Effects of running exercise on fibre-type distribution of soleus and plantaris muscles in diabetic Otsuka Long-Evans Tokushima fatty rats

AIM: Effect of running exercise on fibre-type distributions of the slow soleus and fast plantaris muscles was investigated in male Otsuka Long-Evans Tokushima fatty rats (OLETF) as an animal model of spontaneous type 2 diabetes mellitus. METHODS: Five-week-old OLETF rats were allowed to exercise voluntarily in running wheels for 32 days and the data were compared with those of age-matched non-exercised OLETF and non-diabetic Long-Evans Tokushima Otsuka rats (LETO). RESULTS: In the soleus muscle, a higher percentage of type I fibres was observed in non-exercised OLETF rats compared with LETO rats, and there were no type IIA fibres in non-exercised OLETF rats. In the plantaris muscle, a higher percentage of type IIB fibres and a lower percentage of type I and type IIA fibres were observed in non-exercised OLETF rats compared with LETO rats. In contrast, there were no differences in the fibre-type distribution of soleus and plantaris muscles between exercised OLETF and LETO rats. The body weight and type I fibre percentage of the soleus muscle were related to the running distance in exercised OLETF rats. White adipose tissue weight, HbA(1c) and blood insulin and glucose concentrations were lower in exercised OLETF rats than in non-exercised OLETF rats, irrespective of the running distance. There was a difference in the gene-expression pattern of the soleus muscle among LETO rats, non-exercised OLETF and exercised OLETF rats. CONCLUSION: Running exercise can inhibit diabetes-associated type shifting of fibres, which is more apparent with postnatal growth, in skeletal muscles of diabetic OLETF rats, as a result of mRNA expression change in muscle.     

自发2型糖尿病模型OLETF大鼠不同病程脂肪组织水通道蛋白7mRNA的表达

目的观察自发性2型糖尿病动物模型OLETF大鼠不同病程阶段皮下及肾周脂肪水通道蛋白7（AQP7）mRNA的表达。方法以OLE3T大鼠为研究对象,同种系非糖尿病LETO大鼠为正常对照。分别在8、14、22周龄行口服葡萄糖耐量试验,试验后取皮下及肾周脂肪组织,采用实时PCR方法测定其AQP7mRNA的表达。结果LETO组皮下及肾周脂肪组织均随肥胖增加表达上调,OLETF组皮下及肾周脂肪组织则呈先上调后下调趋势,且与血清甘油变化趋势一致。结论AQP7可能在腹型肥胖的发生中发挥重要作用。     

贝前列腺素钠对2型糖尿病大鼠肾功能及氧化应激水平的影响

目的 观察贝前列腺素钠(BPS)对2型糖尿病大鼠肾功能及氧化应激水平的影响. 方法 将30只SD大鼠随机分为正常对照组(NC组),2型糖尿病组(T2DM组),BPS治疗组(BPS组),T2DM组和BPS组大鼠给予高脂饮食合并小剂量链脲佐菌素( STZ)腹腔注射,建模成功后,BPS组给予0.6 mg/(kg.d)灌胃,其余饲养条件3组相同,最终纳入实验各组6只.给药8周后检测各组大鼠体质量、血糖、24 h尿量、肾质量体质量比(KW/BW)、24h尿蛋白(24 h Ualb),血肌酐(Cr),尿素氮(BUN)以及各组大鼠氧化应激水平及炎症因子指标,包括总超氧化物歧化酶(SOD)、丙二醛(MDA)、还原型谷胱甘肽(GSH)、白介素6(IL-6)、肿瘤坏死因子(TNF-α)、髓过氧化物酶(MPO)、超敏C反应蛋白(hs-CRP). 结果 给药8周后,T2DM组血糖、尿量、KW/BW、24 h Ualb、Cr、BUN、MIDA、IL-6、TNF-α、MPO、hs-CRP水平均较NC组显著升高;体质量、SOD、GSH水平较NC组显著降低(P＜0.01).BPS组较T2DM组血糖、尿量、KW/BW、24 h Ualb、Cr、IL-6、M DA、TNF-α、MPO、hs-CRP水平显著降低(P＜0.05或0.01),体质量、SOD、GSH水平显著升高(P＜0.05). 结论 BPS可通过降低氧化应激水平,减少炎症因子的生成,显著减少糖尿病肾病大鼠尿蛋白排泄量,改善其肾功能,对T2DM大鼠肾脏具有保护作用.     

