GLP-1改善非酒精性脂肪肝病作用机制的研究进展

非酒精性脂肪肝病与肥胖、胰岛素抵抗、2型糖尿病和血脂紊乱等密切相关。随着肥胖和糖尿病的发病率逐渐增加,非酒精性脂肪肝病已成为全球最常见的慢性肝脏疾病。目前,NAFLD的治疗主要是改善生活方式、减轻体重和降脂药物的应用,尚缺乏特效的药物治疗。GLP-1主要用于糖尿病和减重治疗,但最近大量临床和临床前研究表明GLP-1可通过多种 机制减轻NAFLD。本文将GLP-1改善NAFLD的相关机制综述如下,进一步加深我们对GLP-1改善NAFLD分子机制的理解。     

视黄醇结合蛋白4与非酒精性脂肪性肝病关系的研究进展

非酒精性脂肪性肝病（nonalcoholic fatty liver disease,NAFLD）涵盖了非酒精性肝脏脂肪性改变,病理上包括单纯性脂肪肝（nonalcoholic fatty liver,NAFL）及由其演变的脂肪性肝炎（nonalcoholic steatohepatitis,NASH）和脂肪性肝硬化3种类型。近些年来NAFLD的发病率呈持续上升趋势,在我国已成为仅次于病毒性肝炎的第二大肝病。NAFLD与营养过剩（体力活动减少及不适当的饮食）、中心性肥胖、2型糖尿病（T2DM）以及代谢综合征的流行趋势相平行,目前肥胖和糖尿病的广泛流行提示NAFLD的发生率在不久的将来会进一步升高。     

初级保健和内分泌临床中非酒精性脂肪肝诊断和治疗的临床实践指南要点与解读

由于肥胖和2型糖尿病（type 2 diabetes mellitus,T2DM）发病率的增加，非酒精性脂肪性肝病（nonalcoholic fatty liver disease,NAFLD）已达到流行程度，因此需要内分泌科和初级保健临床医生共同参与其早期诊断和管理。T2DM和心血管疾病（cardiovascular disease,CVD）是NAFLD的最重要肝外伴发病，因此NAFLD的管理涉及生活方式、体质量、血压、血糖、血脂各方面，还应包括肝硬化的预防。本指南系统阐述了成人和儿童NAFLD的预防、诊断、治疗策略，为内分泌学家、初级保健临床医生、卫生保健专业人员和其他相关专业人员提供了有关NAFLD诊断和管理的循证建议。     

2型糖尿病合并非酒精性脂肪肝的血生化分析

近年来,随着肥胖和2型糖尿病发病率的增加,糖尿病合并非酒精性脂肪肝（NAFLD）的发病率也明显增加,NAFLD成为危害人们健康的常见病。作者自2006年5月至2010年4月对本院诊断的2型糖尿病（T2DM）合并NAFLD患者的临床血生化指标进行了分析,探讨NAFLD的易患因素,以利于糖尿病及脂肪肝的预防和治疗。现报道如下。     

2型糖尿病合并肥胖患者肠道菌群分布与A-FABP、GLP-1水平的相关性

目的 探讨2型糖尿病合并肥胖患者肠道菌群分布与脂肪型脂肪酸结合蛋白（A-FABP）、胰高血糖素样肽-1(GLP-1)水平的相关性。方法 拟选取2019年1月至2021年12月海安市人民医院就诊的103例2型糖尿病合并肥胖患者作为研究观察组,同期选择50名在本院行健康检查无糖尿病和肥胖者作为对照组,检测两组肠道菌群的分布与血清A-FABP、GLP-1水平,并分析2型糖尿病合并肥胖患者肠道菌群分布与血清A-FABP、GLP-1水平的相关性。结果 观察组肠球菌、肠杆菌检出水平显著高于对照组,差异有统计学意义（t=6.424,10.356,P<0.05）,乳酸杆菌、双歧杆菌、梭杆菌、拟杆菌、类杆菌检出水平显著低于对照组,差异有统计学意义,差异有统计学意义（t=2.050,7.242,4.186,9.845,15.363,P<0.05）;观察组A-FABP水平显著高于对照组,差异有统计学意义（t=10.298,P<0.05）,GLP-1水平显著低于对照组,差异有统计学意义（t=27.819,P<0.05）;肠球菌、肠杆菌与A-FABP水平呈正相关（P<0.05）,乳...     

