losartan-potassium and Insulin-Resistance

Diabetes mellitus (DM) is a significant healthcare concern worldwide that affects more than 165 million individuals leading to cardiovascular disease, nephropathy, retinopathy, and widespread disease of both the peripheral and central nervous systems. The incidence of undiagnosed diabetes, impaired glucose tolerance, and impaired fasting glucose levels raises future concerns in regards to the financial and patient care resources that will be necessary to care for patients with DM. Interestingly, disease of the nervous system can become one of the most debilitating complications and affect sensitive cognitive regions of the brain, such as the hippocampus that modulates memory function, resulting in significant functional impairment and dementia. Oxidative stress forms the foundation for the induction of multiple cellular pathways that can ultimately lead to both the onset and subsequent complications of DM. In particular, novel pathways that involve metabotropic receptor signaling, protein-tyrosine phosphatases, Wnt proteins, Akt, GSK-3beta, and forkhead transcription factors may be responsible for the onset and progression of complications form DM. Further knowledge acquired in understanding the complexity of DM and its ability to impair cellular systems throughout the body will foster new strategies for the treatment of DM and its complications.

Topics: Alzheimer Disease; Animals; Apoptosis; Blood Glucose; Diabetes Mellitus; Erythropoietin; Glycogen Synthase Kinases; GTP-Binding Proteins; Humans; Insulin Resistance; Mitochondria; Models, Biological; Oxidative Stress; Phosphatidylinositol 3-Kinases; Wnt Proteins

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

Topics: Diabetic Nephropathies; Erythropoietin; Glucose Intolerance; Humans; Insulin Resistance; Kidney Failure, Chronic; Renal Dialysis

Topics: Anemia; Electrolytes; Energy Metabolism; Erythropoietin; Exercise; Humans; Insulin Resistance; Kidney Failure, Chronic; Muscles; Proteins

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

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Treatment with recombinant human erythropoietin (rHuEpo) improves insulin sensitivity in patients with end-stage renal disease, and animal studies indicate that Epo increases fat oxidation. However, the metabolic effects of rHuEpo have never been experimentally studied in healthy humans. The aim was to investigate the effects of an acute rHuEpo bolus on substrate metabolism and insulin sensitivity in healthy young men. Ten healthy young men were studied in a single-blinded, randomized crossover design with a 2-wk washout period receiving 400 IU/kg rHuEpo or placebo. Substrate metabolism was evaluated by indirect calorimetry and tracer infusions, and insulin sensitivity by a hyperinsulinemic euglycemic clamp; and PCR and Western blotting measured protein expression and content, respectively. Resting energy expenditure (REE) increased significantly after rHuEpo [basal: 1,863.3 ± 67.2 (kcal/day) (placebo) vs. 2,041.6 ± 81.2 (rHuEpo), P < 0.001; clamp: 1,903.9 ± 68.3 (placebo) vs. 2,015.7 ± 114.4 (rHuEpo), P = 0.03], but the increase could not be explained by changes in mRNA levels of uncoupling protein 2 or 3. Fat oxidation in the basal state tended to be higher after rHuEpo but could not be explained by changes in mRNA levels of CPT1 and PPARα or AMPK and ACC protein phosphorylation. Insulin-stimulated glucose disposal, glucose metabolism, and whole body and forearm protein metabolism did not change significantly in response to rHuEpo. In conclusion, a single injection of rHuEpo acutely increases REE in healthy human subjects. This calorigenic effect is not accompanied by distinct alterations in the pattern of substrate metabolism or insulin sensitivity.

Topics: Blotting, Western; Calorimetry, Indirect; Cross-Over Studies; Energy Metabolism; Erythropoietin; Fatty Acids, Nonesterified; Forearm; Glucose; Hormones; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Muscle Proteins; Muscle, Skeletal; Polymerase Chain Reaction; PPAR gamma; Recombinant Proteins; Regional Blood Flow; Rest; Young Adult

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

Insulin and lipid metabolism were studied in seven patients (19+/-1 years) with end-stage renal disease on continuous cycling peritoneal dialysis (CCPD) before and after 6 months of therapy with human recombinant erythropoietin (EPO) to correct anemia. Hematocrit increased from 22.2+/-1.8% to 34.8+/-1.8% (P<0.001) following EPO treatment. Serum ferritin (P<0.05) and serum iron (P<0.01) decreased significantly after anemia correction. There were no significant differences in the height, weight, anthropometric measures, or intakes of protein and total calories in the patients before and after the 6 months of EPO therapy. There were no differences in serum biochemical parameters, including 1,25-dihydroxyvitamin D3 and parathyroid hormone in these patients before and after 6 months of EPO therapy. Residual renal function and Kt/Vurea were also not different before and after 6 months of EPO therapy. The hyperinsulinemic euglycemic clamp technique was used to measure insulin sensitivity. Before EPO, insulin sensitivity was low in patients on CCPD (238+/-19 mg/m2 per min) compared with controls (320+/-30; P<0.01). After 6 months of EPO therapy, insulin sensitivity increased by 28% (305+/-26, P<0.01 vs. pre-EPO values), so that these values were no longer different from control values. The hyperglycemic clamp technique was used to measure insulin secretion. Before EPO, both early- and late-phase insulin secretion were elevated in patients on CCPD compared with controls (P<0.01 in both cases). These indices of insulin secretion decreased significantly (P<0.01) following 6 months of EPO. Before EPO, plasma triglycerides, total cholesterol, low-density lipoprotein, cholesterol, and apolipoprotein B were elevated in patients compared with controls. These lipid concentrations decreased significantly following 6 months of EPO. Thus, treatment of anemia by EPO is associated with improvements in insulin and lipid abnormalities in uremic patients on CCPD.

