Circulating Reg1α proteins and autoantibodies to Reg1α proteins as biomarkers of β-cell regeneration and damage in type 1 diabetes

Type 1 diabetes is an autoimmune disease where β-cells are in a constant process of death and renewal. Reg genes play a role in β-cells regeneration. Reg proteins may be target of an autoimmune response in type 1 diabetes with consequent production of autoantibodies and failure of regeneration. The objective of this work was to characterize the role of Reg1α proteins and anti-Reg1α antibodies as biomarkers of β-cell regeneration and damage. Serum levels of Reg1α protein were investigated in 87 type 1 diabetic subjects (31 newly diagnosed and 56 long standing), 63 type 2 diabetic subjects, 39 subjects with systemic lupus erythematosus (SLE), a nonpancreatic autoimmune disorder, and 64 healthy subjects. The presence of anti-Reg1α antibodies and correlation with metabolic, immune, and genetic parameters were analyzed in diabetic subjects. Increased levels of Reg1α protein were observed in newly diagnosed (p=0.002), and long standing (p=0.001) type 1 diabetes patients and type 2 diabetic subjects (p<0.001). Anti-Reg1α antibodies were found in 47% of patients with type 1 diabetes. No correlation was found with metabolic, immune, and genetic parameters. Patients with SLE showed no increase in Reg1α protein. We report here for the first time raised serum Reg1α protein in type 1 and type 2 diabetes and anti-Reg1α antibodies in type 1 diabetes. Reg1α levels appear not to be influenced by genetic or metabolic control. These findings allow considering future studies on Reg1α protein and autoantibody as new tools in the evaluation and monitoring of β-cells regeneration and autoimmunity.     

Effects of Relaxation Training on Glucose Tolerance and Diabetic Control in Type II Diabetes

The present study examined the effects of progressive relaxation training and EMG biofeedback on acute glucose disposal in diabetic subjects, as measured by glucose tolerance and three other measures of diabetic metabolic control. Twenty subjects with non-insulin-using Type II diabetes took part in progressive relaxation training and EMG biofeedback in a pre-post treatment versus wait-list experimental design. Treatment effects were assessed on glucose tolerance along with three measures of diabetic control: fasting blood glucose, two-hour postprandial blood glucose, and fructosamine. Stress reduction and relaxation was assessed with two physiological measures and two subjective questionnaires. The training program produced significant reductions in stress, as measured by State Anxiety, and significant changes in physiological measures of muscle activity and skin conductance compared to the control condition. However, no changes were found in glucose tolerance (while practicing relaxation) nor in any of the three measures of general diabetic metabolic control. The major implication of this study is that relaxation training does not appear to directly improve diabetic control in mildly stressed non-insulin-using Type II diabetic patients.     

回春医疗保健操运动对老年2 型糖尿病患者血糖和血脂水平的影响

目的：探讨规律性回春医疗保健操运动对2 型糖尿病老年患者血糖、血脂水平的影响。方法：选择28例老年2 型糖尿病患者 为研究对象,并将其随机分为运动干预组和对照组。运动干预组在前期药物治疗和饮食控制不变的情况下,采用为期12 周回春 医疗保健操进行运动干预,对照组仅给予药物治疗和饮食控制,而不进行运动干预,监测和比较两组患者实验前后血糖、血脂等 指标的变化。结果：运动干预组患者接受12 周回春医疗保健操干预后,受试者空腹血糖、胆固醇、低密度脂蛋白水平均较运动干 预前显著下降,差异均具有统计学意义(P<0.05)。结论：长期的规律性回春医疗保健操运动可有效降低老年2 型糖尿病患者血糖、 血脂水平,且安全易操作,可作为老年2 型糖尿病的临床辅助疗法。     

Altered energetic properties in skeletal muscle of men with well-controlled insulin-dependent (type 1) diabetes

This study asked whether the energetic properties of muscles are changed by insulin-dependent diabetes mellitus (or type 1 diabetes), as occurs in obesity and type 2 diabetes. We used (31)P magnetic resonance spectroscopy to measure glycolytic flux, oxidative flux, and contractile cost in the ankle dorsiflexor muscles of 10 men with well-managed type 1 diabetes and 10 age- and activity-matched control subjects. Each subject performed sustained isometric muscle contractions lasting 30 and 120 s while attempting to maintain 70-75% of maximal voluntary contraction force. An altered glycolytic flux in type 1 diabetic subjects relative to control subjects was apparent from significant differences in pH in muscle at rest and at the end of the 120-s bout. Glycolytic flux during exercise began earlier and reached a higher peak rate in diabetic patients than in control subjects. A reduced oxidative capacity in the diabetic patients' muscles was evident from a significantly slower phosphocreatine recovery from a 30-s exercise bout. Our findings represent the first characterization of the energetic properties of muscle from type 1 diabetic patients. The observed changes in glycolytic and oxidative fluxes suggest a diabetes-induced shift in the metabolic profile of muscle, consistent with studies of obesity and type 2 diabetes that point to common muscle adaptations in these diseases.     

