IR/IGF-1R信号通路在阿尔茨海默病中的作用机制

阿尔茨海默(AD)以进行性神经变性导致的认知功能障碍为特点.近年多项临床研究均描述了Ⅱ糖尿病和神经退行性变及记忆减退之间的关系[1.2],研究发现葡萄糖抵抗和胰岛素分泌异常患者更容易发展为痴呆[3].     

糖尿病性认知功能障碍:一个不容忽视的问题

糖尿病对脑部结构功能有多方面影响,但糖尿病引发的认知功能障碍却常常被忽视.糖尿病性认知功能障碍的发生机制十分复杂,其中糖脂毒性、胰岛素抵抗、低血糖及Ca2+稳态被破坏等可能起要作用.除糖尿病常规治疗方案外,糖尿病性认知功能障碍尚需要探索更加有效的治疗措施.     

胰岛素抵抗对阿尔茨海默病患者认知功能的影响

目的 探讨血清胰岛素水平及胰岛素抵抗对阿尔茨海默病(AD)患者认知功能的影响.方法 随机选取55例AD患者、70名正常对照组,检验其空腹血糖、胰岛素水平、胰岛素抵抗指数.将两组进行统计描述、分析、比较.结果 两组空腹血糖无统计学差异(P ＞0.05)；AD患者胰岛素水平及胰岛素抵抗指数值显著高于对照组(P＜0.05).AD患者血糖水平与MMSE评分无相关性,胰岛素水平及胰岛素抵抗指数均与MMSE评分呈正相关.胰岛素水平及胰岛素抵抗均与AD患者认知功能中的物体命名分、语言理解分、言语表达分呈负相关,并与物体命名分、言语表达分显著相关.结论 AD患者存在胰岛素代谢异常,其特征与痴呆的严重程度有关.     

胰岛素抵抗的原因再认识:从糖代谢为中心向脂毒学说的转变

脂毒学说认为血浆高游离脂肪酸(FFA)进入细胞内,脂质沉积干预胰岛素信号传递,产生胰岛素抵抗,导致骨骼肌对葡萄糖利用减少,肝脏肌肉糖元合成受抑制,对肝脏葡萄糖异生的抑制削弱,胰岛β细胞起初代偿性大量分泌胰岛素,以后功能衰竭.FFA在胰岛素抵抗与β细胞功能障碍的发展中起重要作用.降低FFA应当是治疗胰岛素抵抗和2型糖尿病的重要措施.     

老年2型糖尿病患者轻度认知功能障碍与胰岛素抵抗的相关性

目的探讨2型糖尿病患者轻度认知功能障碍与胰岛素抵抗及胰岛素样生长因子(IGF)-1、转化生长因子(TGF)-β1的相关性。方法用蒙特利尔认知功能筛查(MoCA)量表筛选2型糖尿病患者82例,其中合并轻度认知功能障碍的患者42例,认知功能正常患者40例。分别给予动态血糖监测、测定血糖、血脂、空腹胰岛素(FINS)、糖化血红蛋白(HbA1c)及血清IGF-1、TGF-β1,计算胰岛素抵抗指数(HOMA-IR)。将两组检查结果对照分析,并以Mo CA得分为变量进行多因素回归分析。结果2型糖尿病轻度认知功能障碍患者的血糖波动系数、HOMA-IR、IGF-1水平与认知功能正常患者差异有统计学意义(P<0.05)。2型糖尿病轻度认知功能障碍患者MoCA与HOMA-IR、病程、FINS、HbA1c显著正相关,与IGF-1水平负相关。结论 2型糖尿病患者胰岛素抵抗、IGF-1水平低、病程长、血糖控制差、血糖波动幅度大为其轻度认知功能障碍的主要因素。     

