骨钙素对糖代谢影响的研究进展

骨钙素,亦称γ-羧基骨蛋白、骨谷氨酸蛋白和骨依赖维生素K蛋白,是一种由非增殖期成骨细胞合成的分泌蛋白,经过翻译后加工生成羧化骨钙素而参与骨骼发育。既往研究认为它是骨形成和骨转化的标志。然而最新研究发现,未发生羧化修饰的骨钙素对糖代谢有一定的影响作用,可促进胰腺β细胞增殖和胰岛素分泌,减弱胰岛素抵抗。多项研究证实高血糖可影响骨钙素合成,骨钙素在糖尿病患者中降低,糖尿病患者因胰岛素分泌和作用缺陷对胰岛素受体作用减弱,影响成骨细胞摄取核酸、氨基酸、胶原纤维合成,使其合成分泌骨钙素减少。这些研究确立了骨钙素为一种可以影响糖代谢的重要激素,拓展了对骨骼功能影响的同时也为新型降血糖药物的开发提供了新靶点。本文针对骨钙素对糖代谢的影响做一综述。     

成纤维细胞生长因子21对1型糖尿病动物模型的肝糖代谢影响及机制研究

成纤维细胞生长因子(FGF)-21是FGF家族的成员之一.作为近年发现的一种新的糖代谢调节因子,大量研究表明,FGF-21是一种不依赖胰岛素,能够独立降糖的2型糖尿病治疗潜力型药物.但是,能否应用于1型糖尿病的治疗,国内外目前尚无报道.通过改良传统造模方法,诱导小鼠缓慢产生糖耐量异常,研究FGF-21对此类模型的糖代谢影响及肝糖代谢机制.通过检测FGF-21短期注射和长期注射后模型动物血糖的变化,研究FGF-21在模型动物上对血糖的调控效果.采用实时定量PCR检测FGF-21对模型动物肝脏中葡萄糖转运蛋白(GLUT)1、4 mRNA的表达影响.利用蒽酮法检测模型动物肝脏中糖原合成量.实验结果显示,FGF-21能够调节1型糖尿病动物的血糖水平,并呈剂量依赖性.同时,首次在1型糖尿病动物模型上证实了低剂量FGF-21(0.125 mg/kg)与胰岛素的协同作用效果优于相同剂量FGF-21和胰岛素单独注射的效果.治疗结果表明,FGF-21能够维持1型糖尿病动物模型血糖在正常范围,效果优于胰岛素.实时定量PCR结果发现,与胰岛素上调GLUT4 mRNA表达量不同的是,FGF-21作用动物模型8周后,GLUT1 mRNA表达量显著提高,长期的FGF-21与胰岛素协同注射使GLUT1、4 mRNA表达量同时显著提高.长期FGF-21与胰岛素协同注射组和高剂量FGF-21注射均可显著提高模型动物肝糖原的合成.结果表明,FGF-21促进动物模型糖代谢机制与增加GLUT1表达、增加糖原合成作用有关.为临床应用FGF-21治疗1型糖尿病,增加胰岛素敏感性提供了理论依据.     

抑制胰岛肝脏移植排异反应有新法

作为重度糖尿病的有效疗法,胰岛肝脏移植目前广受关注,但移植后的排异反应严重影响手术的成功率。日本研究人员新开发出一种抑制排异反应的方法,有望促进胰岛肝脏移植的成功。为调节体内血糖浓度,重度糖尿病患者必须每天接受胰岛素注射。胰岛肝脏移植即从捐献者的胰腺内提取负责分泌胰岛素的细胞组织——胰岛,再把它植入重度糖尿病患者的肝脏。接受胰岛肝脏移植手术的     