Prolonged statin administration does not act on the cell-mediated immunity of HIV-infected dyslipidemic patients treated with a steady and effective highly active antiretroviral therapy. A two-year prospective study of statin versus fibrate administration

OBJECTIVE: To assess whether statin administration for HIV-associated hyperlipidemia has long-term effects on immune recovery (as expressed by the trend of mean CD4+ lymphocyte count), in patients on a virologically-active HAART regimen since 12 months or more. METHODS: Single-centre, open-label, prospective study of 301 hyperlipidemic patients treated with statins (99 cases, with a predominant hypercholesterolemia), fibrates (116 subjects, when hypertriglyceridemia prevailed), or a isolated dietary/exercise program (86 patients, used as a control group). Neither epidemiological nor clinical, virological, or immunological differences were detected among the three study groups at baseline. During the subsequent follow-up, patients were excluded from evaluation should virological efficacy was not maintained, and/or initial hypolipidemic therapy was modified or interrupted for any reason. RESULTS: The quarterly assessment of mean CD4+ lymphocyte count did not disclose any statistically significant difference among the three study groups, since baseline and until at least 24 consecutive months of follow-up. Our data tend to exclude relevant in vivo negative activities of statins on immune system recovery of HIV-infected individuals who undergo a virologically effective HAART treatment. CONCLUSIONS: Multiple, pleiotropic features have been attributed to both statins and fibrates, and also apparently significant effects on laboratory markers of HIV disease progression have been recently claimed or expected. Despite some preliminary in vitro and ex-vivo models, both the main hypolipidemic classes administered for the management of HIV-related dyslipidemia (both statins and fibrates) do not seem to act significantly on clinical immune response of patients successfully treated with HAART. Multifactorial pathways are expected to interact with the cell-mediated immune system of HIV-infected patients undergoing successful HAART, and further studies are needed to elucidate whether more subtle immune effects might be prompted by a long-term administration of hypolipidemic drugs in this speciasl setting.     

Metabolomics approach for analyzing the effects of exercise in subjects with type 1 diabetes mellitus

The beneficial effects of exercise in patients with type 1 diabetes (T1D) are not fully proven, given that it may occasionally induce acute metabolic disturbances. Indeed, the metabolic disturbances associated with sustained exercise may lead to worsening control unless great care is taken to adjust carbohydrate intake and insulin dosage. In this work, pre- and post-exercise metabolites were analyzed using a (1)H-NMR and GC-MS untargeted metabolomics approach assayed in serum. We studied ten men with T1D and eleven controls matched for age, body mass index, body fat composition, and cardiorespiratory capacity, participated in the study. The participants performed 30 minutes of exercise on a cycle-ergometer at 80% VO(2)max. In response to exercise, both groups had increased concentrations of gluconeogenic precursors (alanine and lactate) and tricarboxylic acid cycle intermediates (citrate, malate, fumarate and succinate). The T1D group, however, showed attenuation in the response of these metabolites to exercise. Conversely to T1D, the control group also presented increases in α-ketoglutarate, alpha-ketoisocaproic acid, and lipolysis products (glycerol and oleic and linoleic acids), as well as a reduction in branched chain amino acids (valine and leucine) determinations. The T1D patients presented a blunted metabolic response to acute exercise as compared to controls. This attenuated response may interfere in the healthy performance or fitness of T1D patients, something that further studies should elucidate.     

Study of insulin response to oral glucose load after acute and chronic glycemic control in type 2 diabetic subjects

To investigate whether correction of fasting hyperglycemia per se improves the insulin secretion in type 2 diabetic subjects, plasma insulin response to 75 g oral glucose load has been studied after acute and chronic normalization of fasting plasma glucose levels in 7 overt type 2 diabetic subjects. For the acute normalization of elevated fasting plasma glucose levels, an artificial endocrine pancreas was employed. Although fasting plasma glucose concentrations were normalized before the oral glucose challenge, insulin response to oral glucose was not improved compared to those without normalization of fasting plasma glucose levels. After 1-3 month control of hyperglycemia, the insulin response to glucose in the subjects was significantly improved compared to those without treatments. Results indicate that chronic metabolic control is essential for the improvement of insulin response to glucose in type 2 diabetic subjects, and also suggest that the impaired insulin secretion in type 2 diabetes is not due to hyperglycemia per se, but due to the metabolic derangements which lead to chronic hyperglycemia.     

