老年男性高血压病人胰岛素抵抗与脂代谢变化

目的 研究老年男性高血压病人的胰岛素抵抗及脂质代谢变化的特点。 方法 对 3 0例老年男性高血压病人及老年男性正常人的血脂、血糖及胰岛素水平进行测定 ,观察其变化特点。 结果 老年男性高血压病人与老年男性正常人相比有较高的血清甘油三酯水平 [( 1 9± 0 9)mmol·L-1vs ( 1 3± 0 4)mmol·L-1]及胰岛素水平 [( 13 5± 4 3 )mIU·L-1vs ( 9 4± 2 0 )mIU·L-1] ,差异有显著性 (P <0 0 5 ) ;而且胰岛素敏感性 [( 4 3±0 4)vs ( 3 9± 0 5 ) ]也是降低的 (P <0 0 5 )。 结论 老年男性高血压病人不仅存在着脂质代谢紊乱 。

Ⅰ型糖尿病(IDDM)胰岛素治疗若干问题临床观察

IDDM胰岛素治疗中常出现一些问题,本文通过实验组和对照组比较,对胰岛素治疗若干问题进行了临床观察。1 对象和方法1.1 对象:IDDM患者35例,临床及实验室检查均符合1985年WHO诊断标准。35例中男性20例、女性15例,年龄4-33岁,平均23±6.5岁。全部患者随机分为实验组18例,其中饮食控制不理想组6例,固定部位注射组4例。

Hypoglycemic Effect of Intravenous Polyethylene Glycol-Coated Liposomal Insulin on Normal Rats

Aim To evaluate liposome as an injectable delivery system of proteins, insulin was chosen as model drug and the hypoglycemic effect of PEG-coated liposomal insulin was tested.Methods The PEG-coated liposomal insulin was prepared by reversal-phase emulsion evaporation.For pharmacodynamic study, insulin (2.5 IU*kg-1) was intravenously administered in phosphated-buffered saline (PBS) solution, conventional liposomes, and PEG-coated liposomes, separately, to normal Wistar rats.Blood glucose levels were determined by the glucose oxidase method.Results The mean diameter of the PEG-coated liposomal insulin was 58.4 nm, while the encapsulation ratio reached 18.33%.After intravenous administration of insulin solution, insulin liposome, and PEG-coated liposomal insulin, the minimum blood glucose concentrations (Cmin %) reached 25.26±5.75%, 33.92±12.42%, and 42.39±10.5% of the initial level, respectively, and the time periods to reach the minimum blood glucose level (Tmin) were 0.7±0.3 h, 1.2±0.4 h, and 2.3±0.7 h, respectively.The relative pharmacological bioavailabilities of insulin liposome and PEG-coated liposomal insulin were 98.03% and 99.70%, respectively, compared with the control of insulin solution.Conclusion PEG-coated liposome can be developed as a relatively sustained injectable delivery system for insulin.Moreover, the liposome coated with PEG may have advantages over normal liposome.

飞行对血浆葡萄糖、皮质醇、胰岛素、胰高血糖素、甲状腺激素和环核苷酸的影响

用放射免疫法测定24名飞行员血巾皮质醇、胰岛素、胰高血糖素，T3、T4、cAMP、cGMP值，及同时用酶法测定血装葡葡糖，并以相应地面人员33名作对照。结果，飞行前两组间各值和地面人员前后两次检查的各值间均无差异(P>0．05)；飞行员血浆葡萄糖、cAMP飞行后升高显著(P<0．05)，皮质醇和胰高血糖素飞行后也均有明显升高(P<0．001)，脂岛素明显降低(P<0．001)。飞行对T3、T4，cGMP无明显影响（P>0．05)。本文结果提示，飞行可以使血浆萄葡糖及其主要有关激素发生改变。这种变化对飞行保障有一定参考价值。

Effect of Liposome Double-Coated with Chitosan and Chitosan-EDTA Conjugates on Oral Absorption of Insulin

Aim To evaluate the gastrointestinal uptake of the insulin liposomes double-coated with chitosan （Ch） and chitosan-EDTA conjugates （CEC）, and verify their efficiencies. Methods Insulin-liposomes were prepared by reversed-phase evaporation. The hypoglycemic effects of the insulin liposomes coated with Ch or/and CEC were investigated using the glucose oxidase method after oral administration in diabetic rats, normal rats, and beagle dogs. Serum insulin concentrations in beagle dogs were determined by radioimmunoassay and were assessed by Pkanalyst computer program. Results The animals fed the insulin liposomes coated with Ch or/and CEC were able to regulate better the glucose load than the animals receiving PBS or uncoated insulin liposome, and the regulative effects of the insulin liposomes double-coated with Ch and CEC were better than those of the insulin liposomes coated with Ch or CEC alone. After oral administration of the insulin-liposomes double-coated with Ch and CEC to animals, a significant （P 〈 0. 05 ） blood glucose reduction was observed. Their relative pharmacological bioavailability was higher than 9 % in comparison with subcutaneous injection of insulin. In addition, in comparison with subcutaneous injection of insulin, the relative bioavailability was 12. 67 % calculated by area under the curve of serum insulin concentration versus time profile after oral administration of the insulin-liposomes double-coated with Ch and CEC to beagle dogs. Conclusion The insulin-liposomes double-coated with Ch and CEC were conducive to improving oral bioavailability of insulin.

