妊娠期糖尿病患者体内铁负荷状态及氧化应激水平的研究

为了探讨铁代谢在妊娠期糖尿病(GDM)发病中的作用,对GDM患者体内铁负荷状态、氧化应激水平及抗氧化状态进行分析研究.在912例孕24～28周产前检查的孕妇中,按血糖筛查和糖耐量试验筛选出GDM孕妇32例为实验组,随机选择糖耐量正常孕妇26例作为对照组,分别测定两组孕妇的血红蛋白(Hb)等指标,以评价机体铁代谢状况;测...     

Increased Aβ production prompts the onset of glucose intolerance and insulin resistance

Type 2 diabetes (T2D) mellitus and Alzheimer's disease (AD) are two prevalent diseases with comparable pathophysiological features and genetic predisposition. Patients with AD are more susceptible to develop T2D. However, the molecular mechanism linking AD and T2D remains elusive. In this study, we have generated a new mouse model to test the hypothesis that AD would prompt the onset of T2D in mice. To test our hypothesis, we crossed Alzheimer APPswe/PS1dE9 (APP/PS1) transgenic mice with mice partially deficient in leptin signaling (db/+). Body weight, plasma glucose, and insulin levels were monitored. Phenotypic characterization of glucose metabolism was performed using glucose and insulin tolerance tests. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. APP/PS1 coexpression in mice with intact leptin receptor signaling did not show any metabolic perturbations in glucose metabolism or insulin sensitivity. In contrast, APP/PS1 coexpression in db/+ mice resulted in nonfasting hyperglycemia, hyperinsulinemia, and hypercholesterolemia without changes in body weight. Conversely, fasting blood glucose and cholesterol levels remained unchanged. Coinciding with altered glucose metabolism, APP/PS1 coexpression in db/+ mice resulted in glucose intolerance, insulin resistance, and impaired insulin signaling. In addition, histomorphometric analysis of pancreata revealed augmented β-cell mass. Taken together, these findings provide experimental evidence to support the notion that aberrant Aβ production might be a mechanistic link underlying the pathology of insulin resistance and T2D in AD.     

Amelioration of type II diabetes in db/db mice by continuous low-dose-rate gamma irradiation

Low-dose-rate radiation modulates various biological responses including carcinogenesis, immunological responses and diabetes. We found that continuous irradiation with low-dose-rate gamma rays ameliorated type II diabetes in db/db mice, diabetic mice that lack leptin receptors. Whole-body exposure of db/db mice to low dose-rate gamma radiation improved glucose clearance without affecting the response to insulin. Histological studies suggested that degeneration of pancreatic islets was significantly suppressed by the radiation. Insulin secretion in response to glucose loading was increased significantly in the irradiated mice. These results suggest that low-dose-rate gamma radiation ameliorates type II diabetes by maintaining insulin secretion, which gradually decreases during the progression of diabetes due to degeneration of pancreatic islets. We also inferred that protection from oxidative damage is involved in the anti-diabetic effect of low-dose-rate gamma rays because expression and activity of pancreatic superoxide dismutase were significantly elevated by low-dose-rate gamma radiation.     

Anti-diabetic effects of electrolyzed reduced water in streptozotocin-induced and genetic diabetic mice

Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Both an increase in reactive oxygen free radical species (ROS) and a decrease in the antioxidant defense mechanism lead to the increase in oxidative stress in diabetes. Electrolyzed reduced water (ERW) with ROS scavenging ability may have a potential effect on diabetic animals, a model for high oxidative stress. Therefore, the present study examined the possible anti-diabetic effect of ERW in two different diabetic animal models. The genetically diabetic mouse strain C57BL/6J-db/db (db/db) and streptozotocin (STZ)-induced diabetic mouse were used as insulin deficient type 1 and insulin resistant type 2 animal model, respectively. ERW, provided as a drinking water, significantly reduced the blood glucose concentration and improved glucose tolerance in both animal models. However, ERW fail to affect blood insulin levels in STZ-diabetic mice whereas blood insulin level was markedly increased in genetically diabetic db/db mice. This improved blood glucose control could result from enhanced insulin sensitivity, as well as increased insulin release. The present data suggest that ERW may function as an orally effective anti-diabetic agent and merit further studies on its precise mechanism.     

