Changes in the erythrocyte glutathione concentration in the course of diabetes mellitus

Abstract

This study aims to evaluate the significance of the changes of erythrocyte reduced glutathione (GSH) in the course of diabetes mellitus including the pre-diabetes stage and cardiovascular disease co-morbidity. A total of 222 participants (female:male, 107:115) were selected and their erythrocyte GSH levels were measured. The participants were divided into four groups: (i) control; (ii) those with blood glucose level ≥5.6 mmol/l but < 6.9 mmol/l as pre-diabetes mellitus with no other pathology; (iii) diabetes without co-morbidity; and (iv) those with diabetes mellitus and cardiovascular disease. Statistical analysis was by ANOVA followed by a Fisher's LSD post hoc test. We observed that GSH concentration was significantly different between groups (P < 0.04). The Fisher's post hoc test indicated significant differences in erythrocyte GSH levels between the pre-diabetes mellitus and diabetes mellitus groups compared to control (P < 0.005 and P < 0.05, respectively). A statistically significant change (P < 0.001) involving an initial fall followed by a rise in erythrocyte GSH levels was observed when diabetes mellitus and diabetes mellitus+cardiovascular disease groups were combined and assessed with respect to period of diabetes. We conclude that oxidative stress is already present in the pre-diabetes stage as determined by the fall in GSH, representing the initial phase of oxidative stress in diabetes mellitus progression. This finding provides evidence that antioxidant markers such as GSH could be a useful tool for pre-diabetes mellitus screening.     

Atherothrombosis and oxidative stress: the connection and correlation in diabetes

Abstract

Background: Hyperglycaemia-induced depletion of reduced glutathione (GSH) causes erythrocyte oxidative stress (EOS), which leads to vascular events including exacerbation of thrombotic events evidenced by changes in D-dimer level. It would, therefore, appear that there is a complex link between GSH and D-dimer, which are part of an emerging array of biomarkers associated with diabetes. The objective of this study was to investigate evidence of correlation between levels of plasma D-dimer and erythrocyte GSH in diabetes disease progression.

Subjects and methods: A cohort of 69 subjects were selected based on medical history plus clinical findings and equally divided into control, prediabetes and diabetes groups, matched for age and sex. Plasma D-dimer and erythrocyte reduced glutathione (GSH) were determined and separated into quartiles as a means of indicating disease severity. Statistical analysis was by Pearson's correlation coefficient.

Results: Of the three groups, only the diabetes group showed any correlation between GSH and D-dimer. Of importance is that for increasing GSH, the second quartile range of GSH (xbar ± SD = 45 ± 22 mg/100ml) showed a statistically significant negative correlation for ranked D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = ?0.88; P < 0.02). The fourth quartile GSH range (xbar ± SD = 79 ± 40 mg/100 ml) showed a statistically significant positive correlation with D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = 0.91; P < 0.02). Thus, within the diabetes group only, the increasing level of oxidative stress as measured by GSH first indicates a reduction in D-dimer followed by a rise in D-dimer, which led to the proposal of a two-part process of atherosclerosis that reconciles previous contradictory findings.

Conclusions: This study provides not only evidence of a correlation between oxidative stress level and fibrinolysis in diabetes, but also an explanation of why previous studies have found both hypo- or hyperfibrinolysis associated with diabetes.     

Coincident Pre-Diabetes Is Associated with Dysregulated Cytokine Responses in Pulmonary Tuberculosis

Background

Cytokines play an important role in the pathogenesis of pulmonary tuberculosis (PTB) - Type 2 diabetes mellitus co-morbidity. However, the cytokine interactions that characterize PTB coincident with pre-diabetes (PDM) are not known.

Methods

To identify the influence of coincident PDM on cytokine levels in PTB, we examined circulating levels of a panel of cytokines in the plasma of individuals with TB-PDM and compared them with those without PDM (TB-NDM).

Results

TB-PDM is characterized by elevated circulating levels of Type 1 (IFNγ, TNFα and IL-2), Type 17 (IL-17A and IL-17F) and other pro-inflammatory (IL-1β, IFNβ and GM-CSF) cytokines. TB-PDM is also characterized by increased systemic levels of Type 2 (IL-5) and regulatory (IL-10 and TGFβ) cytokines. Moreover, TB antigen stimulated whole blood also showed increased levels of pro-inflammatory (IFNγ, TNFα and IL-1β) cytokines as well. However, the cytokines did not exhibit any significant correlation with HbA1C levels or with bacterial burdens.

