能量代谢分子SIRT1在运动改善2型糖尿病骨代谢中的作用机制

文题释义：沉默信息调节因子1(silent information regulator 1,SIRT1)：是调控能量代谢的关键因子,其通过细胞氧化还原等途径来介导能量代谢、基因转录、细胞衰老等生理学过程。研究发现,SIRT1在调控成骨细胞和破骨细胞分化、增殖和活性上均扮演重要角色。骨代谢：骨的功能是为肌肉收缩提供附着处及保护内脏等重要的生命器官。一般认为骨在细胞水平上是不活跃的,事实上骨的细胞在不停地进行着细胞代谢,不仅骨的细胞之间会相互作用,还存在骨髓中的红细胞生成细胞、基质细胞相互作用,以进行骨的改建和重建。背景：能量代谢调控2型糖尿病骨代谢是近来生命医学领域的研究热点。长期糖、脂等能量代谢的紊乱导致胰岛素抵抗,引发2型糖尿病。而沉默信息调节因子1(SIRT1)作为一种烟酰胺腺嘌呤二核苷酸(NAD+)依赖的组蛋白去乙酰化酶,是调控能量代谢关键因子,还参与骨代谢、基因转录、细胞衰老、凋亡及焦亡等。目的：分析近年来有关SIRT1在运动改善骨代谢中的作用机制的相关文献,研究其现状和研究进展。方法：在PubMed、CNKI等数据库进行检索,中文关键词：SIRT1,运动,2型糖尿病,骨形成,骨吸收;英文关键词：SIRT1, exercise, type 2 diabetes,bone formation, bone resorption。结果与结论：①成骨细胞和破骨细胞的分化和功能发挥以及相互之间的代谢平衡是保障骨代谢稳态的关键。而一旦发生紊乱将会导致骨组织形态结构退化,这也是2型糖尿病并发症骨质疏松发生的重要机制;②能量代谢紊乱是引发2型糖尿病的关键,那么SIRT1作为调控能量代谢关键因子,其可通过Wnt、转化生长因子β等途径介导成骨细胞和破骨细胞分化及功能;③近来,研究发现运动可显著改善2型糖尿病的能量代谢和骨代谢,文章从成骨细胞、破骨细胞出发,通过综述目前国内外相关研究,探究SIRT1在运动改善2型糖尿病骨代谢中的作用机制。ORCID: 0000-0002-3135-9409(张路遥)中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes

Patients with type 1 diabetes (T1D) suffer excessive morbidity and mortality after myocardial infarction (MI) that is not fully explained by the metabolic effects of diabetes. Acute MI is known to trigger a profound innate inflammatory response with influx of mononuclear cells and production of proinflammatory cytokines that are crucial for cardiac repair. We hypothesized that these same pathways might exert "adjuvant effects" and induce pathological responses in autoimmune-prone T1D hosts. Here, we show that experimental MI in nonobese diabetic mice, but not in control C57BL/6 mice, results in a severe post-infarction autoimmune (PIA) syndrome characterized by destructive lymphocytic infiltrates in the myocardium, infarct expansion, sustained cardiac autoantibody production, and T helper type 1 effector cell responses against cardiac (α-)myosin. PIA was prevented by inducing tolerance to α-myosin, demonstrating that immune responses to cardiac myosin are essential for this disease process. Extending these findings to humans, we developed a panel of immunoassays for cardiac autoantibody detection and found autoantibody positivity in 83% post-MI T1D patients. We further identified shared cardiac myosin autoantibody signatures between post-MI T1D patients and nondiabetic patients with myocarditis, which were absent in post-MI type 2 diabetic patients, and confirmed the presence of myocarditis in T1D by cardiac magnetic resonance imaging techniques. These data provide experimental and clinical evidence for a distinct post-MI autoimmune syndrome in T1D. Our findings suggest that PIA may contribute to worsened post-MI outcomes in T1D and highlight a role for antigen-specific immunointervention to selectively block this pathway.     

State of the union between metabolism and the immune system in type 2 diabetes

Lymphocytes and myeloid cells (monocyte/macrophages) have important roles in multiple types of diseases characterized by unresolved inflammation. The relatively recent appreciation of obesity, insulin resistance and type 2 diabetes (T2D) as chronic inflammatory diseases has stimulated interest in understanding the role of immune cells in metabolic imbalance. Myeloid cells regulate inflammation through cytokine production and the adipose tissue remodeling that accompanies hyper-nutrition, thus are critical players in metabolic homeostasis. More recently, multiple studies have indicated a role for T cells in obesity-associated inflammation and insulin resistance in model organisms, with parallel work indicating that pro-inflammatory changes in T cells also associate with human T2D. Furthermore, the expansion of T cells with similar antigen-binding sites in obesity and T2D indicates these diseases share characteristics previously attributed to inflammatory autoimmune disorders. Parallel pro-inflammatory changes in the B-cell compartment of T2D patients have also been identified. Taken together, these studies indicate that in addition to accepted pro-inflammatory roles of myeloid cells in T2D, pro-inflammatory skewing of both major lymphocyte subsets has an important role in T2D disease pathogenesis. Basic immunological principles suggest that alterations in lymphocyte function in obesity and T2D patients are an integral part of a feed-forward pro-inflammatory loop involving additional cell types. Importantly, the pro-inflammatory loop almost inevitably includes adipocytes, known to respond to pro-inflammatory, pro-diabetogenic cytokines originating from the myeloid and lymphoid compartments. We propose a model for inflammation in T2D that functionally links lymphocyte, myeloid and adipocyte contributions, and importantly proposes that tools for B-cell ablation or regulation of T-cell subset balance may have a place in the endocrinologist's limited arsenal.     

