Medication non-adherence and poor glycaemic control in patients with type 2 diabetes mellitus

AimsHyperglycemia causes generation of free radicals which leads to oxidative stress and apoptosis in various cells. The present study was undertaken to investigate the correlation between oxidative stress and apoptotic markers in lymphocytes of diabetic patients with chronic non healing wounds.MethodsThirty healthy, thirty uncontrolled type 2 diabetes mellitus (T2DM) and thirty uncontrolled T2DM with chronic, non healing, neuropathic diabetic foot patients were included in this study. Indices of oxidative stress inside the lymphocyte lysate were estimated by measuring content of superoxide dismutase (SOD), Catalase, Glutathione and malonaldialdehyde (MDA). Protein expression studies of pro and anti apoptotic markers were carried out to elucidate their possible involvement in diabetic context.ResultsSOD and MDA activity was significantly higher in the lymphocytes of diabetic patients having chronic, non healing diabetic wound as compared with healthy (p < 0.001); whereas catalase and GSH activity was significantly reduced (p < 0.001) in the same group. Expressions of pro apoptotic markers (Caspase-3, Fas and Bax) were significantly higher whereas reduced expression of anti-apoptotic marker (Bcl-2) were obtained in lymphocytes of diabetic and non diabetic individuals.ConclusionsHyperglycemia confers pro apoptotic manifestations which are mostly through altered indices of oxidative stress within lymphocytic milieu.     

Metabolic syndrome and the development of type 2 diabetes among professionals living in Beijing, China

Aims

The magnitude of the association between metabolic syndrome (MetS) and incident diabetes is still not widely evaluated in China. This study explored the association of MetS and its components with the development of diabetes among professionals living in Beijing.

Methods

Population-based 6-year prospective study. The cohort consisted of 7922 eligible persons aged ≥20. Either fasting glucose (FPG) level ≥7.0 mmol/l at the follow-up survey or diagnoses of diabetes during the 6-year period were considered incident diabetes cases. MetS was identified by both the definitions proposed by the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF).

Results

The accumulated incidence of diabetes was 3.6% for men and 2.5% for women. MetS associated a 4.7- and 5.7-fold increase of the diabetic risk in men and women, respectively. Hyperglycemia exhibited the highest association with diabetes. FPG of 5.6-5.79 mmol/l already presented a risk of diabetes. However, without hyperglycemia in the clustering of any 1, 2, 3 to 4 metabolic components, the tendency of increased diabetic risk was still observed.

Conclusions

MetS has a strong association with incident diabetes. Of the individual components, hyperglycemia is the strongest predictor of diabetes. Additional numbers of metabolic components increase the risk of developing diabetes.     

The effects of atorvastatin and rosuvastatin on oxidative stress in diabetic patients

Aim

Diabetes is associated with abnormalities in lipid profile and increased oxidative stress. Statins are preferred agents in diabetic patients due to their antioxidant and LDL-C lowering effects. This study is designed to compare the effects of atorvastatin and rosuvastatin on low density lipoprotein cholesterol (LDL-C), lipid hydroperoxide (LOOH), total oxidant status (TOS) and total antioxidant capacity (TAC) in diabetic patients with hyperlipidemia.

Materials and methods

Sixty two patients who have type 2 diabetes mellitus with serum LDL levels more than 100 mg/dL were randomly assigned to receive atorvastatin 20 mg (n = 31) or rosuvastatin 10 mg (n = 31). Blood tests were performed at the beginning of the study and after three months.

Results

There were no statistically significant differences in the pre- and after treatment levels of the LDL-C between groups. TAC values were increased in both groups and statistically significant in the former group (p = 0.007). There was no diferrence between the change percentages ((after treatment TAC − pretreatment TAC) / pretreatment level) of TAC between two treatment groups. The effects of two drugs on the other oxidative parameters were not significantly different.

Conclusion

Both atorvastatin and rosuvastatin may be helpful in reducing increased oxidative stress in diabetic patients with hyperlipidemia.     

