive Protein; Chronic Disease; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Regression Analysis; Severity of Illness Index; Testosterone

In hemodialysis (HD) patients the glycated hemoglobin (Hb(A1c)) level may underestimate glycemic control. The aim of this study is to estimate accurate glycemic control in type 2 diabetic patients on HD. Type 2 diabetes patients (N = 87) who had been receiving maintenance HD for at least one year were enrolled. Hb(A1c) and the percentage of glycated albumin relative to total the serum albumin (%GA) were measured in blood samples and the factors that affected the %GA/Hb(A1c) ratio were examined. There were significant and positive correlations between the plasma glucose and either the Hb(A1c) levels (r = 0.539, P < 0.01) or the %GA level (r = 0.520, P < 0.01). No relationship between the serum albumin levels and %GA levels was observed. A weekly dose of erythropoietin (EPO) was positively correlated with the ratio of %GA/Hb(A1c) and hematocrit (Ht) correlated negatively. There was no significant correlation between the %GA/Hb(A1c) level and the EPO dose in patients with Ht > or = 30%, although a significant correlation was found between those parameters in the Ht < 30% group. The mean of the %GA/Hb(A1c) ratios in patients with Ht > or = 30%, with Ht < 30% and treated with EPO < 100 IU/kg/week, and with Ht < 30% and treated with EPO > or = 100 IU/kg/week were 3.41, 3.56 and 4.13, respectively. In HD patients, accurate glycemic control may be estimated as: Hb(A1c) x 1.14 if Ht > or = 30%; Hb(A1c) x 1.19 if Ht < 30% and treated with low dosages of EPO; and Hb(A1c) x 1.38 if Ht < 30% and treated with high dosages of EPO.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Glucose; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Erythropoietin; Female; Glycated Hemoglobin; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Serum Albumin

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

Alteration in endoplasmic reticulum (ER) stress in diabetic hearts and its effect on cytoprotective signaling are unclear. Here, we examine the hypothesis that ER stress in diabetic hearts impairs phospho-glycogen synthase kinase (GSK)-3beta-mediated suppression of mitochondrial permeability transition pore (mPTP) opening, compromising myocardial response to cytoprotective signaling.. A rat model of type 2 diabetes (OLETF) and its control (LETO) were treated with tauroursodeoxycholic acid (TUDCA) (100 mg . kg(-1) . day(-1) for 7 days), an ER stress modulator. Infarction was induced by 20-min coronary occlusion and 2-h reperfusion.. Levels of ER chaperones (GRP78 and GRP94) in the myocardium and level of nonphoshopho-GSK-3beta in the mitochondria were significantly higher in OLETF than in LETO rats. TUDCA normalized levels of GRP78 and GRP94 and mitochondrial GSK-3beta in OLETF rats. Administration of erythropoietin (EPO) induced phosphorylation of Akt and GSK-3beta and reduced infarct size (% risk area) from 47.4 +/- 5.2% to 23.9 +/- 3.5% in LETO hearts. However, neither phosphorylation of Akt and GSK-3beta nor infarct size limitation was induced by EPO in OLETF rats. The threshold for mPTP opening was significantly lower in mitochondria from EPO-treated OLETF rats than in those from EPO-treated LETO rats. TUDCA restored responses of GSK-3beta, mPTP opening threshold, and infarct size to EPO receptor activation in OLETF rats. There was a significant correlation between mPTP opening threshold and phospho-GSK-3beta-to-total GSK-3beta ratio in the mitochondrial fraction.. Disruption of protective signals leading to GSK-3beta phosphorylation and increase in mitochondrial GSK-3beta are dual mechanisms by which increased ER stress inhibits EPO-induced suppression of mPTP opening and cardioprotection in diabetic hearts.

Topics: Animals; Blood Glucose; Body Weight; Calcium; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Immunoblotting; Intracellular Membranes; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Myocytes, Cardiac; Permeability; Phosphorylation; Rats; Rats, Inbred OLETF; Taurochenodeoxycholic Acid

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Thiazolidinediones (TZDs) are frequently used pharmacotherapeutics for type II diabetes mellitus, which exert their effect through peroxisomal proliferator agonist receptor (PPAR) mediated increased insulin sensitivity. TZDs are known to cause marrow suppression and to stimulate adipogenesis. Case and cohort studies show TZDs worsen thyroid-associated orbitopathy. We present a case consistent with earlier reports of marrow suppressive pancytopenia manifesting as myelodysplastic syndrome, a new implication of hypoerythropoetinemia, and non-Graves'-associated proliferative proptosis.

