肝脏清除胰岛素减少相关的糖代谢衰老

目的探索葡糖糖代谢（GM）的衰老现象。方法纳入2007年3月至2009年10月住解放军第458医院两内科综合病区的空腹受检病例383例及行口服葡萄糖耐量试验（OGTT）的受检病例87例。根据两因素析因方案,将空腹受试者按GM因素分为2型糖尿病组（T2D）、糖尿病前期组（PD）和正常血糖（EG）组,按年龄分为老年组、中年组、青年组：同时将行OGTT者按GM因素分为T2D组、非糖尿病组,按年龄分为老年组、非老年组。检测受试者血糖、胰岛素（Ins）、C肽水平。结果空腹状态下T2D、PD和EG组中,T2D组血糖最高,PD组Ins和C肽水平最高（P〈0．05）;老、中、青3组中,中年组血糖和C肽水平最高,老年组Ins水平最高（P〈0．05）;观察指标均存在GM与年龄两因素的交互作用（P〈0．05）。OGTT刺激后,T2D组Ins早相分泌不足（P〈0．01）;OGTT后1,2,3h老年组血糖低于非老年组,Ins和C肽水平老年组高于非老年组（P〈0．05）。结论GM存在衰老现象,即随年龄增加,空腹Ins升高,GM与年龄两因素存在交互作用;老年人肝脏清除Ins减少,致刺激性分泌的Ins入血增多。     

Effects of Mediterranean diet supplemented with silybin–vitamin E–phospholipid complex in overweight patients with non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease is the most common liver disease worldwide. Aim: The aim of this study is to compare the metabolic effects of the Mediterranean diet versus the diet associated with silybin, phosphatidylcholine and vitamin E complex in overweight patients with non-alcoholic fatty liver disease. Methods: Thirty Caucasian overweight patients were randomized into three groups of 10 (Groups A, B and C). A personalized Mediterranean diet was started in Group A and B patients. In association with the diet, Group B patients were given Realsil complex, daily, for 6 months. Group C patients refused any treatment. Results: We showed that the Mediterranean diet alone, or in association with the Realsil complex, led to the significant variation in BMI, waist circumference, total cholesterol and triglycerides. We also observed a statistically significant decrease in homeostasis model assessment technique in Group B patients.     

非酒精性脂肪肝与胰岛素抵抗相关因素的分析

目的 探讨非酒精性脂肪肝病情与胰岛素抵抗之间的相关关系.方法 根据肝脏B超检查结果将所有纳入病例分为轻、中、重度三组,每组分别测身高、体重、血甘油三酯、胆固醇、肝功能等指标,计算出胰岛素抵抗指数和β细胞指数.比较各组间数据.结果 非酒精性脂肪肝的严重程度与胰岛素抵抗和血脂代谢紊乱是成正相关的.结论 证实了胰岛素抵抗及脂代谢紊乱在非酒精性脂肪肝发病及病情进展方面具有十分重要的地位.     

Long-Term Treatment with n-3 Polyunsaturated Fatty Acids as a Monotherapy in Children with Nonalcoholic Fatty Liver Disease

Objective:

To investigate the efficacy and safety of n-3 polyunsaturated fatty acids (PUFA) treatment in obese children with nonalcoholic fatty liver disease (NAFLD).

Methods:

One hundred and eight obese (body mass index (BMI) >95th percentile for age and sex) adolescents with NAFLD were included in the study. Mean age of the subjects was 13.8±3.9 years (9-17 yrs). The diagnosis of NAFLD was based on the presence of liver steatosis with high transaminases. The subjects were randomly divided into two groups. Group 1 (PUFA group, n=52) received a 1000 mg dose of PUFA once daily for 12 months and lifestyle intervention. Group 2 (placebo group, n=56) received a recommended diet plus placebo and lifestyle intervention for 12 months. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) from fasting samples.