Topics: Adolescent; Adult; Anemia; Erythropoietin; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Kidney Failure, Chronic; Lipids; Lipoproteins; Peritoneal Dialysis; Recombinant Proteins

In erythropoietin (EPO)-producing HepG2 cells, we investigated the effect of trivalent chromium (Cr) on the promotion of EPO production and the induction of insulin resistance. Cr increased hypoxia-inducible factor (HIF)-1α protein, EPO mRNA expression and EPO protein levels in HepG2 cells. The effect of Cr on EPO production was inhibited by inhibition of proliferator-activated receptor γ (PPARγ). Insulin resistance was induced by culturing with insulin resistance induction medium supplemented with palmitic acid for 24 h. When Cr was added to the medium, the increase in glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 mRNA expression levels and the decrease in the ratio of phosphorylated Akt to Akt protein were suppressed, and the induction of insulin resistance prevented. When a PPARγ inhibitor or siPPARγ was added together with Cr, the inhibitory effect of Cr on the induction of insulin resistance disappeared. In addition, pretreatment with siEPO suppressed the increase in EPO mRNA expression, and the inhibitory effect on the induction of insulin resistance due to the addition of Cr was significantly reduced. These results suggest that the inhibition of insulin resistance induction by Cr in HepG2 cells involves the promotion of EPO production mediated by PPARγ, in addition to other PPARγ-mediated activities.

Topics: Chromium; Erythropoietin; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin Resistance; Phosphorylation; Signal Transduction

The blood hormone erythropoietin (EPO), upon binding to its receptor (EpoR), modulates high-fat diet-induced (HFD-induced) obesity in mice, improves glucose tolerance, and prevents white adipose tissue inflammation. Transgenic mice with constitutive overexpression of human EPO solely in the brain (Tg21) were used to assess the neuroendocrine EPO effect without increasing the hematocrit. Male Tg21 mice resisted HFD-induced weight gain; showed lower serum adrenocorticotropic hormone, corticosterone, and C-reactive protein levels; and prevented myeloid cell recruitment to the hypothalamus compared with WT male mice. HFD-induced hypothalamic inflammation (HI) and microglial activation were higher in male mice, and Tg21 male mice exhibited a lower increase in HI than WT male mice. Physiological EPO function in the brain also showed sexual dimorphism in regulating HFD response. Female estrogen production blocked reduced weight gain and HI. Targeted deletion of EpoR gene expression in neuronal cells worsened HFD-induced glucose intolerance in both male and female mice but increased weight gain and HI in the hypothalamus in male mice only. Both male and female Tg21 mice kept on normal chow and HFD showed significantly improved glycemic control. Our data indicate that cerebral EPO regulates weight gain and HI in a sex-dependent response, distinct from EPO regulation of glycemic control, and independent of erythropoietic EPO response.

Topics: Animals; Blood Glucose; Brain; Erythropoietin; Feeding Behavior; Female; Hypothalamus; Inflammation; Insulin Resistance; Male; Mice; Mice, Transgenic; Receptors, Erythropoietin; Sex Factors

To investigate the effect of erythropoietin (EPO) on blood glucoseand plasma insulin level, index of insulin resistance (HOMA-IR), introperitoneal glucose tolerance test (IPGTT), the mRNA and protein level of PR domain-containing 16 (PRDM16), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), fibroblast growth factor 21 (FGF21) of brown adipose tissue (BAT) in mice fed with high fat diet (HFD) in order to provide clues for the mechanism of obesity and complication.. Twenty C57BL/6J male mice fed with HFD were randomly divided into control group (HFD-Con) and EPO group (HFD-EPO), mice in the two groups were injected intraperitoneally normal saline and EPO (200 IU/kg) res pectively, 3 times per week for consecutive 4 weeks.Then the body weight, blood glucose, plasma insulin level, HOMA-IR and IPGTT were detected.The mRNA and protein level of PRDM16, FGF21, p-STAT3/STAT3 in brown adipose tissue were detected by real-time quantitative RT-PCR and Western blot respectively.. After intraperitoneal injection of EPO for 4 weeks, the body weight of the mice in HFD-EPO and HFD-Con groups was (26.65±0.85) g and (31.50±1.6 0) g respectively.The blood glucose of the mice in HFD-EPO group[(62.79±8.09) mg/dl]was significantly decreased compared with that in HFD-Con group[(91.06±9.86) mg/dl].The plasmainsulin level in HFD-EPO group[(10.56±1.06)μU/ml]was significantly decreased compared with that in HFD-Con group[(13.2±1.1)μU/ml,. EPO could promote differentiation of brown adipose tissue by increase in the express ion of PRDM16, and decrease the blood glucose level, ameliorate glucose metabolism in obses mice.