Topics: Diabetes Mellitus, Type 2; Erythropoietin; Exophthalmos; Female; Humans; Hypoglycemic Agents; Lipodystrophy; Middle Aged; Myelodysplastic Syndromes; Rosiglitazone; Thiazolidinediones

Topics: Age Factors; Aged; Albuminuria; Antihypertensive Agents; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Radioimmunoassay

The significance of glycated albumin (GA), compared with casual plasma glucose (PG) and glycated hemoglobin (HbA(1c)), was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. The mean PG, GA, and HbA(1c) levels were 164.5 +/- 55.7 mg/dl, 22.5 +/- 7.5%, and 5.85 +/- 1.26%, respectively, in HD patients with diabetes (n = 538), which were increased by 51.5, 31.6, and 17.7%, respectively, compared with HD patients without diabetes (n = 828). HbA(1c) levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the relationship among the three parameters in patients who had diabetes without renal dysfunction (n = 365), as reflected by the significantly more shallow slope of regression line between HbA(1c) and PG or GA. A significant negative correlation was found between GA and serum albumin (r = -0.131, P = 0.002) in HD patients with diabetes, whereas HbA(1c) correlated positively and negatively with hemoglobin (r = 0.090, P = 0.036) and weekly dose of erythropoietin injection (r = -0.159, P < 0.001), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA(1c) levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartile by HbA(1c) level led to better glycemic control in a significantly higher proportions of HD patients with diabetes than those assessed by GA. Multiple regression analysis demonstrated that the weekly dose of erythropoietin, in addition to PG, emerged as an independent factor associated with HbA(1c) in HD patients with diabetes, although PG but not albumin was an independent factor associated with GA. In summary, it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA(1c) in these patients might lead to underestimation likely as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

Topics: Anemia; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Glycosylation; Humans; Logistic Models; Multivariate Analysis; Regression Analysis; Renal Dialysis; Serum Albumin

Retinal neovascularization in diabetes has been thought to follow the release of local angiogenic factors in the retina. We hypothesize that neovascularization of diabetic retinopathy is a systemic vasculogenesis rather than a local angiogenesis. Thus, we evaluate the concentrations of circulating endothelial progenitor cells (EPCs) and stem cell modulation factors such as vascular endothelial growth factor (VEGF), erythropoietin (Epo), and substance p (SP) in the peripheral blood of diabetic retinopathy patients.. We studied 15 normal controls and 45 type II diabetic patients (no DR group (n=15), NPDR group (n=15), and PDR group (n=15)). We measured circulating CD34+mononuclear cells (CD34+MNCs), c-Kit+mononuclear cells (c-Kit+MNCs) by flow cytometry. VEGF, Epo, and SP in the peripheral blood were measured by ELISA.. The circulating CD34+MNCs and c-Kit+MNCs increased in the NPDR and PDR groups compared with the control group (P<0.01). Serum level of VEGF increased in the NPDR and PDR groups compared with the control group (P<0.05). The level of Epo elevated exclusively in the no DR group compared with the other three groups (P<0.01). Circulating SP level increased in the NPDR and PDR groups compared with the control group (P<0.05). SP and CD34+MNCs were shown to have increased correlation according to the diabetic retinopathy in the NPDR and PDR groups (r=0.440, P<0.05 and r=0.460, P<0.05, respectively).. The present study is the first to demonstrate that CD34+MNCs, c-Kit+MNCs and their modulator are elevated in diabetic retinopathy patients. Therefore, it is possible that circulating EPCs and serum Epo, VEGF, and SP may be involved in the progression of diabetic retinopathy.

Topics: Aged; Aged, 80 and over; Angiogenesis Inducing Agents; Antigens, CD34; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelium, Vascular; Erythropoietin; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Retinal Neovascularization; Severity of Illness Index; Stem Cells; Substance P; Vascular Endothelial Growth Factor A

We investigated erythropoietin (Epo) response in a cohort of diabetic patients with various types of anemia to approach the pathogenesis of some cases of "unexplained" anemia encountered among diabetics. Serum Epo levels were determined totally in 747 evaluable subjects with normal renal and hepatic function, of whom 694 had anemia. Among anemic patients, 237 were diabetics, while among the 53 nonanemic persons, there were also 21 diabetics. Diabetic and nondiabetic subjects were uniformly balanced in relation to their demographic features and were categorized according to the etiology of their anemia. Hemoglobin (Hb) did not differ between diabetic and nondiabetic subjects in all the etiological groups and in the whole population. Diabetic patients had significantly lower serum Epo levels as compared to nondiabetics (36.5+/-61 vs 69.4+/-191 IU/ml, p<0.0001), and this was true for all etiologic groups of anemia with the exception of patients with myeloproliferative disorders and those with megaloblastic anemia. The natural logarithmic (ln)-EpoxHb component was used as an index of response to anemia and was found to be significantly decreased in almost all subgroups of diabetic patients. Serum Epo levels were also negatively correlated with the percentage of glycosylated Hb, HbA1(C) (r=-0.446), and the correlation was stronger with the ln of serum Epo (r=-0.638, p<0.001). Inappropriately low serum Epo level is a uniform feature in patients with type II diabetes mellitus and may represent a constitutive blunted response to anemia or an altered metabolic rate of Epo, probably as a result of abnormal glycosylation of the cytokine.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cytokines; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glycated Hemoglobin; Glycosylation; Hemoglobins; Humans; Hypoxia; Male; Middle Aged

