自噬在非酒精性脂肪肝合并糖尿病中的作用

在一系列应激状态下,自噬会作为一种适应性免疫应答反应出现,是细胞的自我保护机制之一。研究表明,在非酒精性脂肪肝病的早期阶段,自噬增加有助于肝内脂质降解,缓解病情;而在后期阶段,自噬增加却会加剧病情发展。胰岛素抵抗可能会促使非酒精性肝病发生糖尿病,β细胞功能缺陷和胰岛素抵抗是2型糖尿病发病的两种最主要病理生理机制。多项研究证实,自噬增加能提高胰岛素敏感性,对维持胰岛β细胞的结构、数量以及功能也有重要作用。旨在阐述自噬在非酒精性脂肪肝病以及非酒精性脂肪肝病合并糖尿病治疗中的作用。     

ROS与细胞自噬在Ⅱ型糖尿病中的生物学作用

Ⅱ型糖尿病发病因素复杂,长期高血糖和高血脂刺激所产生的氧化应激反应能调节葡萄糖刺激的胰岛素分泌,促进胰岛β细胞凋亡、导致胰岛功能障碍,是糖尿病及其并发症发生发展中的一个重要因素;同时,细胞自噬作为一种分解代谢途径,在维持胰岛细胞内环境稳态中发挥重要作用。活性氧族(Reactive Oxygen Species,ROS)的产生是氧化应激的基本环节,同时与细胞自噬存在复杂密切的关系,ROS既有一定的细胞毒性损伤作用,同时还作为重要的细胞内分子,活化许多信号转导通路,特别是参与自噬的信号转导。本文就ROS与细胞自噬在糖尿病中的生物学作用进行综述,旨在探讨糖尿病的发生机制,为糖尿病的防治寻找新策略。     

我国干细胞治疗糖尿病的基础与临床研究

胰岛β细胞功能衰竭和胰岛素抵抗是导致糖尿病发生发展的主要机制,目前的抗糖尿病药物没有针对糖尿病发病的关键环节,只能解除或缓解症状,延缓疾病进展,不能从根本上治愈该疾病.干细胞通过促进胰岛β细胞原位再生,提高胰岛β细胞自噬能力、调节胰岛巨噬细胞功能修复受损的胰岛β细胞以改善胰岛β细胞功能;通过多种途径活化骨骼肌、脂肪和肝脏IRS(1)-AKT-GLUT4信号通路改善外周组织胰岛素抵抗,为糖尿病的精准治疗提供了新的方向.我国研究者针对不同来源的干细胞使用不同输注方式治疗1型糖尿病和2型糖尿病开展了系列研究,取得了良好的临床疗效,且未发生严重不良反应,为干细胞治疗糖尿病的临床应用奠定了基础.     

氧化应激与2型糖尿病

胰岛素抵抗、胰岛β细胞功能受损是2型糖尿病的主要病因。高血糖、高血脂导致在代谢过程中,线粒体产生大量活性氧,其可损坏线粒体功能,引起氧化应激反应。氧化应激可以激活细胞内的一系列应激信号通路,如JNK／SAPK、p38MAPK、IKKβ／NF-kβ和氨基己醣通路等。这些应激通路的激活可以产生以下结果：（1）阻断胰岛素作用通路,导致胰岛素抵抗;（2）降低胰岛素基因表达水平;（3）抑制胰岛素分泌;（4）促进β细胞凋亡等。本文主要针对活性氧的产生、氧化应激诱导胰岛素抵抗和胰岛β细胞功能受损等机制加以综述,以便进一步阐明2型糖尿病的发病机理。     

胰腺β细胞氧化还原状态对胰岛素加工与分泌的调控及其机制

胰腺β细胞的氧化还原异常不仅会引起β细胞凋亡,而且对胰岛素加工、分泌以及胰岛素抵抗也有重要的影响。近年来,国内外学者就胰腺β细胞氧化还原状态对胰岛素加工、分泌的影响及调控机制开展了大量的研究,取得了丰硕的成果,为2型糖尿病的防治提供了新思路和靶点。该文拟就胰岛素加工、分泌与细胞氧化还原状态的关系进行综述,以期进一步了解、认识2型糖尿病的发生和发展。     

氧化应激与2型糖尿病的研究进展

氧化应激与2型糖尿病(T2DM)的发生、发展密切相关.胰岛素抵搞(Insulin Resistance,IR)、胰岛β细胞功能受损是2型糖尿病的主要病因.而氧化应激可以直接及间接激活细胞内的一系列应激信号通路,如核因子κ-B(Nuclear factor-KappaB,NF-κB)、c-Jun氨基端激酶(NH-terminal Jun kinase,JNK)、蛋白激酶C(protein kinase C,PKC)、p38丝裂原活化蛋白激酶(Mitogen-activated protein kinase,MAPK)等.这些应激通路的激活可以产生以下结果:(1)阻断胰岛素作用通路,导致胰岛素抵抗;(2)降低胰岛素基因表达水平,致胰岛素合成和分泌减少;(3)促进胰岛β细胞凋亡等.本文针对氧化应激诱导胰岛素抵抗和胰岛β细胞功能受损等机制加以综述,以便进一步阐明2型糖尿病的发病机制.     