有氧运动和白藜芦醇对2型糖尿病大鼠肾脏JAK2及TGF-β1的影响

目的: 研究有氧运动和白藜芦醇对2型糖尿病大鼠肾脏Janus激酶2(JAK2)及转化生长因子-β1(TGF-β1)表达的影响,探讨运动与白藜芦醇改善糖尿病肾损伤的可能作用机制。方法: SD大鼠经5周高糖高脂饲料喂养加腹腔注射链脲佐菌素(STZ)建立糖尿病模型后,将糖尿病大鼠随机分为糖尿病安静组(DC组),糖尿病运动组(DE组),糖尿病药物组(DR组)和糖尿病运动药物组(DER组),每组各12只,另设正常对照组(NC组)。运动组大鼠进行8周的有氧运动(跑速为20 m/min),每天运动60 min,每周运动6 d;药物组大鼠进行8周的白藜芦醇灌胃(每天45 mg/kg,7天/周)。8周末,检测血糖、24 h尿白蛋白(24 h UA)、血肌酐(Scr)、血尿素氮(BUN)的变化;采用荧光定量PCR检测肾脏JAK2 mRNA的表达,免疫组织化学法和Western blot法检测肾脏JAK2和TGF-β1的表达。结果: 8周干预后,与NC组相比, DC组血糖浓度、24 h UA、Scr、BUN均显著上升(P＜0.05),肾组织病理损伤加重,肾组织TGF-β1、JAK2和JAK2 mRNA的表达均明显增加(P＜0.05)。与DC组相比,DE、DR和DER组血糖浓度、24 h UA、Scr、BUN均显著下降(P＜0.05),肾组织病理损伤减轻,肾组织TGF-β1、JAK2和JAK2 mRNA的表达均明显减少(P＜0.05),且DER组的降低更显著,与DE、DR组相比差异有显著性(P＜0.05)。结论: 有氧运动、白藜芦醇及联合干预可能通过下调肾脏JAK2 mRNA表达,抑制JAK2蛋白的合成,使TGF-β1表达减少,从而改善糖尿病大鼠肾脏损伤的病理性变化。有氧运动联合白藜芦醇干预减轻肾脏病理损伤的效果优于单一的有氧运动或白藜芦醇干预。     

Oxidative DNA damage and plasma antioxidant capacity in type 2 diabetic patients with good and poor glycaemic control

Diabetes mellitus is a complex metabolic disorder characterized by a disturbance in glucose metabolism. Recent evidence suggests that increased oxidative damage as well as reduction in antioxidant capacity could be related to the complications in patients with type 2 diabetes. The aim of this study was to measure plasma antioxidant status in type 2 diabetic patients with good and poor glycaemic control and its relationship with oxidative DNA damage. Thirty-nine type 2 diabetic patients and eighteen healthy subjects were recruited for this study. We found that diabetic patients had slightly, but not significantly lower antioxidant capacity, measured with the "ferric reducing ability of plasma" (FRAP) assay, than healthy subjects. On the contrary, oxidative DNA damage (measured by the Comet assay) in leukocytes obtained from diabetic patients was significantly higher compared to healthy subjects. Taking into account glucose control, we found that the FRAP level was significantly (p<0.05) lower in diabetic subjects with poor glycaemic control than healthy subjects, while patients with good glycaemic control had FRAP values similar to controls. We also observed an unexpected positive correlation between FRAP values and oxidative DNA damage in diabetic patients; moreover, a positive correlation was found between FRAP and glucose level or HbA(1c) in patients with poor glycaemic control. In conclusion, our results confirm that patients with type 2 diabetes have a higher oxidative DNA damage than healthy subjects and that plasma antioxidant capacity is significantly lower only in patients with poor glycaemic control, moreover, in these patients FRAP values are positively correlated with glycaemic levels and HbA(1c). These observations indicate that a compensatory increase of the antioxidant status is induced as a response to free radical overproduction in type 2 diabetes. Therefore, the addition of antioxidant supplements to the current pharmacological treatment could have potentially beneficial effects in diabetic patients with poor glycaemic control.     