Anaemia is a common finding in patients with diabetic nephropathy. Impaired production of erythropoietin is thought to be the predominant cause, as a result of renal microvascular disease. This study aims to determine the prevalence of functional erythropoietin deficiency in a cross-sectional survey of patients with Type 2 diabetes.. Clinical data on 604 patients with Type 2 diabetes were obtained, including a full blood count, iron indices and detailed history of diabetic complications. Erythropoietin levels were correlated with the presence of anaemia, iron deficiency and renal dysfunction. Functional erythropoietin deficiency was defined by erythropoietin levels in the normal range despite the presence of anaemia.. Nineteen per cent of patients (n = 112) were anaemic, among whom erythropoietin deficiency (76%) and reduced iron availability (58%) were common findings. Over 90% of patients had erythropoietin deficiency, once those with reduced iron stores or availability were excluded. Most of these patients had moderate renal impairment (60%, n = 67). However, even in the absence of renal impairment, 71% of anaemic patients (n = 32/45) had functional erythropoietin deficiency, although most had other evidence of nephropathy. In addition, two-thirds of patients with reduced iron availability were unable to increase erythropoietin above the normal range.. These findings confirm the failure of the kidney to produce erythropoietin in response to a falling haemoglobin is a key component to anaemia in diabetes. The likelihood of functional erythropoietin deficiency as a cause of anaemia is not dependent on the severity of renal impairment or excluded in diabetic patients with reduced iron stores or availability.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Anemia; Biological Availability; Blood Pressure; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney; Male; Middle Aged

Low plasma erythropoietin (EPO) is a key causal factor in the anaemia of diabetic patients. The aim of this study was to investigate the prevalence of anaemia in relation to EPO in patients with Type 2 diabetes.. In a clinic-based cross-sectional study of 161 Type 2 diabetes patients, we measured EPO, ferritin and full blood count. The patients were classified on the basis of the urine albumin:creatinine excretion ratio as normo-, micro- or macroalbuminuric. Serum creatinine, cystatin C and glomerular filtration rate (GFR) calculated from cystatin C were used as markers of renal function. All the patients were assessed for symptoms and signs of diabetic complications, including diabetic peripheral sensory neuropathy (PSN).. Twenty-one (13.0%) patients were anaemic; 80 patients (49.7%) had low EPO (< 5 mU/ml), of whom 28.8% had a GFR < 60 ml/min per 1.73 m2; 57.5% were normoalbuminuric, 33.7% were microalbuminuric and 8.8% macroalbuminuric. Although EPO was significantly higher in anaemic patients compared with non-anaemic patients, the EPO response was inappropriate for the degree of anaemia. Of patients with PSN, 66.7% had low EPO but there was no significant difference in EPO between patients with and without PSN. Log EPO correlated significantly with urine microalbumin:creatinine ratio and logistic regression analysis showed that haemoglobin, age and urine microalbumin: creatinine ratio were the main determinants of EPO.. The degree of microalbuminuria is the most significant determinant of plasma EPO, which is often low or inappropriately normal in diabetic patients with and without anaemia.

Topics: Aged; Albuminuria; Anemia; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Cross-Sectional Studies; Cystatin C; Cystatins; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged

Erythropoietin has been recently found to be increased in the vitreous fluid from ischemic retinal diseases such as proliferative diabetic retinopathy (PDR). The aims of the present study were 1) to measure erythropoietin levels in the vitreous fluid from patients with diabetic macular edema (DME), a condition in which the ischemia is not a predominant event, and 2) to compare erythropoietin mRNA expression between human retinas from nondiabetic and diabetic donors without retinopathy.. Vitreous samples from 12 type 2 diabetic patients with DME without significant retinal ischemia and 12 PDR patients were prospectively analyzed. Ten nondiabetic patients with macular holes served as the control group. Erythropoietin was assessed by radioimmunoassay (milliunits per milliliter). Erythropoietin mRNA expression was measured by quantitative real-time RT-PCR analysis in the retina from eight nondiabetic and eight age-matched diabetic donors without diabetic retinopathy. Intravitreal erythropoietin concentration was higher in both PDR and DME patients than in nondiabetic control subjects (PDR vs. control subjects: median 302 [range 117-1,850] vs. 30 mU/ml [10-75], P < 0.01; DME vs. control subjects: 430 [41-3,000] vs. 30 mU/ml [10-75], P < 0.01). However, no significant differences were found between DME and PDR patients. Erythropoietin mRNA expression was detected in the human retina, and it was higher in the retina from diabetic than from nondiabetic donors.. As occurs in PDR, intravitreous erythropoietin concentrations are strikingly higher in DME. Erythropoietin is expressed in the human retina, and it is upregulated in diabetic patients even without retinopathy. These findings suggest that other factors apart from ischemia are involved in the overexpression of erythropoietin in diabetic retinopathy.

Topics: Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Erythropoietin; Female; Humans; Macular Edema; Male; Middle Aged; Prospective Studies; Radioimmunoassay; Retina; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Albuminuria; Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Europe; Humans; Practice Guidelines as Topic; Prognosis; Quality of Life

Plasma cell differentiation antigen 1 (PC-1) is an inhibitor of insulinreceptor tyrosine-kinase. PC-1 content is elevated in muscle and adipose tissue from insulin-resistant subjects and its elevation correlates with in vivo insulin resistance. It is known that insulin resistance in uraemia may be improved with erythropoietin (EPO) and vitamin D therapy. Therefore, in this study the effects of human recombinant EPO and 1-alpha-D3 treatments on lymphocyte PC-1 expression in patients with end-stage renal failure on haemodialysis (HD) were investigated.. Lymphocyte basal, concanavalin A (Con A), and phorbol-12-myristate13-acetate (PMA)-stimulated PC-1 activity were investigated in HD patients before and after a two-month treatment with subcutaneous EPO (15 patients, 2000-3000 U thrice weekly) or oral 1-alpha-D3 (14 patients, 2 mug thrice weekly). Twenty-nine patients (16 men and 13 women), aged 22-68 years (49+/-7 years), on HD from 13 to 112 months, and 30 healthy controls participated in the study. None was obese and all had normal fasting plasma glucose.. A two-month EPO treatment produced a 41% haematocrit increase, with a rise in haemoglobin from 6.51+/-0.18 g/dL to 9.69+/-0.14 g/dL. Basal lymphocyte PC-1 activity in HD patients was found to be significantly increased (P<0.005) over the level in healthy controls. Treatment of patients with EPO decreased unstimulated lymphocyte PC-1 activity to values significantly lower than before the treatment (P<0.001). Lymphocyte Con A and PMA-stimulated PC-1 activity in patients on HD was found to be slightly increased over the level in healthy controls, but significantly reduced (P<0.005 and 0.05, respectively) after the EPO treatment. A two-month pulse oral 1-alpha-D3 treatment increased haematocrit by 21% and raised haemoglobin from 7.11+/-0.32 g/dL to 8.80+/-0.39 g/dL. This treatment normalized serum alkaline phosphatase activity and slightly reduced serum parathyroid hormone concentration. PC-1 in unstimulated and PMA-stimulated lymphocytes was unchanged, but significantly decreased (P<0.05) in Con A-stimulated lymphocytes after 1-alpha-D3 treatment. Fasting plasma glucose was not changed by the treatment.. An increased lymphocyte PC-1 activity over control was found in HD patients. A two-month EPO therapy significantly decreased PC-1 activity to the control values, suggesting that an effect on PC-1 expression could be implicated in the amelioration of insulin resistance in uraemic patients treated with EPO. Treatment with pulse oral 1-alpha-D3 had an effect only on PC-1 of Con A-transformed lymphocytes of haemodialysed patients and requires further investigation.

Topics: Adjuvants, Immunologic; Administration, Oral; Adult; Aged; Blood Glucose; Carcinogens; Concanavalin A; Diabetes Complications; Diabetes Mellitus, Type 2; Erythropoietin; Female; Humans; Hydroxycholecalciferols; Insulin Resistance; Kidney Failure, Chronic; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Phosphoric Diester Hydrolases; Pyrophosphatases; Recombinant Proteins; Renal Dialysis; Tetradecanoylphorbol Acetate