钙离子信号对胰岛素分泌的调控

胰岛素的分泌及其分泌的调控是维持机体内葡萄糖平衡的重要机制,胰岛素分泌量的不足会导致非胰岛素依赖的糖尿病的发生.胰岛素包裹在致密核心大囊泡中,胰腺β细胞通过调控致密核心大囊泡的胞吐过程来调节胰岛素的分泌.胞内Ca2 浓度是影响胰岛素分泌的重要因素.胰腺β细胞主要通过质膜上的ATP敏感的钾通道、钙通道和胞内钙库的活动改变胞内Ca2 浓度,从而调控β细胞胰岛素的分泌活动.     

运动、自噬和瘦素抵抗

瘦素抵抗是人类肥胖症的主要危险因素,高瘦素水平未能抑制摄食和减轻体重,导致机体能量调节失衡。自噬是一种细胞质量控制机制,可对细胞内物质进行周转。许多人类重大疾病的发生与自噬过程有关,如肥胖症、糖尿病和神经退行性疾病等。当细胞自噬出现障碍即自噬缺陷时,会导致机体发生瘦素抵抗。研究发现,运动是维持细胞稳态的自噬有效诱导剂,机体瘦素敏感性的提高可能与运动促进细胞自噬有关,但目前尚缺乏直接证据。     

保护胰岛β细胞的体外研究进展

糖尿病是一种由胰岛素分泌缺陷和（或）胰岛素作用缺陷引起的高血糖症性代谢疾病。自Edmonton临床试验取得成功后,胰岛移植成为一种新型治愈糖尿病的方法。但胰岛β细胞在体外分离过程中极易发生凋亡或死亡,且长期的体外培养或冷冻储存也容易令其胰岛素分泌功能逐渐丧失。因此,有效维持或改善β细胞的成活率及功能对胰岛移植的成功至关重要。对胰岛β细胞的体外保护方法进行阐述,并对其研究前景进行展望。     

线粒体自噬影响胰岛素抵抗的作用及机制

胰岛素抵抗（IR）是诱发许多代谢疾病的关键因素,包括代谢综合征、非酒精性脂肪性肝病、动脉粥样硬化和2型糖尿病（T2DM）。随着相关代谢疾病日益增多,寻找新的治疗靶点迫在眉睫。线粒体自噬是一种选择性自噬,其通过清除受损和功能失调的线粒体以维持正常线粒体功能和能量代谢。研究发现,线粒体自噬在代谢疾病中有积极作用,线粒体自噬受到各种信号通路与信号分子调控而改善代谢疾病,如AMPK/ULK1、PINK1/Parkin信号通路以及BNIP3/Nix和FUNDC1等信号分子。本文阐述了线粒体自噬在胰岛素抵抗中的作用及调控机制,综述了近年的相关研究进展。     

The role of autophagy in endoplasmic reticulum stress-induced pancreatic β cell death

In pancreatic β-cells, the endoplasmic reticulum (ER) is the crucial site for insulin biosynthesis, as this is where the protein-folding machinery for secretory proteins is localized. Perturbations to ER function of the β-cell, such as those caused by high levels of free fatty acid and insulin resistance, can lead to an imbalance in protein homeostasis and ER stress, which has been recognized as an important mechanism for type 2 diabetes. Macroautophagy (hereafter referred to as autophagy) is activated as a novel signaling pathway in response to ER stress. In this review, we outline the mechanism of ER stress-mediated β-cell death and focus on the role of autophagy in ameliorating ER stress. The development of drugs to take advantage of the potential protective effect of autophagy in ER stress, such as glucagon like peptide-1, will be a promising avenue of investigation.     

UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in β-cells

The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in β-cells and increased β-cell apoptosis attributable at least in part to intracellular toxic oligomers of IAPP (islet amyloid polypeptide). β-cells of individuals with T2DM are also characterized by accumulation of polyubiquitinated proteins and deficiency in the deubiquitinating enzyme UCHL1 (ubiquitin carboxyl-terminal esterase L1 [ubiquitin thiolesterase]), accounting for a dysfunctional ubiquitin/proteasome system. In the present study, we used mouse genetics to elucidate in vivo whether a partial deficit in UCHL1 enhances the vulnerability of β-cells to human-IAPP (hIAPP) toxicity, and thus accelerates diabetes onset. We further investigated whether a genetically induced deficit in UCHL1 function in β-cells exacerbates hIAPP-induced alteration of the autophagy pathway in vivo. We report that a deficit in UCHL1 accelerated the onset of diabetes in hIAPP transgenic mice, due to a decrease in β-cell mass caused by increased β-cell apoptosis. We report that UCHL1 dysfunction aggravated the hIAPP-induced defect in the autophagy/lysosomal pathway, illustrated by the marked accumulation of autophagosomes and cytoplasmic inclusions positive for SQSTM1/p62 and polyubiquitinated proteins with lysine 63-specific ubiquitin chains. Collectively, this study shows that defective UCHL1 function may be an early contributor to vulnerability of pancreatic β-cells for protein misfolding and proteotoxicity, hallmark defects in islets of T2DM. Also, given that deficiency in UCHL1 exacerbated the defective autophagy/lysosomal degradation characteristic of hIAPP proteotoxicity, we demonstrate a previously unrecognized role of UCHL1 in the function of the autophagy/lysosomal pathway in β-cells.     

The role of autophagy in pancreatic β-cell and diabetes

Pancreatic β-cells play a key role in glucose homeostasis in mammals. Although large-scale protein synthesis and degradation occur in pancreatic β-cells, the mechanism underlying dynamic protein turnover in β-cells remains largely unknown. We found low-level constitutive autophagy in β-cells of C57BL/6 mice fed a standard diet; however, autophagy was markedly upregulated in mice fed a high-fat diet. β-cells of diabetic db/db mice contained large numbers of autophagosomes, compared with non-diabetic db/misty controls. The functional importance of autophagy was analyzed using β-cell-specific Atg7 knockout mice. Autophagy-deficient mice showed degeneration of β-cells and impaired glucose tolerance with reduced insulin secretion. While a high-fat diet stimulated β-cell autophagy in control mice, it induced a profound deterioration of glucose intolerance in β-cell autophagy-deficient mutants, partly because of the lack of a compensatory increase in β-cell mass. These results suggest that the degradation of unnecessary cellular components by autophagy is essential for maintenance of the architecture and function of β-cells. Autophagy also serves as a crucial element of stress responses to protect β-cells under insulin resistant states. Impairment of autophagic machinery could thus predispose individuals to type 2 diabetes.     

mTORC2 Signaling: A Path for Pancreatic β Cell's Growth and Function

The mechanistic target of rapamycin (mTOR) signaling pathway is an evolutionary conserved pathway that senses signals from nutrients and growth factors to regulate cell growth, metabolism and survival. mTOR acts in two biochemically and functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which differ in terms of regulatory mechanisms, substrate specificity and functional outputs. While mTORC1 signaling has been extensively studied in islet/β-cell biology, recent findings demonstrate a distinct role for mTORC2 in the regulation of pancreatic β-cell function and mass. mTORC2, a key component of the growth factor receptor signaling, is declined in β cells under diabetogenic conditions and in pancreatic islets from patients with type 2 diabetes. β cell-selective mTORC2 inactivation leads to glucose intolerance and acceleration of diabetes as a result of reduced β-cell mass, proliferation and impaired glucose-stimulated insulin secretion. Thereby, many mTORC2 targets, such as AKT, PKC, FOXO1, MST1 and cell cycle regulators, play an important role in β-cell survival and function. This indicates mTORC2 as important pathway for the maintenance of β-cell homeostasis, particularly to sustain proper β-cell compensatory response in the presence of nutrient overload and metabolic demand. This review summarizes recent emerging advances on the contribution of mTORC2 and its associated signaling on the regulation of glucose metabolism and functional β-cell mass under physiological and pathophysiological conditions in type 2 diabetes.     

Eicosanoids, β-cell function, and diabetes

Arachidonic acid (AA) is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes into eicosanoids, which are involved in diverse diseases, including type 1 and type 2 diabetes. During the last 30 years, evidence has been accumulated that suggests important functions for eicosanoids in the control of pancreatic β-cell function and destruction. AA metabolites of the COX pathway, especially prostaglandin E(2) (PGE(2)), appear to be significant factors to β-cell dysfunction and destruction, participating in the pathogenesis of diabetes and its complications. Several elegant studies have contributed to the sorting out of the importance of 12-LOX eicosanoids in cytokine-mediated inflammation in pancreatic β cells. The role of CYP eicosanoids in diabetes is yet to be explored. A recent publication has demonstrated that stabilizing the levels of epoxyeicosatrienoic acids (EETs), CYP eicosanoids, by inhibiting or deleting soluble epoxide hydrolase (sEH) improves β-cell function and reduces β-cell apoptosis in diabetes. In this review we summarize recent findings implicating these eicosanoid pathways in diabetes and its complications. We also discuss the development of animal models with targeted gene deletion and specific enzymatic inhibitors in each pathway to identify potential targets for the treatment of diabetes and its complications.     