Oxidative damage associated with obesity is prevented by overexpression of CuZn- or Mn-superoxide dismutase

The development of insulin resistance is the primary step in the etiology of type 2 diabetes mellitus. There are several risk factors associated with insulin resistance, yet the basic biological mechanisms that promote its development are still unclear. There is growing literature that suggests mitochondrial dysfunction and/or oxidative stress play prominent roles in defects in glucose metabolism. Here, we tested whether increased expression of CuZn-superoxide dismutase (Sod1) or Mn-superoxide dismutase (Sod2) prevented obesity-induced changes in oxidative stress and metabolism. Both Sod1 and Sod2 overexpressing mice were protected from high fat diet-induced glucose intolerance. Lipid oxidation (F₂-isoprostanes) was significantly increased in muscle and adipose with high fat feeding. Mice with increased expression of either Sod1 or Sod2 showed a significant reduction in this oxidative damage. Surprisingly, mitochondria from the muscle of high fat diet-fed mice showed no significant alteration in function. Together, our data suggest that targeting reduced oxidative damage in general may be a more applicable therapeutic target to prevent insulin resistance than is improving mitochondrial function.     

Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice

Hearts from type 2 diabetic (db/db) mice demonstrate altered substrate utilization with high rates of fatty acid oxidation, decreased functional recovery following ischemia, and reduced cardiac efficiency. Although db/db mice show overall insulin resistance in vivo, we recently reported that insulin induces a marked shift toward glucose oxidation in isolated perfused db/db hearts. We hypothesize that such a shift in metabolism should improve cardiac efficiency and consequently increase functional recovery following low-flow ischemia. Hearts from db/db and nondiabetic (db/+) mice were perfused with 0.7 mM palmitate plus either 5 mM glucose (G), 5 mM glucose and 300 microU/ml insulin (GI), or 33 mM glucose and 900 microU/ml insulin (HGHI). Substrate oxidation and postischemic recovery were only moderately affected by GI and HGHI in db/+ hearts. In contrast, GI and particularly HGHI markedly increased glucose oxidation and improved postischemic functional recovery in db/db hearts. Cardiac efficiency was significantly improved in db/db, but not in db/+ hearts, in the presence of HGHI. In conclusion, insulin and glucose normalize cardiac metabolism, restore efficiency, and improve postischemic recovery in type 2 diabetic mouse hearts. These findings may in part explain the beneficial effect of glucose-insulin-potassium therapy in diabetic patients with cardiac complications.     

Chronic Resveratrol Treatment Protects Pancreatic Islets against Oxidative Stress in db/db Mice

Resveratrol (RSV) has anti-inflammatory and anti-oxidant actions which may contribute to its cardiovascular protective effects. We examined whether RSV has any beneficial effects on pancreatic islets in db/db mice, an animal model of type 2 diabetes. The db/db and db/dm mice (non-diabetic control) were treated with (db-RSV) or without RSV (db-control) (20 mg/kg daily) for 12 weeks. After performing an intraperitoneal glucose tolerance test and insulin tolerance test, mice were sacrificed, the pancreas was weighed, pancreatic β-cell mass was quantified by point count method, and the amount of islet fibrosis was determined. 8-Hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, was determined in 24 h urine and pancreatic islets. RSV treatment significantly improved glucose tolerance at 2 hrs in db/db mice (P = 0.036), but not in db/dm mice (P = 0.623). This was associated with a significant increase in both pancreas weight (P = 0.011) and β-cell mass (P = 0.016). Islet fibrosis was much less in RSV-treated mice (P = 0.048). RSV treatment also decreased urinary 8-OHdG levels (P = 0.03) and the percentage of islet nuclei that were positive for 8-OHdG immunostaining (P = 0.019). We conclude that RSV treatment improves glucose tolerance, attenuates β-cell loss, and reduces oxidative stress in type 2 diabetes. These findings suggest that RSV may have a therapeutic implication in the prevention and management of diabetes.     