临床氧化应激指标与糖尿病周围神经病变的相关研究

目的调查2型糖尿病患者的临床氧化应激指标情况,分析其与2型糖尿病患者伴发周围神经病变的相关性。方法收集2016年10月至2017年5月解放军第306医院内分泌科同期住院的212例2型糖尿病患者一般资料及临床资料。根据2型糖尿病患者伴发周围神经病变诊断标准,将入选患者分为伴发周围神经病变(n=97)和未伴发周围神经病变(n=115)2组。应用SPSS 23.0对2组患者的一般情况及临床资料进行比较,采用logistic回归分析2型糖尿病患者伴发周围神经病变的危险因素。探讨2型糖尿病患者伴发周围神经病变的特点及其与临床氧化应激指标的相关性。结果 2型糖尿病患者伴发周围神经病变组患者年龄、病程、糖化血红蛋白、总胆固醇显著高于未伴发周围神经病变组患者,空腹C肽、血红蛋白和总胆红素显著低于2型糖尿病非周围神经病变组患者(P0.05)。单因素logistic回归分析显示年龄、病程、糖化血红蛋白、总胆红素、血红蛋白可能与2型糖尿病患者伴发周围神经病变相关,进一步多因素logistic回归分析显示病程(OR=1.006,95%CI 1.003~1.010)、糖化血红蛋白(OR=1.403,95%CI 1.118~1.657)、血红蛋白(OR=0.976,95%CI0.958~0.994)是2型糖尿病患者伴发周围神经病变的独立危险因素。结论 2型糖尿病患者伴发周围神经病变患者临床氧化应激指标(总胆红素、血红蛋白)低于2型糖尿病非周围神经病变患者,且具有高龄、糖尿病病程长、血糖控制不佳及胰岛功能差的特点。     

Increasing of oxidative stress from mitochondria in type 2 diabetic patients

BACKGROUND: Recent evidence increasingly indicates that oxidative stress may play an important role in the pathogenesis of diabetic vascular complications. Mitochondria has received much attention as an important organ in the generation of oxidative stress. However, the importance of oxidative stress among diabetic patients without vascular complications is unclear. METHODS: We compared oxidative stress produced from mitochondria of the mononuclear cells in peripheral blood obtained from 26 diabetic subjects without clinical vascular complications and 52 healthy age-matched subjects using a flow cytometer. Oxidative stress from the mononuclear cells was evaluated by measuring fluorescence of oxidized production from dihydrorhodamine-123, which is a pro-fluorescent compound that selectively accumulates in the mitochondria of living cells. Stimulation of the cells was carried out with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator. We then calculated the relative fluorescence variation (RFV) that indicated an increasing rate of oxidative stress levels by stimulation with PMA against the levels obtained at baseline. Additionally, we measured the urinary stress markers, 8-hydroxydeoxyguanosine (8OHdG) and 8-epi-prostaglandin F2alpha (isoprostane). RESULTS: Compared to healthy subjects, diabetic subjects did not exhibit significantly elevated oxidative stress levels at baseline, but did have significantly elevated basal urinary 8OHdG, urinary isoprostane and oxidative stress levels after PMA stimulation as well as RFV. CONCLUSIONS: Among diabetic subjects without clinical vascular complications, there was a possibility that mitochondrial oxidative stress balance between generation and scavenging against the additive PKC stimulation was thought to have already been lost.     