1型糖尿病治疗方法的回顾与展望

1型糖尿病是由包括病毒感染、药物接触及自身免疫在内的各种原因导致的胰岛β细胞凋亡所引起的,主要表现为由血清中胰岛素的绝对缺乏引起的高血糖。在过去数十年中,外源补充胰岛素一直是1型糖尿病的最主要治疗方法。随着人们对1型糖尿病机制的深入了解及生命科学相关技术的发展,科研工作者及临床医生开始探索治疗1型糖尿病的新方法,其中包括将分泌胰岛素的外源胰岛或干细胞移植入体内。或将胰岛素基因直接导入体内,合成并分泌体内缺乏的胰岛素等。本文对胰岛移植、干细胞和基因疗法用于治疗1型糖尿病的主要方式做一简要回顾与综述,并重点讨论近年来的研究进展及其临床应用的可行性。     

Asprosin与代谢等疾病关系的研究进展

白脂素(Asprosin)是2016年由Romere,C.发现的一种新的脂肪因子,由白色脂肪分泌,到达肝脏,促进肝糖释放,具有昼夜节律,其分泌水平受饮食和运动影响,在胰岛素抵抗的人和鼠体内升高。Asprosin以嗅觉受体OLFR734为受体调节肝脏葡萄糖生成,促进肝糖释放,维持葡萄糖稳态;穿过血脑屏障作用于神经元促进摄食;作用于胰腺介导β细胞炎症和β细胞功能障碍;作用于骨骼肌引起胰岛素敏感性降低。近几年,很多研究提示asprosin与糖尿病、肥胖、多囊卵巢综合征及冠心病等多种疾病相关,有望成为这些疾病的潜在治疗靶点。     

胰岛β细胞"质"、"量"的辩证关系——"质"的三要素

高血糖是糖尿病典型的病理特征,血糖的波动是决定糖尿病患者是否出现并发症的重要因素,而由胰岛β细胞合成分泌的胰岛素,是体内唯一可以降低血糖的多肽类激素.胰岛β细胞"质"与"量"决定着体内胰岛素分泌情况和血糖的调控.围绕"促进β细胞损伤修复,提升胰岛β细胞质量是治疗糖尿病的核心"之理念,提出构成胰岛β细胞"质"的三要素:细胞结构、"真""假"胰岛素和胰岛素调节型分泌.旨在为β细胞质量评价和糖尿病机制研究提供一定的理论参考.     

诱导回输胰岛素分泌细胞对大鼠糖尿病的疗效

目的:研究胰岛素分泌细胞的体外诱导方法及其对大鼠糖尿病的疗效.方法:分离培养大鼠骨髓干细胞,用尼克酰胺及肠促胰岛素类似物诱导其分化为胰岛素分泌细胞.将24只Wistar大鼠随机分为对照组、糖尿病组和诱导组.后两组建立糖尿病模型,将该胰岛素分泌细胞回输至诱导组体内,监测大鼠体重、血糖(空腹及OGTT 120分血糖)及空腹...     

葡萄糖激酶激活剂研究进展

葡萄糖激酶分布在体内多个脏器中,可感应葡萄糖和调节糖代谢激素,在稳定血糖水平方面起到重要作用。葡萄糖激酶激活剂系 针对这一靶点而开发,能够通过葡萄糖浓度刺激的胰岛素分泌、降低胰高血糖素浓度和肝糖输出、促进肝糖原合成以及调控肠促胰素释 放等机制来稳定体内血糖水平,近年来已成为2 型糖尿病新型药物研发的热点。介绍现有葡萄糖激酶激活剂药物的开发策略、作用特点 及临床研究进展。     

子宫内膜糖原代谢在胚胎着床中的作用研究进展

糖原的合成与分解可动态调节体内葡萄糖含量以维持细胞内变化的能量需求。胰岛素作为体内唯一降血糖的激素,通过作用于磷脂酰肌醇3-激酶(phosphatidylinositol 3-kinase, PI3K)/蛋白激酶B (Akt)信号通路,促进葡萄糖转运体转位以促进糖原合成,也可抑制糖异生以降低血糖。而子宫内膜糖代谢有其特殊性,不发生糖异生,尚未被利用的葡萄糖均以糖原形式储存。子宫内膜的糖原代谢除受经典糖代谢激素调控外,还受卵巢激素调控。子宫内膜在着床窗口期发生的与着床有关的功能活动都需要葡萄糖供给能量。着床前子宫内膜上皮细胞内大量葡萄糖合成糖原,在着床窗口期分解为葡萄糖,以满足增加的能量需求,保证胚胎着床的顺利进行。糖尿病时子宫内膜糖原代谢受损,糖原合成或分解异常可导致胚胎着床失败、早期流产。本文就子宫内膜的糖原代谢及其在胚胎着床中的作用等方面进行综述,以期为胚胎着床的研究及不孕诊断和治疗提供新思路。     