Effect of Milrinone Induced Insulin Resistance on Glucose and Lipid Metabolism in Rats

Aim To investigate the effects of milrinone (a selective phosphodiesteraseIII inhibitor PDE_3 ) on insulin secretion, blood glucose, plasma free fatty acids (FFA) anddose-response relationship, and assess possible effects of milrinone on glucose metabolism andinsulin sensitivity in conscious rats. Methods The catheterized nonstressed rats were administeredvarious doses of milrinone (1, 5, 25μmoL·kg^(-1)) and were compared with controls. Ahyperinsulinaemic-eugly-caemic clamp was established in counscious rats, andmilrinone(25μmoL·kg^(-1)) and 25% dimethyl sulfoxide (DMSO, as a control) were given at 120 minduring hyperinsulinaemic-euglycaemic clamping. Glucose turnover was determind with by gaschromatograph mass spectrometer (GC-MS). Results After dosing, plasma FFA levels in 3 milrinonegroups significantly increased, compared with the controls and before dosing. The percentages ofelevation of FFA by the different milrinone doses were very similar, 50%, and 52% , 55% for 1, 5,and 25 μmoL·kg^(-1), repectively, at 2 min after dosing. Plasma insulin levels were significantlyelevated in the 5 and 25 μmoL·kg^(-1) groups, and the effect of milrione on glucose concentrationwas detectable only in 25μmoL·kg^(-1) group. During hyperinsulinaemic clamping, there weresignificant increase, in plasma FFA (from 173 +- 15 to 634 +- 87μmoL·kg^(-1)) and hepatic glucoseproduction (HGP), and a significant decrease in glucose infusion rates (GIR) to about 21% and aslight increase in plasma insulin after milrinone treatment. Conclusion Milrinone impaires theability of insulin to suppress lipolysis and HGP, and insulin-mediated glucose utilization inperipheral tissue. Therefore, milrinone administration may induce an acute insulin resistance invivo.

Berberine reverses free-fatty-acid-induced insulin resistance in 3T3-L1 adipocytes through targeting IKKβ

AIM: To investigate the effects and molecular mechanisms of berberine on improving insulin resistance induced by free fatty acids (FFAs) in 3T3-L1 adipocytes. METHODS: The model of insulin resistance in 3T3-L1 adipocytes was established by adding palmic acid (0.5 mmol/L) to the culture medium. Berberine treatment was performed at the same time. Glucose uptake rate was determined by the 2-deoxy-[3H]-D-glucose method. The levels of IkB kinase beta (IKKβ) Ser181 phosphorylation, insulin receptor substrate-1(IRS-1) Ser307 phosphorylation, expression of IKKβ, IRS-1, nuclear transcription factor kappaB p65 (NF-κB p65), phosphatidylinositol-3-kinase p85 (PI-3K p85) and glucose transporter 4 (GLUT4) proteins were detected by Western blotting. The distribution of NF-κB p65 proteins inside the adipocytes was observed through confocal laser scanning microscopy (CLSM). RESULTS: After the intervention of palmic acid for 24 h, the insulin-stimulated glucose transport in 3T3-L1 adipocytes was inhibited by 67%. Meanwhile, the expression of IRS-1 and PI-3K p85 protein was reduced, while the levels of IKKβ Ser181 and IRS-1 Ser307 phosphorylation, and nuclear translocation of NF-κB p65 protein were increased. However, the above indexes, which indicated the existence of insulin resistance, were reversed by berberine although the expression of GLUT4, IKKβ and total NF-κB p65 protein were not changed during this study. CONCLUSION: Insulin resistance induced by FFAs in 3T3-L1 adipocytes can be improved by berberine. Berberine reversed free-fatty-acid-induced insulin resistance in 3T3-L1 adipocytes through targeting IKKβ.