老年非酒精性脂肪性肝病的临床特点及相关危险因素

【目的】探讨老年非酒精性脂肪性肝病（NAFLD）的临床特点及相关危险因素。【方法】对本院82例门诊体检老年NAFLD患者的临床资料进行分析，并随机抽取老年非脂肪肝者80例作为对照组进行比较。【结果】老年NAFLD患病率高，常有肝功能异常；肥胖、2型糖尿病、高脂血症、冠心病、高血压病、胆石症患病率显著高于对照组（P＜0．05）；老年NAFLD的发生与体重指数（BMl）、腰围、空腹血糖、甘油三酯（TG）、总胆固醇（TC）及低密度脂蛋白胆固醇（LDL-C）有关。【结论】肥胖、高TG血症、2型糖尿病是发生老年NAFLD的危险因素，NAFLD是老年慢性血清转氨酶升高的常见原因。     

胰高血糖素样肽-1受体激动剂治疗肥胖的研究进展

肥胖对公共健康的威胁日益严重,使患者生活质量降低,死亡风险增加。药物治疗可以帮助肥胖患者减轻体重,且有助于降低体重反弹的风险,从而减少肥胖相关并发症。胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)受体激动剂(glucagon-like peptide-1 receptor agonists,GLP-1RAs)促进胰岛素分泌,并以葡萄糖依赖的方式减少了胰高血糖素的分泌,使胃排空延迟、肠道运动性降低,并且可以激活下丘脑的神经通路和食欲调节区域,使食欲下降、食物摄入减少,从而治疗肥胖。本研究通过对GLP-1RAs治疗肥胖的机制、临床试验、安全性和耐受性、主要不良反应、禁忌证及优势等进行综述,旨在为肥胖的治疗提供理论依据。     

糖尿病治疗的新靶点——GLP-1类似物的临床应用

随着全球糖尿病发病率不断上升,糖尿病的发病机制和新药开发成为各国学术机构和开发商共同关注的目标,近年来糖尿病治疗的新靶点胰高血糖素样肽1(GLP-1)类似物也应运而生并开始应用于临床,GLP-1类似物作为糖尿病新药物的作用机制、疗效和安全性有待了解和经验总结. 1 GLP-1的来源、结构及作用机制 GLP-1是胰高血糖素原衍生肽,相对分子质量是3 298,有生物活性的GLP-1以GLP-1(7-36)酰胺或GLP-1(7-37)酰胺的形式出现;其中,GLP-1(7-36)酰胺是人体内GLP-1主要的天然形式,约占80％.进食数分钟后体内GLP-1浓度开始升高,并与胰岛β细胞膜上的特异性受体结合发挥其生理效应,餐后30 ～ 60 min内达到峰值,但很快被体内广泛表达的DPP-4所降解.     

胰高血糖素样肽-1在2型糖尿病中的作用

胰高血糖素样肽-1（glucagon-likepeptide-1,GLP-1）是肠促胰岛素的一种,其在2型糖尿病患者中具有促进胰岛素分泌,抑制胰高血糖素分泌,减慢胃排空,抑制食欲,刺激胰岛β细胞增殖分化等作用。GLP-1可以降低2型糖尿病患者的血糖,而又不引起体重的增加,同时还可改善血脂,减轻胰岛素抵抗。因此,GLP-1有望成为治疗2型糖尿病的新药物。     

初发 2 型糖尿病胰岛素泵早期强化对胰高血糖素样肽 -1 变化的价值探讨简

目的探讨采用胰岛素泵早期强化治疗初发2型糖尿病后患者血胰高血糖素样肽-1（GLP-1）水平的变化。方法按照随机数字表法将83例初发2型糖尿病患者分为两组,治疗组（42例）采用胰岛素泵（CSII）强化治疗,对照组（41例）常规皮下注射胰岛素。观察两组治疗后血糖、GLP-1水平、胰岛素用量、血糖达标时间及低血糖发生次数。结果治疗后的两组空腹血糖（FPG）、餐后2小时血糖（2hPG）、GLP-1优于治疗前,差异有显著性（P〈0．05）;治疗组治疗后的FPG、2hPG、GLP-1水平与治疗前的差值和对照组比较,差异有统计学意义（P〈0．05）,治疗组优于对照组;治疗组的胰岛素用量、血糖达标时间、低血糖次数均少于对照组,差异有统计学意义（P〈0．05）。结论胰岛素泵早期强化治疗初发2型糖尿病患者,可使GLP-1水平升高,改善胰岛功能,从而有效控制血糖。     

