牛磺酸对大鼠胰岛素抵抗高血压的影响

目的探讨牛磺酸对胰岛素抵抗高血压大鼠的影响。方法在输注胰岛素和葡萄糖引起动物胰岛素抵抗高血压模型上，测量平均动脉压、心率、血糖，放射免疫法测定血浆胰岛素和内皮素及主动脉组织内皮素，用２－脱氧葡萄糖摄取评估骨骼肌葡萄糖转运活性，用乙醇沉淀法测定肌糖原合成，测定肝胰岛素清除。结果胰岛素抵抗高血压大鼠血压升高，心率加快，血糖和血浆胰岛素含量增加（Ｐ＜０．０１）。牛磺酸治疗可明显改善上述指标，并增加骨骼肌葡萄糖转运活性，促进肌糖原合成和肝胰岛素清除，同时减轻血浆和主动脉内皮素含量。结论牛磺酸治疗胰岛素抵抗高血压大鼠是有效的。     

自噬与糖尿病骨骼肌病变

骨骼肌占人类体成分的40％～ 50％,是摄取和利用葡萄糖的重要组织,70％的葡萄糖通过胰岛素依赖的方式被骨骼肌摄取;同时骨骼肌也是2型糖尿病患者发生胰岛素抵抗的重要靶组织.现有研究发现,2型糖尿病患者骨骼肌内细胞器发生重构、外膜细胞退化及凋亡、肌膜下线粒体减少、肌细胞内脂质沉积、慢肌纤维与快肌纤维比值降低等,在临床上表现为胰岛素抵抗、骨骼肌萎缩等糖尿病骨骼肌肌病特征.糖尿病骨骼肌病变的发病机制至今不甚明确,自噬可能是主要原因之一.     

糖尿病骨骼肌病变发病机制

葡萄糖是细胞生长的重要调节因子,而长期高血糖对机体内环境有着普遍的毒性,引起一系列病理反应.骨骼肌是全身利用葡萄糖最重要的组织之一,也是高血糖损害的主要靶位.肌无力、肌萎缩、肌肉酸痛是糖尿病的常见症状,而糖尿病肌病又加重外周胰岛素抵抗.     

糖尿病与肝病的关系及其诊治对策

肝脏在葡萄糖代谢和能量稳态中起重要作用,因为它是胰岛素作用及摄取和降解的主要器官.生理状态下,从消化道吸收入血的葡萄糖有30%～60%在肝脏被用于合成糖原或转化为氨基酸或脂肪酸.胰岛素促进肝细胞合成糖原并减少糖异生,同时增加骨骼肌摄取血糖并减少脂肪细胞分解.胰岛素抵抗(insulin resistance)或胰岛素缺乏时,脂肪组织分解增加,通过血液进入肝脏的游离脂肪酸增加,肝糖异生释放入血相应增多,伴肝脏合成糖原及骨骼肌摄取血糖减少,结果在诱发脂肪异位的同时可引起血糖升高和糖尿病.     

游离脂肪酸对骨骼肌葡萄糖利用的影响

胰岛素抵抗是2型糖尿病的关键环节,近年来发现在许多胰岛素抵抗状态下均伴有游离脂肪酸水平的升高,游离脂肪酸在胰岛素抵抗的发病机制中占有重要的地位。骨骼肌是胰岛素作用及胰岛素抵抗的主要部位,是葡萄糖代谢的重要组织。游离脂肪酸不仅可以干扰骨骼肌葡萄糖代谢的不同环节,而且还在胰岛素受体及受体后的信号转导方面发挥作用,降低胰岛素刺激的骨骼肌葡萄糖的转运。     

AMPK在运动介导的骨骼肌糖脂代谢中的作用

运动可以调节代谢酶的活性及表达,刺激骨骼肌代谢,增加脂肪酸氧化、葡萄糖转运和糖原合成,从而改善骨骼肌的胰岛素抵抗。AMP激活的蛋白激酶(AMPK)是参与这一过程的重要途径之一。AMPK是一个能量感受器,在运动时,它可以感受骨骼肌中增高的AMP/ATP而被激活,调节骨骼肌的代谢,促进脂肪酸氧化和葡萄糖转运,减少骨骼肌中甘油三酯的堆积,改善胰岛素抵抗。     

骨骼肌线粒体异常在胰岛素抵抗形成中的作用

胰岛素抵抗及其相关疾病与机体的各种代谢异常密切相关.线粒体是调控代谢通路的重要细胞器,其功能的改变可对机体代谢产生极大影响.骨骼肌是胰岛素刺激葡萄糖利用的主要器官,同时也是富含线粒体和依赖氧化磷酸化供能的组织.因此,骨骼肌线粒体异常可能与胰岛素抵抗高度相关,其机制有待阐明.     