Results:

BMI, fasting insulin levels and HOMA-IR values in both groups decreased significantly at the end of the study. In group 1, 67.8% of the patients had a decrease from baseline in the prevalence of steatosis (p<0.001). Frequency of elevated alanine aminotransferase (ALT) levels (39.2% to 14.2%; p<0.01) and elevated aspartate aminotransferase (AST) levels (25% to 17.8%; p=0.01) decreased significantly in the PUFA group. Following a 12-month diet plus placebo and lifestyle intervention treatment, 40.3% (21) of the patients in the placebo group also showed a decrease in frequency of steatosis (p=0.04) and slight decreases in frequency of elevated ALT levels (38.4% to 28.8%; p=0.01) and AST levels (30.7% to 28.8%; p>0.05).

Conclusion:

Our results indicated that n-3 PUFA treatment is safe and efficacious in obese children with NAFLD and can improve ultrasonographic findings and the elevated transaminase levels.     

Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case-control study

BACKGROUND: Non-alcoholic fatty liver disease is a common reason for hepatological consultation and may herald severe hepatic and extra-hepatic disease. The aetiopathogenesis of this condition is an area of increasing interest. AIM: To evaluate anthropometric and biochemical factors associated to non-alcoholic fatty liver disease in a case-control study. Methods. Demographic and biochemical data of 60 consecutive patients with bright liver absent-to-low alcohol consumption, no evidence of viral, genetic and autoimmune diseases, were compared to those of 60 age- and gender-matched historical controls without fatty liver by univariate and multiple logistic regression analysis. RESULTS: Patients were more often hypertriglyceridaemic, obese and diabetic than controls (p<.01). Mean values of alanine transaminase, gammaglutamyltranspeptidase, triglycerides, uric acid, fasting and log insulin, transferrin percent saturation and ferritin were significantly higher in the patients, while transferrin and quantitative insulin sensitivity check index, a quantitative insulin sensitivity index, were lower. No iron storage was found in those who underwent liver biopsy At univariate analysis the relative risk for non-alcoholic fatty liver disease significantly increased (p<0. 05) with increasing body mass index, fasting insulin, alanine transaminase, uric acid, triglycerides and gammaglutamyltranspeptidase; it decreased with increasing transferrin and quantitative insulin sensitivity check index. Multiple logistic regression analysis disclosed only fasting insulin and uric acid to be independent predictors of non-alcoholic fatty liver disease (p<0.05). CONCLUSIONS: Fasting insulin and serum uric acid levels indicating insulin resistance, but not indices of iron overload, are independent predictors of non-alcoholic fatty liver disease.     

Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licensed pharmacological agent to treat it. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain; thus, there is great interest in pharmacological treatments for NAFLD. Metformin is the first-line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent specifically to reduce liver fat accumulation; data from human studies are less convincing. In the present review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies, as well as the underlying proposed mechanisms, to try and understand and reconcile the difference in findings between rodent and human work in this area.     

Oral Insulin: The Rationale for This Approach and Current Developments

Insulin remains the most effective and durable hypoglycemic agent for the treatment of diabetes. The addition of an effective oral insulin dosage form to the antidiabetes armamentarium may have significant benefits in terms of fostering compliance and adherence among patients, as well as physiologic advantages due to the fact that such a dosage form replicates the natural route of insulin secretion and absorption through the portal vein and targets the liver directly. Several companies have developed technological platforms that protect polypeptides and proteins from enzymatic hydrolysis, enable their transport across the epithelial lining, and promote their absorption from the gastrointestinal tract. A review of the potential physiological rationale and advantages, as well as of current pertinent technologies used specifically with insulin, is herewith provided.     