三足鼎立的核心-糖尿病发病与胰岛细胞功能及其临床处理

肝脏、骨骼肌胰岛素抵抗和胰岛细胞功能障碍是2型糖尿病(T2DM)发病的主要病理机制。人们形象的将三者称之为"三重唱"抑或"三足鼎立"[1]。曾经胰岛素抵抗在T2DM发病机理中占主导地位,而如今越来越多的证据表明胰岛细胞功能障碍才是三足鼎立的核心。机体仅出现胰岛素抵抗时TDM难以发生,只有胰岛细胞功能障碍引起     

胰岛素抵抗与脑梗死后认知功能障碍的相关性分析

目的 观察胰岛素抵抗与脑梗死后认知功能障碍的相关性。方法 2003年1月-2006年12月在广西中医学院第一附属医院老年病科根据时间顺序收集符合实验要求的脑梗死恢复期住院病人76例，其中认知功能正常病人15例，认知功能障碍病人35例，轻度痴呆病人15例，中度痴呆病人11例。采取清晨空腹静脉血检测胰岛素（Ins）、血糖（FBS），胰岛素抵抗用胰岛素敏感指数（ISI）表示。结果 认知功能障碍及痴呆的脑梗死病人，胰岛素抵抗较认知功能正常的脑梗死病人重，且随着认知功能损害的加重。其胰岛素抵抗也越重，认知功能障碍病人与认知功能正常病人轻度、中度痴呆病人比较差异均有统计学意义（P〈0．05或P〈0．01）。结论 脑梗死病人认知功能损害与胰岛素抵抗程度有直接的关系，胰岛素抵抗可能是导致认知功能障碍的重要因素之一。     

2型糖尿病患者轻度认知功能障碍的特点及其危险因素

目的 观察2型糖尿病患者轻度认知功能障碍特点及相关危险因素.方法 从无锡地区痴呆的流行病学调查对象中筛选出82例高血压患者,84例糖尿病患者,76例糖尿病合并高血压患者以及年龄、性别及文化程度相匹配的80名正常对照者,以上四组均进行认知功能筛查问卷调查,同时检测胆固醇、甘油三酯、血压.高血压和糖尿病患者进行空腹胰岛素测定,计算胰岛素抵抗指数.糖尿病人给予糖化血红蛋白测定,并对四组人群的认知功能和危险因素进行对照分析.结果 ①糖尿病组在时间定向,个人经历,近事记忆,做事质量,判断力人格变化上与正常老年组有统计学差异(P＜0.05).②糖尿病合并高血压组在近事记忆,语言问题,人格变化等方面与正常老年组有统计学差异(P＜0.05).③糖尿病合并高血压组较糖尿病组在个人经历上有统计学差异(P＜0.01).④糖尿病组较高血压组在语言问题,人格变化上有统计学差异(P＜0.05).⑤高血压组与正常组没有统计学差异(P＞0.05).⑥胰岛索抵抗指数与问卷得分呈负相关.结论 ①2型糖尿病患者较同龄正常老年人存在轻度认知功能障碍,合并高血压的糖尿病患者的认知功能损害更严重.②糖化血红蛋白与胰岛素抵抗是认知功能障碍的危险因素.③糖尿病患者在记忆力损害的同时还存在精神症状和人格变化.     

多囊卵巢综合征卵巢局部胰岛素抵抗的生物学效应

多囊卵巢综合征(PCOS)是生殖功能障碍与代谢异常并存的一种特殊疾病.生殖功能障碍包括卵巢排卵功能障碍和雄激素过多,是PCOS患者临床表现的核心内容;代谢异常主要表现为胰岛素抵抗和高胰岛素血症.近期研究发现PCOS患者除胰岛素作用的经典靶组织--骨骼肌、脂肪和肝脏存在胰岛素抵抗之外,卵巢局部也存在胰岛素抵抗 [1].同时2型糖尿病患者存在胰岛素抵抗和外周高胰岛素血症的表现,但并不常见卵巢功能障碍,很显然以卵巢组织外的胰岛素抵抗和外周的高胰岛素血症来解释卵巢本身的功能异常是不确切的.因此,卵巢本身的胰岛素抵抗对PCOS患者卵巢功能改变有更重要的意义.     