Patients with diabetes commonly have a greater degree of anemia for their level of renal impairment than those presenting with other causes of renal failure. To clarify the contribution and differing roles of diabetes and nephropathy in the development of anemia in diabetic patients, we examined the hematologic and hematinic parameters of diabetic patients without nephropathy.. The study group was comprised of 62 patients with type 2 diabetes who had been followed for a median of 7 years. For the study, these patients had additional samples taken during their annual routine blood testing for the measurement of extra parameters, including serum ferritin, serum erythropoietin (Epo) levels, and the percentage of reticulocytes. These measurements were combined with the routine parameters Hb, hematocrit, HbA(1c), and glomerular filtration rate.. In all, 8 of the 45 male patients (17.8%) and 2 of the 17 female patients (11.8%) were classified as anemic (Hb <13g/dl and <11.5g/dl, respectively). Although only a small number of the patients had anemia as defined by normal values, a retrospective analysis of individual patients over time revealed a sustained though small decrease in Hb from initial presentation. A statistically significant difference in Epo levels (P = 0.016 by Kruskal-Wallis test) was observed from the group with the lowest (Hb < or =11.5) to that with the highest (Hb > or =14.5) Hb values, with a median Epo value of 37 (interquartile range 24-42) vs. 13 (9-15) IU/l, respectively. In contrast, there was no evidence of an increased reticulocyte response to higher levels of Epo (r = 0.134 [Pearsons], P = 0.36). Reticulocyte counts ranged from 44 (38-57) to 76.5 (56-83) in the lowest and highest Hb groups, respectively.. Although only a small number of subjects in the group were overtly anemic, all subjects had an ongoing, small but significant decrease in Hb since presentation. This study of diabetic patients without nephropathy shows an expected increase in Epo production in response to lowering levels of Hb but without the expected reticulocyte response.

Topics: Adult; Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Glycated Hemoglobin; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Reticulocyte Count; Retrospective Studies

Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data.. The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Humans; Kidney Diseases; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Reduction Behavior

Current guidelines give evidence-based advice on how best to manage anaemia in patients with renal disease, but these guidelines do not consider individual patient needs, so tailoring anaemia management to each patient still remains a challenge for the treating physician. Two case studies are described that illustrate some of the key factors that need to be considered. The first case emphasizes that haemoglobin (Hb) targets recommended in current guidelines may not suit all patients. The patient had been stably maintained on subcutaneous epoetin therapy with an average Hb concentration of >13.0 g/dl because he developed angina symptoms when his Hb level fell to 12.2 g/dl. Iron deficiency was identified as the likely cause of falling Hb in this patient. After the patient's iron supplementation was increased, his Hb level was normalized back to >13.0 g/dl without increasing the epoetin dose, and the angina symptoms were resolved. The second case involved a pre-dialysis patient with diabetes, who required a higher dose of epoetin after beginning concomitant antihypertensive treatment with an angiotensin-converting enzyme inhibitor. Previously, the treatment of renal anaemia in pre-dialysis patients has not been the focus of attention. Two ongoing randomized controlled trials have been designed to study early initiation of epoetin treatment in pre-dialysis patients and will provide much needed information in this area.

Topics: Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

We describe here four male patients with long-term and poorly controlled type 2 diabetes mellitus. They shared many common characteristic complications, such as severe autonomic neuropathy, proliferative retinopathy and normocytic normochromic anemia without progressive renal failure and macroangiopathy. They also showed normal levels of erythropoietin and reticulocyte, which was considered relatively low. The coefficient of variation of R-R, a useful method to estimate autonomic failure, showed markedly advanced autonomic neuropathy in all four patients. Coronary angiography did not reveal stenosis, anomaly or collateral vessels, but left ventriclography showed diffuse or partial hypokinesis. Massive proteinuria, high urinary levels of N-acetyl-beta-D-glucosamidase (NAG) and beta2-microglobulin (beta2M) were detected, though creatinine clearance (Ccr) was not so deteriorated. Treatment with recombinant erythropoietin increased their hemoglobin and hematocrit levels. These common points have a possibility to be brought about by tubulointerstitial damage and microangiopathy may be involved in it.

Topics: Adult; Anemia; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Humans; Male; Middle Aged; Reticulocyte Count

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Humans; Renal Insufficiency

Topics: Aged; Anemia; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Kidney; Male

An obese 76-year-old woman with type II diabetes, hypertension, coronary artery disease, and gastroesophageal reflux was found to have a 6-cm lower-pole mass in a solitary functional right kidney. Because her religious beliefs prohibited blood transfusion, minimally invasive surgery--a laparoscopic partial nephrectomy--was performed, with a good result. Minimally invasive surgery, perhaps with administration of erythropoietin, iron-dextran, or both, is often a good option for severely anemic patients or those whose religious beliefs are opposed to transfusion. Methods of minimizing blood loss intraoperatively are reviewed.