不同Child-Pugh分级慢性乙型肝炎肝硬化患者糖代谢、胰岛素分泌情况及其与炎症反应的相关性分析

目的 探讨不同Child-Pugh分级的慢性乙型肝炎(CHB)合并肝硬化患者糖代谢和胰岛素分泌情况及与炎症反应相关性。方法 选取2013年1月-2018年1月广州市红十字会医院收治的CHB合并肝硬化患者147例,另纳入同期65例体检正常的人群作为对照组。收集患者入院12 h内资料,包括年龄、性别、BMI、收缩压、舒张压、HBV DNA载量、总胆固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白、ALT、AST、TNFα、IL-6、中性粒细胞与淋巴细胞比值(NLR)、空腹血糖、血浆胰岛素、C肽水平、胰岛素抵抗指数(HOMA-IR)、胰岛素分泌功能。记录口服葡萄糖耐量试验(OGTT)后2 h血糖、胰岛素及C肽水平,并计算患者此时的NLR。计数资料2组间比较采用χ2检验。计量资料2组间比较采用t检验。等级资料多组间比较和进一步两两比较均采用Kruskal-Wallis H秩和检验。相关性检验采用Pearson分析。结果 CHB合并肝硬化患者的TNFα、IL-6、NLR、胰岛素水平、HOMA-IR明显高于对照组,而胰岛素分泌功能明显低于对照组(P值均<0.05);根据Child-Pugh分级将147例CHB合并肝硬化患者分为3组(Child-Pugh A、B、C),3组间TNFα、IL-6、NLR、胰岛素水平、HOMA-IR、胰岛素分泌功能比较,差异均有统计学意义(P值均<0.05)。CHB合并肝硬化患者OGTT后2 h血糖、胰岛素、C肽水平及NLR、TNFα、IL-6均显著高于对照组(P值均<0.05);3组不同Child-Pugh分级患者OGTT后2 h血糖、胰岛素、NLR、TNFα、IL-6比较,差异均有统计学意义(P值均<0.05)。Child-Pugh评分与OGTT后2 h NLR、血糖、胰岛素水平均呈正相关(r值分别为0.678、0.451、0.644,P值均<0.001);OGTT后2 h NLR与血糖、胰岛素水平均呈正相关(r值分别为0.408、0.795,P值均<0.001)。结论 CHB合并肝硬化患者存在一定程度糖代谢异常和胰岛素抵抗,肝损伤越严重,糖代谢异常和胰岛素抵抗越明显,而炎症反应可能介导上述二者之间的联系。     

Effects of combined low‐dose spironolactone plus vitamin E vs vitamin E monotherapy on insulin resistance,non‐invasive indices of steatosis and fibrosis,and adipokine levels in non‐alcoholic fatty liver disease: a randomized controlled trial

The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non‐alcoholic fatty liver disease (NAFLD). The aim of the present 52‐week randomized controlled trial was to compare the effects of low‐dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non‐invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA‐IR) and non‐invasive indices of steatosis and fibrosis were calculated. Analysis was intention‐to‐treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase‐to‐platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA‐IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low‐dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger‐scale trials are needed to clarify the effect of low‐dose spironolactone on hepatic histology.     

Targeting fatty acid metabolism to improve glucose metabolism

Disturbances in fatty acid metabolism in adipose tissue, liver, skeletal muscle, gut and pancreas play an important role in the development of insulin resistance, impaired glucose metabolism and type 2 diabetes mellitus. Alterations in diet composition may contribute to prevent and/or reverse these disturbances through modulation of fatty acid metabolism. Besides an increased fat mass, adipose tissue dysfunction, characterized by an altered capacity to store lipids and an altered secretion of adipokines, may result in lipid overflow, systemic inflammation and excessive lipid accumulation in non‐adipose tissues like liver, skeletal muscle and the pancreas. These impairments together promote the development of impaired glucose metabolism, insulin resistance and type 2 diabetes mellitus. Furthermore, intrinsic functional impairments in either of these organs may contribute to lipotoxicity and insulin resistance. The present review provides an overview of fatty acid metabolism‐related pathways in adipose tissue, liver, skeletal muscle, pancreas and gut, which can be targeted by diet or food components, thereby improving glucose metabolism.     

B1-3,5-diiodotyrosine insulin: A valid tracer for insulin

Summary Insulin, specifically substituted at the Phe^B1 position with 3,5-diiodotyrosine, has been tested in several biological and immunological systems. Immunoreactivity was assessed using antisera specific for different parts of the insulin molecule. Biological activity in vitro was estimated on isolated rat fat cells. In vivo bioactivity (hypoglycaemia) and metabolism (metabolic and urinary clearance rates, half-life, apparent distribution space) were measured by infusion of the material into greyhounds. The results indicated that this B1-labelled insulin preparation was biologically fully active and, unlike randomly labelled preparations of iodoinsulin, was metabolised with kinetics indistinguishable from those of the unlabelled hormone. We suggest that this material is a valid tracer for insulin, fulfilling the criteria of high specific activity and biological identity to the native hormone.     

