Aerobic exercise can modulate the underlying mechanisms involved in the development of diabetic complications

Diabetes mellitus is a highly prevalent metabolic disorder that affects many molecular pathways, causing a shift from a physiologic to a pathophysiologic state. Alterations in the molecular pathways promote diabetic complications and, thus, many medical and nonmedical therapies have been directed at preventing these complications. Despite the beneficial effects on moderating glycemic control, medical therapies may also have unfavorable side effects. This makes nonmedical therapeutic approaches more attractive due to lower pharmacological side effects of these strategies compared to medical agents. Aerobic exercise is now considered as a major nonmedical strategy that can promote beneficial and protective effects to counteract the development of diabetic complications via attenuation of the major molecular mechanisms involved in diabetes.     

Advanced glycation end-products and the progress of diabetic vascular complications

Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of vascular complications, both in Type 1 and 2 diabetes mellitus. The formation of advanced glycation end-products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications including nephropathy, retinopathy, neuropathy and atherosclerosis. Recent studies have shown that increased formation of serum AGEs exists in diabetic children and adolescents with or without vascular complications. Furthermore, the presence of diabetic complications in children correlates with elevated serum AGEs. The level of serum AGEs could be considered as a marker of later developments of vascular complications in children with Type 1 and 2 diabetes mellitus. The careful metabolic monitoring of young diabetics together with monitoring of serum AGEs can provide useful information about impending AGE-related diabetic complications. It is becoming clear that anti-AGE strategies may play an important role in the treatment of young and older diabetic patients. Several potential drug candidates such as AGE inhibitors have been reported recently.     

Glycemic index in diabetes

The Glycemic Index (GI) is a rating system that ranks carbohydrate-containing foods according to their postprandial blood glucose response relative to the same quantity of available carbohydrate of a standard such as white bread or glucose. The concept of GI was first introduced in the early 80's by Jenkins and coworkers. Since then, numerous trials have been undertaken, many indicating benefits of a low GI diet on glycemic control, as well as lipid profiles, insulin and C-peptide levels, inflammatory and thrombolytic factors, endothelial function and regulation of body weight. As a result, a low-GI diet may prevent or delay the vascular complications of diabetes. However, despite many studies supporting the benefits of the Glycemic Index as part of the treatment of diabetes mellitus, several areas of controversy have been raised in the literature and are addressed here. Clinicians treating diabetic patients should be aware of the potential benefits of low-GI foods in the prevention and treatment of diabetes and its complications.     

Antidiabetic potential of saffron and its active constituents

The prevalence of diabetes mellitus is growing rapidly worldwide. This metabolic disorder affects many physiological pathways and is a key underlying cause of a multitude of debilitating complications. There is, therefore, a critical need for effective diabetes management. Although many synthetic therapeutic glucose-lowering agents have been developed to control glucose homeostasis, they may have unfavorable side effects or limited efficacy. Herbal-based hypoglycemic agents present an adjunct treatment option to mitigate insulin resistance, improve glycemic control and reduce the required dose of standard antidiabetic medications. Saffron (Crocus sativus L.), whilst widely used as a food additive, is a natural product with insulin-sensitizing and hypoglycemic effects. Saffron contains several bioactive β carotenes, which exert their pharmacological effects in various tissues without any obvious side effects. In this study, we discuss how saffron and its major components exert their hypoglycemic effects by induction of insulin sensitivity, improving insulin signaling and preventing β-cell failure, all mechanisms combining to achieve better glycemic control.     

Relationship of Serum γ‐Glutamyltransferase to Atherogenic Dyslipidemia and Glycemic Control in Type 2 Diabetes