Relationship between advanced glycation end products and increased lipid peroxidation in semen of diabetic men

Aims

Majority of diabetic male patients have disturbances in their reproductive systems. However, the mechanisms underlying these disturbances are largely unknown. Since advanced glycation end products (AGE) have a key role in oxidative stress and cell damage in diabetic complications, we hypothesize that AGEs may be involved sperm lipid peroxidation.

Methods

Total AGEs in seminal plasma of 32 diabetic and 35 non-diabetic men was determined by spectrofluorimetric method and carboxy methyl lysine (CML) level was assayed using ELISA. Contents of lipid peroxidation in sperm and seminal plasma were determined by thiobarbituric acid reaction. Total antioxidant capacity (TAC) was measured by a colorimetric assay.

Results

Total AGEs were found significantly higher in seminal plasma of diabetic men than non-diabetic group (p < 0.001) whereas no significant differences in seminal plasma CML values between two groups was observed. Moreover, sperm and seminal plasma lipid peroxidation were significantly higher in diabetic subjects than non-diabetic men and a significantly lower TAC was detected in diabetic group compare to non-diabetics.

Conclusions

These results showed an increment in AGEs in seminal plasma of diabetic subjects and may suggest a key role for glycation process and increased oxidative stress in reproductive system dysfunction.     

Augmented NADPH oxidase activity and p22phox expression in monocytes underlie oxidative stress of patients with type 2 diabetes mellitus

Background

This study was to test the hypothesis that enhanced oxidative stress is induced in monocytes with over-activated NADPH oxidase during the development of type 2 diabetes mellitus.

Methods

Levels of glucose and lipids were analyzed in 73 diabetic patients and 36 controls. Superoxide dismutase (SOD), malondialdehyde (MDA), reactive oxygen species (ROS) and protein carbonylation were tested. Expression of NADPH oxidase was examined and p47phox translocation was assessed.

Results

With the abnormality of glucose and lipid metabolism, diabetic patients showed a higher oxidative stress state indicated by decreased SOD activity but elevated MDA and protein carbonylation level. Monocytes in diabetes also showed elevated ROS generation and protein carbonylation level. Furthermore, NADPH oxidase was highly activated in monocytes represented by p22phox up-regulation and p47phox translocation. Significant positive bivariate correlation was found between glucose and MDA level as well as p22phox expression. In vitro experiments also indicated that glucose could stimulate ROS generation in a NADPH oxidase dependent manner. Moreover, we carried out same measurement in 40 diabetic patients with anti-diabetic intervention and obtained the reinforced results.

Conclusions

Hyperglycemia is the main factor which induces oxidative stress mainly by activation of NADPH oxidase in monocytes of diabetic patients.     

Elevated micronuclei frequency in type 2 diabetes with high glycosylated hemoglobin

Aim

The role of oxidative damage to DNA due to hyperglycemia is well known. In the current study we have evaluated the induction of micronuclei due to increased glycosylation in type 2 diabetes.

Methods

Forty-nine subjects divided into two groups of normoglycemic controls and type 2 diabetic cases were recruited in the study. Whole blood was cultured and micronuclei were scored in all the cases. This was correlated with age, sex, blood glucose levels and glycosylated hemoglobin.

Results

Age and sex matched diabetic patients had an increased micronuclei frequency in response to elevated glycosylation of hemoglobin (R² = 0.229, p = 0.037) compared to normoglycemic subjects.

Conclusion

The increased glycosylation seems to induce oxidative damage in the DNA of the diabetic patients, which manifests as an increased micronuclei frequency. This has a potential to be used as a biomarker for subsequent diabetic complications.     

Vitamin D3 modulates T lymphocyte responses in hepatitis C virus-infected liver transplant recipients

Background

Aim of the present study was to investigate whether 1,25(OH)(2)D(3) (Vitamin D3) modulates T lymphocyte functions in patients transplanted for hepatitis C virus-related cirrhosis.

Methods

Sixteen patients and ten healthy subjects were investigated. T lymphocytes were activated in vitro in the presence or absence of Vitamin D3 and then the proliferative response and IFN-γ and TNF-α production were assessed.