Topics: Adipose Tissue, Brown; Animals; Diet, High-Fat; DNA-Binding Proteins; Erythropoietin; Fibroblast Growth Factors; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Phosphorylation; STAT Transcription Factors; Transcription Factors

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

Erythropoietin (EPO), clinically used as a hematopoietic drug, has received much attention due to its nonhematopoietic effects. EPO reportedly has beneficial effects on obesity and diabetes mellitus. We investigated whether interscapular brown adipose tissue (iBAT: main part of classical BAT) could play a role in EPO's anti-obesity and anti-diabetic effects in diet-induced obese mice. Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD-Con), and half were additionally given an intraperitoneal injection of recombinant human EPO (200 IU/kg) (HFD-EPO) thrice a week for four weeks. At 8 weeks, EPO-injected mice showed significantly reduced body weight with reduced epididymal and subcutaneous white fat mass and unchanged caloric intake and locomotor activity. HOMA-IR (insulin resistance index) and glucose levels during intraperitoneal glucose tolerance test (IPGTT) were significantly lower in HFD-EPO mice than in HFD-Con mice. EPO-injected mice also showed increased oxygen consumption, indicative of metabolic rate, and skin temperature around iBAT tissue masses. EPO significantly upregulated the PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), a transcriptional factor with a crucial role in brown adipocyte differentiation. EPO significantly increased phosphorylated signal transducer and activator of transcription 3 (STAT3), which is downstream of erythropoietin receptor (EpoR) and known to stabilize PRDM16. EPO's suppression of myocyte enhancer factor 2c (Mef2c) and microRNA-133a (miR-133a) via β3-adrenergic receptor caused PRDM16 upregulation. EPO-mediated enhancement of EpoR/STAT3 and β-adrenergic receptor/Mef2c/miR-133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis. Furthermore, EPO activated BAT's endocrine functions. EPO facilitated fibroblast growth factor 21 (FGF21) production and excretion in iBAT, associated with reduction of liver gluconeogenesis-related genes. Thus, EPO's improvement of obesity and glucose homeostasis can be attributed to increased iBAT thermogenic capacity and activation of BAT's endocrine functions.

Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Diet, High-Fat; DNA-Binding Proteins; Energy Metabolism; Erythropoietin; Fibroblast Growth Factors; Glucose Intolerance; Glucose Tolerance Test; Insulin Resistance; Male; Mice, Inbred C57BL; Obesity; Thermogenesis; Transcription Factors

Erythropoietin (EPO) has been identified as being crucial for obesity modulation; however, its erythropoietic activity may limit its clinical application. EPO-derived Helix B-surface peptide (pHBSP) is nonerythrogenic but has been reported to retain other functions of EPO. The current study aimed to evaluate the effects and potential mechanisms of pHBSP in obesity modulation. We found that pHBSP suppressed adipogenesis, adipokine expression and peroxisome proliferator-activated receptor γ (PPARγ) levels during 3T3-L1 preadipocyte maturation through the EPO receptor (EPOR). In addition, also through EPOR, pHBSP attenuated macrophage inflammatory activation and promoted PPARγ expression. Furthermore, PPARγ deficiency partly ablated the anti-inflammatory activity of pHBSP in macrophages. Correspondingly, pHBSP administration to high-fat diet (HFD)-fed mice significantly improved obesity, insulin resistance (IR) and adipose tissue inflammation without stimulating hematopoiesis. Therefore, pHBSP can significantly protect against obesity and IR partly by inhibiting adipogenesis and inflammation. These findings have therapeutic implications for metabolic disorders, such as obesity and diabetes.

Topics: 3T3-L1 Cells; Adipogenesis; Adipokines; Animals; Biomarkers; Cytokines; Diet, High-Fat; Erythropoietin; Gene Expression Regulation; Hematopoiesis; Inflammation; Inflammation Mediators; Insulin Resistance; Macrophages; Mice; Obesity; Peptides; PPAR gamma

Erythropoietin (EPO) has beneficial effects on glucose metabolism and insulin resistance. However, the mechanism underlying these effects has not yet been elucidated. This study aimed to investigate how EPO affects hepatic glucose metabolism. Here, we report that EPO administration promoted phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation in palmitic acid (PA)-treated HepG2 cells and in the liver of high-fat diet (HFD)-fed mice, whereas adenovirus-mediated silencing of the erythropoietin receptor (EPOR) blocked EPO-induced AKT signalling in HepG2 cells. Importantly, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist and PPARγ small interfering RNA (siRNA) abrogated the EPO-induced increase in p-AKT in HepG2 cells. Lentiviral vector-mediated hepatic PPARγ silencing in HFD-fed C57BL/6 mice impaired EPO-mediated increases in glucose tolerance, insulin sensitivity and hepatic AKT activation. Furthermore, EPO activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) signalling pathway, and AMPKα and SIRT1 knockdown each attenuated the EPO-induced PPARγ expression and deacetylation and PPARγ-dependent AKT activation in HepG2 cells. In summary, these findings suggest that PPARγ is involved in EPO/EPOR-induced AKT activation, and targeting the PPARγ/AKT pathway via EPO may have therapeutic implications for hepatic insulin resistance and type 2 diabetes.