Topics: Aged; Carcinoma, Renal Cell; Coronary Disease; Diabetes Mellitus, Type 2; Erythropoietin; Female; Gastroesophageal Reflux; Humans; Hypertension; Iron-Dextran Complex; Jehovah's Witnesses; Kidney Neoplasms; Laparoscopy; Nephrectomy

Erythropoietin (EPO)-deficient anaemia has been described in Type 1 diabetic patients with both severe autonomic neuropathy (AN) and proteinuria. This study was aimed at distinguishing between the effects of AN and nephropathy on haemoglobin and EPO levels in Type 2 diabetic patients at an early stage of diabetic nephropathy.. In 64 Type 2 diabetic patients (age 52 +/- 10 years, duration 10 +/- 9 years) without overt nephropathy and other causes of anaemia or EPO deficit, we assessed cardiovascular tests of AN, 24-h blood pressure (BP) monitoring, urinary albumin excretion rate (UAE), a full blood count, and serum EPO.. Although the Type 2 diabetic patients with AN did not show differences in haemoglobin and EPO when compared with patients without AN, the presence of haemoglobin < 13 g/dl was associated with the presence of AN (chi(2)= 3.9, P < 0.05) and of postural hypotension (chi(2)= 7.8, P < 0.05). In a multiple regression analysis including as independent variables gender, body mass index, duration of diabetes, smoking, creatinine, 24-h UAE, 24-h diastolic BP, ferritin, erythrocyte sedimentation rate, and autonomic score, we found that the only variables independently related to haematocrit were autonomic score, ferritin and erythrocyte sedimentation rate. Finally, the physiological inverse relationship between EPO and haemoglobin present in a control group of 42 non-diabetic non-anaemic subjects was completely lost in Type 2 diabetic patients. The slopes of the regression lines between EPO and haemoglobin of the control subjects and the Type 2 diabetic patients were significantly different (t = 14.4, P < 0.0001).. This study documents an early abnormality of EPO regulation in Type 2 diabetes before clinical nephropathy and points to a contributory role of AN in EPO dysregulation.

Topics: Adult; Aged; Albuminuria; Autonomic Nervous System Diseases; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Female; Hemoglobins; Humans; Hypotension, Orthostatic; Male; Middle Aged

Diabetes is known to be a risk factor for the severity of anemia in non-dialyzed patients with renal failure. The aim of this study was to evaluate differences in hemoglobin (Hb) response to erythropoietin (EPO) in diabetic and nondiabetic patients on chronic hemodialysis (CHD). Sixty-four patients on CHD were included in the study: 24 type 2 diabetics (mean age, 59+/-11 years; 10 men, 14 women) and 40 nondiabetics (age, 53+/-14 years; 21 men, 19 women). All patients received a fixed dose of 50 mg ferric saccharate and EPO per week, dosed individually to achieve a target Hb level of 12 g/dl. Hb levels, ferritin, transferrin saturation (TSAT), EPO requirement (IU/kg/week), folic acid, vitamin B12 and C-reactive protein (CRP) were measured every two months. Additionally, the incidence of infectious diseases during the observation period of six months was evaluated, and a univariate correlation analysis of CRP and EPO requirements was performed in both groups. Patients with and without diabetes were divided into two groups each: those with normal CRP and those with elevated CRP. The EPO requirements of these groups were compared. Under identical iron substitution the mean Hb level increased more, but not significantly, in non-diabetic patients than in diabetic patients. After 6 months the mean Hb levels were 12.1+/-1.2 versus 11.5+/-1.2 g/dl (NS), although the actual EPO requirement was higher in diabetic than in non-diabetic subjects (244+/-122 versus 183+/-118 IU/kg/week; p<0.05). CRP after 6 months was significantly higher in diabetic than in non-diabetic patients (2.6+/-2.2 versus 1.5+/-1.3 mg/dl; p<0.05), as was the incidence of infectious disease (n/patient/month) (0.24 versus 0.08; p<0.05). The correlation coefficient between CRP and EPO requirements was statistically significant in both diabetic (r=0.547 p<0.01) and non-diabetic subjects (r=0.577; p<0.001). All other laboratory indices were similar in both groups. In the diabetic patients with normal CRP (n=6) the Hb levels achieved after six months were similar to those of non-diabetic patients (n=10) with normal CRP (11.9+/-1.1 versus 12.1+/-1.2%), and the required EPO was comparable. We conclude that the Hb response to EPO is reduced in diabetic patients on CHD. This elevated EPO requirement may be explained by a greater prevalence of infectious diseases, characterized by a significantly higher CRP level, in these patients. Other causes for the elevated EPO requirement could be excluded.