Conclusion

Our data reveal that pre-diabetes in PTB individuals is characterized by heightened cytokine responsiveness, indicating that a balanced pro and anti - inflammatory cytokine milieu is a feature of pre-diabetes - TB co-morbidity.     

Immunoglobulin E and mast cell proteases are potential risk factors of human pre-diabetes and diabetes mellitus

Background

Recent studies have suggested that mast-cell activation and inflammation are important in obesity and diabetes. Plasma levels of mast cell proteases and the mast cell activator immunoglobulin E (IgE) may serve as novel inflammatory markers that associate with the risk of pre-diabetes and diabetes mellitus.

Methods and Results

A total of 340 subjects 55 to 75 years of age were grouped according to the American Diabetes Association 2003 criteria of normal glucose tolerance, pre-diabetes, and diabetes mellitus. The Kruskal-Wallis test demonstrated significant differences in plasma IgE levels (P = 0.008) among groups with different glucose tolerance status. Linear regression analysis revealed significant correlations between plasma levels of chymase (P = 0.030) or IgE (P = 0.022) and diabetes mellitus. Ordinal logistic regression analysis showed that IgE was a significant risk factor of pre-diabetes and diabetes mellitus (odds ratio [OR]: 1.674, P = 0.034). After adjustment for common diabetes risk factors, including age, sex, hypertension, body-mass index, cholesterol, homeostatic model assessment (HOMA) index, high-sensitivity C-reactive protein (hs-CRP), and mast cell chymase and tryptase, IgE remained a significant risk factor (OR: 1.866, P = 0.015). Two-variable ordinal logistic analysis indicated that interactions between hs-CRP and IgE, or between IgE and chymase, increased further the risks of developing pre-diabetes and diabetes mellitus before (OR: 2.204, P = 0.044; OR: 2.479, P = 0.033) and after (OR: 2.251, P = 0.040; OR: 2.594, P = 0.026) adjustment for common diabetes risk factors.

Conclusions

Both IgE and chymase associate with diabetes status. While IgE and hs-CRP are individual risk factors of pre-diabetes and diabetes mellitus, interactions of IgE with hs-CRP or with chymase further increased the risk of pre-diabetes and diabetes mellitus.     

Optimal Cut-Off Points of Fasting Plasma Glucose for Two-Step Strategy in Estimating Prevalence and Screening Undiagnosed Diabetes and Pre-Diabetes in Harbin,China

To identify optimal cut-off points of fasting plasma glucose (FPG) for two-step strategy in screening abnormal glucose metabolism and estimating prevalence in general Chinese population. A population-based cross-sectional study was conducted on 7913 people aged 20 to 74 years in Harbin. Diabetes and pre-diabetes were determined by fasting and 2 hour post-load glucose from the oral glucose tolerance test in all participants. Screening potential of FPG, cost per case identified by two-step strategy, and optimal FPG cut-off points were described. The prevalence of diabetes was 12.7%, of which 65.2% was undiagnosed. Twelve percent or 9.0% of participants were diagnosed with pre-diabetes using 2003 ADA criteria or 1999 WHO criteria, respectively. The optimal FPG cut-off points for two-step strategy were 5.6 mmol/l for previously undiagnosed diabetes (area under the receiver-operating characteristic curve of FPG 0.93; sensitivity 82.0%; cost per case identified by two-step strategy ¥261), 5.3 mmol/l for both diabetes and pre-diabetes or pre-diabetes alone using 2003 ADA criteria (0.89 or 0.85; 72.4% or 62.9%; ¥110 or ¥258), 5.0 mmol/l for pre-diabetes using 1999 WHO criteria (0.78; 66.8%; ¥399), and 4.9 mmol/l for IGT alone (0.74; 62.2%; ¥502). Using the two-step strategy, the underestimates of prevalence reduced to nearly 38% for pre-diabetes or 18.7% for undiagnosed diabetes, respectively. Approximately a quarter of the general population in Harbin was in hyperglycemic condition. Using optimal FPG cut-off points for two-step strategy in Chinese population may be more effective and less costly for reducing the missed diagnosis of hyperglycemic condition.     