Topics: AMP-Activated Protein Kinases; Animals; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Enzyme Activation; Erythropoietin; Glucose; Glucose Tolerance Test; Hep G2 Cells; Hepatocytes; Humans; Insulin Resistance; Male; Mice; PPAR gamma; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Signal Transduction; Sirtuin 1

The haematopoietic activity of erythropoietin (EPO) is mediated by the classic EPO receptor (EpoR) homodimer, whereas tissue-protective effects are mediated by a heterocomplex between EpoR and the β-common receptor (βcR). Here, we investigated the effects of a novel, selective ligand of this heterocomplex - pyroglutamate helix B surface peptide (pHBSP) - in mice fed a diet enriched in sugars and saturated fats.. Male C57BL/6J mice were fed a high-fat high-sucrose diet (HFHS) for 22 weeks. pHBSP (30 μg·kg(-1) s.c.) was administered for the last 11 weeks. Biochemical assays, histopathological and immunohistochemical examinations and Western blotting were performed on serum and target organs (liver, kidney and skeletal muscle).. Mice fed with HFHS diet exhibited insulin resistance, hyperlipidaemia, hepatic lipid accumulation and kidney dysfunction. In gastrocnemius muscle, HFHS impaired the insulin signalling pathway and reduced membrane translocation of glucose transporter type 4 and glycogen content. Treatment with pHBSP ameliorated renal function, reduced hepatic lipid deposition, and normalized serum glucose and lipid profiles. These effects were associated with an improvement in insulin sensitivity and glucose uptake in skeletal muscle. Diet-induced overproduction of the myokines IL-6 and fibroblast growth factor-21 were attenuated by pHBSP and, most importantly, pHBSP markedly enhanced mitochondrial biogenesis in skeletal muscle.. Chronic treatment of mice with an EPO derivative, devoid of haematopoietic effects, improved metabolic abnormalities induced by a high-fat high-sucrose diet, by affecting several levels of the insulin signalling and inflammatory cascades within skeletal muscle, while enhancing mitochondrial biogenesis.

Topics: Animals; Blood Glucose; Dietary Fats; Dietary Sucrose; Erythropoietin; Fatty Liver; Hyperlipidemias; Insulin Resistance; Kidney; Liver; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Oligopeptides; Renal Insufficiency

Studies detected an association between visfatin and markers of iron metabolism in patients with insulin resistance. In this study, such a relation was evaluated in hemodialysis (HD) patients. Also relations between visfatin and hepcidin, demands for recombinant human erythropoietin (rHuEpo), inflammation, and situations characterized by insulin resistance were evaluated.. After a four-week washout period from iron treatment, 33 HD patients and 20 healthy volunteers enrolled in the study. Serum visfatin, hepcidin, and interleukin-6 (IL-6) were assessed by means of enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin, and transferrin saturation (TSAT) were also measured.. Visfatin was markedly increased in HD patients. Visfatin levels did not differ between diabetics and non-diabetics. No relation was detected between visfatin and body mass index or IL-6 in HD patients. From the markers of iron metabolism, the hepcidin included, visfatin was related only to TSAT. A strong positive relation was revealed between visfatin and hemoglobin, whereas visfatin was inversely related to rHuEpo dose. Resistance to rHuEpo index was inversely and independently of TSAT related to visfatin.. Visfatin is increased in HD patients and it is associated with decreased demands for rHuEpo.

Topics: Aged; Anemia; Case-Control Studies; Cytokines; Erythropoietin; Female; Healthy Volunteers; Humans; Insulin Resistance; Iron; Kidney Failure, Chronic; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Recombinant Proteins; Renal Dialysis

Reduced insulin sensitivity might increase the susceptibility to acute mountain sickness (AMS). The diabetogenic side effects of dexamethasone should therefore be considered for AMS treatment. To examine whether reduced insulin sensitivity is predictive of AMS and how it is affected by dexamethasone at high altitude, we analyzed endocrine and metabolic parameters obtained from healthy mountaineers in Zurich (LA; 490 m), and 2 and 4 days after fast ascent to the Capanna Regina Margherita (HA2, HA4; 4559 m). 14 of 25 participants developed AMS and were treated with dexamethasone starting in the evening of HA2. Before and after ingestion of an 1800 kJ meal, plasma was analyzed for erythropoietin (EPO) and cholecystokinin (CCK). Insulin sensitivity (HOMA-S) and beta cell activity were calculated. HOMA-S (p<0.01) and EPO levels (p<0.05) were lower in Zurich in the group developing AMS and given dexamethasone, i.e., before treatment and exposure to hypoxia. CCK was lower (p<0.01) and glucose and insulin were higher on HA4 in the dexamethasone group compared to the untreated group. Individuals with low baseline insulin sensitivity and low baseline EPO levels were more susceptible to AMS. Reduced CCK may contribute to the beneficial effect of dexamethasone on high altitude anorexia. However, reduced insulin sensitivity questions the widespread use of dexamethasone to prevent/treat AMS.