地鳖多肽提取物的抗氧化衰老机制

目的探讨地鳖多肽（ESW polypeptide）提取物抗氧化衰老机制的研究。方法小鼠连续腹腔注射D-半乳糖20 d,建立衰老模型,同时小鼠灌服不同剂量地鳖多肽提取物每日（0、40、80、160 mg/kg）,观察小鼠的正常活动、运动和耐应激能力。分别采用黄嘌呤氧化酶法、分光光度法检测小鼠血液和不同组织中超氧化物歧化酶（SOD）、过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSH-PX）活力,以及丙二醛（MDA）和还原型谷胱甘肽（GSH）含量;免疫荧光法检测细胞核转录因子2（Nrf2）在Caco-2细胞的表达。结果与对照和多肽组比较,衰老组小鼠体重增重缓慢、组织脏器系数降低、运动时间缩短、抗应激能力降低、组织中抗氧化酶活力降低。随着地鳖多肽剂量增加,多肽组小鼠体重增加明显,肝脏、脾脏和肾脏指数增加显著,小鼠静力和动力运动时间明显延长,小鼠耐缺氧、耐高温和运动时间延长并接近对照组,血液和不同组织中的SOD、CAT、GSH-PX活力及GSH含量显著提高,但MDA含量降低。与对照组比较,地鳖多肽组Caco-2细胞核内Nrf2表达量明显增加,接近阳性对照组。结论地鳖多肽可能通过启动Nrf2-ARE抗氧化信号通路,提高D-半乳糖致衰老小鼠抗应激和抗氧化能力,从而延缓小鼠氧化衰老。     

In vivo therapeutic exploring for Mori folium extract against type 2 diabetes mellitus in rats

Background: The study was aimed to investigate the potential therapeutic effect of Mori folium aqueous extracts (MFAE) on type 2 diabetes mellitus (T2DM) in vivo.Methods and results: A rat model of T2DM was established with the combination of high sugar and high-fat diet (HSFD) and streptozotocin (STZ). The T2DM rats were administrated with low (2 g.kg⁻¹) and high (5 g.kg⁻¹) doses of MFAE for 60 consecutive days. The biochemical indices of glucose metabolism disorders, insulin resistance and oxidative stress were observed. The results indicated that MFAE significantly promoted the synthesis of hepatic glycogen, reduced the levels of fasting blood glucose and fasting blood insulin, and improved the insulin sensitivity index (ISI). MFAE administration also remarkably increased the levels of superoxide dismutase (SOD) and reduced the levels of malondialdehyde (MDA).Conclusion: MFAE showed a therapeutic effect on T2DM with the bioative effect of improve glucose metabolism disorders, decrease insulin resistance, and ameliorate the antioxidative ability.     

Reduction of diabetes-induced renal oxidative stress by a cantaloupe melon extract/gliadin biopolymers, oxykine, in mice

Oxidative stress is implicated as an important mechanism by which diabetes causes nephropathy. Oxykine is the cantaloupe melon extract rich in vegetal superoxide dismutase covered by polymeric films of wheat matrix gliadin. In this study, we examined whether chronic oral administration of oxykine could prevent the progression of diabetic nephropathy induced by oxidative stress using preclinical rodent model of type 2 diabetes. We used female db/db mice and their non-diabetic db/m littermates. The mice were divided into the following three groups: non-diabetic db/m; diabetic db/db, and diabetic db/db treated with oxykine. Blood glucose level, body weight, urinary albumin, and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured during the experiments. Histological and 8-OHdG immunohistochemical studies were preformed on 12 weeks from the beginning of treatment. After 12 weeks of treatment, the levels of blood glucose and the body weight were not significantly different between the oxykine-treated group and the non-treated db/db group, however both groups kept significantly high levels rather than db/m mice. The relative mesangial area calculated by mesangial area/total glomerular area ratio was significantly ameliorated in the oxykine treated group compared with non-treated db/db group. The increases in urinary albumin and 8-OHdG at 12 weeks of treatment were significantly inhibited by chronic treatment with oxykine. The 8-OHdG immunoreactive cells in the glomeruli of non-treated db/db mice were more numerous than that of oxykine-treated db/db mice. In this study, treatment of oxykine ameliorated the progression and acceleration of diabetic nephropathy for rodent model of type 2 diabetes. These results indicated that the oxykine reduced the diabetes-induced oxidative stress and renal mesangial cell injury. In conclusion, oxykine might be a novel approach for the prevention of diabetes nephropathy.     