Polymorphic variations in manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1), and catalase (CAT) contribute to elevated plasma triglyceride levels in Chinese patients with type 2 diabetes or diabetic cardiovascular disease

Manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1), and catalase (CAT) provide the primary antioxidant defense system. Impaired antioxidant defense increases oxidative stress and contributes to the development of type 2 diabetes and diabetic cardiovascular disease (CVD). We preformed a case-control study in Chinese type 2 diabetes patients, to determine if the MnSOD Val16Ala (T→C), GPX1 Pro198Leu (C→T), and CAT -262C/T (C→T) functional polymorphisms contribute to the development of type 2 diabetes or diabetic CVD. Patients with type 2 diabetes (n = 168) were divided into the non-CVD group (n = 83, >10 year since diagnosis) and CVD group (n = 85, history of ischemic CVD). Genotyping was performed using PCR-restriction fragment length polymorphism (PCR-RFLP) or PCR-based direct sequencing. The genotypic distribution in the non-CVD- and CVD-group and the clinical parameters in genotypic groups were not significantly different in the three polymorphic sites, respectively. Among eight genotypic combinations, the most common TT+CC+CC genotype (59.5%) was associated with higher triglyceride levels than the TT+CT+CC genotype, the second frequent one (14.9%; 1.77 ± 0.12 vs. 1.21 ± 0.11 mmol/l, P = 0.001), and all non-TT+CC+CC genotypes (40.5%; 1.77 ± 0.12 vs. 1.43 ± 0.12 mmol/l, P = 0.048). In the CVD group, significantly elevated triglyceride levels were also observed in patients with TT+CC+CC compared to patients with TT+CT+CC (2.00 ± 0.18 vs. 1.37 ± 0.16 mmol/l, P = 0.018) or non-TT+CC+CC genotypes (2.00 ± 0.18 vs. 1.65 ± 0.19 mmol/l, P = 0.070). The common MnSOD, GPX1, and CAT TT+CC+CC genotype may contribute to hypertriglyceridemia in Chinese patients with type 2 diabetes or diabetic CVD.     

Type 1 diabetes in pre-school children - long-term metabolic control, associated autoimmunity and complications

Diabet. Med. 29, 1291-1296 (2012) ABSTRACT: Aims To identify clinical characteristics and co-morbidity rates of children diagnosed with Type 1 diabetes mellitus at younger than 6?years of age. Methods Data were obtained from a retrospective chart review of 103 patients diagnosed with Type 1 diabetes at younger than 6?years (study group) and 220 patients at older than 6?years (comparison group). Measures of glycaemic control and occurrence of co-morbidities (coeliac disease, autoimmune thyroid disease, hypertension, nephropathy and retinopathy) were compared. Results The mean follow-up period was more than 8?years. For the study group, mean HbA(1c) levels ranged from 64?mmol/mol to 66?mmol/mol (8.0-8.2%) until age 10?years, and then rose to 73?mmol/mol (8.8%). The HbA(1c) levels were higher in the study than in the comparison group for comparable ages (P?=?0.003). After adjustment for duration of diabetes this difference was not significant. The overall rate of severe hypoglycaemic events was greater in the study group than in the comparison group (P?=?0.03). Kaplan-Meier diagnosis rates of celiac disease, 10?years after Type 1 diabetes diagnosis, were 14.4% and 4.2% in the study and comparison groups, respectively (P log-rank?=?0.03). There were no differences in rates of autoimmune thyroid disease, hypertension, nephropathy or retinopathy. Conclusions Children diagnosed with Type 1 diabetes before the age of 6?years were in greater risk of developing celiac disease, compared with children diagnosed after the age of 6?years. For children diagnosed with Type 1 diabetes aged under 6?years, good metabolic control was achievable until age 10?years, after which it deteriorated. Higher HbA(1c) levels observed in children diagnosed before the age of 6?years were associated with longer duration of disease.     