Topics: Adult; Altitude; Altitude Sickness; Blood Glucose; Cholecystokinin; Dexamethasone; Energy Intake; Erythropoietin; Female; Glucocorticoids; Homeostasis; Humans; Hydrocortisone; Hypoxia; Insulin Resistance; Insulin-Secreting Cells; Interleukin-6; Islet Amyloid Polypeptide; Male; Middle Aged; Models, Biological; Oxygen; Retrospective Studies; Time Factors; Young Adult

Recombinant human erythropoietin (rHuEPO) reduces serum insulin levels, increases insulin sensitivity, and reduces insulin resistance (IR). However, the mechanisms behind these effects are unclear. This study aimed to investigate the mechanism by which rHuEPO effects IR in 3T3L1 adipocytes. After treatment with different concentrations of rHuEPO, glucose consumption, and tumor necrosis factor (TNF-α), adiponectin, and leptin levels were assayed with a commercial enzyme-linked immunosorbent assays. Endogenous erythropoietin receptor (EPOR) expression was inhibited using small interfering RNA (siRNA). EPOR protein and mRNA expression was detected via immunofluorescence and real-time PCR analyses, respectively. The expression of pAKT/AKT and p-STAT5/STAT5 was determined via Western blot analysis. rHuEPO treatment improved glucose uptake, increased adiponectin levels, and reduced TNF-α and leptin levels in 3T3L1 adipocytes with dexamethasone-induced IR. Whereas EPOR protein and gene expression was absent in preadipocytes, it was observed in mature 3T3L1 adipocytes. However, the expression of EPOR in insulin resistant 3T3L1 adipocytes was significantly decreased (p<0.05). rHuEPO increased the expression of EPOR, and upregulated the expression of pAKT/AKT and pSTAT5/STAT5 in 3T3L1 adipocytes (p<0.05), which was blocked by siEPOR, the phosphatidylinositol-3-kinase (PI3K) inhibitor, LY294002, and a STAT5 inhibitor, respectively. In summary, rHuEPO reduced IR in adipocytes by increasing glucose uptake and improving the adipokine profile. rHuEPO-induced EPOR protein expression and subsequent induction of pAKT and pSTAT5 suggest that the EPO-EPOR system may play a role in glucose metabolism within adipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Adiponectin; Animals; Cell Differentiation; Cell Proliferation; Erythropoietin; Gene Expression Regulation; Glucose; Humans; Insulin Resistance; K562 Cells; Leptin; Mice; Models, Biological; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger; Signal Transduction; Staining and Labeling; Tumor Necrosis Factor-alpha

Primary hyperparathyroidism (PHPT) is associated with cardiovascular disease. The aims of this study were to investigate lipid and glucose metabolism in mild PHPT, and to identify whether insulin sensitivity correlates with circulating levels of adiponectin, SHBG, and osteocalcin before and after parathyroidectomy (PTX).. Forty-five patients with PHPT were examined before and 1 year after PTX. Circulating levels of triglycerides, total cholesterol, HDL-cholesterol, insulin, glucose, adiponectin, SHBG, osteocalcin, and erythropoietin were measured.. At baseline, the mean serum levels of total cholesterol, LDL-cholesterol and triglycerides were above the upper reference limit or in the upper normal range, and insulin sensitivity was reduced as assessed using the HOMA index. One year after parathyroidectomy, serum lipids as well as HOMA index and erythropoietin were unchanged while adiponectin had increased (p < 0.05), and SHBG and osteocalcin had decreased (p < 0.05 and p < 0.0001, respectively). HOMA index correlated negatively with circulating levels of adiponectin, SHBG and osteocalcin. In multiple regression analysis SHBG was the most important predictor of insulin sensitivity, both pre- and postoperatively.. Untreated mild PHPT is associated with a moderate derangement of lipid and glucose metabolism. As previously shown in population-based cohorts, insulin sensitivity is positively associated with circulating concentrations of adiponectin, SHBG and osteocalcin. One year after PTX, the mean level of adiponectin was increased, but the levels of SHBG and osteocalcin had decreased and the levels of serum lipids and the insulin sensitivity remained unchanged as compared with baseline.