Results

Vitamin D3 potently reduced T-lymphocyte proliferation in a dose-related fashion. Similarly, FACS analysis and ELISA testing demonstrated that Vitamin D3 significantly decreased the response frequency and the response intensity of IFN-γ and TNF-α production in the whole CD3-positive T lymphocyte population as well as in “naive” CD4+ CD45RA+ and “memory” CD4+ CD45RO+ T lymphocyte subsets. The inhibitory effect of Vitamin D3 on T-cell proliferation and cytokine production was not different between patients and controls. No toxic effects were exerted by Vitamin D3 even at the higher concentration used (10 nM). Finally, no statistically significant correlation was found between 25(OH)D serum levels and the proliferative response or cytokine production of T lymphocytes from transplanted patients.

Conclusions

This study demonstrates that in patients transplanted for hepatitis C virus-related cirrhosis Vitamin D3 modulates T lymphocyte activation, and provides a rationale for the evaluation of this compound as an immunosuppressive agent in liver-transplanted patients.     

Treatment of diabetic foot ulcers: a comparative study of extracorporeal shockwave therapy and hyperbaric oxygen therapy

Objective

This study compared the effectiveness of extracorporeal shockwave therapy (ESWT) and hyperbaric oxygen therapy (HBOT) in chronic diabetic foot ulcers.

Patients and methods

The ESWT group (39 patients/44 feet) received shockwave therapy twice per week for total six treatments. The HBOT group (38 patients/40 feet) received hyperbaric oxygen therapy daily for total 20 treatments. Evaluations included clinical assessment, blood flow perfusion scan and histopathological examination.

Results

The overall clinical results showed completely healed ulcers in 57% and 25% (P = 0.003); ≥50% improved ulcers in 32% and 15% (P = 0.071); unchanged ulcers in 11% and 60% (P < 0.001) and none worsened for the ESWT and the HBOT group respectively. The blood flow perfusion rates were comparable between the two groups before treatment (P = 0.245), however, significant differences were noted after treatment favoring the ESWT group (P = 0.002). Histopathological examination revealed considerable increases in cell proliferation and decreases in cell apoptosis in the ESWT group as compared to the HBOT group.

Conclusion

ESWT is more effective than HBOT in chronic diabetic foot ulcers. ESWT-treated ulcers showed significant improvement in blood flow perfusion rate and cell activity leading to better healing of the ulcers relative to HBOT in chronic diabetic foot ulcers.     

Increased epicardial adipose tissue in type 1 diabetes is associated with central obesity and metabolic syndrome

Aims

The present study evaluated the relationship between metabolic syndrome (MS), body fat composition and epicardial adipose tissue (EAT) in type 1 diabetes. Epicardial adipose tissue is a new independent marker of coronary artery disease (CAD).

Methods

Forty-five type 1 diabetic women were evaluated (age 36 ± 9 years; body mass index 24.6 ± 4.4 kg/m²). Metabolic syndrome was defined by the World Health Organization criteria. Body fat composition and EAT were analyzed by dual-energy-X-ray absorptiometry and echocardiogram, respectively.

Results

Twenty patients (45%) had MS. Patients with MS had greater android (central) fat deposition than patients without MS (41.9 ± 2.0% vs. 33.7 ± 1.8%, p = 0.004). Total body fat and gynoid (peripheric) fat distribution were similar between the groups. Mean EAT was higher in patients with MS (6.15 ± 0.34 mm vs. 4.96 ± 0.25 mm; p = 0.006) and EAT was positively correlated with android (central) fat distribution (r = 0.44; p = 0.002), however no correlation was found with gynoid (peripheric) fat distribution.

Conclusions

There was a high incidence of MS in type 1 diabetes related to increased central adiposity, despite the absence of obesity. Metabolic syndrome and central obesity were associated with increased EAT. Thus, young non-obese type 1 diabetic women with central adiposity and/or MS may have increased EAT, what may predict CAD risk.     

Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial

Aims

To identify better cells for the treatment of diabetic critical limb ischemia (CLI) and foot ulcer in a pilot trial.

Methods

Under ordinary treatment, the limbs of 41 type 2 diabetic patients with bilateral CLI and foot ulcer were injected intramuscularly with bone marrow mesenchymal stem cells (BMMSCs), bone marrow-derived mononuclear cells (BMMNCs), or normal saline (NS).