The lipid accumulation product is associated with increased mortality in normal weight postmenopausal women

Lipid accumulation product (LAP) is an emerging cardiovascular risk factor, which is calculated from waist circumference (WC) and triglyceride (TG) levels. The aim of this study was to elucidate the relationship between LAP and cardiovascular mortality as well as the presence of type 2 diabetes with respect to gender-specific differences. We determined WC and fasting TG levels and the cardiovascular and metabolic phenotypes coronary artery disease (CAD), hypertension, metabolic syndrome, and diabetes mellitus in 2,279 men and 875 postmenopausal women who were routinely referred to coronary angiography. The LAP was calculated as (WC (cm)--65) × (TG (mmol/l)) for men and as (WC (cm)--58) × (TG (mmol/l)) for women. LAP levels were independently associated with congestive heart failure mortality in all postmenopausal women and with all-cause mortality in diabetic postmenopausal women but not in men. Multivariable-adjusted hazard ratios (with 95% confidence intervals) for all-cause, cardiovascular, and congestive heart failure mortality in the third compared to the first LAP tertile were 4.28 (1.94-9.44; P < 0.001), 3.47 (1.28-9.40; P = 0.015), and 10.77 (1.21-95.88; P = 0.033), respectively, in normal weight postmenopausal women, whereas no significant associations were found in men. LAP levels were highly associated with type 2 diabetes in all subjects, postmenopausal women, and men. High LAP values are predictive of mortality independently of other cardiovascular risk factors in normal weight and diabetic postmenopausal women but not in men. Type 2 diabetes (T2DM) was highly associated with LAP in women and men. Our study validates an inexpensive and simple risk profiling that may allow identifying postmenopausal women at high cardiovascular risk.     

Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The pathogenesis of DPN is complex and involves an intertwined array of mechanisms. The purposes of this study were to evaluate the association of oxidative stress and vascular risk factors with the prevalence of DPN and to determine the role of these biochemical parameters in the prognosis of DPN. One hundred patients with type 2 diabetes mellitus and 40 clinically healthy individuals were evaluated. The patients were divided into two groups. Group 1 included 40 diabetic patients without peripheral neuropathy, and group 2 consisted of 60 patients with DPN. Erythrocytes glutathione (GSH) level, plasma malondialdehyde (MDA), nitrite/nitrate (NOx) and homocysteine (Hcy) levels as well as serum ceruloplasmin (Cp), total antioxidants (TAO), endothelin-1 (ET-1) levels and γ-glutamyl transferase (GGT) activity were estimated. A significant decrease of erythrocyte GSH was observed in groups 1 and 2 relative to the controls. An increase in glycosylated haemoglobin (HbA1c), MDA, NOx, GGT, Cp, TAO, Hcy and ET-1 was noted in patients with DPN. In conclusion, oxidative stress biomarkers and vascular risk factors could be important in the pathogenesis of DPN. The measurement of serum GGT and Hcy in addition to HbA1c and disease duration could facilitate the early detection of neuropathy in diabetic patients.     

Circulating oxidized LDL and inflammation in extreme pediatric obesity

Oxidative stress and inflammation have not been well-characterized in extreme pediatric obesity. We compared levels of circulating oxidized low-density lipoprotein (oxLDL), C-reactive protein (CRP), and interleukin-6 (IL-6) in extremely obese (EO) children to normal weight (NW) and overweight/obese (OW/OB) children. OxLDL, CRP, IL-6, BMI, blood pressure, and fasting glucose, insulin, and lipids were obtained in 225 children and adolescents (age 13.5 ± 2.5 years; boys 55%). Participants were classified into three groups based on gender- and age-specific BMI percentile: NW (<85th, n = 127), OW/OB (85th- <1.2 times the 95th percentile, n = 64) and EO (≥1.2 times the 95th percentile or BMI ≥35 kg/m(2), n = 34). Measures were compared across groups using analysis of covariance, adjusted for gender, age, and race. Blood pressure, insulin, and lipids worsened across BMI groups (all P < 0.0001). OxLDL (NW: 40.8 ± 9.0 U/l, OW/OB: 45.7 ± 12.1 U/l, EO: 63.5 ± 13.8 U/l) and CRP (NW: 0.5 ± 1.0 mg/l, OW/OB: 1.4 ± 2.9 mg/l, EO: 5.6 ± 4.9 mg/l) increased significantly across BMI groups (all groups differed with P < 0.01). IL-6 was significantly higher in EO (2.0 ± 0.9 pg/ml) compared to OW/OB (1.3 ± 1.2 pg/ml, P < 0.001) and NW (1.1 ± 1.0 pg/ml, P < 0.0001) but was not different between NW and OW/OB. Extreme pediatric obesity, compared to milder forms of adiposity and NW, is associated with higher levels of oxidative stress and inflammation, suggesting that markers of early cardiovascular disease and type 2 diabetes mellitus are already present in this young population.     