胰岛素在糖尿病认知障碍发病中的作用

糖尿病是认知障碍的独立危险因素.而胰岛素在糖尿病认知障碍的发病中占有重要地位.作为人体胰岛分泌的重要激素,胰岛素不仅参与脑内葡萄糖代谢,同时对脑内神经元有营养支持和保护作用.当胰岛素缺乏、胰岛素转运异常、受体障碍或胰岛素受体后信号通路发生异常时,均可参与认知损害的发生,加快轻度认识障碍期(MCI)和阿尔茨海默病(AD)的进程.早期使用胰岛素对糖尿病引起的中枢神经病变有防治作用.     

Alzheimer's Disease Is Type 3 Diabetes�CEvidence Reviewed

Alzheimer''s disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.     

胰岛素抵抗与阿尔茨海默病关系研究进展

糖尿病与认知功能损害都是中老年人易患疾病。糖尿病是脑卒中的已知危险因素,会导致血管性痴呆,但与阿尔茨海默病之间的相关性仍无定论,大多数研究认为两者呈正相关,部分研究认为两者无关。阿尔茨海默病有明显的脑内胰岛素抵抗现象,胰岛素及其增敏剂类药物不仅能够提高胰岛素受体的敏感度,还能够减轻炎症反应、促进Aβ淀粉样蛋白的释放和清除,有益于记忆功能的改善。     

胰岛素生成,胰岛素分泌及2型糖尿病:问题的核心在于β细胞

近年来,有人将2型糖尿病(T2DM)定义为由胰岛素抵抗引起的一种疾病,作为代谢综合征的一部分。胰岛素抵抗确实存在于T2DM,但同时也以同样程度存在于许多并无糖尿病的人群中,这些人可有或无代谢综合征。因而单独胰岛素抵抗不可能是T2DM的决定性致病因素。T2DM从其最早的阶段包括糖耐量受损(IGT)及空腹血糖受损(IFG),甚或在可测出的这些血糖变化之前的“糖尿病前期”就出现胰岛素释放动力学的障碍;其主要特征是对葡萄糖反应的胰岛素释放第一相丧失,随之而来的是逐渐加重的第二相胰岛素和总胰岛素分泌的受损。第一相胰岛素反应丧失的后果为肝脏未能迅速胰岛素化,延迟了对肝葡萄糖输出的抑制,从而引起餐后高血糖。在某些研究中,确已发现T2DM时β细胞量总体的减少,但并非所有研究中都有此同样结果,故对此尚须进一步证实。现已明确,糖尿病易发人群的β细胞的分泌适应能力是有限的,在胰岛素抵抗或热量负荷对胰岛素释放要求增加时,就难以胜任。此外,即使轻度的高血糖也会严重影响胰岛素的分泌并减少胰岛素原的合成,从而使代谢所需的胰岛素进一步减少。转录因子PDX-1在此损伤过程中起关键作用。因而,及早并有效地将T2DM血糖控制于接近正常水平至关重要,尤其是对胰岛素一相分泌的恢复更是如此。     

SHIP 2基因与2型糖尿病

2型糖尿病主要特征是胰岛素分泌异常和胰岛素抵抗,环境因素和遗传因素交互作用共同促成了糖尿病的发生。研究发现多种基因参与糖尿病的发生,最近发现SHIP2基因与胰岛素抵抗及2型糖尿病相关,该基因可抑制胰岛素分泌、降低机体对胰岛素的敏感性,研究也表明当该基因不起作用时,胰岛素分泌就会失控,可导致严重的低血糖发生,因此,SHIP2基因可成为2型糖尿病的一个重要的治疗靶点。     