Topics: Adult; Aged; C-Reactive Protein; Chi-Square Distribution; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hemoglobins; Humans; Male; Middle Aged; Patient Selection; Prospective Studies; Renal Dialysis; Time Factors; Transferrin

Recent report demonstrates that inadequate iron mobilization and defective iron utilization may cause recombinant erythropoieitin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. The effect of intravenous ascorbic acid (IVAA) in HD patients selected on the basis of iron overload and EPO resistance also has been proven. However, it is uncertain whether IVAA still works in diabetic ESRD patients with hyperferritinemia. Therefore, the aim of this study focusing on diabetic ESRD patients was to analyze the potential effect of low dose IVAA on improvement of anemia and erythropoiesis-related parameters when compared with control period.. This study consisted of 22 chronic hemodialysis patients with type II diabetes in a single dialysis unit. In studies of this type, all eligible patients are followed up, but the primary comparison is still between different sequentially treatment including control period and post-IVAA period in same patients. IVAA patients received ascorbic acid, 100 mg each administered intravenously three times per week for eight weeks of treatment and four months of post-treatment follow-up.. The demographic characteristics of 22 diabetic uremic patients show that mean age is 63.6 +/- 10.2 years old. The ratio of sex (M/F) = 10/12. Mean duration of HD is 46.7 +/- 33.2 months. As for the urea kinetic study between these two periods including KT/V, nPCR, and URR, there is no significantly different. As for anemia-related parameters, Hb and Hct increased significantly in post-IVAA period after 3 months compared with control period, while MCV did not increase significantly. Serum ferritin significantly decreased at study completion. The same situation is for iron. As for TS, it significantly increased at one month and further markedly increased at subsequent three months.. This study has demonstrated that short-term low dose IVAA therapy can facilitate iron release from reticuloendothelial system but also increase iron utilization in diabetic hemodialysis patients with iron overload. Therefore, IVAA is a potential adjuvant therapy to treat erythropoeitin-hyporesponsive anemia in iron-overloaded patients.

Topics: Aged; Anemia; Ascorbic Acid; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Follow-Up Studies; Free Radical Scavengers; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Prospective Studies; Recombinant Proteins; Renal Dialysis; Serum Albumin; Taiwan; Time Factors; Treatment Outcome

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

Two patients with non-insulin-dependent diabetes mellitus (NIDDM) and moderate chronic renal failure experienced a worsening of glycaemic control when recombinant human erythropoietin (r-HuEPO) was introduced, leading to insulin therapy. A 71-year-old woman with a 20-year history of NIDDM had presented histologically documented diabetic nephropathy for 2 years during which glucose control was stabilized by a diet and glibenclamide 10 mg. In the 6 months following introduction of r-HuEPO, hyperglycaemic symptoms developed, and HbA1C increased from 8.9% to 12.3%. During this period, no intercurrent events occurred, except epistaxis due to accelerated hypertension one month after r-HuEPO was started. A 62-year-old man had a 15-year history of NIDDM, with proliferative retinopathy, macroproteinuria and chronic renal failure for 4 years. The day after the first injection of r-HuEPO, capillary glucose level rose dramatically. In both of these cases, antihypertensive treatment was increased and insulin introduced. The role of r-HuEPO in hyperglycaemia was probable in the first case and highly probable in the second. Reports about the effects of r-HuEPO on glucose metabolism in uraemic patients are conflicting. Short- and long-term effects can differ, although long-term benefit is likely. The fact that our patients were not dialized may have been important. Clinicians should be aware that glucose control may deteriorate with r-HuEPO, requiring some uraemic NIDDM patients to undergo insulin therapy.

Topics: Aged; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Erythropoietin; Female; Humans; Insulin; Male; Middle Aged; Recombinant Proteins; Uremia

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

We encountered two patients with non-insulin-dependent diabetes mellitus (DM) who developed normocytic normochromic anemia. Routine hematological examinations revealed no specific causes except for the reduced serum levels of erythropoietin. Since their renal functions were preserved, the anemias may not have been due to chronic renal failure. Treatment with human recombinant erythropoietin (rHuEPO) improved anemia, ascribing the cause of anemia to low levels of erythropoietin in these patients. Underlying common clinical features of the two patients were longstanding poorly controlled diabetes mellitus accompanied with advanced neuropathy. Since erythropoietin production is regulated in part by autonomic nervous system, the results suggest that erythropoietin production could be prematurely impaired in patients with severe diabetic autonomic neuropathy.