Type 2 diabetic patients and their offspring show altered parameters of iron status, oxidative stress and genes related to mitochondrial activity

Type 2 diabetes (T2D) is directly related to alterations in iron status, oxidative stress and decreased mitochondrial activity, but the possible interaction of these parameters among T2D patients and their offspring is unclear. The whole study included 301 subjects: 77 T2D patients and one of their offspring and 51 control subjects with one of their offspring. The offspring were older than 20?years old. We measured parameters of iron status (serum iron, ferritin and transferrin receptor), diabetes (pre and post-prandial glucose, insulin, lipids), oxidative stress (Heme oxygenase activity, TBARS, SOD, GSH, Vitamin E), as well as the expression of genes in blood leukocytes related to mitochondrial apopotosis (mitofusin and Bcl/Bax ratios). The offspring of T2D patients had increased levels of serum ferritin (P?相似文献   

Neuroprotective effect of mexiletine in the central nervous system of diabetic rats

Both experimental and clinical studies suggests that oxidative stress plays an important role in the pathogenesis of diabetes mellitus type 1 and type 2. Hyperglycaemia leads to free radical generation and causes neural degeneration. In the present study we investigated the possible neuroprotective effect of mexiletine against streptozotocin-induced hyperglycaemia in the rat brain and spinal cord.30 adult male Wistar rats were divided into three groups: control, diabetic, and diabetic-mexiletine treated group. Diabetes mellitus was induced by a single injection of streptozotocin (60 mg/kg body weight). Mexiletine (50 mg/kg) was injected intraperitoneally every day for six weeks. After 6 weeks the brain, brain stem and cervical spinal cord of the rats were removed and the hippocampus, cortex, cerebellum, brain stem and spinal cord were dissected for biochemical analysis (the level of Malondialdehide [MDA], Nitric Oxide [NO], Reduced Glutathione [GSH], and Xanthine Oxidase [XO] activity). MDA, XO and NO levels in the hippocampus, cortex, cerebellum, brain stem and spinal cord of the diabetic group increased significantly, when compared with control and mexiletine groups (P < 0.05). GSH levels in the hippocampus, cortex, cerebellum, brain stem and spinal cord of the diabetic group decreased significantly when compared with control and mexiletine groups (P < 0.05).This study demonstrates that mexiletine protects the neuronal tissue against the diabetic oxidative damage.     

In vivo rates of erythrocyte glutathione synthesis in adults with sickle cell disease

Despite reports of lower GSH concentration in sickle cell disease (SCD), the in vivo kinetic mechanism(s) responsible for GSH deficiency is unknown. To determine whether suppressed synthesis was responsible for the lower erythrocyte GSH concentration, we used a primed intermittent infusion of [(2)H(2)]glycine to measure erythrocyte GSH synthesis in vivo in 23 individuals with homozygous beta(s) SCD and 8 healthy controls. Erythrocyte cysteine concentration, the rate-limiting precursor for GSH synthesis, plasma markers of oxidant damage, and dietary intakes of energy and protein were also measured. Compared with values of controls, SCD subjects had significantly lower erythrocyte GSH (P < 0.04) and cysteine concentrations (P < 0.004) but significantly faster fractional rates of GSH synthesis (P < 0.02). The absolute rates of GSH synthesis in SCD subjects compared with control subjects was greater by approximately 57% (P = 0.062). However, the concentrations of markers of oxidative damage, plasma derivatives of reactive oxygen metabolites, plasma nitrotyrosine, urinary isoprostane-to-creatinine ratio, and GSH-to-GSSG ratio, as well as dietary intakes of energy, protein, and GSH precursor amino acids, were not different between SCD subjects and controls. The findings of this study suggest that the lower erythrocyte GSH of SCD patients is not due to suppressed synthesis or impaired regeneration but rather to increased consumption. In addition, the lower erythrocyte cysteine concentration plus the faster rate of GSH synthesis strongly suggest that the endogenous cysteine supply is not sufficient to meet all anabolic demands; hence, cysteine may be a conditionally essential amino acid in individuals with SCD.     

