The effect of oral alpha-lipoic acid on oxidative stress in adolescents with type 1 diabetes mellitus

Background:  Oxidative stress has been implicated in the pathophysiology of diabetic complications. Alpha-lipoic acid (LA), a potent antioxidant, has been shown to be an effective treatment for diabetic neuropathy when given intravenously. Recently, an oral controlled-release formulation of alpha-lipoic acid (CRLA) was developed, and a pharmacokinetic study demonstrated that CRLA maintained significant plasma levels for 67% longer than a common quick-release formulation.
Objective:  To determine if CRLA is an effective antioxidant in type 1 diabetes mellitus (T1D) by measuring its effects on markers of oxidative damage and total antioxidant status.
Methods:  Forty pubertal and postpubertal adolescents with T1D underwent a double-blind, randomized, placebo-controlled study of CRLA for 3 months. 8-hydroxy-2'-deoxyguanosine, 2-thiobarbituric acid-reactive substances, protein carbonyl, total reactive antioxidant potential, hemoglobin A1c (HbA1c), and spot random urine collected for albumin to creatinine ratio were measured before and after treatment.
Results:  There was no significant change in any measurement of oxidative damage, total antioxidant status, HbA1c, or microalbuminuria prevalence after treatment with either placebo or CRLA.
Conclusion:  In this pilot study, CRLA was not an effective treatment for decreasing oxidative damage in T1D, although efficacy may have been limited by issues with compliance.     

Increased TLR2 expression in patients with type 1 diabetes: evidenced risk of microalbuminuria

Ururahy MAG, Loureiro MB, Freire‐Neto FP, Souza KSC, Zuhl I, Brandão‐Neto J, Hirata RDC, Doi SQ, Arrais RF, Hirata MH, Almeida MG, Rezende AA. Increased TLR2 expression in patients with type 1 diabetes: evidenced risk of microalbuminuria. Objective: To study the activation of an inflammatory cascade through leukocyte mRNA expression of TLR2, TLR4, MyD88, and pro‐inflammatory cytokines in individuals with childhood onset type 1 diabetes. Design and methods: Seventy‐six type 1 diabetic patients and 100 normoglycemic subjects (NG) 6 to 20 years old were recruited. Type 1 diabetic patients (DM1) were considered to have good (DM1G) or poor (DM1P) glycemic control according to the values of glycated hemoglobin. TLR2, TLR4, MyD88, interleukin ‐1β (IL‐1β), IL‐6, and tumor necrosis factor alpha (TNF‐α) mRNA expressions were measured in peripheral blood leukocytes (PBL) by real‐time polymerase chain reaction (PCR). Urea, creatinine, albumin, and total protein serum levels were determined. Urinary albumin‐to‐creatinine ratio (ACR) was calculated. Results: DM1 and DM1P patients showed higher glycated hemoglobin (10 and 11%, respectively) and serum glucose concentrations (208 and 226 mg/dL, respectively) compared to NG (Glycated hemoglobin: 7% and glucose: 76 mg/dL) (p < 0.05). PBL mRNA expressions of TLR2, MyD88, IL‐1β, IL‐6, and TNF‐α were higher in DM1 and TLR2, IL‐1β, and IL‐6 expressions were higher in DMP1 compared to NG (p < 0.05). In DM1, serum albumin and total protein were lower, while serum urea and ACR were higher in comparison to NG (p < 0.05). However, these differences compared to NG were more pronounced in DM1P, which included nine individuals with microalbuminuria. Conclusions: Increased mRNA expression of TLR2, MyD88, and pro‐inflammatory cytokines in leukocytes of patients with childhood onset type 1 diabetes indicates the development of a TLR2‐mediated pro‐inflammatory process, which may also be associated with an early inflammatory process in the kidney and the occurrence of microalbuminuria.     

Urinary cytokine response to asymptomatic bacteriuria in type 1 diabetic children and young adults

