强肝胶囊对非酒精性脂肪性肝病患者胰岛素抵抗指数和肝纤维化评分的影响

目的观察强肝胶囊对非酒精性脂肪性肝病(NAFLD)患者肝纤维化评分和胰岛素抵抗指数的影响。方法选取2014年8月-2015年7月在上海市第八人民医院就诊的NAFLD患者85例,随机分为治疗组(n=45)和对照组(n=40)。治疗组给予强肝胶囊,对照组给予多烯磷脂酰胆碱胶囊,2组疗程均为24周。观察2组治疗前后血清转氨酶(AST、ALT)、稳态模型胰岛素抵抗指数(HOMA-IR)以及NAFLD肝纤维化评分(NAFLDFS)的变化。计量资料组间比较采用成组t检验,组内治疗前后比较采用配对t检验;计数资料组间比较采用χ2检验。结果 2组治疗后ALT、AST水平均较同组治疗前明显改善,差异均有统计学意义(P值均0.05);与治疗前比,治疗组HOMA-IR、NAFLDFS治疗后均明显下降,差异均有统计学意义(3.58±0.85 vs 2.48±0.78,t=6.40,P0.05;-1.78±1.24 vs-2.35±0.98,t=2.40,P0.05)。2组间治疗后比较,治疗组HOMA-IR、NAFLDFS较对照组显著下降,差异均有统计学意义(2.48±0.78 vs 3.09±0.89,t=3.36,P0.01;-2.35±0.98 vs-1.48±1.08,t=3.80,P0.01)。整个疗程未见明显不良反应。结论强肝胶囊不仅能降低血清转氨酶水平,还可改善胰岛素抵抗和减轻NAFLD患者肝纤维化程度。     

Liver steatosis,but not fibrosis,is associated with insulin resistance in nonalcoholic fatty liver disease

Background To address the hypothesis that liver steatosis causes systemic insulin resistance, we sought to determine the liver histological feature that most strongly contributes to insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Methods Liver biopsy specimens were obtained from 131 patients with clinically suspected NAFLD. The stage, grade of nonalcoholic steatohepatitis (NASH), and level of steatosis were scored and analyzed in relation to the homeostasis model assessment of insulin resistance (HOMA-IR) and the metabolic clearance rate (MCR), measured using the glucose clamp method. Results In the univariate analysis, the degree of hepatic steatosis (r = 0.458, P < 0.001), stage (r = 0.360, P < 0.001), and grade (r = 0.349, P < 0.01) of NASH were significantly correlated with the HOMA-IR. Multiple regression analysis adjusting for age, sex, body mass index, and each histological score showed that steatosis was significantly and independently associated with HOMA-IR (coefficient = 1.42, P < 0.001), but not with the stage (coefficient = 0.33, P = 0.307) or grade (coefficient = 0.67, P = 0.134) of NASH. Similar independent relationships were observed between steatosis and MCR, but the relationship was weaker (coefficient = −0.98, P = 0.076). Conclusions Steatosis of the liver, but not the stage or the grade of NASH, is associated with insulin resistance in patients with NAFLD.     

针药联合治疗对非酒精性脂肪肝及胰岛素抵抗的效果

[目的]探讨针灸联合中药汤剂治疗非酒精性脂肪肝并发胰岛素抵抗患者的治疗效果及应用价值。[方法]选择我院治疗的非酒精性脂肪肝并发胰岛素抵抗患者144例,随机分为观察组和对照组,对照组采用水飞蓟宾葡甲胺片治疗,观察组在对照组基础上联合针灸和口服中药汤剂治疗,观察2组的治疗效果。[结果]观察组治疗总有效率为94.44%,对照组治疗总有效率为79.17%,组间比较差异有统计学意义（P〈0.05）。观察组治疗后甘油三酯、总胆固醇、丙氨酸氨基转移酶与对照组治疗后比较,差异有统计学意义（P〈0.05）。观察组治疗后空腹血糖、空腹胰岛素浓度、胰岛素抵抗指数与对照组治疗后比较,差异有统计学意义（P〈0.05）。[结论]采用针灸联合中药汤剂治疗非酒精性脂肪肝并发胰岛素抵抗患者疗效可靠,能有效改善患者血脂和肝脏功能,同时可以改善胰岛素抵抗的状态,值得临床推广使用。     