Novel protective mechanism of reducing renal cell damage in diabetes: Activation AMPK by AICAR increased NRF2/OGG1 proteins and reduced oxidative DNA damage

Exposure of renal cells to high glucose (HG) during diabetes has been recently proposed to be involved in renal injury. In the present study, we investigated a potential mechanism by which AICAR treatment regulates the DNA repair enzyme, 8-oxoG-DNA glycosylase (OGG1) in renal proximal tubular mouse cells exposed to HG and in kidney of db/db mice. Cells treated with HG for 2 days show inhibition in OGG1 promoter activity as well as OGG1 and Nrf2 protein expression. In addition, activation of AMPK by AICAR resulted in an increase raptor phosphorylation at Ser⁷⁹² and leads to increase the promoter activity of OGG1 through upregulation of Nrf2. Downregulation of AMPK by DN-AMPK and raptor and Nrf2 by siRNA resulted in significant decease in promoter activity and protein expression of OGG1. On the other hand, downregulation of Akt by DN-Akt and rictor by siRNA resulted in significant increase in promoter activity and protein expression of Nrf2 and OGG1. Moreover, gel shift analysis shows reduction of Nrf2 binding to OGG1 promoter in cells treated with HG while cells treated with AICAR reversed the effect of HG. Furthermore, db/db mice treated with AICAR show significant increased in AMPK and raptor phosphroylation as well as OGG1 and Nrf2 protein expression that associated with significant decrease in oxidative DNA damage (8-oxodG) compared to non-treated mice. In summary, our data provide a novel protective mechanism by which AICAR prevents renal cell damage in diabetes and the consequence complications of hyperglycemia with a specific focus on nephropathy.     

Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice

This study examines whether anti-diabetic effects of genistein and daidzein are mediated by hepatic glucose and lipid regulating enzyme activities in type 2 diabetic animals. Male C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice and age-matched non-diabetic littermates (db/+) were used in this study. The db/db mice were divided into control, genistein (0.02%, w/w) and daidzein (0.02%, w/w) groups. The blood glucose and HbA(1c) levels were significantly lower in the genistein and daidzein groups than in the control group, while glucose tolerance only was significantly improved in the genistein-supplemented group. The plasma insulin and C-peptide levels did not differ significantly between groups, yet the glucagon level was lower in the genistein and daidzein groups compared to that in the control db/db or db/+ group. The genistein and daidzein supplements increased the insulin/glucagon ratio in the type 2 diabetic animals. While the hepatic glucokinase activity was significantly lower in the db/db control group, the glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities were significantly higher in the control group compared to the db/+ group. Interestingly, these hepatic glucose metabolizing enzyme activities were reversed by the genistein and daidzein supplementation in db/db mice compared to the control group. The hepatic fatty acid synthase, beta-oxidation and carnitine palmitoyltransferase activities were all significantly lower in the genistein and daidzein groups than in the control group. The genistein and daidzein supplements also improved the plasma total cholesterol, triglyceride, HDL-cholesterol/total cholesterol, free fatty acid and hepatic triglyceride concentrations in the db/db mice. These results suggest that genistein and daidzein exert anti-diabetic effect in type 2 diabetic conditions by enhancing the glucose and lipid metabolism.     

Is oxidative stress induced by iron status associated with gestational diabetes mellitus?

Gestational diabetes mellitus (GDM) is a common pregnancy complication in high risk populations, and is associated with increased perinatal and long term outcomes for both mothers and newborns. Both its prevention and early management can be reinforced by identifying risks factors, particularly those factors influencing glucose metabolism. On the other hand, several epidemiological studies have shown an increased oxidative stress (OS) in pregnant women with GDM. Elevated OS was also reported in pregnant women supplemented with iron, which can generate OS and may also influence insulin resistance. This review summarizes the current state of knowledge, highlighting the potential relationship between OS induced by iron status and the development of GDM.     

Nrf2 prevents diabetic cardiomyopathy via antioxidant effect and normalization of glucose and lipid metabolism in the heart

Metabolic disorders and oxidative stress are the main causes of diabetic cardiomyopathy. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts a powerful antioxidant effect and prevents the progression of diabetic cardiomyopathy. However, the mechanism of its cardiac protection and direct action on cardiomyocytes are not well understood. Here, we investigated in a cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) the direct effect of Nrf2 on cardiomyocytes in DCM and its mechanism. In this study, cardiomyocyte-restricted Nrf2 transgenic mice (Nrf2-TG) were used to directly observe whether cardiomyocyte-specific overexpression of Nrf2 can prevent diabetic cardiomyopathy and correct glucose and lipid metabolism disorders in the heart. Compared to wild-type mice, Nrf2-TG mice showed resistance to diabetic cardiomyopathy in a streptozotocin-induced type 1 diabetes mouse model. This was primarily manifested as improved echocardiography results as well as reduced myocardial fibrosis, cardiac inflammation, and oxidative stress. These results showed that Nrf2 can directly act on cardiomyocytes to exert a cardioprotective role. Mechanistically, the cardioprotective effects of Nrf2 depend on its antioxidation activity, partially through improving glucose and lipid metabolism by directly targeting lipid metabolic pathway of AMPK/Sirt1/PGC-1α activation via upstream genes of sestrin2 and LKB1, and indirectly enabling AKT/GSK-3β/HK-Ⅱ activity via AMPK mediated p70S6K inhibition.     