蜕皮甾酮对2型糖尿病大鼠肾组织氧化应激的影响

目的探讨蜕皮甾酮对2型糖尿病(T2DM)大鼠肾组织氧化应激的影响。方法选择70只雄性SD大鼠,高脂喂养8周后,对60只用链脲佐菌素腹腔注射建立T2DM模型,然后分T2DM组、蜕皮甾酮治疗组(A组)、阿托伐他汀治疗组(B组)、吡格列酮治疗组(C组);另10只为正常对照组(对照组)。干预治疗6周后杀检,检测各组空腹血糖(FPG)、尿素氮(BUN)、血肌酐(SCr)、血脂及尿肌酐清除率(Ccr),用ELISA法检测肾组织超氧化物岐化酶(SOD)、丙二醛(MDA)、一氧化氮合酶(NOS)。结果与对照组比较,各组FPG、BUN、血脂、Ccr、SOD、MDA、NOS升高,SCr降低,均以T2DM组明显(P<0.05或<0.01);与B、C组比较,A组Ccr、LDL-C、NOS、MDA降低,SOD升高(P<0.05或<0.01)。结论皮甾酮能降低T2DM大鼠的Ccr,其可能通过减少肾组织MDA、NOS,升高SOD发挥抗氧化效应,因而具有防治DKD的作用。     

Vascular proliferation and transforming growth factor-beta expression in pre- and early stage of diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats

The roles of transforming growth factor (TGF)-beta 1 in vascular proliferation, atherosclerosis, and plaque still remain controversial. TGF-beta 1 has been previously reported to inhibit the proliferation and migration of vascular smooth muscle cells and endothelial cells, in vitro. On the other hand, administration or transgenic overexpression of TGF-beta 1 enhances extracellular matrix synthesis and cellular hyperplasia of the intima and media in the normal artery and injured artery in vivo. We evaluated the correlation of arterial proliferation with plasma levels of TGF-beta 1 and TGF-beta receptor type II, respectively, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new strain of spontaneous non-insulin-dependent diabetes mellitus (NIDDM) models. OLETF rats (n=30) were divided into three groups aged 5,15, and 30 weeks. Long-Evans Tokushima Otsuka (LETO) rats (n=30) were used as age-matched non-diabetic controls. Plasma TGF-beta1 and insulin were determined by enzyme-linked immunosorbent assay. Immunoreactive TGF-beta receptor type II antigen was detected by immunohistochemistry on the thoracic artery. Arterial media area was measured microscopically. Oral glucose tolerance test was performed to examine the stage of diabetes mellitus. The thoracic aorta wall section area increased significantly from the age of 15 weeks in OLETF rats, versus LETO rats. In both OLETF and LETO rats, plasma TGF-beta 1 increased significantly from the age of 15 weeks. In OLETF rats, plasma TGF-beta 1 increased significantly over that in LETO rats (P<0.001). Furthermore, TGF-beta receptor type II was detected on aortic wall as strong signals in OLETF rats, but only weakly in LETO rats. OLETF rats showed hyperinsulinemia and insulin resistance from the age of 15 weeks. With oral glucose tolerance test, from the age of 15 weeks, the high glucose level in OLETF rats was prolonged to 2 h after loading, and the insulin levels at both fasting and after loading were significantly higher than those of LETO rats (P<0.001). There are significant linear relations between plasma TGF-beta 1 antigen and aorta wall section area, and plasma TGF-beta 1 antigen and fasting insulin level (P<0.001, respectively). We found that plasma TGF-beta 1 and vascular TGF-beta type II receptors existed to a greater extent in pre- and early stages of diabetes mellitus (DM) in OLETF rats compared with LETO rats. The greater extent of each in OLETF rats was associated with hyperinsulinemia and/or vascular thickening.     