Bile acids and insulin resistance: implications for treating nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease is characterized by an accumulation of excess triglycerides in hepatocytes, and insulin resistance is now considered the fundamental operative mechanism throughout the prevalence and progression of the disease. Besides their role in dietary lipid absorption and cholesterol homeostasis, evidence has accumulated that bile acids are also signaling molecules that play two important roles in glucose and lipid metabolism: in the nuclear hormone receptors as farnesoid X receptors (FXR), as well as ligands for G‐protein‐coupled receptors TGR5. The activated FXR‐SHP pathway regulates the enterohepatic recycling and biosynthesis of bile acids and underlies the down‐regulation of hepatic fatty acid and triglyceride biosynthesis and very low density lipoprotein production mediated by sterol‐regulatory element‐binding protein‐1c. The bile acid‐TGR5‐cAMP‐D2 signaling pathway in human skeletal muscle in the fasting–feeding cycle increases energy expenditure and prevents obesity. Therefore, a molecular basis has been provided for a link between bile acids, lipid metabolism and glucose homeostasis, which can open novel pharmacological approaches against insulin resistance and nonalcoholic fatty liver disease.     

小檗碱对非酒精性脂肪肝胰岛素抵抗及血清脂联素的影响

目的观察小檗碱对非酒精性脂肪肝（nonalcoholic fatty liver disease,NAFLD）胰岛素抵抗及血清脂联素（adiponectin,APN）的影响。方法选取我院门诊就诊的NAFLD患者68例,分为对照组（30例）和治疗组（38例）;健康体检者30例为健康组。治疗前分别测定NAFLD组及健康组的APN、血糖、血脂、空腹胰岛素（FINS）、胰岛素抵抗指数（HOMA-IR）、胰岛素敏感性指数（HOMA-IAI）及肝功能水平的变化。治疗组予小檗碱0.5g/次,3次/d,连续3月;对照组予低脂饮食,治疗3月后测定上述各指标。结果 NAFLD患者空腹血糖（FPG）、总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）、FINS、HOMA-IR及体质量指数（BMI）均明显升高,胰岛素敏感性降低,APN水平明显减少（P〈0.05）。口服小檗碱治疗后,治疗组FPG、TC、TG、LDL-C、FINS、HOMA-IR及BMI均明显下降,胰岛素敏感性,APN水平则明显升高（P〈0.05）,对照组各指标无变化（P〉0.05）。结论小檗碱治疗后,NAFLD患者血清APN水平明显升高,改善了胰岛素敏感性,降低了胰岛素抵抗。     

Current concepts in the pathogenesis of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of chronic liver disease, representing the leading cause of hepatology referral in some centres. However, its pathophysiology is not completely understood. Insulin resistance is one of the major mechanisms involved in disease prevalence and progression. Owing to the lack of an effective pharmacological therapy, recommendations on treatment are scarce and are based mainly on lifestyle changes, including diet and exercise. A review of the current literature on pathogenesis of NAFLD is presented in this article.     

Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease

Background Nonalcoholic fatty liver diseases are often associated with obesity, insulin resistance, and excessive visceral fat accumulation. The aims of this study were (1) to evaluate the relationship between the severity of fatty liver and visceral fat accumulation in nonalcoholic fatty liver diseases, and (2) to investigate the relationships of fatty liver with biochemical data and insulin resistance. Methods One hundred twenty-nine subjects (63 women) with fatty liver diagnosed by ultrasonography were enrolled. Subjects positive for hepatitis B virus, hepatitis C virus, or autoimmune antibodies and those whose alcohol intake was over 20 g/day were excluded. The visceral fat area at the umbilical level and the liver–spleen ratio were evaluated by computed tomography. Results The severity of fatty liver evaluated by ultrasonography showed a significant positive relationship with the visceral fat area and waist circumstance (fatty liver severity: mild, 92.0 ± 30.9 cm²; moderate, 122.1 ± 32.6 cm²; severe, 161.0 ± 48.4 cm²; P < 0.0001). The visceral fat area and liver–spleen ratio were negatively correlated (r = −0.605, P < 0.0001). The severity of fatty liver showed strong positive relationships with serum aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, fasting plasma insulin, and insulin resistance. The severity of fatty liver was positively related to the visceral fat area in 49 nonobese subjects (body mass index <25). Conclusions The severity of fatty liver was positively correlated with visceral fat accumulation and insulin resistance in both obese and nonobese subjects, suggesting that hepatic fat infiltration in nonalcoholic fatty liver disease may be influenced by visceral fat accumulation regardless of body mass index.     

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress-induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.     

Role of nonalcoholic fatty liver disease in the development of insulin resistance and diabetes

Nonalcoholic fatty liver disease (NAFLD) is a common disease that is usually accompanied by insulin resistance (IR). Whether or how NAFLD and IR are temporally and mechanistically related is controversial. Recent studies focus on their epidemiology, the importance of dietary fat, the role of adipocytokines and the sterol regulatory element-binding protein-1c. NAFLD and IR may progress to severe diseases, such as cirrhosis, diabetes or both, and understanding the pathogenesis of the precursor conditions has preventive and therapeutic implications. This review focuses on the possible relationships between NAFLD and IR and the treatment options available.     

非酒精性脂肪肝胰岛素抵抗及血清瘦素和脂联素水平的研究

[目的]研究非酒精性脂肪肝(NAFLD)患者胰岛素抵抗指数(IRI)、瘦素和脂联素水平的变化,探讨疾病发病中胰岛素抵抗(IR)、瘦素和脂联素的作用.[方法]测定体检和住院人群中NAFLD并肥胖(NAFLD)组、单纯性肥胖(肥胖)组和正常对照组空腹血糖、空腹血清胰岛素,采用稳态模型法计算IRI,同时检测瘦素和脂联素水平.[结果]NAFLD组空腹胰岛素水平和IRI显著高于肥胖组和对照组(P＜0.05);NAFLD组和肥胖组的瘦素水平显著高于对照组(P＜0.05);NAFLD组和肥胖组的脂联素水平显著低于对照组(P＜0.05);直线相关分析后,IRI与血清瘦素水平呈显著正相关(r=0.169 3,P＜0.01);而与血清脂联素水平呈显著负相关(r=-0.218 7,P＜0.01).[结论]IR可能是NAFLD发生、发展的基础,IR构成NAFLD患者基本特征之一,中央型肥胖是NAFLD的危险因素;NAFLD患者瘦素水平升高而脂联素水平降低,瘦素和脂联素通过不同机制参与了IR的发生、发展,进而影响NAFLD的发病.     

Treating nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic illness with multiple consequences. The spectrum of disease ranges from simple steatosis, with benign prognosis, to a potentially progressive form, nonalcoholic steatohepatitis, which may lead to liver fibrosis and cirrhosis, leading to an increase in morbidity and mortality. Furthermore, hepatocellular carcinoma incidence in NAFLD is comparable with that observed in hepatitis C-infected patients once cirrhosis is established. Current therapy is limited to lifestyle changes and control of associated metabolic disorders; however, new treatments are on the way from basic research to bedside. A review of the current literature on treatment of nonalcoholic fatty liver disease is presented in this article.     