Results

The ulcer healing rate of the BMMSC group was significantly higher than that of BMMNCs at 6 weeks after injection (P = 0.022), and reached 100% 4 weeks earlier than BMMNC group. After 24 weeks of follow-up, the improvements in limb perfusion induced by the BMMSCs transplantation were more significant than those by BMMNCs in terms of painless walking time (P = 0.040), ankle-brachial index (ABI) (P = 0.017), transcutaneous oxygen pressure (TcO₂) (P = 0.001), and magnetic resonance angiography (MRA) analysis (P = 0.018). There was no significant difference between the groups in terms of pain relief and amputation and there was no serious adverse events related to both cell injections.

Conclusions

BMMSCs therapy may be better tolerated and more effective than BMMNCs for increasing lower limb perfusion and promoting foot ulcer healing in diabetic patients with CLI.     

Incidence and mortality of heart failure: A community-based study

Background

Data on the incidence and mortality of heart failure (HF) in community-based populations of developed countries are limited. We estimated the trends of the incidence and, the mortality of HF.

Methods

Prospective population-based study in a white, low-middle class Mediterranean community of 267,231 inhabitants in Spain. Participants were all the patients (= > 14 years), newly diagnosed with HF (4793), according to the Framingham criteria, from January 1, 2000 through December 31, 2007. Main outcome were incidence and mortality following an HF diagnosis.

Results

Incidence of HF increased among both men and women, and among persons with systolic and non-systolic HF. Incidence of HF increased from 296 per 100,000 person-years in 2000 to 390 per 100,000 person-years in 2007 (RR 1.32, CI 95% 1.27-13.7, P < .01). Although, risk-adjusted mortality declined from 2000 to 2007, the prognosis for patients with newly diagnosed HF remains poor. In 2007, risk-adjusted 30-day, 1-year, and 4-years mortality was 12.1%, 28.8%, and 61.4%, respectively. Incidence and mortality of systolic HF were higher than those of non-systolic HF (P < 0.05).

Conclusions

During the last 8 years, in a white, middle class population of the south of Europe, the increased incidence and the decreased mortality of heart failure have resulted in an increased prevalence of heart failure. Incidence and mortality of systolic heart failure were higher than those of non-systolic heart failure.     

Breast conserving treatment (BCT) for stage I-II breast cancer in elderly women: Analysis of 927 cases

Introduction

Few breast conserving treatment (BCT) data include women older than 70.

Material

910 women older than 70 were treated by BCT for stage I-II BC, with 670 pT₁ (72.3%), 245 pT₂ (26.4%) and 12 pT_x (1.3%). Axillary nodal involvement occurred in 30.7% of cases. ER and PgR were positive in 85% and 71% of cases. Radiotherapy (RT) was delivered in all patients, tamoxifen in 55.8% and chemotherapy in 4.8%.

Results

With a 65-month median follow-up, 28 (3%) local recurrences (LR) and 83 (9.1%) metastases occurred. Second cancer occurred in 51 (5.6%) patients. The 8-year overall survival (OS) and disease-specific survival (DSS) rates were 74% and 90%. The 8-year OS and DSS rates were 77% and 92% versus 65% and 84% in pT₁ versus pT₂ patients (p = 0.01). 676 patients were in complete remission (74.3%); 22 were evolutive (2.4%). 206 patients died (22.6%).

Conclusion

Our study confirms the excellent local control in elderly patients treated by BCT with RT and identifies subgroups at high risk of distant relapse that should be treated more aggressively.     

Association between serum soluble TNFα receptors and renal dysfunction in type 2 diabetic patients without proteinuria

Aim

The aim of our study was to investigate whether serum levels of soluble tumor necrosis factor α receptor (sTNFR) 1 and 2 are markers for renal dysfunction in type 2 diabetic patients without overt proteinuria.

Methods

Japanese type 2 diabetic patients without overt proteinuria (n = 168) enrolled in the prospective observational follow-up study in 2001 were retrospectively analyzed. At baseline, the serum levels of sTNFR1 and sTNFR2 were measured by sandwich ELISA. The associations between these markers and change in estimated glomerular filtration rate (eGFR) after 5 years were evaluated.