Desaturase activities and metabolic control in type 2 diabetes

The aim of this study was to elucidate the effects of a poor glycemic control on fatty acid composition and desaturase activities in type 2 diabetic patients. Plasma phospholipid fatty acid composition and desaturase activities (estimated from fatty acid product to precursor ratios) were measured in 30 type 2 diabetic patients during poor metabolic control and after achieving a good metabolic control. Significant changes were recorded in the percentages of palmitic, stearic, dihomo-gamma-linolenic, docosatetraenoic and docosapentaenoic acid. The delta-5 desaturase activity was significantly higher with poor than with good metabolic control. The changes identified in plasma phospholipid fatty acid composition and the desaturase activity in type 2 diabetic patients go in the opposite direction to those described in similar conditions in type 1 diabetic patients and may be relevant to a better understanding of the role of metabolic control in the progression of chronic complications in type 2 diabetic patients.     

Myostatin信号通路在4周离心耐力运动改善2型糖尿病大鼠骨骼肌萎缩中的作用

目的：观察4周离心耐力运动对2型糖尿病大鼠代谢障碍及肌萎缩的影响,探讨myostatin/Smad3/atrogin-1信号通路在肌萎缩中的作用。方法：9周高脂饲养联合STZ注射建立2型糖尿病大鼠模型。将普通饲料组大鼠随机分为对照组（C,n=6）和运动组（E,n=9;将2型糖尿病模型组大鼠随机分为糖尿病对照组（D,n=8）和糖尿病运动组（DE,n=12）。运动方案：坡度-5°,跑速16 m/min,每次60 min、每日一次,每周训练5 d,连续4周。最后一次运动后禁食12 h,测定空腹血糖（FBG）、空腹胰岛素（FINS）,计算稳态模式胰岛素抵抗指数（HOMA-IR）和胰岛素敏感指数（ISI）,进行葡萄糖耐量试验。取比目鱼肌观察肌萎缩现象并检测myostatin、Smad3、p-Smad3和atrogin-1表达情况。结果：①与对照组相比,糖尿病组大鼠体重、比目鱼肌质量/胫骨长和肌纤维平均横截面积、FINS和ISI显著降低（P<0.01）,FBG、HOMA-IR和血糖曲线下面积（AUC_BG）以及myostatin、Smad3、p-Smad3、atrogin-1表达均显著升高（P<0.01）。②4周离心运动后,与糖尿病组相比,糖尿病运动组大鼠肌纤维平均横截面积显著升高（P<0.01）,AUC_BG、HOMA-IR及myostatin、p-Smad3、atrogin-1表达显著降低（P<0.05,P<0.01）。结论：myostatin/Smad3/atrogin-1信号通路上调是导致2型糖尿病肌萎缩的重要原因,4周离心耐力运动可能通过下调myostatin、p-Smad3和atrogin-1表达抑制肌萎缩,进而改善2型糖尿病代谢障碍,提高胰岛素敏感性。     

Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes.

Glucagon-like peptide 1 (GLP-1) was discovered as an incretin (insulinotropic gut) hormone. Biological actions of GLP-1 in healthy and type 2 diabetic subjects include (a) stimulation of insulin secretion in a glucose-dependent manner, (b) suppression of glucagon, (c) reduction in appetite and food intake, (d) deceleration of gastric emptying. In animal experiments, in addition, (e) stimulation of beta-cell neogenesis, growth and differentiation in animal and tissue culture experiments, and (f) in vitro inhibition of beta-cell apoptosis induced by different agents have been observed. Since the incretin effect--the higher insulin secretory response to oral as compared to intravenous glucose loads - is reduced in patients with Type 2 diabetes, GLP-1 has been used to pharmacologically replace incretin. Intravenous GLP-1 can normalise, and subcutaneous GLP-1 can significantly lower plasma glucose in the majority of patients with Type 2 diabetes. The magnitude of this effect does not greatly depend on patient characteristics such as age, sex, obesity, or baseline insulin and glucagon, with minor influences of previous antidiabetic therapy and actual metabolic control. GLP-1 itself, however, is inactivated rapidly in vivo by the protease DPP IV and can only be used for short-term metabolic control, such as in intensive care units (potentially useful in patients with acute myocardial infarction, coronary surgery, cerebrovascular events, septicaemia, during the perioperative period and while on parenteral nutrition). For more long-term metabolic control, incretin mimetics (agonists at the GLP-1 receptor) with more favourable pharmacokinetic profiles should be used.     