We evaluated possible interactions between BMI and serum γ‐glutamyltransferase (GGT) concentration and their effects on the prevalence of poor glycemic control and common comorbidities of diabetes. We assessed whether the association of BMI with poor glycemic control, hypertension, atherogenic dyslipidemia (i.e., high triglycerides and/or low high‐density lipoprotein (HDL) cholesterol), hypercholesterolemia, and hyperuricemia differed according to serum GGT concentration in a cohort of 3,633 type 2 diabetic individuals. The associations of BMI with different outcome measures were significant, but the associations varied remarkably by GGT concentration. As GGT concentration increased, the association of BMI with atherogenic dyslipidemia and glycemic control strengthened (P = 0.01 and 0.004 for interactions, respectively); in contrast, the association of BMI with hypertension, hypercholesterolemia, and hyperuricemia did not change substantially across GGT quartiles. For example, within the lowest GGT quartile, BMI was not associated with atherogenic dyslipidemia or poor glycemic control, whereas in the highest GGT quartile, the prevalence rates ranged from 62.3 to 74.7% for dyslipidemia and from 75.3 to 83% for poor glycemic control. The results remained unchanged after adjustment for sex, age, alcohol consumption, diabetes duration, and diabetes treatment. In conclusion, our findings show that BMI was associated with atherogenic dyslipidemia and poor glycemic control only when serum GGT activity was in its high‐normal range. These findings suggest that obesity itself may not be a sufficient risk factor for atherogenic dyslipidemia or poor glycemic control in people with type 2 diabetes.     

Antioxidant alpha-tocopherol ameliorates glycemic control of GK rats, a model of type 2 diabetes

We have shown recently that oxidative stress by chronic hyperglycemia damages the pancreatic beta-cells of GK rats, a model of non-obese type 2 diabetes, which may worsen diabetic condition and suggested the administration of antioxidants as a supportive therapy. To determine if natural antioxidant alpha-tocopherol (vitamin E) has beneficial effects on the glycemic control of type 2 diabetes, GK rats were fed a diet containing 0, 20 or 500 mg/kg diet alpha-tocopherol. Intraperitoneal glucose tolerance test revealed a significant increment of insulin secretion at 30 min and a significant decrement of blood glucose levels at 30 and 120 min after glucose loading in the GK rats fed with high alpha-tocopherol diet. The levels of glycated hemoglobin A1c, an indicator of glycemic control, were also reduced. Vitamin E supplementation clearly ameliorated diabetic control of GK rats, suggesting the importance of not only dietary supplementation of natural antioxidants but also other antioxidative intervention as a supportive therapy of type 2 diabetic patients.     

低血糖与2型糖尿病

糖尿病（DM）是一种慢性终身性疾病,目前已成为严重威胁人类健康的世界性公共卫生问题,2型糖尿病患者也逐渐增加。流行病学调查显示,目前全球大约有近2亿糖尿病患者,其中2型糖尿病占90%～95%。2型糖尿病发病机理是胰岛素分泌的相对或绝对不足伴有或不伴有胰岛素抵抗,持续的高血糖可严重抑制胰岛功能。严格的血糖控制能够延缓糖尿病慢性并发症的发生和发展,延长了患者的预期寿命。但是随着血糖控制达标,发生低血糖的危险性增加了,低血糖不仅严重阻碍了良好血糖控制,而且严重低血糖还是2型糖尿病致死、致残的重要原因。本文探讨2型糖尿病患者治疗中低血糖发生的原因、诱发因素以及可能的解决方案。     

Low-carbohydrate diet and oxidative stress in diabetic and nondiabetic rats

Hyperglycemia of diabetes has been implicated in increased tissue oxidative stress, with consequent development of secondary complications. Thus, stabilizing glucose levels near normal levels is of utmost importance. Because diet influences glycemic control, this study investigated whether a low-carbohydrate (5.5%) diet confers beneficial effects on the oxidative status of the heart, kidney, and liver in diabetes. Male and female normal and diabetic rats were fed standard chow (63% carbohydrates) or low-carbohydrate diet for 30 days. Elevated glucose, HbA(1c), and alanine and aspartate aminotransferases in diabetic animals were reduced or normalized by the low-carbohydrate diet. While diabetes increased cardiac activities of glutathione peroxidase and catalase, low-carbohydrate diet normalized cardiac glutathione peroxidase activity in diabetic animals, and reduced catalase activity in females. Diabetic rats fed low-carbohydrate diet had altered activities of renal glutathione reductase and superoxide dismutase, but increased renal glutathione peroxidase activity in diabetic animals was not corrected by the test diet. In the liver, diabetes was associated with a decrease in catalase activity and glutathione levels and an increase in glutathione peroxidase and gamma-glutamyltranspeptidase activities. Decreased hepatic glutathione peroxidase activity and lipid peroxidation were noted in diet-treated diabetic rats. Overall, the low-carbohydrate diet helped stabilize hyperglycemia and did not produce overtly negative effects in tissues of normal or diabetic rats.     