Effects of carvedilol versus metoprolol on endothelial function and oxidative stress in patients with type 2 diabetes mellitus

BACKGROUND: Data suggest that carvedilol possesses antioxidant properties that might provide vascular protection. We sought to compare the effects of carvedilol and metoprolol tartrate on endothelial function and oxidative stress in a head-to-head trial. METHODS: Thirty-four patients with type 2 diabetes mellitus (T2DM) and hypertension were randomized to receive either carvedilol (n = 16) or metoprolol (n = 18) in addition to their current antihypertensive medications for 5 months. The following variables were measured pre- and posttreatment: blood pressure, fasting glucose and insulin, insulin resistance by homeostasis-model assessment, hemoglobin A1c, lipids, C-reactive protein (CRP), 8-isoprostane, asymmetric dimethylarginine, oxidized LDL cholesterol, ultrasound assessment of brachial-artery flow-mediated dilation (FMD), nitroglycerin-induced endothelium-independent dilation (EID), brachial and carotid artery distension, distensibility and compliance, and carotid artery intima-media thickness (cIMT). RESULTS: Both carvedilol and metoprolol treatment resulted in significant and similar decreases in systolic (P < .05) and diastolic (P < .0001) blood pressure. Compared with metoprolol, carvedilol significantly improved FMD (P < .001). No differences between groups were noted for any of the glycemic or lipid variables except for HDL cholesterol, which significantly decreased (P < .05) in the metoprolol group compared with the carvedilol group. No differences were observed between groups for CRP, the markers of oxidative stress, EID, arterial stiffness, or cIMT. CONCLUSIONS: Compared with metoprolol, carvedilol significantly improves endothelial function in patients with T2DM. Changes in glycemic control and oxidative stress do not seem to explain the observed improvements in FMD, which suggests that other mechanisms may be involved.     

2型糖尿病微量白蛋白尿与氧化应激的关系

目的探讨2型糖尿病患者微量白蛋白尿与氧化应激状态的关系。方法将72例2型糖尿病患者分为无微量白蛋白尿的糖尿病组（DM组）和伴有微量白蛋白尿的糖尿病肾病组（DN组）,选择30例无糖尿病患者作正常对照组（NGT组）,测定三组的血清丙二醛（MDA）水平、生化指标及年龄、身高、体质量指数。结果DN组MDA水平明显高于NGT组及DM组,MDA水平与尿微量白蛋白排泄率（UAER）有显著相关性。结论与无微量白蛋白尿的糖尿病患者相比,糖尿病肾病患者存在着严重的氧化应激状态,这可能与UAER的严重程度相关。     

Effects of pioglitazone and rosiglitazone combined with metformin on body weight in people with diabetes

Currently, pioglitazone and rosiglitazone are the thiazolidinediones available for clinical use. In the literature, there are different studies concerning the efficacy, safety and tolerability of thiazolidinediones as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin alone. Metformin and thiazolidinediones are both antihyperglycaemic drugs, both lower blood glucose concentrations in type 2 diabetes without causing overt hypoglycaemia and both require the presence of insulin to generate their therapeutic effects, but act without stimulating insulin secretion. Some authors reported that the improved glycaemic control obtained with thiazolidinediones is associated with an increase in body weight with an estimated 2–3 kg weight gain for every 1% decrease in HbA_1c which could negate some of the benefits of the improved metabolic control. Some other authors, instead, reported that thiazolidinediones give a better improvement in the glycaemic control compared with metformin alone without giving weight gain. The emerging discrepancies from these studies could be because of the study design, the patient selection, the degree of glycaemic control and/or the methods to measure body weight. We have undertaken a thorough literature search on Medline and Embase to evaluate the effects of thiazolidinediones plus metformin combination in people with diabetes on the body weight.     

Fermented mushroom milk-supplemented dietary fibre prevents the onset of obesity and hypertriglyceridaemia in Otsuka Long-Evans Tokushima fatty rats