Insulin resistance and pathological brain ageing

Sir Harold Himsworth's prescient observations 75 years ago have recently been expanded to include a clear relationship between insulin resistance and central nervous system function. Insulin is a master regulator of corporeal ageing in all known species, determining the rate and expression of ageing in multiple body systems. Thus, it is not surprising that insulin also plays an important role in brain ageing and cognitive decline that is associated with pathological brain ageing. Brain ageing is accompanied by reduced insulin effectiveness, either by an inadequate cellular response to insulin or by insulin deficiency attributable to reduced insulin transport across the blood-brain barrier. Age-associated brain insulin abnormalities may contribute to cognitive decline in ageing, as have been documented in older adults with Type 2 diabetes mellitus and hypertension. With more extreme pathology, brain insulin resistance may be associated with neurogenerative diseases such as Alzheimer's disease, and the condition which precedes Alzheimer's disease, known as amnestic mild cognitive impairment. In the following review, we discuss the mechanisms through which insulin resistance may induce or potentiate pathological brain ageing and thereby create a neurobiological environment that promotes neurodegeneration and associated cognitive decline. This topic is timely, given that insulin resistance-associated conditions such as diabetes and obesity have reached epidemic proportions. The prevalence of such chronic conditions, in combination with a rapidly ageing population, may result in a corresponding increase in the prevalence of Alzheimer's disease and other cognitive disorders. Fortunately, insulin resistance-associated conditions are amenable to both pharmacologic and lifestyle interventions that may reduce the deleterious impact of insulin resistance on the ageing brain.     

Innovative biomarkers for predicting type 2 diabetes mellitus: relevance to dietary management of frailty in older adults

Type 2 diabetes mellitus (T2DM) increases in prevalence in the elderly. There is evidence for significant muscle loss and accelerated cognitive impairment in older adults with T2DM; these comorbidities are critical features of frailty. In the early stages of T2DM, insulin sensitivity can be improved by a “healthy” diet. Management of insulin resistance by diet in people over 65 years of age should be carefully re-evaluated because of the risk for falling due to hypoglycaemia. To date, an optimal dietary programme for older adults with insulin resistance and T2DM has not been described. The use of biomarkers to identify those at risk for T2DM will enable clinicians to offer early dietary advice that will delay onset of disease and of frailty. Here we have used an in silico literature search for putative novel biomarkers of T2DM risk and frailty. We suggest that plasma bilirubin, plasma, urinary DPP4-positive microparticles and plasma pigment epithelium-derived factor merit further investigation as predictive biomarkers for T2DM and frailty risk in older adults. Bilirubin is screened routinely in clinical practice. Measurement of specific microparticle frequency in urine is less invasive than a blood sample so is a good choice for biomonitoring. Future studies should investigate whether early dietary changes, such as increased intake of whey protein and micronutrients that improve muscle function and insulin sensitivity, affect biomarkers and can reduce the longer term complication of frailty in people at risk for T2DM.     

社区老年2型糖尿病患者合并轻度认知功能障碍危险因素分析

目的探讨分析2型糖尿病患者轻度认知功能障碍（mild cognitive impairment,MCI）的相关危险因素。方法以简易智能精神状态量表（MMSE）对社区老年2型糖尿病患者进行认知功能测评,收集MCI患者82例（MCI组）,认知功能正常者86例（NC组）。问卷调查受试者病史、年龄、糖尿病肾病、糖尿病足等资料;测定受试者血压、身高、体质量、血脂、血糖、胰岛素（Ins）、糖化血红蛋白（HbA1c）;计算胰岛素抵抗指数（HOMA-IR）、胰岛素分泌指数（HOMA-β）、体质量指数（BMI）、腰臀比（WHR）并筛查其危险因素。结果（1）与NC组比较,MCI组患者糖尿病病程、糖尿病肾病、空腹血糖（FBG）、餐后2h血糖（2hPBG）、空腹胰岛素（Fins）、HbA1c、HOMA—IR水平显著升高;而2组间年龄、糖尿病足、BMI、WHR、血压、餐后2h胰岛素（2hlns）、HOMA-B及血脂水平比较,差异均无统计学意义。（2）MCI患者MMSE量表评分与糖尿病病程、FBG、2hPBG、Fins、HOMA—IR具有相关性;而NC组仅发现与糖尿病病程、FBG相关。（3）Logistic回归分析显示糖尿病病程、FBG、HOMA-IR可能与糖尿病患者MCI独立相关。结论糖尿病病程、血糖控制水平、胰岛素抵抗程度等可能与2型糖尿病患者发生MCI密切相关,有效控制各危险因素有助于预防认知功能障碍的发生发展。     