The PNPLA3 I148M polymorphism is associated with insulin resistance and nonalcoholic fatty liver disease in a normoglycaemic population

Background and Aims: The adiponutrin/patatin‐like phospholipase‐3 (PNPLA3) I148M polymorphism has recently been found to contribute to differences in hepatic lipid content. Nonalcoholic fatty liver disease (NAFLD) has recently been considered a hepatic component of insulin resistance and a risk factor in the emergence of type 2 diabetes. However, whether there is an association between PNPLA3 I148M and insulin resistance and NAFLD in a normoglycaemic population is still unknown. Methods: This study enrolled 156 normoglycaemic individuals with NAFLD and 723 controls. All participants received complete biochemical and clinical workups including liver ultrasonography. They were then genotyped for the PNPLA3 I148M polymorphism. Results: We found significant differences in the genotype and the dominant model of the PNPLA3 I148M polymorphism between the NAFLD groups and the controls (P=0.018 and P=0.01 respectively). Furthermore, there was a dose effect of the PNPLA3 I148M genotype, in that CG heterozygotes had a risk of NAFLD between CC and GG homozygotes [adjusted odds ratio (OR)=2.03, 95% confidence interval (CI)=1.23–3.375 for the GG genotype and adjusted OR=1.55, 95% CI=1.02–2.35 for the CG genotype]. The dominant model of the PNPLA3 I148M polymorphism showed higher waist circumference, fasting insulin, Homeostasis Model Assessment (HOMA‐IR), alanine aminotransferase concentrations and ferritin level. Multivariate analysis showed the PNPLA3 I148M polymorphism to be independently and significantly associated with NAFLD in our normoglycaemic participants. Conclusion: This study reports an association between the PNPLA3‐I148M polymorphism and insulin resistance and NAFLD in a normoglycaemic population.     

非酒精性脂肪肝患者血浆抵抗素水平测定及与胰岛素抵抗的相关性

目的 探讨血浆抵抗素水平变化在非酒精性脂肪肝（NAFLD）发病中的作用及与胰岛素抵抗（IR）的关系。方法选择32例单纯NAFLD患者（F组）、29例NAFLD并2型糖尿病患者（FD组）和30例体检正常者（对照组）,分别测定空腹血浆抵抗素、空腹血糖（FPG）及胰岛素（FINS）水平,计算胰岛素敏感指数（ISI）,并分析其相关性。结果F组和FD组血浆抵抗素水平、FINS及ISI均明显高于对照组,尤以FD组为著;且血浆抵抗素水平与FINS、FPG呈正相关,与ISI呈负相关。结论NAFLD患者血浆抵抗素水平升高（尤以并2型糖尿病者为著）,并与ISI呈负相关;此可能在NAFLD等IR相关性疾病的发生、发展中具有一定作用。     

Differential effects of the circadian system and circadian misalignment on insulin sensitivity and insulin secretion in humans

Glucose tolerance is lower at night and higher in the morning. Shift workers, who often eat at night and experience circadian misalignment (i.e. misalignment between the central circadian pacemaker and the environmental/behavioural cycles), have an increased risk of type 2 diabetes. To determine the separate and relative impacts of the circadian system, behavioural/environmental cycles, and their interaction (i.e. circadian misalignment) on insulin sensitivity and β‐cell function, the oral minimal model was used to quantitatively assess the major determinants of glucose control in 14 healthy adults using a randomized, cross‐over design with two 8‐day laboratory protocols. Both protocols involved 3 baseline inpatient days with habitual sleep/wake cycles, followed by 4 inpatient days with the same nocturnal bedtime (circadian alignment) or with 12‐hour inverted behavioural/environmental cycles (circadian misalignment). The data showed that circadian phase and circadian misalignment affect glucose tolerance through different mechanisms. While the circadian system reduces glucose tolerance in the biological evening compared to the biological morning mainly by decreasing both dynamic and static β‐cell responsivity, circadian misalignment reduced glucose tolerance mainly by lowering insulin sensitivity, not by affecting β‐cell function.     