It has been reported that urinary interleukin-6 (IL-6) and IL-8 levels are decreased in adult diabetic women with asymptomatic bacteriuria (ASB) when compared with non-diabetic women with ASB. Such impaired cytokine excretion might play a role in the higher prevalence of ASB among diabetic subjects. The aim of this study was to examine the urinary IL profile in children and young adults with type 1 diabetes mellitus (T1DM) with and without ASB. Midstream clean voiding urine samples were collected and cultured from 133 patients with T1DM (age: 15.6 +/- 5.7 yr) and 178 controls (14.1 +/- 4.7 yr) for two consecutive days. ASB was diagnosed in the case of >or=10(5) bacteria/mL. The urinary IL-6 and IL-8 concentrations were determined, and the presence of leukocyturia was also recorded. The prevalence of ASB was 16.5% in diabetic subjects and 2.8% in controls (p = 0.001). There was no difference between the diabetic and the control groups in the prevalence of 'IL-6-uria' (21.9 vs. 18.0%; p = 0.41), but IL-8 was more frequently detectable in the diabetic group (47.4 vs. 27.5%; p = 0.001). In individuals with ASB, the IL-8 level was similar in the diabetic (median: 70.0 pg/mg creatinine) and control group (42.3 pg/mg creatinine; p = 0.8). Indeed, the IL-8 levels were higher in diabetic subjects with ASB as compared with those without it (70.0 vs. <3.1 pg/mg creatinine; p = 0.001), and there was a significant association between the urinary IL-8 concentration and the bacterial count (p = 0.001). Diabetic patients with leukocyturia had higher IL-8 concentration than those without it (20.9 vs. <3.1 pg/mg creatinine; p = 0.003). Weak significant correlation was found between urinary IL-8 and hemoglobin A1c (HbA1c) (r = 0.4; p = 0.002). The sensitivity and specificity of leukocyturia were 50 and 89.9% in the whole population and those of IL-8 were 74.1 and 67.5%, respectively. In diabetic patients, 36.4% of the bacteriuria were gram-negative and 63.6% gram-positive. Our results suggest that diabetic children with ASB mount an IL-8 response to pathogens, which is comparable to non-diabetic children with bacteriuria. Thus, early in the natural history of diabetes, there are no significant changes in the IL response of children with ASB, as previously reported in adults.     

Glycemic control in adolescents with type 1 diabetes mellitus improves lipid serum levels and oxidative stress

Introduction:  Atherosclerosis begins in childhood, and diabetes is a risk factor for coronary heart disease. Dyslipidemia is prevalent in children with type 1 diabetes mellitus (T1DM), with an association between elevated hemoglobin A1c (HbA1c), serum lipid levels, and oxidative stress. Our aim was to examine the effect of metabolic control on serum lipid levels and oxidative stress in adolescents with T1DM.
Methods:  Twenty-six adolescents (13 boys and 13 girls), aged 15.65 ± 1.5 yr, with disease duration of 5.9 ± 2.8 yr and average HbA1c 10.8 ± 1.9% were assigned to intensive insulin therapy for 3 months. Comparisons for HbA1c, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, total triglycerides (TG), total cholesterol (TC), apolipoprotein AI, apolipoprotein AII, apolipoprotein B (ApoB), and thiobarbituric acid reactive substances (TBARS) were done between patients whose HbA1c improved by 0.5% or more (GR1) and the rest of the cohort (patients whose HbA1c improved by <0.5%, did not change, or increased) (GR2).
Results:  ApoB (p = 0.047) and TBARS (p = 0.01) were significantly lower at the end of the study in GR1. In GR2, TC (p = 0.01) and LDL (p = 0.03) were significantly higher at study end. Overall, significant beneficial changes in TC (p = 0.006), TG (p = 0.04), LDL (p = 0.02), ApoB (p = 0.015), and oxidative stress (p = 0.001) were found in GR1 compared with GR2.
Conclusions:  We provide direct evidence for the beneficial effect of tight metabolic control on serum lipids and oxidative stress in adolescents with T1DM, indicating that tight metabolic control may reduce cardiovascular risk in these patients.     

Health-related quality of life in intensively treated young patients with type 1 diabetes

Abstract:  This study aimed to analyse the impact of the disease and treatment on health-related quality of life (HRQOL) in intensively treated young patients with diabetes. Our main hypothesis was that metabolic control, gender, age and socio-economic status predict HRQOL. All children and adolescents (n = 400, 191 girls) and parents in a geographic population of two paediatric clinics in Sweden [mean age 13.2 yr, ±SD 3.9, range 2.6–19.6; mean duration of diabetes 5.1 yr, ±SD 3.8, range 0.3–17.6; yr mean haemoglobin A1c (HbA1c) 7.1%, ±SD 1.2, range 4.0–10.7] received the DISABKIDS questionnaire, a validated combined chronic generic and condition-specific HRQOL measure for children, and the EuroQol-5D questionnaire. Parents as proxy perceived HRQOL lower than their children. Adolescents with separated parents reported lower generic HRQOL (GeHRQOL) and diabetes-specific HRQOL (DiHRQOL) than those with parents living together (p = 0.027 and p = 0.043, respectively). Adolescent girls reported lower GeHRQOL (p = 0.041) and DiHRQOL (p = 0.001) than boys did. Parents of girls <8 yr of age reported lower DiHRQOL (p = 0.047) than did parents of boys <8 yr. In addition, a difference was found in HRQOL between centres. Intensive insulin therapy did not seem to lower HRQOL. If anything, along with better metabolic control, it increased HRQOL. A correlation between DiHRQOL and HbA1c was found in adolescents (r = −0.16, p = 0.046) and boys aged 8–12 yr (r = −0.28, p = 0.045). We conclude that the diabetes team can influence the HRQOL of the patients as there was a centre difference and because HRQOL is influenced by glycaemic control and insulin regimen. Girls seem to need extra support.     