Attenuation of fatty accumulation in hepatocyte by incretin--expectation of novel medicine for treatment of NASH

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been recognized as a metabolic disorder characterized by fatty accumulation of the liver without alcohol consumption. The progression of the diseases has been considered to link to metabolic syndrome, consisting of obesity, diabetes mellitus(DM), dyslipidemia and hypertension. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP) function as incretin and stimulate glucose-mediated insulin production by pancreatic beta cells. Incretin was also reported to have various kinds of extrapancreatic effects including the regulation of hepatic glucose production, the inhibition of pancreatic exocrine secretion, cardioprotective and cardiotropic effects, the regulation of appetite and satiety, and stimulation of afferent sensory nerves. Therefore, incretins are also expected as therapeutic agents for NFLD and NASH.     

Nonalcoholic fatty liver disease and COVID-19: An epidemic that begets pandemic

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic, affecting all the individuals across the planet. COVID-19 has gained significant attention due to its high prevalence among individuals with diabetes, nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome. NAFLD is the hepatic manifestation of metabolic syndrome and can be associated with a high risk of developing type 2 diabetes. The association of COVID-19 and NAFLD has also gained more attention because NAFLD is highly associated with the epidemic of obesity. NAFLD is a potential risk factor for SARS-CoV-2 infection and severe COVID-19, independent of metabolic syndrome. Importantly, it is not yet clear whether the epidemics of obesity and NAFLD have perpetuated the current pandemic of COVID-19. Further research is urgently needed to assess the following: (1) Whether NAFLD is a high risk factor for SARS-CoV-2 infection; (2) Whether NAFLD is associated with the severe form of COVID-19; and (3) Whether the presence of NAFLD can explain the racial variation in the morbidity and mortality associated with COVID-19. This review summarizes the interactions between COVID-19 and NAFLD, mechanism of liver injury by COVID-19, and effect of lockdown due to COVID- 19 on patients with NAFLD.     

Relationship between non-alcoholic fatty liver disease and coronary heart disease

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and considered a liver manifestation of metabolic syndrome. It is in close relationship with insulin resistance, obesity, diabetes mellitus, all of which increase risk of cardiovascular disease (CVD). Besides, many studies point out that NAFLD independently contributes to the development of atherosclerosis and CHD. On the other hand, CVDs are the leading cause of death in NAFLD patients. Many pathophysiological changes and molecular mechanisms play an important role in NAFLD for CVD formation. Atherosclerosis is common in NAFLD, which also mainly contributes to the CVD formation and CHD. Many studies linking atherosclerotic CHD and NAFLD are present in the literature. Subclinical CHD, mainly detected by coronary computed tomography views, have been detected more common in NAFLD patients. Presence of NAFLD has been found to be more common in patients with severe CHD and in stable CHD, NAFLD has been found to be associated with more diffuse disease. In acute coronary syndromes, especially in acute myocardial infarction, patients with NAFLD have been found to have poor prognosis when compared with NAFLD free patients. In this review, our aim is to evaluate the relationship between NAFLD and CHD in detail and go over the pathophysiological mechanisms underlying this relationship.     

Nonalcoholic Fatty Liver Disease: Review of Management for Primary Care Providers

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the United States and worldwide. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplant. Comorbidities associated with NAFLD development and NASH include type 2 diabetes, obesity, metabolic syndrome, and dyslipidemia. Extrahepatic morbidity and mortality are considerable as NAFLD is associated with an increased risk of cardiovascular disease and chronic kidney disease. Once NAFLD is diagnosed, the presence of liver fibrosis is the central determinant of hepatic prognosis. Severe liver fibrosis requires aggressive clinical management. No pharmacologic agents have regulatory approval in the United States for the treatment of NAFLD or NASH. Management is centered on efforts to reduce underlying obesity (lifestyle, medications, surgical or endoscopic interventions) and metabolic derangements (prediabetes, type 2 diabetes, hypertension, hyperlipidemia, and others). Current pharmacologic therapy for NAFLD is limited mainly to the use of vitamin E and pioglitazone, although other agents are being investigated in clinical trials. Cardiovascular and metabolic risk factors must also be assessed and managed. Here, NAFLD evaluation, diagnosis, and management are considered in the primary care setting and endocrinology clinics.     

Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. NAFLD represents a large spectrum of diseases ranging from (i) fatty liver (hepatic steatosis); (ii) steatosis with inflammation and necrosis; and (iii) cirrhosis. Although the molecular mechanism leading to the development of hepatic steatosis in the pathogenesis of NAFLD is complex, recent animal models have shown that modulating important enzymes in fatty acid synthesis in liver may be key for the treatment of NAFLD. This review discusses recent advances in the field.     

Insulin sensitizers in nonalcoholic fatty liver disease and steatohepatitis: Current status

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%–220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.     

Therapy for Nonalcoholic Fatty Liver Disease: Current Options and Future Directions

PurposeNonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that is driven by the metabolic syndrome. NAFLD encompasses nonalcoholic fatty liver, >5% fat in the liver without inflammation of fibrosis, nonalcoholic steatohepatitis (NASH), fat plus varying degrees of inflammation and fibrosis, and cirrhosis of the liver from NASH. As facets of the metabolic syndrome, particularly diabetes and obesity, become more common worldwide, the incidence of new NAFLD is increasing.MethodsA qualitative systematic review was performed via searches of PubMed and ClinicalTrials.gov for therapeutic interventions for NAFLD.FindingsCurrent therapies rely on metabolic syndrome risk factor control and lifestyle changes to achieve weight loss. Because sustained weight loss is difficult for many patients, there is a critical unmet need for pharmacotherapy to treat NAFLD, especially the progressive form, NASH, to prevent cirrhosis of the liver. New therapies for NAFLD focus on the subset of patients with NASH and some degree of fibrosis. Novel mechanisms of action, including farnesoid X nuclear receptor agonism, C–C motif chemokine receptor 2 and receptor 5 antagonism, stearoyl-CoA desaturase-1, and thyroid hormone receptor β agonism, are currently under investigation as monotherapy. The products also hold potential for use in combination with and without insulin sensitizers and other established drugs in the future.ImplicationsThis review of NASH treatments details the interventions that are currently available as well as those in late-stage clinical trials that may represent the future of NASH therapy.     

Targeting the glucagon receptor family for diabetes and obesity therapy

Diabetes is a debilitating disease characterized by chronic hyperglycemia and is often associated with obesity. With diabetes and obesity incidence on the rise, it is imperative to develop novel therapeutics that will not only lower blood glucose levels, but also combat the associated obesity. The G protein-coupled receptors (GPCRs) for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon are emerging as targets to treat both hyperglycemia and obesity. GIP is rapidly released from intestinal K-cells following food intake and stimulates glucose-dependent insulin secretion from β-cells and the storage of fat in adipocytes. Both GIP receptor agonists and antagonists have been demonstrated to display therapeutic potential to treat diabetes and obesity. Similar to GIP, GLP-1 is released from intestinal L-cells following food intake and potentiates glucose-dependent insulin secretion from β-cells. In addition, GLP-1 reduces glucagon levels, suppresses gastric emptying and reduces food intake. As such, GLP-1 receptor agonists effectively lower blood glucose levels and reduce weight. Finally, glucagon is released from α-cells and raises blood glucose levels during the fasting state by stimulating gluconeogenesis and glycogenolysis in the liver. Thus, molecules that antagonize the glucagon receptor may be used to treat hyperglycemia. Given the structural similarity of these peptides and their receptors, molecules capable of agonizing or antagonizing combinations of these receptors have recently been suggested as even better therapeutics. Here we review the biology of GIP, GLP-1 and glucagon and examine the various therapeutic strategies to activate and antagonize the receptors of these peptides.     

Clinical workup of fatty liver for the primary care provider

Nonalcoholic fatty liver disease (NAFLD) is quickly emerging as a global epidemic in parallel with the rise in obesity and the Metabolic Syndrome. NAFLD, once seen simply as a passive consequence of the Metabolic Syndrome (MetS), has been found to interact with other features of MetS to exacerbate insulin resistance, diabetes, and cardiovascular disease. NAFLD is also becoming the top indication for liver transplant and an important risk factor for hepatocellular carcinoma. Treatment of this disorder is limited mainly to lifestyle modifications to promote weight loss along with consideration for off-label use of certain medications, but recent progression in clinical trials means more effective treatments are on the horizon. Therefore, the primary care provider must be prepared to recognize and determine the severity of this disorder in order to optimize management. In this review, we will discuss risk factors for NAFLD, workup and differential, and finally, offer recommendations on screening.