Topics: Adiponectin; Aged; Aged, 80 and over; Blood Glucose; Erythropoietin; Female; Humans; Hyperparathyroidism, Primary; Insulin; Insulin Resistance; Lipids; Male; Middle Aged; Osteocalcin; Parathyroidectomy

Recent studies reported cardioprotective effects of erythropoietin (EPO) against ischemia-reperfusion (I/R) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been reported to be impaired in diabetes and insulin resistance syndrome, we examined whether EPO-induced cardioprotection was maintained in rat models of type 1 diabetes and insulin resistance syndrome. Isolated hearts were obtained from three rat cohorts: healthy controls, streptozotocin (STZ)-induced diabetes, and high-fat diet (HFD)-induced insulin resistance syndrome. All hearts underwent 25 min ischemia and 30 min or 120 min reperfusion. They were assigned to receive either no intervention or a single dose of EPO at the onset of reperfusion. In hearts from healthy controls, EPO decreased infarct size (14.36 ± 0.60 and 36.22 ± 4.20% of left ventricle in EPO-treated and untreated hearts, respectively, p < 0.05) and increased phosphorylated forms of Akt, ERK1/2, and their downstream target GSK-3β. In hearts from STZ-induced diabetic rats, EPO did not decrease infarct size (32.05 ± 2.38 and 31.88 ± 1.87% in EPO-treated and untreated diabetic rat hearts, respectively, NS) nor did it increase phosphorylation of Akt, ERK1/2, and GSK-3β. In contrast, in hearts from HFD-induced insulin resistance rats, EPO decreased infarct size (18.66 ± 1.99 and 34.62 ± 3.41% in EPO-treated and untreated HFD rat hearts, respectively, p < 0.05) and increased phosphorylation of Akt, ERK1/2, and GSK-3β. Administration of GSK-3β inhibitor SB216763 was cardioprotective in healthy and diabetic hearts. STZ-induced diabetes abolished EPO-induced cardioprotection against I/R injury through a disruption of upstream signaling of GSK-3β. In conclusion, direct inhibition of GSK-3β may provide an alternative strategy to protect diabetic hearts against I/R injury.

Topics: Animals; Apoptosis; Cardiotonic Agents; Diabetes Mellitus, Experimental; Dietary Fats; Erythropoietin; Glucose; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hemodynamics; In Vitro Techniques; Insulin Resistance; MAP Kinase Signaling System; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptors, Erythropoietin

Insulin resistance and anemia secondary to erythropoietin deficiency characterize patients with end-stage kidney disease. In a cross-sectional analysis, we examined the relationship between erythropoietin-mediated correction of anemia and insulin sensitivity in nondiabetic hemodialysis patients. Insulin sensitivity (euglycemic-hyperinsulinemic clamp) and endogenous glucose production (primed-continuous infusion of [6,6-(2)H(2)]glucose) were determined in two groups of patients with normal hemoglobin (n:8; mean hemoglobin: 14.0 ± 0.3 g/dl) or with mild anemia (n:10; mean hemoglobin: 12.1 ± 0.9 g/dl). The patients with normal hemoglobin were receiving higher (P < 0.05) erythropoietin doses than those with mild anemia (171 ± 73 and 91 ± 39 U kg(-1) wk(-1), respectively). The two groups were matched for all other potential determinants of insulin resistance. Endogenous glucose production was similar in the two groups of patients in the postabsorptive state and was completely suppressed by insulin infusion. During the hyperinsulinemic clamp, the rate of glucose infusion to maintain euglycemia was significantly lower (P < 0.01) in the patients with normal hemoglobin levels [166 ± 31 mg (m(2))(-1) min(-1)] than in those with mild anemia [251 ± 49 mg (m(2))(-1) min(-1)] and in a group of matched controls [275 ± 68 mg (m(2))(-1) min(-1)]. In pooled patients, individual values of hemoglobin concentrations inversely correlated with the rates of insulin-mediated glucose infusion, both as absolute values (r = -0.58; P < 0.05) and as values normalized by steady-state plasma insulin concentration (r = -0.74; P < 0.001). In conclusion, this exploratory study indicates that complete correction of anemia by erythropoietin treatment in patients with end-stage kidney disease on hemodialysis is associated with impaired insulin sensitivity.

Topics: Adult; Aged; Anemia; Cross-Sectional Studies; Erythropoiesis; Erythropoietin; Female; Glucose; Glucose Clamp Technique; Hematinics; Humans; Insulin; Insulin Resistance; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

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

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

Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days. HOMA analysis suggested an improvement in insulin sensitivity, and this effect was confirmed by a hyperinsulinemic-euglycemic clamp. Uptake of (14)C-2-deoxy-D-glucose indicated that animals dosed with CNTO 530 transported more glucose into skeletal muscle and heart relative to control animals. In conclusion, CNTO530 has a profound effect on glucose tolerance in insulin-resistant rodents likely because of improving peripheral insulin sensitivity. This effect was observed with epoetin-α and darbepoetin-α, suggesting this is a class effect, but the effect with these compounds relative to CNTO530 was decreased in duration and magnitude.