AIM: Fermented milk product containing edible mushroom water extracts (mushroom yogurt; MY) has been reported to have glycaemic control and triglyceride-lowering effects in streptozotocin (STZ)-induced diabetic rats and Zucker diabetic fatty (ZDF) rats. Here, we investigated how MY-supplemented dietary fibre (10 and 20%, v/w) influences the onset of obesity and hypertriglyceridaemia in Otsuka Long-Evans Tokushima fatty (OLETF) rats. METHODS: The OLETF rats were fed a powdered chow diet supplemented with MY at the levels of 10 (v/w) and 20% for 6 weeks from 10 weeks of age, but the OLETF control rats were not supplemented. Their weight, fat distribution and lipid profile have been determined. RESULTS: The body weights in MY-fed rats were reduced compared with the control rats. The perirenal fat was decreased in both MY groups, but the visceral and epididymal fats reduced only in the MY 20% group. The concentrations of serum triglyceride and non-esterified fatty acid in MY-fed rats were decreased in a dose-dependent manner. However, the levels of other serum lipid profiles [total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol] were comparable among all rats. CONCLUSION: Anti-obesity and triglyceride lowering by MY-supplemented dietary fibre in OLETF rats might have resulted from the synergistic effect of components in the fermented mushroom-milk product.     

Correlation between changes of blood pressure with insulin resistance in type 2 diabetes mellitus with 4 weeks of pioglitazone therapy

OBJECTIVE:

To examine effects of pioglitazone (PIO) on systolic, diastolic, pulse and mean blood pressures (SBP, DBP, PP and MP, respectively) in type 2 diabetes mellitus (T2DM).

MATERIALS AND METHODS:

One hundred and six normotensive patients with T2DM with mean fasting blood glucose (FBS; 183 ± 6 mg/dl) were randomly divided into two groups. Test group was treated with 15 mg of PIO in addition to metformin 500 mg three times per day in both groups. SBP, DBP, PP and MP and fasting insulin, FBS and lipid profiles were measured before and after PIO therapy.

RESULTS:

There was a significant reduction in SBP (123 ± 2 vs. 118 ± 2 mmHg, P < 0.05), PP (41 ± 1 vs. 37 ± 1 mmHg, P < 0.05), and MP (95 ± 1 vs. 91 ± 1, P < 0.05). Clinical reduction in DBP was observed but not significant (82 ± 2 vs. 81 ± 1 mmHg, P > 0.05). There was a significant correlation between decline in SBP and DBP with respective baseline values (r = 0.76, P < 0.001 and r = 0.62, P < 0.001, respectively). Changes in PP and MP strongly correlated with baseline values (r = 0.51, P < 0.05 and r = 0.56, P < 0.05, respectively). There was a parallel reduction of FBS (183 ± 2 vs. 121 ± 3, P < 0.001) but reduction in IR or lipid profiles was not significant in test group. Changes in BP were not significant in control group ( P > 0.05).

CONCLUSION:

PIO treatment of T2DM showed early reduction of SBP and MP within first 4 weeks. Results suggest that pharmacodynamic effects of PIO mainly affect the systolic component. We hereby suggest that reduction of BP by PIO is independent from mechanisms of changes in IR and dyslipidaemia in normotensive diabetic patients.     

Pramlintide reduced markers of oxidative stress in the postprandial period in patients with type 2 diabetes

BACKGROUND: The production of oxidative stress as a result of postprandial hyperglycaemia is now recognized as an important contributing factor in the development of diabetes complications. The objective of this study was to examine the effects of pramlintide on plasma concentrations of glucose and several markers of oxidative stress in patients with type 2 diabetes following a standardized meal. METHODS: This was a randomized, single-blind, placebo-controlled, crossover study conducted at two clinical research centres in the United States. A total of 19 subjects (9 men and 10 women) with type 2 diabetes using mealtime insulin participated in the study. Pramlintide (120 microg), or placebo, and rapid-acting mealtime insulin were administered prior to a standardized meal on two separate study days. Plasma concentrations of glucose, nitrotyrosine (NT), oxidized-LDL cholesterol (OxLDL-C), and total radical trapping parameter (TRAP) were assessed during the 4-h postprandial period. RESULTS: Compared to placebo, pramlintide treatment reduced postprandial excursions of glucose, NT, and OxLDL-C and protected TRAP from consumption. Correlation analysis revealed positive associations between placebo-corrected glucose incremental AUC(0-4 h) and both NT and OxLDL-C and a negative association between placebo-corrected glucose incremental AUC(0-4h) and TRAP. CONCLUSIONS: The reduction in postprandial glucose excursions achieved with addition of pramlintide to rapid-acting insulin in type 2 diabetes was associated with a reduction in postprandial markers of oxidative stress.     