Tanis与胰岛素抵抗

Tanis是新发现的由189个氨基酸残基组成的蛋白质,在肝脏、脂肪和骨骼肌等组织都有其基因表达．可能作为血清淀粉样蛋白A受体参与糖代谢,并与胰岛素抵抗、Ⅱ型糖尿病的发生与发展密切相关。Tanis在胰岛素抵抗、Ⅱ型糖尿病和代谢综合征动物模型的肝脏中表达水平与血糖及胰岛素浓度呈负相关．与血浆甘油三酯浓度呈正相关。Tanis的基因表达在禁食24h后的糖尿病动物模型中显增加,说明受葡萄糖调节。从目前的研究资料看,Tanis有可能成为治疗胰岛素抵抗、Ⅱ型糖尿病的新靶点而受到重视。     

Micro RNAs: tiny sequences with enormous potential

The liver plays a central role in glucose homeostasis in the whole-body by responding to environmental factors including nutrients, hormones, and oxygen. In conditions of metabolic overload such as diabetes mellitus and obesity, coordinated regulation between oxygen supply and consumption has been reported to be disrupted and subsequently cause tissue hypoxia, although pathological significance of the disease-related hypoxia remains elusive. To investigate the role of tissue hypoxia in the liver on systemic glucose homeostasis, mice lacking HIF-1α gene, a critical component of a master regulator of hypoxic response, in hepatocytes were exposed to high fat/sucrose diet (HFSD). Exposure to HFSD for 5 weeks elicited liver hypoxia with a transient increase in HIF-1α protein expression in the liver of control mice. Glucose disposal was marginally impaired in control mice when challenged oral glucose tolerance test, but such impairment was enhanced in the mutant mice. This alteration was accompanied by a complete inhibition of glucokinase induction with a significant reduction of hepatic glucose uptake. Mice fed HFSD for 20 weeks exhibited fasting hyperglycemia and glucose intolerance, whereas these metabolic phenotypes deteriorated considerably with severe insulin resistance in skeletal muscles and adipose tissues in the mutant mice. These findings suggest that HIF-1 in hepatocytes plays protective roles against the progression of diabetes mellitus.     

Diabetes and apoptosis: liver

The liver is a central regulator of glucose homeostasis and stores or releases glucose according to metabolic demands. In insulin resistant states or diabetes the dysregulation of hepatic glucose release contributes significantly to the pathophysiology of these conditions. Acute or chronic liver disease can aggravate insulin resistance and the physiological effects of insulin on hepatocytes are disturbed. Insulin resistance has also been recognized as an independent risk factor for the development of liver injury. In the healthy liver tissue homeostasis is achieved through cell turnover by apoptosis and dysregulation of the physiological process resulting in too much or too little cell death can have potentially devastating effects on liver tissue. The delineation of the signaling pathways that mediate apoptosis changed the paradigms of understanding of many liver diseases. These signaling events include cell surface based receptor-ligand systems and intracellular signaling pathways that are regulated through kinases on multiple levels. The dissection of these signaling pathways has shown that the regulators of apoptosis signaling events in hepatocytes can also modulate insulin signaling pathways and that mediators of insulin resistance in turn influence liver cell apoptosis. This review will summarize the potential crosstalk between apoptosis and insulin resistance signaling events and discuss the involved mediators.     