AMPK在运动介导的骨骼肌糖脂代谢中的作用

运动可以调节代谢酶的活性及表达，刺激骨骼肌代谢，增加脂肪酸氧化、葡萄糖转运和糖原合成，从而改善骨骼肌的胰岛素抵抗。AMP激活的蛋白激酶(AMPK)是参与这一过程的重要途径之一。AMPK是一个能量感受器，在运动时，它可以感受骨骼肌中增高的AMP／ATP而被激活，调节骨骼肌的代谢，促进脂肪酸氧化和葡萄糖转运，减少骨骼肌中甘油三酯的堆积，改善胰岛素抵抗。     

糖尿病性骨骼肌病变的研究进展

骨骼肌是葡萄糖摄取和利用的重要组织,也是胰岛素发挥作用的靶组织.骨骼肌病变可加重胰岛素抵抗(IR),进一步影响机体的糖代谢.糖尿病性骨骼肌病变常因其临床表现不典型而被忽视,其发病机制复杂,与血管性因素、神经性因素、代谢性因素、氧化应激、细胞凋亡、慢性炎性反应等均有关.因此,明确其临床特点及发病机制是近年来研究糖尿病性骨骼肌病变的重点.     

糖尿病治疗新药——葡萄糖激酶激活剂

糖尿病是由不同病因导致胰岛B细胞分泌胰岛素不足，及／或周围组织胰岛素抵抗，而引起的以血葡萄糖水平增高为特征的代谢性疾病群，表现为糖代谢异常、脂代谢异常及多种并发症的发生。高血糖是糖尿病的主要生化特征，其产生与肝脏及外周组织对葡萄糖的利用减少、肝糖生成增多有关。葡萄糖激酶（GK）近些年来逐渐被科研人员所重视，基于该靶点的小分子激活剂也就是葡萄糖激酶激活剂的研究也非常活跃。     

Effect of Chronic Alcoholism on Human Muscle Glycogen and Glucose Metabolism

To determine the effect of alcohol on carbohydrate metabolism, 48 human muscle biopsies from chronic alcoholics were studied. The level of glycogen and the activities of the enzymes catalyzing glycogen and glucose metabolism were analyzed. Chronic alcohol intake produced an increase in glycogen concentration and a decrease in pyruvate kinase activity before the first signs of myopathy appeared. When myopathy was present, glycogen decreased. These changes may contribute to the decline in skeletal muscle performance in these patients.     

肾上腺疾病中的骨骼肌胰岛素抵抗现象

多种肾上腺疾病存在骨骼肌胰岛素抵抗(IR)现象.醛固酮通过影响胰岛素受体功能和信号转导,或通过诱导氧化应激导致骨骼肌IR;糖皮质激素干扰胰岛素信号和糖原合成,或促进脂肪分解,减少骨骼肌胰岛素介导的葡萄糖摄取;儿茶酚胺诱导或加重骨骼肌IR,可能与血清脂联素水平下降有关;肾上腺偶发瘤患者骨骼肌IR发生率增加,这可能与亚临床...     

Obstructive Jaundice Results in Increased Liver Expression of Uncoupling Protein 2 and Intact Skeletal Muscle Glucose Metabolism in the Rat

Background: A majority of patients with pancreatic cancer have obstructive jaundice and diabetes with skeletal muscle insulin resistance. Surgery for these patients is associated with significant morbidity. Uncoupling protein 2 (UCP2) has been proposed to regulate energy expenditure and promote liver vulnerability. The effects of obstructive jaundice on muscle glucose metabolism and expression of UCP2 in liver and muscle are unknown. Methods: Rats were operated with bile duct ligation (BDL). After 7 days, UCP2 mRNA levels were determined in liver and muscle. Simultaneously, insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle were analyzed in vitro. Results: The jaundiced rats lost more weight than pair-fed controls. UCP2 mRNA levels were increased 5-fold in liver but not in muscle in jaundiced rats compared to pair-fed controls. The jaundiced rats were hypoglycemic and hypoinsulinemic but demonstrated intact or enhanced insulin action on skeletal muscle glucose transport and glycogen synthesis in vitro. Muscle glycogen content was increased in the jaundiced rats. Conclusions: Experimental obstructive jaundice in the rat is associated with increased liver expression of UCP2, rapid weight loss, and intact insulin action on skeletal muscle glucose metabolism. Obstructive jaundice, by upregulated liver UCP2, may contribute to the cachexia and high surgical morbidity observed in these patients, but not to skeletal muscle insulin resistance in pancreatic cancer patients.     