Evolution of a pulmonary insulin delivery system (Exubera) for patients with diabetes

Many patients with diabetes fail to meet recommended glycemic goals regardless of the recognition of optimal glycemic control as a key component for improving clinical outcomes and quality of life in patients with diabetes. Patient- and physician-related barriers to the adoption of insulin therapy include fear and anxiety about injecting insulin, concerns about side effects, and personal health beliefs in regard to the use of insulin. There is an unmet need for an alternative insulin therapy that provides optimal glycemic control, is well tolerated, and improves patient adherence. Of the several inhaled insulin devices that are in various stages of development, the Exubera (INH) formulation is the first to be approved for use in the United States and in Europe. Exubera is a novel, rapid-acting inhaled human insulin formulation that has been developed for prandial insulin use. Clinical studies have shown that INH consistently improves glycemic control, in combination with longer-acting subcutaneous (SC) insulin regimens in patients with type 1 or type 2 diabetes, or is used to supplement or replace oral antidiabetic therapy in patients with type 2 diabetes. INH has demonstrated long-term safety and tolerability, with a risk for hypoglycemia similar to that of SC insulin, and no clinically meaningful changes in pulmonary function have been noted with its use. Patients treated with INH in clinical studies reported high levels of satisfaction with treatment, and many patients with diabetes choose inhaled insulin when it is offered as a treatment option. Taken together, these findings suggest that INH represents an important new development in the treatment of diabetes that may improve glycemic control in many patients with diabetes.     

Evaluating the effect of health education program on outcomes of type I diabetic patients: A randomized controlled study

Background; findings from the meta-analysis have shown that patients present improvements in glycaemic control, and in the prevention and control of the acute and chronic complications, when they receive effective treatment, self-management support and regular monitoring. The present study aimed to evaluate the effect of implementing a health education program on outcomes of type I diabetic patients. Quasi-experimental study design was used to fulfill the aim of the study. The study was conducted in the outpatient diabetic clinic at Asyut University Hospital; 60 adult male and female patients who attended the outpatient diabetic clinic were included. Two tools were used in this study; structured interviewing questionnaire with three parts; part one: demographic patient variables, part two: patient's medical data and part three: patient's knowledge regarding diabetes, the second tool is evaluation of type I diabetic patients' outcomes (pre/post). Results revealed that the highest percentage of the studied samples were in the age group 18 to less than 30 years, 90.0% of the study group and 83.4% of the control group were having a family history of diabetes, a statistically significant difference was found in the study group patients pre and post application of the program regarding insulin injection and glycemic control. Conclusion: this study demonstrated the effectiveness of health education program implementation on the outcomes of type I diabetic patients in terms of improved knowledge and practicing exercise, teeth care, feet care and on glycemic control.     

Statins restore ischemic limb blood flow in diabetic microangiopathy via eNOS/NO upregulation but not via PDGF-BB expression

3-Hydroxy-3-methyl-glutaryl CoA reductase inhibitors, or statins, have pleiotropic effects and can protect the vasculature in a manner independent of their lipid-lowering effect. The effectiveness of statins in reducing the risk of coronary events has been shown even in patients with diabetes, and their effects on diabetic complications have been reported. Using a model of severe hindlimb ischemia in streptozotocin-induced diabetic mice (STZ-DM), we investigated the effects and mechanisms of statin therapy in diabetic angiopathy in ischemic hindlimbs. As a result, STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Supplementation with statins significantly prevented autoamputation. We previously showed that diabetic vascular complications are caused by impaired expression of PDGF-BB, but statin therapy did not enhance PDGF-BB expression. Statins helped enhance endogenous endothelial nitric oxide (NO) synthase (eNOS) expression. Furthermore, the inhibition of NO synthesis by the administration of N(omega)-nitro-l-arginine methyl ester impaired the ability of statins to prevent STZ-DM mouse limb autoamputation, indicating that the therapeutic effect of statins in hindlimb ischemia in STZ-DM mice occurs via the eNOS/NO pathway. A combination therapy of statins and PDGF-BB gene supplementation was more effective for diabetic angiopathy than either therapy alone. In conclusion, these findings indicate that statin therapy might be useful for preventing intractable diabetic foot disease in patients with diabetic angiopathy.     

The True Value of HbA1c as a Predictor of Diabetic Complications: Simulations of HbA1c Variables

Aim

The updated mean HbA1c has been used in risk estimates of diabetic complications, but it does not take into account the temporal relationship between HbA1c and diabetic complications. We studied whether the updated mean HbA1c underestimated the risk of diabetic complications.