Eryptosis and oxidative damage in type 2 diabetic mellitus patients with chronic kidney disease

It has been suggested that oxidative stress may participate in the progression of diabetes and its complications. Long-term complications of type 2 diabetes mellitus (T2DM) include retinopathy, atherosclerosis, shortened life span of erythrocytes, nephropathy, and chronic kidney disease (CKD). Oxidative damage has been associated with erythrocyte apoptosis induction in other pathological conditions. Our aim was to study the presence of eryptosis and its possible relationship with oxidative damage in patients with T2DM without CKD (T2DM/CKD(-)) and in patients with T2DM and CKD (T2DM/CKD(+)).Oxidative damage of lipids erythrocytes were increased in diabetic patients. The highest lipoperoxidation was found in T2DM/CKD(+). Likewise, the lower plasma total antioxidant capacity, GSH/GSSG ratio, and GSH in erythrocytes were found in T2DM/CKD(+) patients. A negative correlation was found between plasma total antioxidant capacity and oxidative damage. Phosphatidylserine (PS) externalization was measured in erythrocytes to evaluate eryptosis. Annexin binding in erythrocytes of T2DM/CKD(+) patients was higher than in healthy subjects and T2DM/CKD(-) patients. A positive correlation between lipoperoxidation and PS externalization in erythrocytes was found. This work showed that the erythrocytes of diabetic patients have increased oxidative damage, a reduction of antioxidant systems and more erythrocyte PS externalization. The duration of diabetes and the presence of CKD increase both oxidative damage and eryptosis. It is possible that a longer time of evolution induces an increase in erythrocyte oxidative damage and the consumption of blood antioxidant systems, adding to the osmotic stress in CKD and so contributes to an increase in PS externalization in diabetic patients.     

Melatonin Modulates Hippocampus NMDA Receptors, Blood and Brain Oxidative Stress Levels in Ovariectomized Rats

We investigated the effects of melatonin administration on ovariectomy-induced oxidative toxicity and N-methyl-d-aspartate receptor (NMDAR) subunits in the blood of rats. Thirty-two rats were studied in three groups. The first and second groups were control and ovariectomized rats. Melatonin was daily administrated to the ovariectomized rats in the third group for 30 days. Blood, brain cortical and hippocampal samples were taken from the three groups after 30 days. Brain cortical, erythrocyte and plasma lipid peroxidation (LP) levels were higher in the ovariectomized group than in controls, although the LP level was decreased in the ovariectomized group with melatonin treatment. Brain cortical and plasma concentrations of vitamins A, C and E as well as the NMDAR 2B subunit were lower in the ovariectomized group than in controls, although, except for plasma vitamin C, they were increased by the treatment. Brain cortical and erythrocyte reduced glutathione (GSH) levels were lower in the ovariectomized group than in controls, although erythrocyte GSH levels were higher in the melatonin group than in the ovariectomized group. Brain cortical and erythrocyte glutathione peroxidase activity and NMDAR 2A subunit concentrations were not found to be different in all groups statistically. Oxidative stress has been proposed to explain the biological side effect of experimental menopause. Melatonin prevents experimental menopause–induced oxidative stress to strengthen antioxidant vitamin and NMDAR 2A subunit concentrations in ovariectomized rats.     

Plasma and erythrocytes antioxidant status and trace element levels in proteinuric patients with moderate glomerular function.

The objective of the study was to investigate the effect of moderate glomerular dysfunction on oxidative stress. We determined the plasma and erythrocyte malondialdehyde (MDA) levels, as a marker of lipid peroxidation, erythrocyte glutathione (GSH) levels and activities of GSH-Px, GSH Red and SOD as an antioxidant enzymes, and plasma trace element levels containing Fe, Cu and Zn in twenty proteinuric patients (6.8 +/- 5.1 g/day) with moderate glomerular function and in 20 anemic control subjects. We found that the erythrocyte and plasma MDA levels and erythrocyte GSH-Px activities were significantly higher (p < 0.001, p < 0.001, p < 0.001, respectively) and the erythrocyte GSH levels and activities of GSH-Red and SOD activities were significantly lower (p < 0.001, p < 0.001, p < 0.001, respectively) in the patients than in the anemic subjects. Plasma Fe and Zn levels were not to be found significantly different in the patients compared to the anemic subjects. But plasma Cu levels were significantly higher in the patients (p < 0.05) when compared with the levels of anemic subjects. This study was concluded that cellular antioxidant activity decreases in proteinuric patients with moderate glomerular function. This may increase lipid peroxidation reactions by causing oxidative stress in erythrocyte membranes.     