Differential effect of pioglitazone (PGZ) and rosiglitazone (RGZ) on postprandial glucose and lipid metabolism in patients with type 2 diabetes mellitus: a prospective, randomized crossover study

BACKGROUND: Postprandial metabolism is impaired in patients with type 2 diabetes (T2Dm). Two thiazolidinediones pioglitazone (PGZ) and rosiglitazone (RGZ) have similar effects on glycaemic control but differ in their effects on fasting lipids. This study investigated the effects of RGZ and PGZ on postprandial metabolism in a prospective, randomized crossover trial. METHODS: Seventeen patients with T2Dm were randomized to RGZ or PGZ for 12 weeks, with an 8-week wash-out period. Fasting blood samples were taken for glucose (FPG), insulin, HbA(1c), lipids, apolipoproteins (apo), lipoprotein (LPL) and hepatic lipase (HL), and cholesterol ester transfer protein (CETP) activity. A standardized breakfast was served and postprandial glucose, insulin, and lipid subfraction profiles were determined. RESULTS: RGZ and PGZ treatment resulted in a similar improvement in FPG, HbA(1c) and homeostasis model assessment. Fasting and postprandial triglyceride (TG) levels were significantly lower following PGZ therapy (fasting: -0.35 vs 0.44 mmol/L; p < 0.04; postprandial AUC-TG: -195.6 vs 127.9 mmol/L/min; p < 0.02) associated with changes in VLDL-2-TG (-0.10 vs 0.21 mmol/L; p = 0.23) and VLDL-3-TG (0.0 vs 0.34 mmol/L; p < 0.04). Fasting cholesterol increased with RGZ compared to PGZ (0.06 vs 0.59 mmol/L; p < 0.04), particularly in VLDL-2-C (-0.30 vs 0.59 mmol/L; p < 0.03) and VLDL-3-C (-0.85 vs 2.11 mmol/L; p < 0.02). Postprandial VLDL lipid and protein content increased after RGZ and decreased after PGZ. Fasting apoB, apoA-I, apoC-II/C-III-ratio, and LPL activity did not differ. CETP activity decreased after RGZ and increased after PGZ (-6.2 vs 4.2 p/mol/mL/min; p < 0.002). CONCLUSIONS: Both the glitazones had similar effects on glucose metabolism. The additional beneficial effect of PGZ on lipid metabolism may be related to its effects on insulin-independent VLDL production and CETP activity.     

Melatonin improves oxidative stress parameters measured in the blood of elderly type 2 diabetic patients

Abstract: An elevated oxidative status in the aging organism may be involved in the development of non‐insulin dependent diabetes mellitus (NIDDM). Melatonin, a potent antioxidant agent, is essential for glucose homeostasis and regulation. The aim of this study was to determine the influence of melatonin supplementation on the oxidative stress parameters in elderly NIDDM patients. The malondialdehyde (MDA) concentration, Cu‐Zn superoxide dismutase (SOD‐1) activity in erythrocytes, the level of nitrate/nitrite in plasma and morning melatonin concentration and oxidase activity of ceruloplasmin (Cp) in serum in 15 elderly NIDDM patients at baseline and after the 30 days of melatonin supplementation (5 mg daily) in comparison with levels in 15 healthy elderly volunteers were determined. A significant increase of MDA level and decrease of SOD‐1 activity and melatonin concentration were observed in NIDDM patients. Cp oxidase activity and nitrate/nitrite level were similar in both examined groups. Melatonin administration in NIDDM patients resulted in a significant increase in the morning melatonin concentration and SOD‐1 activity, and a reduction in the MDA level and Cp oxidase activity. Statistically significant alterations in nitrate/nitrite levels were not observed. These results indicate an improvement of antioxidative defense after melatonin supplementation in the NIDDM individuals and suggest melatonin supplementation as an additional treatment for the control of diabetic complications.