严重烫伤大鼠肝脏胰岛素抵抗发生机制的研究

目的：探讨严重烫伤后胰岛素信号在肝细胞转导缺陷的环节，以阐明严重烫伤后肝脏胰岛素抵抗的发生机制。方法：以30％体表面积背部皮肤全层(Ⅲ度)烫伤大鼠为模型，采用WGA-Sepharuse 4B亲和层析技术部分纯化大鼠肝细胞胰岛素受体，通过胰岛素受体结合实验、受体蛋白γ-^32P-ATP自身磷酸化SDS—聚丙烯配胺凝胶电泳(SDS-PAGE)放射自显影和外源性底物磷酸化，观察烫伤大鼠早期肝细胞胰岛素受体结合行为、受体β—亚基自身磷酸化和受体酪氨酸蛋白激酶(TPK)活性的变化。结果：严重烫伤大鼠伤后3d肝细胞膜岛素受体最大结合容量及亲和力无明显改变；但受体β—亚基自身磷酸化能明显下降；受体TPK活性亦明显降低并对胰岛素刺激的反应性明显减退。结论：严重烫伤后胰岛素信号在肝细胞转导发生偶联障碍，导致胰岛素生物效应受体后缺陷可能是严重烫伤后肝脏胰岛素抵抗发生的分子机制。     

严重烧伤后骨骼肌胰岛素受体信号缺陷机制的研究

在创伤、烧伤及其他应激状态下，胰岛素刺激的外周组织（肌肉和脂肪）对葡萄糖的摄取和处理能力下降，机体出现胰岛素抵抗和糖代谢紊乱。Ｂｌａｃｋ等［１］认为创伤后胰岛素抵抗可能涉及胰岛素受体后缺陷，机制尚不清楚。本研究以３０％体表面积皮肤全层烫伤（ＴＢＳＡ）...     

磷脂酶D参与胰岛素和收缩引起的Ⅰ型肌纤维葡萄糖跨膜转运的信号转导体系

目的:研究磷脂酶D(phospholipase D,PLD)是否参与胰岛素和收缩引起的I型肌纤维葡萄糖跨膜转运的信号转导体系.方法:利用PLD的抑制剂丁醇,观察其对胰岛素和肌肉收缩引起的I型肌纤维占大多数的离体大鼠比目鱼肌葡萄糖跨膜转运的影响,了解PLD在信号转导体系中的作用.用同位素双标法测定胰岛素或肌肉收缩引起的葡萄糖跨膜转运速率,同时观察收缩力总量和收缩输出量时间变化曲线.结果:同对照相比,丁醇可显著降低由胰岛素或肌肉收缩引起的肌细胞葡萄糖跨膜转运摄取速率(P<0.01),还明显影响肌肉的收缩力(P<0.01).结论:同在II型肌纤维中的作用一样,PDL也参与I型肌纤维中由胰岛素或肌肉收缩引起的肌细胞葡萄糖跨膜转运的信号转导系统.     

耐力训练对饮食性肥胖大鼠胰岛素作用的影响

为观察耐力训练对饮食性肥胖鼠胰岛素作用的影响，选用４４只雄性离乳ＳＤ大鼠，３６只饲以高脂饲料。饲养１０周后，１８只确定为饮食诱发肥胖鼠（ＤＩＯ），其中８只进行耐力训练（跑台６５－７５％Ｖｏ２ｍａｘ），所有大鼠继续饲养８周后处死。测定各组大鼠的血中胰岛素，细胞膜胰岛素受体。处死前进行葡萄糖负荷实验。实验结果如下：肥胖鼠存在高胰岛素血症，胰岛素敏感性下降及胰岛素抵抗，葡萄糖负荷实验，血胰岛素分泌峰值和分泌曲线下面积均增加，细胞膜胰岛素受体结合下降。耐力训练可通过增加肝细胞、脂肪细胞和白肌细胞膜胰岛素受体结合力，减轻胰岛素抵抗，提高胰岛素敏感性，改善高胰岛素血症。提示，高胰岛素血症，胰岛素敏感性下降及胰岛素抵抗是高脂饲料诱发肥胖大鼠的特征之一，耐力训练是通过改善肥胖鼠的代谢失常而降低其体脂的有效方法。     