Kaempferol alleviates palmitic acid-induced lipid stores,endoplasmic reticulum stress and pancreatic β-cell dysfunction through AMPK/mTOR-mediated lipophagy

Kaempferol, a natural flavonoid, has the beneficial effects of preserving pancreatic β-cell mass and function, but its action on β-cell lipid metabolism still remains elusive. Recently, autophagy has been reported to play a major role in lipid metabolism in various cell types, but its role in pancreatic β-cell's lipid metabolism is rarely reported. Here, we investigated the role of kaempferol-induced autophagy in inhibition of lipid stores, ER stress and β-cell dysfunction in palmitic acid-challenged RIN-5F cells and isolated pancreatic islets. The lipid-lowering effect of kaempferol was determined by Oil Red O staining, triglyceride assay, BODIPY labeling, RT-PCR and immunoblot analysis of PLIN2 (the lipid droplet coat protein) expression. Further, the involvement of AMPK/mTOR-mediated lipophagy was established by pharmacological and genetic inhibitors of autophagy and AMPK. The co-localization studies of lipid droplets with autophagosomes/lysosomes by BODIPY-MDC-LysoTracker co-staining, LC3/BODIPY labeling and LC3/PLIN2 double immunolabeling further strengthened the findings. Kaempferol treatment exhibited decreased lipid stores and increased co-localization of lipid droplets with autophagosomes and lysosomes in palmitic acid–challenged β-cells. Moreover, inhibition of autophagy led to decreased co-localization and increased lipid droplets accumulation. Kaempferol-induced alleviation of ER stress and β-cell dysfunctions was established by immunoblot analysis of CHOP-10 (a key mediator of cell death in response to ER stress) and insulin content/secretion analysis respectively. Together, these findings suggest that kaempferol prevents ectopic lipid accumulation and ER stress, thus restoring β-cell function through AMPK-mediated lipophagy. The current data implies that kaempferol may be a potential therapeutic candidate to prevent obesity-linked diabetic complications.     

Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

The phenomenon of lipid-induced pancreatic β-cell dysfunction ("lipotoxicity") has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.     

The emerging role of autophagy in the pathophysiology of diabetes mellitus

An emerging body of evidence supports a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus. Persistent high concentrations of glucose lead to imbalances in the antioxidant capacity within the cell resulting in oxidative stress-mediated injury in both disorders. An anticipated consequence of impaired autophagy is the accumulation of dysfunctional organelles such as mitochondria within the cell. Mitochondria are the primary site of the production of reactive oxygen species (ROS), and an imbalance in ROS production relative to the cytoprotective action of autophagy may lead to the accumulation of ROS. Impaired mitochondrial function associated with increased ROS levels have been proposed as mechanisms contributing to insulin resistance. In this article we review and interpret the literature that implicates a role for autophagy in the pathophysiology of type 1 and type 2 diabetes mellitus as it applies to β-cell dysfunction, and more broadly to organ systems involved in complications of diabetes including the cardiovascular, renal and nervous systems.     

Lentinan protects against pancreatic β-cell failure in chronic ethanol consumption-induced diabetic mice via enhancing β-cell antioxidant capacity

Chronic ethanol consumption is a well-established independent risk factor for type 2 diabetes mellitus (T2DM). Recently, increasing studies have confirmed that excessive heavy ethanol exerts direct harmful effect on pancreatic β-cell mass and function, which may be a mechanism of pancreatic β-cell failure in T2DM. In this study, we evaluated the effect of Lentinan (LNT), an active ingredient purified from the bodies of Lentinus edodes, on pancreatic β-cell apoptosis and dysfunction caused by ethanol and the possible mechanisms implicated. Functional studies reveal that LNT attenuates chronic ethanol consumption-induced impaired glucose metabolism in vivo. In addition, LNT ameliorates chronic ethanol consumption-induced β-cell dysfunction, which is characterized by reduced insulin synthesis, defected insulin secretion and increased cell apoptosis. Furthermore, mechanistic assays suggest that LNT enhances β-cell antioxidant capacity and ameliorates ethanol-induced oxidative stress by activating Nrf-2 antioxidant pathway. Our results demonstrated that LNT prevents ethanol-induced pancreatic β-cell dysfunction and apoptosis, and therefore may be a potential pharmacological agent for preventing pancreatic β-cell failure associated with T2DM and stress-induced diabetes.