Role of reactive oxygen species in injury-induced insulin resistance

Acute insulin resistance is common after injury, infection, and critical illness. To investigate the role of reactive oxygen species (ROS) in critical illness diabetes, we measured hepatic ROS, which rapidly increased in mouse liver. Overexpression of superoxide dismutase 2, which decreased mitochondrial ROS levels, protected mice from the development of acute hepatic insulin resistance. Insulin-induced intracellular signaling was dramatically decreased, and cellular stress signaling was rapidly increased after injury, resulting in the hyperglycemia of critical illness diabetes. Insulin-induced intracellular signaling, activation of stress (c-Jun N-terminal kinase) signaling, and glucose metabolism were all normalized by superoxide dismutase 2 overexpression or by pretreatment with antioxidants. Thus, ROS play an important role in the development of acute hepatic insulin resistance and activation of stress signaling after injury.     

姜黄素对db/db小鼠基因组DNA甲基化的影响

目的:观察姜黄素对2型糖尿病模型db/db小鼠糖尿病症状的改善作用,并从表观遗传角度分析其对小鼠外周血DNA甲基化水平的影响。方法:2型糖尿病模型db/db小鼠随机分为糖尿病组和姜黄素干预组(给予250 mg/kg姜黄素溶液),连续灌胃8周。OGTT检测葡萄糖耐量,ELISA法测定空腹胰岛素并计算HOMA-IR和HOMA-β,RRBS技术检测外周血基因组DNA甲基化水平。结果:与糖尿病组相比,姜黄素干预小鼠的血糖、空腹胰岛素和HOMA-IR显著降低,葡萄糖耐量显著改善(P<0.05);且小鼠外周血基因组启动子区、CGI岸和5’-非编码区CpG甲基化水平显著降低(P<0.05);对两组间差异甲基化基因进行功能富集分析,筛选出前10位显著富集的可能与2型糖尿病相关的差异基因包括Hdac7、Micall1、Vangl2、Dhcr24、Kcnj8、Gnas、Tcf7l2、Dgkh、Dlgap1和Plekhg4。结论:姜黄素能够改善db/db小鼠的葡萄糖耐量及胰岛素抵抗,并且其外周血中存在显著低甲基化改变,提示姜黄素可能是通过抑制糖尿病小鼠中某些基因的异常甲基化修饰而发挥抗糖尿病作用。     

Antioxidative effects of Cinnamomi cassiae and Rhodiola rosea extracts in liver of diabetic mice

Both Cinnamomi cassiae and Rhodiola rosea extracts are used as anti-diabetic folk medicines. Recently, increased oxidative stress was shown to play an important role in the etiology and pathogenesis of diabetes mellitus and its complications. This study was designed to examine the effects of Cinnamomi cassiae and Rhodiola rosea extracts on blood glucose, lipid peroxidation, the level of reduced glutathione and its related enzymes (glutathione reductase, glutathione S-transferase), and the activity of the antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) in the liver of db/db mice. Diabetic C57BL/Ks db/db mice were used as experimental models. Mice were divided into control (n=10), Cinnamomi cassiae (200 mg/kg/day, n=10), and Rhodiola rosea (200 mg/kg/day, n=10) treated groups for 12 weeks of treatment. These type II diabetic mice were used to investigate the effects of Cinnamomi cassiae and Rhodiola rosea on blood glucose, reduced glutathione, glutathione reductase, glutathione S-transferase, glutathione peroxidase, lipid peroxidation, catalase and superoxide dismutase. Cinnamomi cassiae and Rhodiola rosea extracts significantly decreased on blood glucose, increased levels of reduced glutathione and the activities of glutathione reductase, glutathione S-transferase, glutathione peroxidase, catalase and superoxide dismutase in the liver. Extract treatment also significantly decreased lipid peroxidation. Cinnamomi cassiae and Rhodiola rosea extracts may be effective for correcting hyperglycemia and preventing diabetic complications.