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Erythropoietin; Female; Humans; Kidney Function Tests; Male; Middle Aged; Recombinant Proteins

Recent data indicated the importance of urinary losses of erythropoietin (Epo) in the pathogenesis of anaemia in patients with nephrotic syndrome. In the present study we aimed to investigate plasma and urinary Epo levels and their renal handling in relation to beta 2-microglobulin (beta 2m), sodium metabolism and the renin-angiotensin-aldosterone system (RAAS), respectively, in patients with sub-nephrotic range proteinuria (SNP), microalbuminuric diabetics and hypertensives, and in healthy subjects studied on a standardized diet containing 120 mmol sodium and 70 g protein per day. We found that patients with SNP were characterized by lower plasma levels of Epo than healthy subjects but no differences were found in urinary excretion of Epo, endogenous Epo clearance and its fractional excretion (FEEpo). There were no differences between groups in FE beta 2m and FENa and plasma aldosterone levels but plasma renin activity was higher in patients with SNP than in the controls. No relationships were found between Epo levels and activity of the RAAS and sodium metabolism, respectively. Our data suggest that lower levels of plasma Epo in patients with SNP and normal renal excretory function are not due to urinary losses of Epo but rather to the decreased production/degradation ratio.

Topics: Adult; Albuminuria; beta 2-Microglobulin; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Hypertension; Nephrotic Syndrome; Proteinuria; Renin-Angiotensin System; Sodium

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

Regardless of type, uncontrolled diabetes represents a serious disruption of fuel homeostasis with consequences throughout the body. This may hamper the applicability of predeposited autologous blood transfusion in diabetic patients because metabolic changes are expected as a consequence of repeated bleeding. We undertook this study to determine whether the presence of non-insulin-dependent diabetes mellitus (NIDDM) influences the erythropoietin (EPO) response to repeated phlebotomies with respect to normal subjects. We included 22 consecutive patients scheduled for major surgery during a 2-year period in which clinical and metabolic complications were excluded and renal and liver function was considered unaffected. Selected biochemical and hematologic variables were serially measured during donation of several units of blood in a 12- to 29-day period. Bleeding produced a significant decrease in serum glucose, cholesterol, triglyceride, and apoprotein B concentration in diabetic patients. Except for glucose, this effect was not observed in controls. Both groups were comparable with respect to initial hemoglobin concentrations and all hematologic variables measured. The decrease in hemoglobin concentration did not produce clinical symptoms in these patients, and recovery was regarded as normal in both groups. Serum EPO levels in diabetic patients were negatively influenced by the initial hemoglobin A1c (HbA1c) proportion. Moreover, three nonrespondent diabetic patients with poor glycemic control responded normally 6 to 13 months later, in a second operation, when glycemic control had improved significantly. In conclusion, NIDDM may limit the donation of requested units for major surgery only if poor glycemic control is present. When possible, phlebotomies should be delayed and metabolic control reinforced.

Topics: Adult; Aged; Blood Cell Count; Bloodletting; Diabetes Mellitus, Type 2; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Lipids; Male; Middle Aged

52 patients with diabetes mellitus type II (23 of them were treated by diabetic diet, 12 were on oral antidiabetic drugs and 17 were treated by insulin), and in 31 healthy subjects the serum concentrations of erythropoietin (EPO), ferritin, iron, TIBC and hematocrit value, haemoglobin concentration and erythrocytes were measured. In diabetic patients higher but in insulin treated patients significantly higher plasma erythropoietin concentrations were found than in healthy subjects. In diabetic patients the physiological negative correlation between plasma erythropoietin concentration, haematocrit value, haemoglobin concentration and erythrocytes respectively was absent. In diabetic patients plasma ferritin concentrations were significantly higher than in normals.. patients with diabetes mellitus type II are characterized by elevated plasma erythropoietin and ferritin concentrations and dissociation of the physiological feedback between plasma erythropoietin and intensity of erythropoiesis.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Diet, Diabetic; Erythrocyte Count; Erythropoietin; Ferritins; Hematocrit; Hemoglobins; Humans; Hypoglycemic Agents; Insulin; Middle Aged; Reference Values

The plasma erythropoietin activity in diabetes patients was studied using methods for biological testing on posthypoxic polycythemic mice, based on the incorporation of 59Fe in the newly-formed red blood cells of the animals. The data are read on an automatic scintillation gamma-counter. Considerably higher erythropoietin activity of the plasma obtained from diabetics (p less than 0.01) compared with clinically health individuals has been obtained, as well as a statistically significant difference in the percentage of 59F incorporated in the newly-formed erythrocytes of the animals treated with that plasma, compared with the animals treated with saline. A dependence has been found between the chronic hyperglycaemia and the plasma erythropoietin level.

Topics: Animals; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hemoglobins; Humans; Hypoxia; Iron; Iron Radioisotopes; Lipoproteins; Male; Mice; Middle Aged; Polycythemia