Correction of insulin sensitivity and glucose disposal after pancreatic islet transplantation: preliminary results

Aims: Pancreatic islet transplantation (PIT) represents a potential curative treatment for patients with type 1 diabetes, but only 10–15% of patients remain insulin independent 5 years post‐transplant. It is not known whether intrinsic insulin resistance exacerbated by immunosuppression plays a pivotal role in low graft survival. The study objective was to understand the changes in insulin resistance, glucose effectiveness (S_g) and free fatty acid dynamics (FFAd) before and after PIT. Methods: Insulin sensitivity index (S_i), S_g and FFAd were measured before and after PIT in 10 lean patients, 8 of whom reached insulin independence. Modified Bergman minimal model of frequently sampled intravenous glucose tolerance tests were performed pretransplant and at 12 months post‐transplant. Nine non‐diabetic control (NDC) subjects matched by age, gender and BMI were used. Results: Pretransplant S_i and S_g were 3.5 ± 0.8 × 10^?5/min/(pmol/l) and 0.74 ± 0.24 × 10^?2/min, respectively. S_i was significantly lower than matched NDCs [10.8 ± 0.6 × 10^?5/min/(pmol/l), p < 0.004]; S_g did not reach statistical significance (1.27 ± 0.22 × 10^?2/min, p = 0.25). Compared to pretransplant values, mean post‐transplant S_i and S_g were 9.6 ± 1.3 × 10^?5/min/(pmol/l)and 1.28 ± 0.22 ×10^?2/min, respectively, indicating significant improvement for S_i but not S_g (p = 0.008and p = 0.06). Twelve‐month post‐PIT compared to NDC values were not significantly different (p = 0.58 and 0.97, respectively). In addition, fractional disposal rate for FFA which directly depends on the endogenous insulin release (10–20 min) nearly normalized after PIT (p = 0.06). Conclusion: These preliminary findings demonstrate that PIT can restore glucose disposal and insulin sensitivity and partially correct glucose effectiveness and FFAd.     

microRNAs and the regulation of glucose and lipid metabolism

Over recent years, metabolic disorders such as type 2 diabetes have finally become recognized as a major challenge to global health. The attention of scientists therefore has to focus on improving our understanding of the molecular mechanisms behind these diseases and towards the design of new drug therapy strategies. The pathophysiology of diabetes is undoubtedly complex, oftentimes characterized by varying states of insulin resistance and impaired β-cell function; however, the identification of new pathways is constantly improving our understanding of the disease. We and others have recently shown that microRNAs (miRNAs) can play a role in insulin secretion and glucose homostasis. Thus, in this review, we will discuss the potential role of miRNAs in type 2 diabetes and related metabolic diseases.     

Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulin-dependent diabetes mellitus

The effects on lipoprotein and glucose metabolism of addition of n-3 fatty acids were studied in 14 non-insulin-dependent diabetic patients who were given 10 g of MaxEPA (3 g n-3 fatty acids) or placebo (olive oil) per day in a randomized double-blind cross-over study during two consecutive 8-week periods. After MaxEPA treatment, there was a marked increase in long-chain polyunsaturated fatty acids of the n-3 series in the plasma lipid esters and in the platelet phospholipids, while the n-6 fatty acid content decreased. The very low density lipoprotein (VLDL) triglyceride concentrations decreased significantly (by 22%) on MaxEPA treatment. However, these changes were not significantly different from those observed during the placebo period. The blood glucose concentration tended to increase during MaxEPA treatment, and to decrease during the placebo period, the changes under the two regimes being significantly different (P less than 0.01). In addition, the rate constant for glucose disappearance (k value) for the intravenous insulin-tolerance test, which reflected the peripheral insulin sensitivity, tended to decrease during MaxEPA treatment and increase during administration of the placebo, there being a significant difference (P less than 0.03) between the changes during the two treatments. The reason for the observed changes in blood glucose concentration and peripheral insulin sensitivity is still unclear.     