胰岛素治疗对烫伤脓毒症骨骼肌蛋白高降解的影响

目的探讨胰岛素对烫伤脓毒症骨骼肌蛋白高降解的调节。方法沸水烫伤并注射内毒素建立烫伤和脓毒症兔模型,使用胰岛素控制血糖。检测伸趾长肌蛋白降解率和蛋白酶体的基因与蛋白表达变化。结果胰岛素治疗显著降低了伤后骨骼肌蛋白降解率和蛋白酶体的表达。结论胰岛素能抑制泛素-蛋白酶体途径活性的增强,减轻烫伤和脓毒症时骨骼肌蛋白高降解。     

缺氧和肾上腺素对骨骼肌葡萄糖转运的影响

目的:研究缺氧和肾上腺素对胰岛素和收缩诱导的骨骼肌葡萄糖转运速率的影响和作用机理。方法:利用同位素双标法,测定缺氧和肾上腺素存在条件下,胰岛素或肌肉收缩引起大鼠离体比目鱼肌2 -脱氧葡萄糖(2 -DG)和3-甲基葡萄糖(3-MG)转运的速率。结果及结论:(1)在缺氧和胰岛素联合刺激下,肌肉2 -DG转运速率部分叠加,而3-MG则没有,表明葡萄糖转运速率增加是磷酸化加速而非跨膜转运加快所致。(2 )缺氧和收缩双重刺激导致比目鱼肌葡萄糖转运速率出现部分叠加作用,提示收缩和缺氧调节葡萄糖转运的机制可能因肌纤维不同而有所不同。(3)药理性大剂量肾上腺素引起静态肌肉葡萄糖转运速率下降,可能与骨骼肌血管壁α-肾上腺素能受体和β-肾上腺素能受体同时兴奋有关。(4)大剂量肾上腺素可抑制胰岛素或收缩诱导的2-DG和3-MG转运,表明当胰岛素或收缩存在时,肾上腺素可在跨膜和磷酸化两个位点影响葡萄糖的转运摄取。     

老年高血压病患者的胰岛素抵抗

目的：了解老年男性高血压患者有无胰岛素抵抗。方法：对４９例老年男性高血压病患者和３７例正常老年男性，测定空腹及服７５ｇ葡萄糖２ｈ后的血糖和胰岛素浓度。结果：老年男性高血压病患者血胰岛素的升高伴有葡萄糖升高，胰岛素敏感性指数降低。结论：老年男性高血压病患者存在胰岛素抵抗。     

磷脂酶D参与胰岛素和收缩引起的I型肌纤维葡萄糖跨膜转运的信号转导体系

目的 :研究磷脂酶D(phospholipaseD ,PLD)是否参与胰岛素和收缩引起的I型肌纤维葡萄糖跨膜转运的信号转导体系。方法 :利用PLD的抑制剂丁醇 ,观察其对胰岛素和肌肉收缩引起的I型肌纤维占大多数的离体大鼠比目鱼肌葡萄糖跨膜转运的影响 ,了解PLD在信号转导体系中的作用。用同位素双标法测定胰岛素或肌肉收缩引起的葡萄糖跨膜转运速率 ,同时观察收缩力总量和收缩输出量时间变化曲线。结果 :同对照相比 ,丁醇可显著降低由胰岛素或肌肉收缩引起的肌细胞葡萄糖跨膜转运摄取速率 (P <0 .0 1) ,还明显影响肌肉的收缩力 (P <0 .0 1)。结论 :同在II型肌纤维中的作用一样 ,PDL也参与I型肌纤维中由胰岛素或肌肉收缩引起的肌细胞葡萄糖跨膜转运的信号转导系统。     