Changes in peripheral immune cell numbers and functions in octogenarian walkers – an acute exercise study

Background

Age-related changes of the immune system, termed immunosenescence, may underlie the increased risk of infections and morbidity in the elderly. Little is known about the effects of acute exercise on peripheral immune parameters in octogenarians. Therefore, we investigated acute exercise-induced changes in phenotype and function of the immune system in octogenarians participating in the 2013 edition of the Nijmegen Four Days Marches. Blood sampling was performed at baseline and immediately after 4 days of the walking exercise (30 km/day). A comprehensive set of adaptive and innate immune traits were enumerated and analyzed by flow-cytometry. Peripheral blood mononuclear cells, isolated before and after walking were stimulated with LPS and supernatants were analysed for IL-1β, IL-6, IL-8 and TNF-α concentrations by ELISA. CMV serostatus was determined by ELISA.

Results

The walking exercise induced a clear leucocytosis with numerical increases of granulocytes, monocytes and lymphocytes. These exercise-induced changes were most profound in CMV seropositive subjects. Within lymphocytes, numerical increases of particularly CD4+ T cells were noted. Further T cell differentiation analysis revealed profound increases of naïve CD4+ T cells, including naïve Treg. Significant increases were also noted for CD4+ memory T cell subsets. In contrast, only slight increases in naïve and memory CD8+ T cell subsets were detected. Exercise did not affect markers of immune exhaustion in memory T cell subsets. NK cells demonstrated a numerical decline and a change in cellular composition with a selective decrease of the mature CD56^dim NK cells. The latter was seen in CMV seronegative subjects only. Also, a higher IL-6 and IL-8 production capacity of LPS-stimulated PBMC was seen after walking.

Conclusion

In this exceptional cohort of octogenarian walkers, acute exercise induced changes in immune cell numbers and functions. A clear response of CD4+ T cells, rather than CD8+ T cells or NK cells was noted. Remarkably, the response to exercise within the CD4+ T cell compartment was dominated by naïve CD4+ subsets.

     

Antagonism of CD11b with Neutrophil Inhibitory Factor (NIF) Inhibits Vascular Lesions in Diabetic Retinopathy

Leukocytes and proteins that govern leukocyte adhesion to endothelial cells play a causal role in retinal abnormalities characteristic of the early stages of diabetic retinopathy, including diabetes-induced degeneration of retinal capillaries. Leukocyte integrin αmβ2 (CD11b/CD18, MAC1), a protein mediating adhesion, has been shown to mediate damage to endothelial cells by activated leukocytes in vitro. We hypothesized that Neutrophil Inhibitory Factor (NIF), a selective antagonist of integrin αmβ2, would inhibit the diabetes-induced degeneration of retinal capillaries by inhibiting the excessive interaction between leukocytes and retinal endothelial cells in diabetes. Wild type animals and transgenic animals expressing NIF were made diabetic with streptozotocin and assessed for diabetes-induced retinal vascular abnormalities and leukocyte activation. To assess if the leukocyte blocking therapy compromised the immune system, animals were challenged with bacteria. Retinal superoxide production, leukostasis and leukocyte superoxide production were increased in wild type mice diabetic for 10 weeks, as was the ability of leukocytes isolated from diabetic animals to kill retinal endothelial cells in vitro. Retinal capillary degeneration was significantly increased in wild type mice diabetic 40 weeks. In contrast, mice expressing NIF did not develop any of these abnormalities, with the exception that non-diabetic and diabetic mice expressing NIF generated greater amounts of superoxide than did similar mice not expressing NIF. Importantly, NIF did not significantly impair the ability of mice to clear an opportunistic bacterial challenge, suggesting that NIF did not compromise immune surveillance. We conclude that antagonism of CD11b (integrin αmβ2) by NIF is sufficient to inhibit early stages of diabetic retinopathy, while not compromising the basic immune response.     

Monocyte Activation in HIV/HCV Coinfection Correlates with Cognitive Impairment

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects’ GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates.     

Effect of optimal glycaemic control with continuous subcutaneous insulin infusion on energy expenditure in type I diabetes mellitus.