2型糖尿病大鼠骨质疏松模型的建立

BACKGROUND: Diabetes mellitus can give rise to bone metabolic disorders that may involve long-term hyperglycemia, hypoglycemic agents, diet control, estrogen, insulin-like growth factor, leptin, body mass, sex and age.     

Structure and metabolism of lipoproteins

Lipoproteins constitute in plasma a dynamic system allowing lipid transport. For this purpose, apolipoproteins play a very important part. They control and regulate lipid transfer between lipoproteins themselves and among cells, from their hepatic as intestinal synthesis sites to their hepatic as peripheral degradation sites. Enzymatic systems and specific receptors are involved to operate this metabolic pathway.     

Prevention of type 2 diabetes

The prevalence of diabetes is increasing worldwide. The World Health Organisation has estimated that there will be around 300 million diabetics by 2025. The largest increase will occur in Asia. The prevalence of type 2 diabetes is increasing due to a combination of factors: increasing lifespan, sedentary lifestyle, excessive intake of high energy foods, increasing prevalence of overweight/obese people. The Finnish Diabetes Prevention Study Group has clearly shown that changes in the lifestyle of both overweight men and women with impaired glucose tolerance can reduce the incidence of type 2 diabetes by 58%. This finding was confirmed by the Diabetes Prevention Programme which found that lifestyle intervention in individuals with impaired fasting glucose or impaired glucose tolerance reduced the risk of developing type 2 diabetes by 58%, whereas treatment with metformin reduced the risk of type 2 diabetes by only 31%. Both acarbose and troglitazone have also been shown to reduce the progression to diabetes in individuals who are at high risk of developing type 2 diabetes. Since the cure for diabetes remains some way off our concerted efforts should be directed at prevention of diabetes in order to curb the increasing prevalence of diabetes worldwide. Lifestyle changes are more beneficial than long term drug therapy in the prevention of diabetes and should be actively promoted.     

Specificity of the lipoproteins metabolism in rats

The article reviews the data on rat lipoproteins metabolism and points to some principal differences from that in humans. Sixteen such differences are described concerning spectrum of lipoproteins, their quantity and chemical composition, characteristics of biosynthesis and catabolism, absence of the systems of lipid transport between some classes of lipoproteins.     

Hyperhomocysteinaemia and type 2 diabetes

OBJECTIVES: Hyperhomocysteinaemia is associated with cardiovascular events in nondiabetic individuals. The present study was aimed to explore the implication of hyperhomocysteinemia in development of cardiovascular events in patients with type 2 diabetes. DESIGN: A total of 185 patients with type 2 diabetes (115 women and 70 men, 30 to 93 years of age) have been included consecutively in the ambulatory unit at the Saint-Philibert Hospital. For each patient the concentration of homocysteine, cholesterol and triglyceride levels and HbA1c have been measured. In the studied population, 121 patients presented cardiovascular events (myocardial infarctus, peripheric arteriopathy, cerebrovascular accident). RESULTS: The patients with cardiovascular events were older, the concentration of homocysteine and creatinine were higher. The plasma homocysteine levels adjusted for age and creatinine levels were higher in patients with cardiovascular events than in patients without cardiovascular events (15.4 +/- 3.52 micromol/L and 13.13 +/- 2.26 micromol/L respectively; p = 2. 10(-5)). CONCLUSIONS: Hyperhomocysteinemia is an independant risk factor for cardiovascular events in type 2 diabetes, independent of age and renal function.     

Structure and metabolism of plasma lipoproteins

Blood plasma contains lipoproteins of which the structure and the composition are not constant during the time and that depend on their metabolic evolution from their synthesis rate in intestine or liver to their utilization in the liver or the peripheral tissues. The composition and the pathway of the different lipoprotein classes (chylomicrons, VLDL, LDL, HDL) are reviewed, as also the main pathological perturbations that attack them.     

Hypothalamic pathogenesis of type 2 diabetes

There have recently been increasing experimental and clinical evidences suggesting that hypothalamic dysregulation may be one of the underlying mechanisms of abnormal glucose metabolism. First, increased hypothalamic-pituitary-adrenal axis activity induced by uncontrollable excess stress may cause diabetes mellitus as well as dyslipidemia, visceral obesity, and osteoporosis with some resemblance to Cushing's disease. Second, several molecules are known to be expressed both in pancreas and hypothalamus; adenosine triphosphate-sensitive potassium channels, malonyl-CoA, glucokinase, and AMP-activated protein kinase. Those molecules appear to form an integrated hypothalamic system, which may sense hypothalamic fuel status, especially glucose level, and inhibit action of insulin on hepatic gluconeogenesis, thereby forming a brain-liver circuit. Third, hypothalamic resistance to insulin as an adiposity signal may be involved in pathogenesis of peripheral insulin resistance. The results with mice with a neuron-specific disruption of the insulin receptor gene or those lacking insulin receptor substrate 2 in hypothalamus supported this possibility. Finally, it has very recently been suggested that dysregulation of clock genes in hypothalamus may cause abnormal glucose metabolism. Taken together, it is plausible that some hypothalamic abnormality may underlie at least some portion of type 2 diabetes or insulin resistance in humans, and this viewpoint of hypothalamic pathogenesis of type 2 diabetes may lead to the development of new drugs for type 2 diabetes.