35%TBSA Ⅲ度烫伤大鼠肠内补液时葡萄糖电解质液的吸收效率研究

目的观察35% TBSA Ⅲ度烫伤早期肠内补液时电解质和水的吸收效率变化,了解葡萄糖对小肠吸收电解质溶液的影响。方法雄性Wistar大鼠30只,20%乌拉坦(100mg/kg)肌注麻醉后,行十二指肠和回肠插管,与输液泵相连。将林格液或葡萄糖-林格液作为灌流液置于37℃恒温水浴箱中,通过输液泵控制流速进行肠内补液并形成肠内灌流环路(灌流液-十二指肠插管-十二指肠-回肠-回肠插管-灌流液)。实验动物随机分为假烫补林格液组(假烫LR组)、烫伤补林格液组(烫伤LR组)和烫伤补葡萄糖-林格液组(烫伤LR/G组,林格氏液中加入20g/L的葡萄糖粉),每组10只。烫伤组采用沸水法(100℃,15s)造成35%TBSA Ⅲ度烫伤。各组于烫伤后0.5h按1/2Parkland公式量和速率(2ml.1%TBSA-1.kg-1)进行肠内补液,测定肠道对水分和Na 的吸收速率。伤后4h处死动物测定血Na 浓度和血细胞比容。结果与假烫LR组比较,两烫伤组小肠对水和Na 的吸收以及血Na 浓度均显著降低(P<0.01),血细胞比容显著增高(P<0.01),伤后3h烫伤LR组水和Na 的吸收效率仅为伤前的29.7%和34.5%。烫伤LR/G组对水和Na 的吸收优于烫伤LR组,从伤后2h起差别显著(P<0.05);伤后4h烫伤LR/G组血细胞比容显著低于烫伤LR组(P<0.05),但两组血Na 浓度无显著差异(P>0.05)。结论大鼠35% TBSA Ⅲ度烫伤早期小肠对水和电解质液的吸收效率显著降低,肠内补液时葡萄糖-电解质液的吸收效率和扩容效果优于单纯电解质溶液。     

骨骼肌丝裂原活化蛋白激酶信号级联与运动

运动是一个非常重要的刺激因素,可对骨骼肌中的多种代谢和转录过程起调节作用.MAPK信号级联中有多种独立的信号途径参与了骨骼肌运动性适应的细胞调控过程,对骨骼肌中葡萄糖转运,胰岛素信号转导,钾离子转运,工作肌的可塑性等产生影响.     

Sending the signal: molecular mechanisms regulating glucose uptake

The molecular signaling mechanisms by which insulin leads to increased glucose transport and metabolism and gene expression are not completely elucidated. We have characterized the nature of insulin signaling defects in skeletal muscle from Type 2 diabetic patients. Insulin receptor substrate (IRS-1) phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and glucose transport activity are impaired as a consequence of functional defects, whereas insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, and glycogen synthase activity are normal. Using biotinylated photoaffinity labeling, we have shown that reduced cell surface GLUT4 levels can explain glucose transport defects in skeletal muscle from Type 2 diabetic patients under insulin-stimulated conditions. Current work is focused on mechanisms behind insulin-dependent and insulin-independent regulation of glucose uptake. We have recently determined the independent effects of insulin and hypoxia/AICAR exposure on glucose transport and cell surface GLUT4 content in skeletal muscle from nondiabetic and Type 2 diabetic subjects. Hypoxia and AICAR increase glucose transport via an insulin-independent mechanism involving activation of 5'-AMP-activated kinase (AMPK). AMPK signaling is intact, because 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside (AICAR) increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation to a similar extent in Type 2 diabetic and nondiabetic subjects. However, AICAR responses on glucose uptake were impaired. Our studies highlight important AMPK-dependent and independent pathways in the regulation of GLUT4 and glucose transport activity in insulin resistant skeletal muscle. Understanding signaling mechanisms to downstream metabolic responses may provide valuable clues to a future therapy for Type 2 diabetes.     

Skeletal muscle pathways of contraction-enhanced glucose uptake

Muscle contraction acutely increases glucose transport in both healthy and type 2 diabetic individuals. Since glucose uptake during muscle contraction has been observed in the absence of insulin, the existence of an insulin-independent pathway has been suggested to explain this phenomenon. However, the exact mechanism behind the translocation of GLUT4 vesicles through the sarcolemma during muscle contraction is still unknown. Some substances, such as AMPK and calcium activated proteins, have been suggested as potential mediators but the exact mechanisms of their involvement remain to be elucidated. A hypothetical convergence point between the insulin cascade and the potential pathways triggered by muscle contraction has been suggested. Therefore, the earliest concept that two different routes exist in skeletal muscle has been progressively modified to the notion that glucose uptake is induced by muscle contraction via components of the insulin pathway. With further consideration, increased glucose uptake and enhanced insulin sensitivity observed during/after exercise might be explained by a metabolic- and calcium-dependent activation of several intermediate molecules of the insulin cascade. This paper aimed to review the literature in order to examine in detail these concepts behind muscle contraction-induced glucose uptake.     