Diabetes mellitus: Metabolic effects and oxidative stress

Diabetes mellitus is a complex polygenic pathology, which is characterized by numerous metabolic disorders. Progressive hyperglycemia developing during this disease causes clinically significant tissue damage and is considered as a main risk factor of micro- and macrovascular complications leading to retinopathy, nephropathy, and neuropathy. Hyperglycemia-depended oxidative stress and impairments in nitric oxide bioavailability play an essential role in the pathogenesis of diabetes and its complications. Homeostasis of glucose maintained by metabolic effects of insulin includes an increase of glucose uptake by skeletal muscles and suppression of glucose production by the liver. M. Brownlee (2005) put forward a hypothesis assuming that oxidative stress is the main mechanism of diabetic tissue damages. According to this hypothesis, mitochondrial dysfunction and superoxide anion radical hyperproduction by mitochondria is the principal mechanism of activation of four pathways of hyperglycemia-induced impairments under diabetes. Two cell signaling cascades regulate the glucose homeostasis: insulin-mediated glucose uptake (IMGU) in skeletal muscles, liver, and heart and glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. In addition to nonspecific irreversible oxidative damage of DNA, protein and lipid molecules reactive oxygen and nitrogen species induce cell and tissue damage, activating a number of cell stress-sensitive signaling cascades. Stress-dependent serine phosphorylation of insulin receptor substrate (IRS) proteins decreases its capacity for tyrosine phosphorylation and may accelerate degradation of IRS. This process underlies the molecular mechanism of oxidative stress-induced insulin resistance.     

Metabolic regulation through the endosomal system

The endosomal system plays an essential role in cell homeostasis by controlling cellular signaling, nutrient sensing, cell polarity and cell migration. However, its place in the regulation of tissue, organ and whole body physiology is less well understood. Recent studies have revealed an important role for the endosomal system in regulating glucose and lipid homeostasis, with implications for metabolic disorders such as type 2 diabetes, hypercholesterolemia and non‐alcoholic fatty liver disease. By taking insights from in vitro studies of endocytosis and exploring their effects on metabolism, we can begin to connect the fields of endosomal transport and metabolic homeostasis. In this review, we explore current understanding of how the endosomal system influences the systemic regulation of glucose and lipid metabolism in mice and humans. We highlight exciting new insights that help translate findings from single cells to a wider physiological level and open up new directions for endosomal research.     

Lipid-induced Muscle Insulin Resistance Is Mediated by GGPPS via Modulation of the RhoA/Rho Kinase Signaling Pathway

Elevated circulating free fatty acid levels are important contributors to insulin resistance in the muscle and liver, but the underlying mechanisms require further elucidation. Here, we show that geranylgeranyl diphosphate synthase 1 (GGPPS), which is a branch point enzyme in the mevalonic acid pathway, promotes lipid-induced muscle insulin resistance through activation of the RhoA/Rho kinase signaling pathway. We have found that metabolic perturbation would increase GGPPS expression in the skeletal muscles of db/db mice and high fat diet-fed mice. To address the metabolic effects of GGPPS activity in skeletal muscle, we generated mice with specific GGPPS deletions in their skeletal muscle tissue. Heterozygous knock-out of GGPPS in the skeletal muscle improved systemic insulin sensitivity and glucose homeostasis in mice fed both normal chow and high fat diets. These metabolic alterations were accompanied by activated PI3K/Akt signaling and enhanced glucose uptake in the skeletal muscle. Further investigation showed that the free fatty acid-stimulated GGPPS expression in the skeletal muscle was able to enhance the geranylgeranylation of RhoA, which further induced the inhibitory phosphorylation of IRS-1 (Ser-307) by increasing Rho kinase activity. These results implicate a crucial role of the GGPPS/RhoA/Rho kinase/IRS-1 pathway in skeletal muscle, in which it mediates lipid-induced systemic insulin resistance in obese mice. Therefore, skeletal muscle GGPPS may represent a potential pharmacological target for the prevention and treatment of obesity-related type 2 diabetes.     