HbA1c Alone Is a Poor Indicator of Cardiometabolic Risk in Middle-Aged Subjects with Pre-Diabetes but Is Suitable for Type 2 Diabetes Diagnosis: A Cross-Sectional Study

Objectives

Glycated haemoglobin A_1c (HbA_1c) measurement is recommended as an alternative to fasting plasma glucose (FPG) for the diagnosis of pre-diabetes and type 2 diabetes. However, evidence suggests discordance between HbA_1c and FPG. In this study we examine a range of metabolic risk features, pro-inflammatory cytokines, acute-phase response proteins, coagulation factors and white blood cell counts to determine which assay more accurately identifies individuals at increased cardiometabolic risk.

Materials and Methods

This was a cross-sectional study involving a random sample of 2,047 men and women aged 46-73 years. Binary and multinomial logistic regression were employed to examine risk feature associations with pre-diabetes [either HbA_1c levels 5.7-6.4% (39-46 mmol/mol) or impaired FPG levels 5.6-6.9 mmol/l] and type 2 diabetes [either HbA_1c levels >6.5% (>48 mmol/mol) or FPG levels >7.0 mmol/l]. Receiver operating characteristic curve analysis was used to evaluate the ability of HbA_1c to discriminate pre-diabetes and diabetes defined by FPG.

Results

Stronger associations with diabetes-related phenotypes were observed in pre-diabetic subjects diagnosed by FPG compared to those detected by HbA_1c. Individuals with type 2 diabetes exhibited cardiometabolic profiles that were broadly similar according to diagnosis by either assay. Pre-diabetic participants classified by both assays displayed a more pro-inflammatory, pro-atherogenic, hypertensive and insulin resistant profile. Odds ratios of having three or more metabolic syndrome features were also noticeably increased (OR: 4.0, 95% CI: 2.8-5.8) when compared to subjects diagnosed by either HbA_1c (OR: 1.4, 95% CI: 1.2-1.8) or FPG (OR: 3.0, 95% CI: 1.7-5.1) separately.

Conclusions

In middle-aged Caucasian-Europeans, HbA_1c alone is a poor indicator of cardiometabolic risk but is suitable for diagnosing diabetes. Combined use of HbA_1c and FPG may be of additional benefit for detecting individuals at highest odds of type 2 diabetes development.     

Influence of proteinuria on vascular disease,blood pressure,and lipoproteins in insulin dependent diabetes mellitus.

Patients with insulin dependent diabetes mellitus who develop proteinuria may die prematurely, whereas those who do not develop this complication have a comparatively normal life span. The excess mortality in diabetics with proteinuria is from cardiovascular as well as renal disease, but the reason is unclear. Risk factors for vascular disease were therefore assessed in 22 insulin dependent diabetics with proteinuria, but not renal failure, who were matched for sex, age, duration of diabetes, and glycated haemoglobin (HbA1) values with a similar number who had normal urinary albumin excretion rates. Macrovascular disease (ischaemic heart disease and peripheral vascular disease) was present in 10 patients with proteinuria but in only three with normal albumin excretion rates, and proliferative retinopathy was detected in 11 and four patients in the two groups. There was no significant excess of smokers in the group with proteinuria. Blood pressure was, however, higher in the patients with proteinuria--mean systolic pressure 161 (SD 18) mm Hg compared with 135 (19) mm Hg (95% confidence interval of difference between means 15 to 38 mm Hg); mean diastolic pressure 90 (SD 12) mm Hg compared with 79 (15) mm Hg (confidence interval 3 to 19 mm Hg). The concentration of serum high density lipoprotein (HDL) cholesterol isolated by precipitation was lower in the patients with proteinuria (confidence interval 0.02 to 0.41 mmol/l). Their concentration of HDL2 cholesterol isolated by ultracentrifugation was also decreased (confidence interval 0.02 to 0.40 mmol/l), whereas HDL3 cholesterol tended to be increased (confidence interval -0.01 to 0.23 mmol/l). There was also a trend for serum cholesterol concentrations to be higher in the presence of proteinuria (confidence interval -0.39 to 1.20 mmol/l). The aggregation of risk factors for atherosclerosis in insulin dependent diabetes mellitus complicated by proteinuria helps to explain the increased prevalence of ischaemic heart disease and peripheral vascular disease reported in these patients. Early renal disease in insulin dependent diabetes may have an important role in hypertension and altered lipoprotein metabolism.     