Results

The levels of sTNFR1 and sTNFR2 closely correlated. At baseline, sTNFR1 and sTNFR2 associated inversely with eGFR. After 5 years, patients with high level of both sTNFR1 and sTNFR2 showed a greater decline in eGFR (−13.8 ± 15.5% versus −8.5 ± 11.8%, P = 0.027) and a 4-fold higher risk for a GFR decline of ≥25% than those with high level of only one receptor or low level of both receptors. These associations were enhanced in diabetic women.

Conclusions

The higher levels of sTNFR1 and sTNFR2 were associated with a greater decline in eGFR in type 2 diabetic patients without proteinuria, especially in diabetic women.     

Pazopanib, a multitargeted tyrosine kinase inhibitor, reduces diabetic retinal vascular leukostasis and leakage

Objective

To determine the efficacy of pazopanib eye drops in the streptozotocin induced diabetic retinopathy rat model.

Methods

A 0.5% w/v pazopanib suspension was prepared in phosphate buffered saline (PBS, pH 7.4) in the presence of 0.5% w/v sodium carboxymethyl cellulose. Brown Norway rats were divided into three groups (n = 4) — (1) healthy, (2) diabetic, and (3) diabetic with treatment. The drug suspension was administered twice daily as eye drops to group 3 for 30 days. Efficacy parameters including the number of adherent leukocytes in the retinal vasculature (leukostasis), blood-retinal FITC-dextran leakage, and vitreous-to-plasma protein ratio were measured.

Results

Pazopanib suspension in the form of eye drops significantly reduced leukostasis (32%), FITC-dextran leakage (39%), and the vitreous-to-plasma protein ratio (64%) in diabetic animals compared to untreated diabetic group.

Conclusion

Pazopanib eye drops can alleviate retinal complications of diabetic retinopathy.     

Anti-endothelial and anti-neuronal effects from auto-antibodies in subsets of adult diabetes having a cluster of microvascular complications

Aims

To test autoantibodies from subsets of diabetes with painful neuropathy, maculopathy and nephropathy for effects in neurons.

Methods

Protein-A eluates from plasma of 27 diabetic and 19 age-matched controls were tested for effects on endothelial cell survival, and neurite outgrowth in rat pheochromocytoma PC12 cells. Painful diabetic neuropathy or control autoantibodies were compared for binding to PC12-derived heparan sulfate proteoglycans. The mechanism of the effects from pathologic autoantibodies was investigated by changes in intracellular calcium in endothelial cells, whole cell current in neurons, or using the Rho kinase inhibitor Y27632.

Results

Autoantibodies from diabetic patients with maculopathy, nephropathy, and painful neuropathy (n = 5) caused significantly greater mean inhibition of neurite outgrowth (p < 0.005) than diabetic or control patients with fewer or no complications (n = 30). Painful diabetic autoantibodies (3 μg/mL) bound neuronal heparan sulfate proteoglycan (HSPG) more than autoantibodies from diabetic or control subjects without painful neuropathy (p < .0001). Inhibition of PC12 neurite outgrowth by the painful neuropathy antibodies was completely prevented by 1 μM concentrations of Y27632.

Conclusion

These results suggest anti-endothelial and anti-neuronal effects from auto-antibodies in a subset of diabetic patients with a cluster of microvascular complications.     

Association of homocysteine with peripheral neuropathy in Chinese patients with type 2 diabetes

Aim

To explore the relationship between plasma total homocysteine concentration and diabetic neuropathy in Chinese patients with type 2 diabetes.

Methods

Chinese patients with type 2 diabetes (n = 249) were enrolled in a cross-sectional hospital based study. Diabetic neuropathy status was documented by presence of clinical signs and confirmed by electromyography. Plasma total homocysteine concentration was measured using fluorescence polarization immunoassay. Traditional risk factors for diabetic neuropathy were obtained from fasting blood samples and interviewer-questionnaire.