烧伤后大鼠不同类型骨骼肌蛋白降解率的变化规律及其与糖皮质激素间的关系

为了解烧伤后不同类型骨骼肌蛋白降解率和血浆中糖皮质激素含量的变化 ,比较不同类型骨骼肌对烧伤刺激的反应 ,分析烧伤后骨骼肌萎缩的调节因子 ,应用 30 %Ⅲ度烫伤大鼠模型 ,借助骨骼肌充分氧供离体孵育系统 ,采用氨基酸全谱分析仪测定大鼠伤后不同时间点伸趾长肌和比目鱼肌蛋白降解率 ,用放射免疫分析测定大鼠血浆中糖皮质激素含量。结果发现 :烧伤后大鼠伸趾长肌总蛋白降解率和肌纤维蛋白降解率均明显增加 ,以烧伤后 12h和 2 4h为著 ,其中肌纤维蛋白降解率增幅明显 ;比目鱼肌总蛋白降解率和肌纤维蛋白降解率烧伤后均无显著变化 ;烧伤后不同时间点血浆糖皮质激素含量较正常对照组均显著增加 (P <0 0 1) ;伸趾长肌蛋白降解率与血浆糖皮质激素增加密切相关。说明烧伤后骨骼肌萎缩主要是由于肌纤维蛋白大量降解所致 ,快白肌比慢红肌对烧伤刺激敏感 ;糖皮质激素可能是导致骨骼肌蛋白降解增强的重要调节因子。     

Exercise and insulin sensitivity: a review

Physical activity has a beneficial effect on insulin sensitivity in normal as well as insulin resistant populations. A distinction should be made between the acute effects of exercise and genuine training effects. Up to two hours after exercise, glucose uptake is in part elevated due to insulin independent mechanisms, probably involving a contraction-induced increase in the amount of GLUT4 associated with the plasma membrane and T-tubules. However, a single bout of exercise can increase insulin sensitivity for at least 16 h post exercise in healthy as well as NIDDM subjects. Recent studies have accordingly shown that acute exercise also enhances insulin stimulated GLUT4 translocation. Increases in muscle GLUT4 protein content contribute to this effect, and in addition it has been hypothesized that the depletion of muscle glycogen stores with exercise plays a role herein. Physical training potentiates the effect of exercise on insulin sensitivity through multiple adaptations in glucose transport and metabolism. In addition, training may elicit favourable changes in lipid metabolism and can bring about improvements in the regulation of hepatic glucose output, which is especially relevant to NIDDM. It is concluded that physical training can be considered to play an important, if not essential role in the treatment and prevention of insulin insensitivity.     

老年人外周血液淋巴细胞β肾上腺素能受体的变化

在建立人外周血液淋巴细胞β受体放射配基结合分析法的基础上,观察了35名老年人外周血淋巴细胞β受体系统的变化。发现老年人的β受体B_(max)值明显低于青年人,其淋巴细胞对异丙肾上腺素刺激的反应性及腺苷酸环化酶活力均告降低。     

严重体表烫伤后大鼠比目鱼肌蛋白质代谢与TNF作用的机制探讨

为探讨重度烧（烫）伤早期局部和远隔部位骨骼肌蛋白质代谢变化不一致的机制，以包括一侧后肢的３７％体表皮肤全层严重烫伤大鼠为模型，观察伤后第３天双后肢比目鱼肌蛋白质代谢变化及肿瘤坏死因子的作用。结果表明，烫伤局部骨骼肌蛋白质分解速率与ＴＮＦ浓度明显增高，证实ＴＮＦ可以增强在体骨骼肌蛋白质分解代谢，而ＴＮＦ单抗可以使伤肢比目鱼肌增高了的蛋白质分解代谢有明显的减轻作用，由此说明，ＴＮＦ在创伤早期局部骨骼肌     