To assess the role of insulin in the control of body weight energy expenditure was measured by indirect calorimetry in eight patients of normal weight with type I diabetes initially while poorly controlled during conventional insulin treatment and later during optimal glycaemic control achieved by using the continuous subcutaneous insulin infusion pump. Their response to seven days of fat supplementation was also assessed and the results compared with those in eight non-diabetic subjects. After a mean of 5.3 months of continuous subcutaneous insulin infusion the diabetic subjects had gained on average 3.5 kg. In the poorly controlled diabetic state the resting metabolic rate was raised but decreased by a mean of 374 kJ (90 kcal) per 24 hours with optimal glycaemic control. The thermic response to infused noradrenaline was reduced by 59% in the diabetic subjects, was not improved by continuous subcutaneous insulin infusion, but was improved when three of the subjects were given metformin in addition. The diabetic subjects had no abnormality in the thermic response to a meal while taking their usual diabetic diet. During fat supplementation, however, this thermic response was reduced when glycaemic control was poor but not when control was precise. Fat supplementation did not alter the resting metabolic rate or the reduced noradrenergic thermic response in the diabetic subjects. These findings suggest that precise glycaemic control could produce weight gain if energy intake remained unaltered, for diabetic subjects do not compensate for the decrease in metabolic rate by an increase in noradrenergic and dietary thermic responses. Also precise glycaemic control using continuous subcutaneous insulin infusion does not correct all the metabolic abnormalities of diabetes mellitus.     

Normal tissue plasminogen activator and plasminogen activator inhibitor activity in plasma from patients with type 1 diabetes mellitus.

The fibrinolytic system was investigated in 38 patients (21 males and 17 females) affected by type 1 diabetes mellitus (18 free from complications, 10 with retinopathy, and 10 with autonomic neuropathy) and in 8 healthy controls. Two separate fibrinolysis-stimulating tests were done: standardized venous occlusion and 1-desamino-8-D-arginine vasopressin infusion. Plasma tissue plasminogen activator antigen and activity and plasma plasminogen activator inhibitor activity were measured. All the patients were in good metabolic control (mean HbA1c 7.4%, range 6.1-8.0%). No significant differences were observed either between the diabetic patients and the control subjects, nor among the subgroups of diabetic patients. The fibrinolytic system is probably not involved in type 1 diabetes mellitus.     

A Novel Glycated Hemoglobin A1c-Lowering Traditional Chinese Medicinal Formula,Identified by Translational Medicine Study

Diabetes is a chronic metabolic disorder that has a significant impact on the health care system. The reduction of glycated hemoglobin A1c is highly associated with the improvements of glycemic control and diabetic complications. In this study, we identified a traditional Chinese medicinal formula with a HbA1c-lowering potential from clinical evidences. By surveying 9,973 diabetic patients enrolled in Taiwan Diabetic Care Management Program, we found that Chu-Yeh-Shih-Kao-Tang (CYSKT) significantly reduced HbA1c values in diabetic patients. CYSKT reduced the levels of HbA1c and fasting blood glucose, and stimulated the blood glucose clearance in type 2 diabetic mice. CYSKT affected the expressions of genes associated with insulin signaling pathway, increased the amount of phosphorylated insulin receptor in cells and tissues, and stimulated the translocation of glucose transporter 4. Moreover, CYSKT affected the expressions of genes related to diabetic complications, improved the levels of renal function indexes, and increased the survival rate of diabetic mice. In conclusion, this was a translational medicine study that applied a “bedside-to-bench” approach to identify a novel HbA1c-lowering formula. Our findings suggested that oral administration of CYSKT affected insulin signaling pathway, decreased HbA1c and blood glucose levels, and consequently reduced mortality rate in type 2 diabetic mice.     

HSP70 as a biomarker of the thin threshold between benefit and injury due to physical exercise when exposed to air pollution

Physical exercise has acute and chronic effects on inflammatory balance, metabolic regulation, and redox status. Exercise-induced adaptations are mediated by enhanced 70-kDa heat shock protein (HSP70) levels and an improved heat shock response (HSR). Therefore, exercise could be useful against disease conditions [obesity, diabetes mellitus (DM), and exposure to atmospheric pollutants] marked by an impaired HSR. However, exercise performed by obese or diabetic subjects under pollution conditions might also be dangerous at certain intensities. Intensity correlates with an increase in HSP70 levels during physical exercise until a critical point at which the effort becomes harmful and impairs the HSR. Establishing a unique biomarker able to indicate the exercise intensity on metabolism and cellular fatigue is essential to ensure adequate and safe exercise recommendations for individuals with obesity or DM who require exercise to improve their metabolic status and live in polluted regions. In this review, we examined the available evidence supporting our hypothesis that HSP70 could serve as a biomarker for determining the optimal exercise intensity for subjects with obesity or diabetes when exposed to air pollution and establishing the fine threshold between anti-inflammatory and pro-inflammatory exercise effects.     

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.