1型糖尿病生物学标志物研究进展

1型糖尿病(T1D)是一种自身免疫性疾病,目前仍缺乏有效预防和治愈方法,临床上通过早期干预可显著改善T1D的发展进程和预后,而有效的生物学标志物对于T1D早期预测和早期诊断具有重要意义。因此,近年来国内外研究者致力于探索T1D相关生物标志物,发现并确定了一些可作为T1D临床诊断和预测疾病风险的生物标志物,包括遗传标志物、胰岛β细胞自身抗体、T细胞生物标志物及新兴的"组学"生物标志物等。文章总结了已建立的T1D生物标志物及其研究进展。     

1型糖尿病患儿反复发生酮症酸中毒的原因

目的　分析 1型糖尿病患儿反复发生酮症酸中毒 (DKA)的原因。方法　回顾总结 2 0年来在我院诊治的 1型糖尿病患儿 85 0例次 ,其中因DKA住院 2 2 5例次 ,2次或 2次以上者 5 6例 ,131例次 ,将其分为前 10年和后 10年两组进行分析。结果　两组DKA患儿占总糖尿病人数比率及反复发生DKA人数相比有显著差异 ,后 10年显著少于前 10年 (P <0 .0 1)。在诱因方面感染占第 1位 ,平均 71.8% ;不控制饮食而暴饮暴食 19% ;因停用胰岛素 9.2 % ,两组相比无显著差异 (P >0 .0 5 )。结论　对糖尿病病人进行系统的管理和教育是降低DKA发生率的重要手段     

Modulation of type 1 and type 2 diabetes risk by the intestinal microbiome

The prevalence of type 1 and type 2 diabetes have both risen dramatically over the last 50 years. Recent findings point towards the gut microbiota as a potential contributor to these trends. The hundred trillion bacteria residing in the mammalian gut have established a symbiotic relation with their host and influence many aspects of host metabolism, physiology, and immunity. In this review, we examine recent data linking gut microbiome composition and function to anti‐pancreatic immunity, insulin‐resistance, and obesity. Studies in rodents and human longitudinal studies suggest that an altered gut microbiome characterized by lower diversity and resilience is associated with type 1 and type 2 diabetes. Through its metabolites and enzymatic arsenal, the microbiota shape host metabolism, energy extracted from the diet and contribute to the normal development of the immune system and to tissue inflammation. Increasing evidence underscores the importance of the maternal microbiome, the gestational environment and the conditions of newborn delivery in establishing the gut microbiota of the offspring. Perturbations of the maternal microbiome during gestation, or that of the offspring during early infant development may promote a pro‐inflammatory environment conducive to the development of autoimmunity and metabolic disturbance. Collectively the findings reviewed herein underscore the need for mechanistic investigations in rodent models and in human studies to better define the relationships between microbial and host inflammatory activity in diabetes, and to evaluate the potential of microbe‐derived therapeutics in the prevention and treatment of both forms of diabetes.     

Erythrocyte indicators of oxidative stress in gestational diabetes

Foetuses born to mothers with gestational diabetes are at increased risk of developing respiratory distress, foetal macrosomia, foetal anomalies and platelet hyperaggregability. High blood glucose level induces oxidative stress and decreases antioxidant defences. The present study discusses the possibility of lipid peroxidation and protein oxidation in both maternal and foetal erythrocytes as an indicator of oxygen radical activity. The level of lipid peroxidation and protein oxidation in erythrocytes was estimated in 20 mothers with gestational diabetes and their newborns. The maternal age varied between 19 and 42 y and foetal age ranged between 34 and 39 weeks. The proteolytic activities in the erythrocyte lysates obtained from mothers with gestational diabetes and their newborns were significantly greater [(mean ± SD) 24.41 ± 9.05 and 16.70 ± 3.36μM of amino groups/g haemoglobin, n = 20, respectively] than those from control group (10.18 ± 4.84 and 14.64 ± 6.21 μM amino groups/g haemoglobin, n = 15, respectively; p < 0:05 in both cases). Similarly erythrocyte malondialdehyde levels were significantly elevated in babies born to mothers with gestational diabetes (10.11 ±2.21 nM/g haemoglobin) when compared to controls (6.8 ± 3.75 nM/g haemoglobin) (p < 0:05). In the erythrocytes of mothers with gestational diabetes, malondialdehyde levels correlated significantly with glycated haemoglobin levels (p < 0:01). The results of this study indicate that the oxidative stress induced by gestational diabetes manifests as increased lipid peroxidation and protein oxidative damage in the erythrocytes of both mothers with gestational diabetes and their newborn infants.