Method

Continuous HbA1c curves for 10,000 hypothetical diabetes patients were simulated over an average of 7 years. Simulations were based on HbA1c values encountered in clinical practice. We assumed that each short time interval of the continuous HbA1c curves had a long-lasting effect on diabetic complications, as evidenced by earlier studies. We tested several different HbA1c variables including various profiles, e.g. different duration, of such a long-lasting effect. The predictive power of these variables was compared with that of the updated mean HbA1c.

Results

The predictive power of the constructed HbA1c variables differed considerably compared to that of the updated mean HbA1c. The risk increase per standard deviation could be almost 100% higher for a constructed predictor than the updated mean HbA1c.

Conclusions

The importance of good glycemic control in preventing diabetic complications could have been underestimated in earlier hallmark studies by not taking the time-dependent effect of HbA1c into account.     

Endurance training and insulin therapy need to be associated to fully exert their respective beneficial effects on oxidant stress and glycemic regulation in diabetic rats

Abstract

In type 1 diabetic subjects, hyperglycemia-induced oxidant stress (OS) plays a central role in the onset and development of diabetes complications. This study aimed to assess the benefits of an endurance training program and insulin therapy, alone or in combination, on the glycemic regulation, markers for OS, and antioxidant system in diabetic rats. Forty male Wistar rats were divided into diabetic (D), insulin-treated diabetic (D-Ins), diabetic trained (D-Tr), or insulin-treated diabetic trained (D-Ins+ Tr) groups. An additional healthy group served as control group. Insulin therapy (Lantus, insulin glargine, Sanofi) and endurance training (a treadmill run of 60 min/day, 25 m/min, 5 days/week) were initiated 1 week after streptozotocin-induced diabetes (45 mg/kg) and lasted for 8 weeks. At the end of the protocol, blood glucose and fructosamine levels, markers for skeletal muscle OS (CML, isoprostanes, GSH/GSSG) and antioxidant system (SOD and GPx activity, ORAC) were assessed. In diabetic rats, the glycemic control was altered and OS marker levels were increased, while the antioxidant system activity remained unchanged. Insulin treatment improved the glycemic regulation, the pro-antioxidant status, and contributed to the reduction of OS marker levels. Endurance training decreased OS marker levels without improving the antioxidant enzyme activity. Endurance training and insulin therapy acted independently (by different ways), but their association prolonged the insulin action and allowed a better adaptation of the antioxidant system. To conclude, our results demonstrate that combination of insulin treatment and endurance training leads to greater benefits on the glycemic regulation and oxidant status.     

Effects of lifestyle modifications on patients with type 2 diabetes: the Japan Diabetes Complications Study (JDCS) study design, baseline analysis and three year-interim report.

BACKGROUND: Lifestyle modifications may affect the development of diabetes and prevent complications. However, there is no direct evidence to show that lifestyle intervention is beneficial for patients with established type 2 diabetes. OBJECTIVE: The ultimate goal is to determine whether long-term lifestyle intervention can improve glycemic control and prevent complications in patients with type 2 diabetes. This initial report on a multi-year study describes protocols and the analysis of baseline data and three-year interim results. DESIGN: The study was a randomized, controlled, multi-centre, prospective intervention trial. The trial included patients from 59 Japanese institutes specializing in diabetes care. PATIENTS: The study enrolled 2 205 patients with previously diagnosed type 2 diabetes. INTERVENTION: The lifestyle modification program included intensive lifestyle management at each outpatient clinic visit and frequent telephone counseling. The intervention group received educational materials concerning the importance of lifestyle and behavioural changes, a diary to record progress of laboratory and other data, and a pedometer. MEASUREMENTS: Parameters and indices related to glycemic control, diabetic complications, dyslipidemia, hypertension, obesity, and atherosclerosis were measured several times a year. RESULTS: Small but significant differences in HbA1c levels between the intervention (INT) and conventional (CON) therapy groups appeared as early as two years after the start of intervention and were maintained in the third year (CON group, 7.78 +/- 1.27 % vs. INT group, 7.62 +/- 1.20 %, the initial HbA1c level was 7.80 +/- 1.42 % for the CON group and 7.68 +/- 1.28 % for the INT group). Data on differences in occurrence of micro- or macrovascular complications are not yet available. CONCLUSIONS: The effect of lifestyle modification on improving the glycemic control of patients with established type 2 diabetes mellitus was small but significant three years after initiation of the intervention.     