Insulin sensitivity of the human brain

The brain is an insulin sensitive organ and insulin signaling is important to regulate feeding behavior, body weight, and cognitive processes. Insulin resistance in peripheral tissues is a hallmark in the development of type 2 diabetes mellitus (T2DM), yet the finding of insulin resistance in the brain is relatively novel. Studies in humans revealed that environmental factors like obesity, age, and the genetic background have an impact on central insulin sensitivity. According to the physiological effects of insulin in the brain, disturbances of this signaling chain lead to an impairment of cognitive functions and a deterioration of eating behavior with a potential role in the pathogenesis of obesity and T2DM. First attempts to treat insulin resistance not only in peripheral tissues but also in the CNS have therefore come on its way: Cerebral insulin resistance can at least partially be overcome by intranasal treatment with insulin or by commercial insulins that exhibit specific effects in the brain due to their pharmacokinetic properties. Despite the advances towards a better understanding of insulin function in the human brain in the last years, achieving a more profound knowledge of mechanisms behind central insulin function and identifying further strategies to overcome insulin resistance must be a main goal of future research.     

Cardiovascular risk in double diabetes mellitus--when two worlds collide

Historically, clinical management of patients with type 1 diabetes mellitus (T1DM) has been focused on glycaemic control, which is sometimes achieved at the expense of weight gain on intensive insulin regimes. Although HbA(1c) level is an important contributor to increased macrovascular risk, several prospective studies have concluded that factors related to obesity, metabolic syndrome and insulin resistance are more important than HbA(1c) for the prediction of cardiovascular risk, especially for coronary heart disease events. 'Double diabetes mellitus' describes a combination of T1DM with characteristics associated with type 2 diabetes mellitus, including central adiposity and exacerbation of insulin resistance. In lean patients with T1DM, portal insulinopaenia might actually confer cardioprotective effects via changes in hepatic lipid profiles (mainly increased HDL cholesterol levels) and a reduction in hepatic steatosis. In patients with double diabetes mellitus, this situation is reversed and atherothrombotic pathophysiology is potentially accelerated by the combination of chronic hyperglycaemia and abnormal lipid partitioning. The prevalence of double diabetes mellitus is increasing in parallel with the societal trend of increased adiposity. This Review discusses how to identify patients susceptible to double diabetes mellitus and suggests alterations to their clinical management that might reduce their risk of future premature coronary disease.     

Metabolic neuroimaging of the brain in diabetes mellitus and hypoglycaemia

Functional neuroimaging techniques can be used to study changes in regional brain activation, using changes in surrogate markers such as regional cerebral perfusion and rates of glucose uptake or metabolism. These approaches are shedding new light on two major health problems: the increasing burden of type 2 diabetes mellitus (T2DM), which is driven by the rising prevalence of insulin resistance and obesity; and recurrent intractable problematic hypoglycaemia, which is driven by the cognitive impairment that can occur in association with iatrogenic hypoglycaemic episodes. Some patients with diabetes mellitus lose awareness of being hypoglycaemic, which puts them at risk of severe hypoglycaemia as they are unlikely to take action to prevent the condition worsening. Involvement of corticolimbic brain and centres serving higher executive functions as well as the hypothalamus has been demonstrated in both situations and has implications for therapy. This Review describes the relevant principles of functional neuroimaging techniques and presents data supporting the notion that the dysregulation of central pathways involved in metabolic regulation, reward and appetite could contribute to problematic hypoglycaemia during therapy for diabetes mellitus and to insulin-resistant obesity and T2DM. Understanding these dysregulations could enable the development of novel clinical interventions.