Topics: Animals; Darbepoetin alfa; Diabetes Mellitus, Experimental; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Receptors, Erythropoietin; Recombinant Fusion Proteins; Recombinant Proteins; Time Factors

Insulin resistance is a characteristic feature of uremia. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Treatment with recombinant human erythropoietin (rHuEPO) was said to be associated with improvement in insulin sensitivity in uremic patients. The aim of this study was to compare insulin resistance in adult uremic hemodialysis (HD) patients including diabetic patients treated with or without rHuEPO. A total of 59 HD patients were studied, patients were divided into 2 groups of subjects: 30 HD patients on regular rHuEPO treatment (group A), and 29 HD patients not receiving rHuEPO (group B) diabetic patients were not excluded. Full medical history and clinical examination, hematological parameters, lipid profile, serum albumin, parathyroid horomone, Kt/V, fasting glucose, and insulin levels were measured in all subjects. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used to compare insulin resistance. The results of this study showed that the mean insulin level of HD patients treated with rHuEPO (group A) (17.5 +/- 10.6 microU/mL) was significantly lower than patients without rHuEPO (group B) (28.8 +/- 7.7 microU/mL), (P<0.001). Homeostasis Model Assessment of Insulin Resistance levels in group A were significantly lower than in group B (3.8 +/- 2.97, 7.98 +/- 4.9, respectively, P<0.001). Insulin resistance reflected by HOMA-IR levels among diabetic patients in group A was significantly lower than among diabetic patients in group B (3.9 +/- 3.2, 9.4 +/- 7.2, respectively, P<0.001). Also, HOMA-IR levels among nondiabetic patients in group A were significantly lower than among nondiabetic patients in group B (3.7 +/- 2.85, 6.9 +/- 1.43, respectively, P<0.01). We found a statistically significant negative correlation between duration of erythropoietin treatment, fasting blood glucose, insulin levels, and insulin resistance (r=-0.62, -0.71, and -0.57, P<0.001). Patients treated with rHuEPO showed less insulin resistance compared with patients not treated with rHuEPO in diabetic and nondiabetic patients and, duration of erythropoietin treatment is negatively correlated with insulin levels and insulin resistance in HD patients.

Topics: Blood Glucose; Case-Control Studies; Erythropoietin; Female; Humans; Insulin; Insulin Resistance; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Previous studies have reported that glucose tolerance can be improved by short-term altitude living and activity. However, not all literature agrees that insulin sensitivity is increased at altitude. The present study investigated the effect of a 25-day mountaineering activity on glucose tolerance and its relation to serum levels of dehydroepiandrosterone-sulfate (DHEA-S) and tumor necrosis factor-alpha (TNF-alpha) in 12 male subjects. On day 3 at altitude, we found that serum DHEAS was reduced in the subjects with initially greater DHEA-S value, whereas the subjects with initially lower DHEA-S remained unchanged. To further elucidate the role of DHEA-S in acclimatization to mountaineering activity, all subjects were then divided into lower and upper halves according to their sea-level DHEA-S concentrations: low DHEA-S (n = 6) and high DHEA-S groups (n = 6). Glucose tolerance, insulin level, and the normal physiologic responses to altitude exposure, including hematocrit, hemoglobin, erythropoietin (EPO), and cortisol were measured. We found that glucose and insulin concentrations on an oral glucose tolerance test were significantly lowered by the mountaineering activity only in the high DHEA-S group. Similarly, hematocrit and hemoglobin concentration in altitude were increased only in the high DHEA-S group. In contrast, the low DHEA-S subjects exhibited an EPO value at sea level and altitude greater than the high DHEA-S group, suggesting an EPO resistance. The findings of the study imply that DHEA-S is essential for physiologic acclimatization to mountaineering challenge.

Topics: Acclimatization; Adult; Dehydroepiandrosterone; Erythropoietin; Glucose Tolerance Test; Hematologic Tests; Humans; Hydrocortisone; Insulin; Insulin Resistance; Male; Mountaineering; Oxygen Consumption; Tumor Necrosis Factor-alpha

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 end-stage renal disease (ESRD) are known to have insulin resistance. Treatment with EPO is associated with improvement in insulin sensitivity in uremic patients. The aim of this study was to compare insulin sensitivity and pancreatic B cell function in adult non-diabetic uremic hemodialysis patients treated with or without rHuEPO.. Three groups of subjects were included to the study: hemodialysis patients treated with rHuEPO [EPO(+) group] or without rHuEPO [EPO(-) group], and healthy controls. Anthropometrical parameters, lipid levels, fasting glucose and insulin levels were measured in all subjects. Homeostasis Model Assessment (HOMA) was used to compare insulin sensitivity. ANOVA, independent t-test, and Pearson correlation were used for statistical analysis.. Mean insulin level of control group (20.04 +/- 7.2 pmol/l) was significantly lower than EPO(+) group (p < 0.04) and EPO(-) group (p < 0.0001). HOMA-(%B) levels in the EPO(+) group were significantly lower than in the EPO(-) group (106 +/- 42, 140 +/- 63 respectively, p < 0.02). HOMA-(%B) levels in the control group (66 +/- 17) were significantly lower than in the EPO(+) and EPO(-) group (p < 0.005 and p < 0.0001 respectively). HOMA-(%S) levels in the EPO(+) groups was significantly higher than in the EPO(-) group (91 +/- 40, 56 +/- 26, respectively; p < 0.01). HOMA-(%S) levels of control group (125 +/- 24 ) was significantly higher than EPO(+) and EPO(-) groups (p < 0.02, p < 0.0001 respectively). We found a positive correlation between duration of erythropoietin treatment and insulin sensitivity (r = 0.484, p < 0.002).. Firstly, patients treated with EPO are insulin sensitive compared to patients not treated with EPO. Secondly, duration of erythropoietin treatment is positively correlated with insulin sensitivity in hemodialysis patients.