Obstructive jaundice results in increased liver expression of uncoupling protein 2 and intact skeletal muscle glucose metabolism in the rat

BACKGROUND: A majority of patients with pancreatic cancer have obstructive jaundice and diabetes with skeletal muscle insulin resistance. Surgery for these patients is associated with significant morbidity. Uncoupling protein 2 (UCP2) has been proposed to regulate energy expenditure and promote liver vulnerability. The effects of obstructive jaundice on muscle glucose metabolism and expression of UCP2 in liver and muscle are unknown. METHODS: Rats were operated with bile duct ligation (BDL). After 7 days, UCP2 mRNA levels were determined in liver and muscle. Simultaneously, insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle were analyzed in vitro. RESULTS: The jaundiced rats lost more weight than pair-fed controls. UCP2 mRNA levels were increased 5-fold in liver but not in muscle in jaundiced rats compared to pair-fed controls. The jaundiced rats were hypoglycemic and hypoinsulinemic but demonstrated intact or enhanced insulin action on skeletal muscle glucose transport and glycogen synthesis in vitro. Muscle glycogen content was increased in the jaundiced rats. CONCLUSIONS: Experimental obstructive jaundice in the rat is associated with increased liver expression of UCP2, rapid weight loss, and intact insulin action on skeletal muscle glucose metabolism. Obstructive jaundice, by upregulated liver UCP2, may contribute to the cachexia and high surgical morbidity observed in these patients, but not to skeletal muscle insulin resistance in pancreatic cancer patients.     

Negative regulation of glucose metabolism in human myotubes by supraphysiological doses of 17β-estradiol or testosterone

Objective

Exposure of skeletal muscle to high levels of testosterone or estrogen induces insulin resistance, but evidence regarding the direct role of either sex hormone on metabolism is limited. Therefore, the aim of this study was to investigate the direct effect of acute sex hormone exposure on glucose metabolism in skeletal muscle.

Materials/Methods

Differentiated human skeletal myotubes were exposed to either 17β-estradiol or testosterone and metabolic characteristics were assessed. Glucose incorporation into glycogen, glucose oxidation, palmitate oxidation, and phosphorylation of key signaling proteins were determined.

Results

Treatment of myotubes with either 17β-estradiol or testosterone decreased glucose incorporation into glycogen. Exposure of myotubes to 17β-estradiol reduced glucose oxidation under basal and insulin-stimulated conditions. However, testosterone treatment enhanced basal palmitate oxidation and prevented insulin action on glucose and palmitate oxidation. Acute stimulation of myotubes with testosterone reduced phosphorylation of S6K1 and p38 MAPK. Exposure of myotubes to either 17β-estradiol or testosterone augmented phosphorylation GSK3β^Ser9 and PKCδ^Thr505, two negative regulators of glycogen synthesis. Treatment of myotubes with a PKC specific inhibitor (GFX) restored the effect of either sex hormone on glycogen synthesis. PKCδ silencing restored glucose incorporation into glycogen to baseline in response to 17β-estradiol, but not testosterone treatment.

Conclusion

An acute exposure to supraphysiological doses of either 17β-estradiol or testosterone regulates glucose metabolism, possibly via PKC signaling pathways. Furthermore, testosterone treatment elicits additional alterations in serine/threonine kinase signaling, including the ribosomal protein S6K1 and p38 MAPK.     

Effect of dietary fish oil on insulin sensitivity and metabolic fate of glucose in the skeletal muscle of normal rats

The aim of this work was to study the effect of the administration of cod liver oil on the non-oxidative and oxidative fate of glucose metabolism in the skeletal muscle of normal rats. To achieve this goal, the gastrocnemius was examined regarding glucose oxidation, glycogen synthase activity and glycogen storage both at baseline and during euglycemic hyperinsulinemic clamping. The results show that dietary fish oil decreases plasma insulin levels without alteration in glucose homeostasis (at baseline). In addition, the observed enhancement in whole body glucose utilization during clamping suggests an increased peripheral insulin sensitivity. Furthermore, under insulin-stimulated glucose disposal, an enhancement in the glycolytic pathway (increased levels of muscle glucose-6-phosphate and plasma lactate) rather than changes in the oxidation (pyruvate dehydrogenase complex) and storage components of glucose metabolism was observed in the skeletal muscle of rats fed dietary fish oil. These results coupled with the hypolipidemic effects of fish oil may have implications for the prevention and/or management of some pathological states manifested by insulin resistance with or without dyslipidemia.     