Results

Plasma total homocysteine levels were higher in subjects with diabetic neuropathy than without (12.8 (9.2-14.8) μmol/l vs. 8.0 (7.7-9.1) μmol/l, p = 0.005). The association of homocysteine with diabetic neuropathy was independent of major traditional risk factors for diabetic neuropathy (duration of diabetes, HbA1c) and determinants of higher homocysteine concentration (age, gender, serum folate and vitamin B12, renal status, and Biguanide use) (OR: 1.12 (1.00-1.25), p = 0.042). Furthermore, per increase of 4.0 μmol/l plasma homocysteine was related to neuropathy, after controlling for per unit increase of other factors (OR: 1.17 (0.94-1.33), p = 0.045).

Conclusion

Plasma total homocysteine concentration was independently associated with occurrence of diabetic neuropathy in Chinese people. Future prospective studies are warranted to clarify the relationship.     

Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients

Aim

Advanced research has radically changed both diagnosis and treatment of diabetes during last three decades; a number of classes of oral antidiabetic agents are currently available for better glycemic control. Present study aims to evaluate the effect of metformin on different stress and inflammatory parameters in diabetic subjects.

Methods

208 type 2 diabetes patients were randomly assigned for metformin and placebo.

Results

Reactive oxygen species generation, advanced oxidation protein products (179.65 ± 13.6, 120.65 ± 10.5 μmol/l) and pentosidine (107 ± 10.4, 78 ± 7.6 pmol/ml) were found to be reduced by metformin treatment compared to placebo. On the other hand metformin administration enhanced total thiol and nitric oxide level (p < 0.05). But nutrient level (Mg⁺², Ca⁺²) in plasma was not altered by the treatment. Significant restoration of C reactive protein (p < 0.05) was noticed after metformin therapy. Metformin administration also improved Na⁺K⁺ATPase activity (0.28 ± 0.08, 0.41 ± 0.07 μmol Pi/mg/h) in erythrocyte membrane.

Conclusions

This study explores that metformin treatment restores the antioxidant status, enzymatic activity and inflammatory parameters in type 2 diabetic patients. Metformin therapy improves the status of oxidative and nitrosative stress altered in type 2 diabetes. This study unfolds the cardio protective role of metformin as an oral hypoglycemic agent.     

Serum asymmetric dimethylarginine levels in diabetic patients with neuropathy

Objective

The goal of our study was to evaluate the role of asymmetric dimethylarginine (ADMA) in patients with diabetic neuropathy.

Materials and methods

In this study, 58 diabetic patients and 26 healthy volunteers were included. In both groups ADMA measurements were performed together with other biochemical examinations. Nerve conduction studies and Neuropathy Symptom Score (NSS) were administered to the diabetic patients.

Results

ADMA levels were found significantly higher in diabetic patients compared to the control group (p = 0.0001). However, ADMA levels were not statistically significant between diabetic patients with neuropathy and without neuropathy (p = 0.86 and p = 0.47).

Conclusion

These results demonstrate that there is not any significant relationship between ADMA and diabetic neuropathy.     

Prediction of Incident Hypertension Risk in Women with Currently Normal Blood Pressure

Background

We examined whether a hypertension risk prediction model based on clinical characteristics and blood biomarkers might improve on risk prediction based on current blood pressure alone.

Methods

A prospective cohort of 14,822 normotensive women aged 45 years and older were followed over 8 years beginning in 1992 for the development of hypertension. Among a randomly selected two-thirds sample (N = 9427), hypertension prediction models were developed using 52 potential predictors and compared with a model based on blood pressure alone. Each prediction model was validated in the remaining one third (N = 5395).

Results

In the development cohort, the best prediction model for incident hypertension included age, blood pressure, ethnicity, body mass index, total grain intake, apolipoprotein B, lipoprotein(a), and C-reactive protein (Bayes Information Criteria [BIC] = 8788). Although this model was superior to a model based on blood pressure alone (BIC = 8957), it was only marginally better than a simplified model including age, blood pressure, ethnicity, and body mass index (BIC = 8820). In the validation cohort, the simplified model demonstrated adequate calibration, a c-index similar to that of the best model (0.703 vs 0.705), and when compared with the model based on blood pressure alone, reclassified 1499 participants to hypertension risk categories that proved to be closer to observed risk in all but one instance.

Conclusion

In this prospective cohort of initially normotensive women, a model based on readily available clinical information predicted incident hypertension better than a model based on blood pressure alone.