Topics: Adult; Aged; Blood Pressure; Calcitriol; Erythropoietin; Female; Humans; Insulin; Insulin Resistance; Islets of Langerhans; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Decreased sensitivity to the hypoglycaemic action of insulin is an almost universal phenomenon in uraemic patients, and it is attributed either to uraemic toxins or to anaemia or even to secondary hyperparathyroidism. Considering the conflicting data of few existing studies, we examined the influence of erythropoietin (EPO) treatment on insulin resistance and tested the probable correlation of this influence with sympathetic nervous system (SNS) activity.. We studied 8 non-obese, non-diabetic, stable dialysis patients using the euglycaemic insulin clamp technique before administration of EPO (phase A), 10 days after (phase B), and after the correction of the haematocrit level, at least 8 weeks later (phase C). We estimated the indices (glucose infusion rate, mg/kg/min), M/G (glucose clearance), and M/I (tissue sensitivity to insulin), and we measured haematocrit, haemoglobin, triglyceride, ferritin, EPO, and fasting insulin levels in each phase. During each phase, we tested the SNS activity using the response of blood pressure to persistent handgrip and the response of blood pressure to the standing position.. Our patients appeared to have an increased insulin resistance in phase A (M(A) = 6.24 +/- 1.01) which was significantly improved 10 days after the beginning of EPO treatment and before the rise of haematocrit (M(B) = 7.71 +/- 1.54, p < 0.05). There was no further improvement in phase C. Indices M/G and M/I behaved similarly. The serum triglyceride levels decreased in response to the increased insulin sensitivity. The patients studied did not demonstrate fasting hyperinsulinaemia, while the SNS activity was abnormal and remained unchanged throughout the study period in spite of some individual improvement.. Our study proves the beneficial effect of EPO treatment on insulin resistance in dialysis patients which could be attributed to the EPO itself and not to the correction of anaemia and is accompanied by improvement in triglyceride levels. Amelioration of insulin resistance did not influence the SNS activity, making the association between EPO treatment and SNS-derived changes in blood pressure quite improbable.

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Glucose Clamp Technique; Humans; Hypertension; Insulin Resistance; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors

The effects of recombinant human erythropoietin (rHuEPO) on the glucose metabolism were evaluated by intravenous glucose tolerance test in 20 maintenance hemodialysis patients. In 8 cases the glucose tolerance tests were performed before and after a single intravenous injection of 50 IU/kg of rHuEPO and in 12 cases before and after 3 months of rHuEPO therapy at doses of 50 IU/kg three times/week and 2 weeks after rHuEPO withdrawal. For each test glucose, immunoreactive insulin (IRI) and C peptide (C-p) plasma values were measured, and glucose constant decay, whole IRI (area IRI) and C-p area C-p) production, insulinogenic index, and insulin resistance index were calculated. After 3 months of rHuEPO therapy, the glucose constant decay increased significantly, area IRI, area C-p, and insulin resistance index decreased significantly, and the insulinogenic index did not change. No correlations were found between changes in hemoglobin values and changes in glucose metabolism parameters. Acute rHuEPO administration and rHuEPO withdrawal had no effect on glucose metabolism, despite significant changes in plasma erythropoietin levels. Long-term rHuEPO therapy improves glucose metabolism in maintenance hemodialysis patients significantly, mainly by reduction of insulin resistance. Neither anemia correction nor a direct effect of rHuEPO on some metabolic steps seem to be responsible of these effects.

Topics: Adult; Aged; C-Peptide; Erythropoietin; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors

Ten patients (18 +/- 1 yr) on chronic hemodialysis (HD) with anemia were studied before and after treatment with erythropoietin (EPO) for 9 mo. Six patients had evidence of iron overload (serum ferritin over 300 ng/ml; group I) and the other four patients (serum ferritin below 300 ng/ml; group II) did not. Before treatment, both groups of patients were glucose tolerant but insulin resistant and hyperinsulinemic. There was equal correction of anemia but no significant changes in serum biochemistry (apart from iron studies) or anthropometric measurements in both groups. With amelioration of anemia and iron overload in group I, insulin sensitivity increased by 53% to within normal values. Insulin secretion also normalized. With amelioration of anemia but no change in iron status in group II, insulin sensitivity (increased by 60%) and insulin secretion also normalized. Thus correction of anemia by EPO reversed insulin resistance and hyperinsulinemia in HD patients with or without iron overload. The effects of correction of anemia rather than iron overload may be more important in the pathogenesis of insulin abnormalities in end-stage renal disease.

Topics: Adolescent; Adult; Anemia; Erythropoietin; Ferritins; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hyperinsulinism; Insulin Resistance; Kidney Failure, Chronic; Renal Dialysis; Uremia

Topics: Adolescent; Erythropoietin; Humans; Infusions, Intravenous; Insulin Resistance; Insulin-Like Growth Factor I; Male; Recombinant Proteins

Topics: Adult; Anemia; Diabetic Nephropathies; Erythropoietin; Female; Humans; Insulin Resistance; Male; Middle Aged; Renal Dialysis