Carbohydrate metabolism in skeletal muscle: an update of current concepts

We have reviewed carbohydrate metabolism in skeletal muscle with an emphasis on recent information. In this review a significant number of points have been made. These are summarized below. 1. CP and glycogen are concomitantly metabolized during short-term (less than or equal to 10 s) intense exercise. 2. Both epinephrine and contractile activity regulate glycogen use in muscle. 3. Glycogen sparing during exercise is promoted by fatty acids and probably glucose. 4. Glycogenesis increases during exercise in exercising muscle. 5. Ingested glucose is easily metabolized during exercise. 6. The heterogeneity in glucose uptake among muscles at rest and during exercise is likely not caused by blood flow differences per se. 7. Insulin binding, glucose transporters, glucose uptake, and glycogenesis are greater in ST than in FT muscles. 8. Acute changes in glucose metabolism are not always attributable to concomitant changes in insulin binding to its receptor. 9. Contractile activity alone will increase glucose uptake in muscle, and insulin is not required. 10. Insulin and contractile effects on glucose uptake are additive, suggesting that these stimuli mobilize different pools of glucose transporters. 11. Glycogen loss occurs in exercising and non-exercising muscle; therefore this substrate is not an appropriate index of muscle contractile activity. 12. Carbohydrate mobilization does not appear to be strictly determined by need for this substrate nor by the rate of muscle metabolism. 13. Glyconeogenesis from lactate occurs in ST and FT muscles and is regulated by pH.     

Decreased glucose uptake in the fetus after maternal exercise

Glucose uptake by muscle is stimulated by exercise. However, during pregnancy, insulin resistance develops in maternal skeletal muscle as a mechanism to spare glucose for use by the developing fetus. The purpose of this study was to determine whether a bout of exercise adversely affects glucose availability to the fetus by increasing glucose uptake in maternal muscle tissue. Pregnant (P) and nonpregnant (NP) rats were divided into rest and exercise groups. Immediately following a 50-min treadmill run, a bolus of glucose (1 g.kg-1) and tracer [1-3H]2-deoxyglucose was injected i.v., and rats underwent a 60-min i.v. glucose tolerance test (IVGTT), after which they were sacrificed. Although glucose levels were lower for P vs NP rats at all time points, prior exercise did not affect glucose levels in either P or NP rats. Plasma insulin levels were augmented in P compared with NP rats and were not significantly altered by prior exercise. Glucose/tracer accumulation was enhanced in red and white gastrocnemius in both P and NP rats, and in soleus of NP rats, by exercise. However, glucose/tracer accumulation in the fetus was decreased by 40% (P less than 0.01) in the exercised dams. These results indicate that uptake of glucose by the fetus is compromised following exercise, as a result of increased glucose uptake by maternal skeletal muscles.     

Muscle insulin resistance amended with exercise training: role of GLUT4 expression

PURPOSE: Muscle insulin resistance is characterized by the inability of a normal insulin concentration to produce a favorable rate of glucose uptake. The muscle of the obese Zucker rat is highly insulin resistant. The purpose of this review is to discuss the cellular defects associated with the muscle insulin resistance of the obese Zucker rat, as well as the mechanisms by which exercise training alleviates or compensates for these defects. Emphasis will be given to the importance of an increased GLUT4 expression on alleviating muscle insulin resistance. METHODS: A review of the relative research from my laboratory and the scientific literature was performed to obtain information on the muscle insulin resistance of the obese Zucker rat and its response to exercise training. RESULTS: The insulin resistance of the obese Zucker rat results from defects in the insulin signaling cascade, which limits translocation of the glucose transporter GLUT4 to the plasma membrane upon insulin binding to its receptor. Exercise training improves the muscle insulin resistance of obese Zucker rat but does not correct the defects in insulin signaling or GLUT4 translocation. The improvement in insulin resistance, i.e., glucose transport, is correlated with an increased expression of GLUT4 protein. Preventing GLUT4 overexpression during exercise training will inhibit the improvement in insulin-stimulated glucose transport. CONCLUSION: Exercise training does not correct but compensates for the defects in muscle insulin resistance by increasing expression of GLUT4. This increase in GLUT4 protein is essential for the improvement in muscle insulin resistance.