Abnormal glucose tolerance in young male patients with nonalcoholic fatty liver disease

Objective: The association of nonalcoholic fatty liver disease (NAFLD) with insulin resistance and metabolic syndrome has been documented for obese men and middle‐aged men. This study was designed to determine the relationship between NAFLD and the oral glucose tolerance test (OGTT) to predict preclinical diabetes in nondiabetic young male patients (<30 years old). Methods: A total of 75 male patients who had elevated liver enzymes and who were diagnosed with NAFLD were enrolled in this study. A standard 75 g OGTT was carried out on all patients. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were defined as a fasting plasma glucose (FPG) level ≥100 mg/dl but <126 mg/dl, and a 2‐h post‐load glucose on the OGTT of ≥140 mg/dl, but <200 mg/dl respectively. Results: According to the OGTT results, 24 (32%) patients were diagnosed as having IGT and 12 (16%) patients were diagnosed as having diabetes. Among the 48 patients with normal fasting glucose, 18 (37.6%) patients showed abnormal glucose tolerance (15 had IGT and three had diabetes). The NAFLD patients with abnormal glucose tolerance showed significant differences in age, weight, body mass index, waist–hip ratio, alanine aminotransferase, total bilirubin, total cholesterol, low‐density lipoprotein cholesterol, triglyceride, insulin, FPG and homeostasis model for insulin resistance (HOMA‐IR). Multiple regression analysis showed that age, FPG and HOMA‐IR were independent predictors of abnormal glucose tolerance. Conclusions: Although the patients were young men, an OGTT should be recommended for NAFLD patients with elevated liver enzymes and IFG to predict the risk of type 2 diabetes.     

非酒精性脂肪肝与胰岛素抵抗

目的探讨非酒精性脂肪性肝病（NAFLD）与胰岛素抵抗（IR）的关系。方法NAFLD组52例,非NAFLD组50例,比较两组间BMI、WHR、TC、TG、CRP、HDL-C、LDL-C、ALT、Cr、FBG、FINS和HOMA-IR的差异,并进行Logistic回归分析。结果NAFLD组与非NAFLD组在BMI（26.7±2.3与22.4±2.5,P〈0.01）、WHR（0.94±0.06与0.83±0.05,P〈0.01）、TG（2.4±0.6与1.8±0.6,P〈0.01）、ALT（37.3±8.3与28.1±7.2,P〈0.05）、FBG（6.2±1.4与5.2±0.7,P〈0.01）、FINS（23.6±13.6与8.6±3.5,P〈0.01）、HOMA-IR（6.7±4.7与2.0±1.6,P〈0.01）的差异有统计学意义,Logistic回归分析显示BMI（P〈0.01）、WHR（P〈0.01）、TG（P〈0.01）、ALT（P〈0.05）、HOMA-IR（P〈0.01）是NAFLD的独立影响因素。结论BMI、WHR、TG、ALT、HOMA-IR是NAFLD的独立影响因素。     

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随着中国人民生活水平的提高和生活方式的改变,糖尿病和脂肪肝的发病率均呈逐年升高趋势,糖尿病与肝病两者关系密切,相互影响,糖尿病能导致肝脏结构及功能损害而肝脏疾病导致糖耐量异常及糖尿病,二者形成恶性循环,最终预后不良。这里仅就糖尿病与肝病作以评述。     

Impact of body weight,diet and lifestyle on nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis is part of the broader spectrum of nonalcoholic fatty liver disease, strongly associated with insulin resistance, obesity and the metabolic syndrome. Its increasing prevalence appears to be closely related to the increased frequency of overweight or obesity; which is associated with changes in dietary habits, including an increased consumption of hypercaloric food and saturated fat, often concurrent with decreased activity and energy expenditure. Weight loss through dieting and increasing energy expenditure through the practice of regular exercise has been shown to be effective in improving nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, and is considered the mainstay of treatment. The effectiveness of these lifestyle interventions seems to rely chiefly on an improvement in insulin sensitivity. At present, disease management using a multidisciplinary team is probably pivotal for patient-centered quality of care.     

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver

Background and Aims

Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance.

Methods

We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at‐risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population‐based Dallas Heart Study (DHS).

Results

Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long‐term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases.

Conclusion

These data suggest that long‐term hepatic fat accumulation plays a causal role in the development of chronic liver disease.