高血压病的胰岛素抵抗

对 17例治疗的 ,2 0例未治疗的高血压病人和 2 5例正常对照者 ,测定空腹及 75 g葡萄糖刺激后血浆葡萄糖和胰岛素浓度、红细胞胰岛素受体、血脂及脂蛋白。结果表明 :治疗和未治疗的高血压病人 ,血糖和胰岛素对葡萄糖刺激后的反应及胰岛素释放指数均显著高于对照组 ,血甘油三酯 (TG)、低密度脂蛋白(L DL )显著增高 ,高密度脂蛋白 (HDL )显著降低 ,红细胞胰岛素受体分析各组间差异无显著性。葡萄糖刺激后血浆胰岛素反应曲线下面积 (AIA )与收缩期和舒张期血压呈显著正相关 ,与TG,TC,L DL 也呈显著正相关 ,调整年龄、体重指数和血糖后 ,其相关性依然存在 ,说明高血压病存在着胰岛素抵抗 ,后者在高血压病因和临床中起重要作用     

Pulsatile intravenous insulin replacement in streptozotocin-diabetic rats is more efficient than continuous delivery: effects on glycaemic control,insulin-mediated glucose metabolism and lipolysis

Summary Short-term exposure of tissues to pulses of insulin generally leads to an enhancement of insulin action. We have investigated the possible beneficial effects of long-term near-physiological continuous vs pulsatile intravenous insulin treatment of insulin-deficient streptozotocin (70 mg/kg) diabetic rats on blood glucose control, in vivo insulin action and in vitro insulin action in isolated adipocytes. First, we determined the 24-h peripheral plasma insulin profiles in normal rats under precisely controlled meal-feeding conditions. Basal plasma insulin levels (40±9 U/ml) oscillate with a periodicity of 11.9±0.9 min (p<0.05), and an amplitude of 60±10%. Subsequently, the 24-h insulin profile was mimicked in diabetic (D) rats by a continuous (c) or pulsatile (p) (6-min double, 6-min off) insulin infusion rate for 2 weeks, using a programmable pump-swivel unit. Control (C) rats received vehicle treatment. In Cc, Dc, Cp and Dp daily urinary glucose loss and average plasma glucose levels were 0±0, 7.5±4.4, 0±0, 0.8±0.4 mmol and 6.7±0.2, 11.5±2.7, 6.6±0.1, 5.9±1.4 mmol/l, respectively. Hypoglycaemia (<3 mmol/l) was observed in 10 and 20% of the blood samples collected from Dc and Dp rats, respectively. After 2 weeks of treatment, in vivo peripheral and hepatic insulin action was measured by the hyperinsulinaemic euglycaemic (6 mmol/l) clampwith[3-³H]-glucoseinfusion. Pre-clampcounter-regulatory hormone levels were similar among rats. Compared to Cc and Cp, Dc showed a reduction in insulin sensitivity and responsiveness for peripheral glucose uptake whereas Dp only showed a reduction in insulin sensitivity. Suppression of hepatic glucose production by insulin was similar among rats. After 2.5 weeks of treatment, epididymal adipocytes were isolated. Specific [¹²⁵I]-insulin binding, basal and insulin-stimulated [U-¹⁴C]-glucose uptake and isoproterenol-stimulated glycerol output were comparable among rat adipocytes. The inhibition of glycerol output by insulin was identical in Cp and Dp (V_max=48.6±6.1 and 42.3±4.6%) but blunted in Dc vs Cc (V_max=8.2±4.6 vs 44.0±7.2%, p<0.01) adipocytes, suggesting a post-binding defect in the antilipolytic action of insulin in Dc rats. In conclusion, long-term near-physiological pulsatile intravenous insulin replacement in insulin-deficient diabetic rats is more efficient than continuous delivery in reducing blood glucose, lowering glucosuria, increasing insulin sensitivity and inhibiting lipolysis.Abbreviations IDDM Insulin-dependent diabetes mellitus - AUC area under the curve - CV coefficient of variation