Does polyamine oxidase activity influence the oxidative metabolism of children who suffer of diabetes mellitus?

Diabetes mellitus is a metabolic disease characterized by inadequate secretion of insulin. Polyamine oxidase (PAO), a FAD-containing enzyme is involved in the biodegradation of Sp and Spd, catalyzing the oxidative deamination of Sp and Spd, resulting in production of amonia (NH₃), corresponding amino aldehydes and H₂O₂. Malondialdehyde (MDA) and acrolein (CH2=CHCHO), potentially toxic agents, which induce oxidative stress in mammalian cells, are then spontaneously formed from aminoaldehydes. The main signs of oxidative stress in diabetic children were the values of HbA1c and MDA levels. Polyamines have an insulin-like action. Antiglycation property of spermine and spermidine has been recently confirmed. There are no data in the literature about plasma polyamine oxidase (PAO) activities in children with type 1 diabetes. The idea of this study was to evaluate the polyamine metabolism through the estimation of polyamine oxidase activity. We have study children with newly diagnosed type 1 diabetes mellitus (n = 35, age group of 5–16 years, as well as age-matched healthy control subjects (n = 25). The biochemical investigations were done on diabetic children who have the pathological values of glucose (9.11–17.33 mmol/l) and glycosylated Hb (7.57–14.49% HbA_1c). The children in the control group have referent values of glucose and glycated hemoglobin (4.11-5.84 mmol/L and HbA_1c 4.22-6.81% of the total Hb. Glucose levels in blood plasma and glycosylated hemoglobin in erythrocythes hemolysates (HbA1c) were measured by using standard laboratory methods. PAO activity in venous blood plasma and the amount of malondialdehyde (MDA) were measured by the spectrophotometric methods. PAO activity, glycemia, HbA1c and MDA were significantly increased in diabetic children compared to the control subjects. PAO activity in children with type 1 diabetes mellitus was very high. The findings of higher blood HbA_1C and MDA levels confirm the presence of oxidant stress in children with type 1 diabetes mellitus and demonstrate that PAO activity may participate in these circumstances.     

The Impact of Diabetes Mellitus and Corresponding HbA1c Levels on the Future Risks of Cardiovascular Disease and Mortality: A Representative Cohort Study in Taiwan

Background

This study explored the relationship between the glycated hemoglobin (HbA1c) level in patients with or without diabetes mellitus and future risks of cardiovascular disease and death.

Methods

Based on a national representative cohort, a total of 5277 participants (7% with diabetes) were selected from Taiwan''s Triple High Survey in 2002. The comorbidities, medication usages, and outcomes of cardiovascular disease and death, were extracted from the Taiwan’s National Health Insurance Research Database and National Death Registry.

Results

After a median follow-up of 9.7 years, participants with diabetes had higher incidence of new onset cardiovascular disease (17.9 versus 3.16 cases per 1000 person-years) and death (20.1 versus 4.96 cases per 1000 person-years) than those without diabetes (all P < 0.001). Diabetes showed increased risk of all-cause death after adjusting for all confounders (adjusted hazard ratio [HR]: 2.29, 95% confidence interval [CI]: 1.52-3.45). Every 1% increment of HbA1c was positively associated with the risk of total cardiovascular disease (HR: 1.2, 95% CI: 1.08-1.34) and the risk of death (HR: 1.14, 95% CI: 1.03-1.26) for all participants. As compared to the reference group with HbA1c below 5.5%, participants with HbA1c levels ≥7.5% had significantly elevated future risks of total cardiovascular disease (HR: 1.82, 95% CI: 1.01-3.26) and all-cause death (HR: 2.45, 95% CI: 1.45-4.14).

Conclusions/Interpretation

Elevated HbA1C levels were associated with increased risks of cardiovascular disease and death, the suboptimal glycemic control with HbA1c level over 7.5% (58.5 mmol/mol) was strongly associated with increased risks of cardiovascular disease and all-cause death.