Obesity and insulin resistance: lessons learned from the Pima Indians

Diabetes and obesity are epidemic in the Pima Indians of the Southwestern United States, and the prevalence of diabetes is increasing. The most likely link between obesity and diabetes is tissue insulin resistance. If obesity is defined as an excess of body fat, then it can only be accurately assessed by measurements of body composition and not by approximations such as body mass index or percent of ideal weight. To compare the metabolic data of individuals of varying size, an accurate measure of metabolic size is needed. Total body weight is not an appropriate means of comparing individuals since obese subjects have a greater proportion of nonmetabolizing mass (triglyceride). Body surface area shows a sex difference, and this may distort data if both sexes are present. From studies of metabolic rate we have determined that metabolic rate is directly proportional to the fat-free mass plus 18 kg, and we suggest that this weight can be equated with metabolic size. Glucose storage in skeletal muscle appears to be important in the disposal of an intravenous glucose load. Consistent with its role in glycogen storage, glycogen synthase enzyme is activated in proportion to the ability to dispose of glucose during a hyperinsulinemic, euglycemic clamp. The role of glycogen synthase is most notable at supraphysiological plasma insulin concentrations; and since glucose uptake at these insulin concentrations is highly familial independent of the degree of obesity, we suggest that there may be a specific genetic defect expressed in skeletal muscle that reduces insulin responsiveness in some subjects. The lack of correlation between 24 hour respiratory quotient measured in a metabolic chamber (a measure of the proportion of fat derived calories) and degree of obesity indicates that in obese Pima Indians insulin resistance is not due to an inhibition of glucose metabolism by free fatty acids (glucose-fatty acid-ketone cycle). Obesity is associated with an increase in fat-free mass almost kilogram- for kilogram with fat mass when compared to the lean state. A role for this increase in fat-free tissue in producing insulin resistance has been given insufficient attention in the past. With an increase in fat-free mass, muscle cells are hypertrophied and capillaries in muscle are more widely spaced. We propose that these biophysical changes in muscle mediate, at least in part, the effects of obesity to produce a reduction in insulin sensitivity and the abnormal kinetics of insulin action found in the obese.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hyperglycaemia compensates for the defects in insulin-mediated glucose metabolism and in the activation of glycogen synthase in the skeletal muscle of patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary Insulin resistance and a defective insulin activation of the enzyme glycogen synthase in skeletal muscle during euglycaemia may have important pathophysiological implications in Type 2 (non-insulin-dependent) diabetes mellitus. Hyperglycaemia may serve to compensate for these defects in Type 2 diabetes by increasing glucose disposal through a mass action effect. In the present study, rates of whole-body glucose oxidation and glucose storage were measured during fasting hyperglycaemia and isoglycaemic insulin infusion (40 mU·m^–2min^–1, 3 h) in 12 patients with Type 2 diabetes. Eleven control subjects were studied during euglycaemia. Biopsies were taken from the vastus lateralis muscle. Fasting and insulin-stimulated glucose oxidation, glucose storage and muscle glycogen synthase activation were all fully compensated (normalized) during hyperglycaemia in the diabetic patients. The insulin-stimulated increase in muscle glycogen content was the same in the diabetic patients and in the control subjects. Besides hyperglycaemia, the diabetic patients had elevated muscle free glucose and glucose 6-phosphate concentrations. A positive correlation was demonstrated between intracellular free glucose concentration and muscle glycogen synthase fractional velocity insulin activation (0.1 mmol/l glucose 6-phosphate: r=0.65, p<0.02 and 0.0 mmol/l glucose 6-phosphate: r= 0.91, p<0.0001). In conclusion, this study indicates an important role for hyperglycaemia and elevated muscle free glucose and glucose 6-phosphate concentrations in compensating (normalizing) intracellular glucose metabolism and skeletal muscle glycogen synthase activation in Type 2 diabetes.