Lutein effect on retina and hippocampus of diabetic mice

Oxidative stress markers and functional tests were studied to confirm early biochemical and functional changes in retina and hippocampus of diabetic mice. The effects of lutein treatment were also tested. Mice were induced diabetic by alloxan injection and divided into subgroups: control, control+lutein, diabetic, diabetic+lutein, diabetic+insulin, and diabetic+insulin+lutein. Treatments started on Day 4 after alloxan injection and animals were sacrificed on Day 14. Malondialdehyde and glutathione concentrations and glutathione peroxidase activity were measured as oxidative stress markers. The following functional tests for retina and hippocampus were performed: electroretinogram and Morris water maze test. NFkappaB activity was also measured. Oxidative stress and NFkappaB activity increase in the retina and hippocampus after 15 days of diabetes. Impairment of the electroretinogram and a correlation between latencies of the water maze test and glycated hemoglobin (HbA1c) levels were observed. Lutein prevented all these changes even under hyperglycemic conditions. Retina appears to be affected earlier than hippocampus by diabetes-induced oxidative stress. Although a proper glycemic control is desirable in preventing the development of diabetic complications, it is not sufficient to prevent them completely. Lutein could be an appropriate coadjuvant treatment for the changes observed in this study.     

Dietary glycemic load, whole grains, and systemic inflammation in diabetes: the epidemiological evidence

PURPOSE OF REVIEW: The aim of this article is to present recent findings from epidemiological studies on the effects of dietary glycemic load and whole grain foods on systemic inflammation in diabetic patients and to postulate potential mechanisms. RECENT FINDINGS: Diets low in glycemic index/load or high in whole grain products have been associated with decreased concentrations of inflammatory markers and increased adiponectin levels among diabetic patients. These associations appear to be independent of body weight, glycemic control, and other cardiovascular risk factors. The protective effects of low glycemic load and high whole grains on systemic inflammation may be explained, in part, by reduction in hyperglycemia-induced overproduction of oxidative stress and by amelioration in insulin resistance, adiposity, dyslipidemia, and hypertension. SUMMARY: Diets low in glycemic load and high in whole grains may have a protective effect against systemic inflammation in diabetic patients. Such diets can be recommended to diabetic patients for the prevention of cardiovascular complications.     

Protein carbonyl content in erythrocyte membranes in type 2 diabetic patients.

Protein carbonyl groups result from free radical-induced protein oxidation; their level in tissues and plasma is a relatively stable marker of oxidative damage. Protein carbonyl contents in erythrocyte membranes were investigated in the type 2 diabetic patients with good (n = 16) and poor (n = 30) glycemic control. Diabetic patients were classified as patients with (n = 20) and without (n = 26) angiopathy. Protein carbonyl content was evaluated using the 2,4-dinitro-phenyl-hydrazine method. Protein carbonyl content and GHb levels were significantly higher in both patients with poor and good glycemic control than in control subjects (p < 0.001 in each case). There was a significant difference in protein carbonyl content between patients with poor and good glycemic control (p < 0.001). Diabetic patients with angiopathy had significantly higher protein carbonyl content and GHb levels than the diabetic patients without angiopathy (p < 0.001). These results suggest that impaired glycemic control is connected to protein oxidation, and protein oxidation may be related to underlying metabolic abnormalities and complications of diabetes.     

新型低热量甜味剂——D-阿洛酮糖的研究进展

寻找适合糖尿病人服用的甜味剂具有重要的经济价值。D-阿洛酮糖是D-果糖的C3差向异构体,是一种稀有糖。作为一种新型低热量甜味剂,D-阿洛酮糖近年来日益引起人们的重视。本文对国际上近年来发表的关于D-阿洛酮糖的药理活性资料进行了系统的总结。D-阿洛酮糖几乎不提供热量,具有显著的降血糖、降血脂效果,对糖尿病动物的胰岛β细胞有明显的保护作用。此外,D-阿洛酮糖无毒副作用,是一种食用安全的糖。这些研究结果说明:D-阿洛酮糖在预防和治疗糖尿病方面具有极大的潜力,可以作为糖尿病人食用的新型甜味剂,具有良好的市场前景。