Construction of pancreas–muscle–liver microphysiological system (MPS) for reproducing glucose metabolism

Although in vitro models are widely accepted experimental platforms, their physiological relevance is often severely limited. The limitation of current in vitro models is strongly manifested in case of diseases where multiple organs are involved, such as diabetes and metabolic syndrome. Microphysiological systems (MPS), also known as organ-on-a-chip technology, enable a closer approximation of the human organs and tissues, by recreating the tissue microenvironment. Multiorgan MPS, also known as multiorgan-on-a-chip or body-on-a-chip, offer the possibility of reproducing interactions between organs by connecting different organ modules. Here, we designed a three-organ MPS consisting of pancreas, muscle, and liver, to recapitulate glucose metabolism and homeostasis by constructing a mathematical model of glucose metabolism, based on experimental measurement of glucose uptake by muscle cells and insulin secretion by pancreas cells. A mathematical model was used to modify the MPS to improve the physiological relevance, and by adding the liver model in the mathematical model, physiological realistic glucose and insulin profiles were obtained. Our study may provide a methodological framework for developing multiorgan MPS for recapitulating the complex interaction between multiple organs.     

Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction

The liver plays a central role in the control of glucose homeostasis and is subject to complex regulation by substrates, insulin, and other hormones. To investigate the effect of the loss of direct insulin action in liver, we have used the Cre-loxP system to inactivate the insulin receptor gene in hepatocytes. Liver-specific insulin receptor knockout (LIRKO) mice exhibit dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations are paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the LIRKO liver exhibits morphological and functional changes, and the metabolic phenotype becomes less severe. Thus, insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function.     

Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice

The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21 days (10 mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-α, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action.     

Melatonin modulates glucose homeostasis during winter dormancy in a vespertilionid bat,Scotophilus heathi

The role for melatonin in glucose homeostasis and insulin resistance is not very clear and has recently been an active area of investigation. The present study investigated the role of melatonin in seasonal accumulation of adipose tissue in Scotophilus heathi, with particular reference to its role in glucose homeostasis and development of insulin resistance. The circulating melatonin levels correlated positively (p < 0.05) with the changes in body mass due to fat accumulation and circulating insulin level, but correlated negatively with the blood glucose level in S. heathi. The bats showed high circulating blood glucose levels and impaired glucose tolerance during the period of fat deposition suggesting insulin resistance condition which improves after winter when most of the fat has been utilized as a metabolic fuel. The high circulating melatonin levels during the period of maximum body fat at the beginning of winter prepare the bats for winter dormancy by modulating the glucose homeostasis through affecting blood glucose levels, muscle and liver glycogen stores, insulin receptor and glucose transporter 4 (GLUT 4) expression. This is also confirmed by in vivo study in which melatonin injection improves the glucose tolerance, increases muscle insulin receptor and GLUT 4 expression, and enhances glucose clearance from the blood. The results of present study further showed that the effect of melatonin injection on the blood glucose levels is determined by the metabolic state of the bats and may protect from decrease in blood glucose level during extreme starvation, however, melatonin when injected during fed state increases glucose clearance from the blood. In summary, the present study suggested that melatonin interferes with the glucose homeostasis through modulating intracellular glucose transport and may protect bats from hypoglycemia during winter dormancy.     

骨骼的新认识——骨内分泌

骨骼被认为是一个动态结缔组织,具有重塑能力,以维持钙稳态和造血等功能。大量的研究显示,骨骼不仅作为结构支架,也作为内分泌器官调控代谢过程。除了传统的OPG、SOST、DKK等在骨形成、骨构成、骨重建以及骨稳态中扮演重要角色,骨骼还分泌特异性激素--骨钙素(osteocalcin, OCN)和成纤维细胞生长因子23(fibroblast growth factor 23, FGF23)。其中,骨钙素可促进β细胞增殖、胰岛素分泌、提高胰岛素敏感性,还可调节脂肪细胞、男性性腺内分泌活动和神经系统活性;成纤维细胞生长因子23通过对肾调节维持血磷内稳态。