Visceral fat and insulin resistance as predictors of non-alcoholic steatohepatitis

AIM： To examine whether visceral fat is associated with non-alcoholic steatohepatitis （NASH）, to assess for parameters associated with visceral adiposity and to investigate for factors associated with fibrotic severity in NASH. METHODS： Thirty NASH and 30 control subjects underwent biochemical tests, anthropometric assessment, bioelectrical impedance, dual energy X-ray absorptiometry and abdominal fat study by CT scan. Liver biopsies were graded according to the Brunt criteria. RESULTS： NASH subjects had elevated blood pressure, body mass index, waist circumference and waist-to-hip ratio. A greater number of diabetes rnellitus, impaired glucose tolerance test and HOMA-IR 〉 3.5 were found in NASH patients. HOMA-IR 〉 2.8 （OR 20.98, 95% CI 3.22-136.62; P 〈 0.001） and visceral fat area 〉 158 cm^2 （OR 18.55, 95% CI 1.60-214.67; P = 0.019） were independent predictors for NASH. Advanced stage of NASH was found in 15 （50%） patients. HOMA-IR 〉 3.5 （OR 23.12, 95% CI 2.00-266.23; P = 0.012） and grading of portal inflammation （OR 7.15, 95% CI 1.63-31.20; P = 0.009） were determined as independent risk factors for advanced stage of NASH. CONCLUSION： Obesity （especially central obesity） and metabolic syndrome are common in Thai NASH. Insulin resistance and elevated visceral fat are risk factors for the presence of NASH. The advanced stage of thedisease is related to insulin resistance.

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD)in rats

Objective： The prevalence of non-alcoholic fatty liver disease （NAFLD） has markedly increased. Insulin resistance has been implicated in the pathogenesis of NAFLD. This study was aimed at observing the relationship between insulin resistance and NAFLD, and evaluating the role of pioglitazone （PGZ） acting as insulin-sensitizing agents in the prevention and treatment of rat fatty liver induced by high fat feeding. Methods： The rats were separated randomly into 6 groups： model group Ⅰ were fed high fat diet for 8 weeks, PGZ prevention group were given PGZ 4 mg/（kg.d） simultaneously, while control group Ⅰ were fed normal food for 8 weeks; model group Ⅱ were fed high fat diet for 16 weeks, PGZ treatment group were given PGZ 4 mg/（kg.d） orally simultaneous with high fat diet for 8 weeks after high fat feeding for 8 weeks, control group Ⅱ were fed normal food for 16 weeks. The rats were sacrificed after 8 weeks and 16 weeks respectively. Liver weight, body weight, serum activities of alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, alkaline phosphatase （ALP）, tumor necrosis factor alpha （TNF-α）, fasting blood glucose （FBG）, fasting plasma insulin （FINS）, HOMA （homeostasis model assessment） insulin resistance index （HOMA-IR）, and the liver histology of rats of all groups were assayed. Results： After 8 weeks, the liver in model group Ⅰ showed typical steatosis, accompanied with mild to moderate lobular inflammatory cell infiltration, liver indexes and serum levels of ALT, AST, ALP, TNF-α were significantly increased （P〈0.05） compared with control group Ⅰ. Whereas, the degree of hepatic injury was attenuated in PGZ prevention group, liver indexes and serum levels of ALT, ALP were significantly decreased （P〈0.05） compared with model group Ⅰ. After 16 weeks, notable steatosis, and lobular inflammation were observed in model group Ⅱ rat liver, while the degree of hepatic injury was attenuated in the PGZ treatment group. Liver index, serum levels ofALT, AST, ALP, FINS and HOMA-IR were significantly increased （P〈0.05） in model group Ⅱ compared with control group Ⅱ. Whereas, in PGZ treatment group, serum levels of AST and FINS showed decreasing tendency, liver indexes, serum levels of ALT, ALP, TNF-α and HOMA-IR were significantly decreased compared with model group Ⅱ. Conclusion： Insulin resistance plays a role in the pathogenesis of NAFLD in rats. Pioglitazone can attenuate insulin resistance and biochemical and histological injury in high fat-induced fatty liver in rats.

FTIR Characterization of the Secondary Structure of Insulin Encapsulated within Liposome

Aim To determine the secondary structure of insulin encapsulated withinliposome. Methods The secondary structure of native insulin, mixture of insulin with liposome(sample Ⅰ) and insulin encapsulated within liposome( sample Ⅱ) were determined by FTIR (FourierTransform Infrared) spectroscopy. Results The secondary structure of insulin encapsulated withinliposome(Ⅱ) are similar with the secondary structure of native insulin. The difference existed inthe amount of α-helices (from 36% of insulin to 31% of sample Ⅱ) and β-sheet(from 48% of insulinto 51% of sample Ⅱ). The content of α-helices and β-sheet of insulin in sample Ⅰ was found to bevery close to that of sample Ⅱ. The results revealed that the insulin encapsulated within liposomepossibly spread on the surface of liposome, without inserting into the liposome membrane.Conclusion The secondary structure of insulin encapsulated within liposome is similar with thenative insulin.

Non-invasive means of measuring hepatic fat content

Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver biopsy. However, it is an invasive procedure and its use is limited, particularly in children. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Ultrasound is widely used to detect hepatic steatosis, but its sensitivity is reduced in the morbidly obese and also in those with small amounts of fatty infiltration. It has been used to grade hepatic fat content, but this is subjective. CT can detect hepatic steatosis, but exposes subjects to ionising radiation, thus limiting its use in longitudinal studies and in children. Recently, magnetic resonance (MR) techniques using chemical shift imaging have provided a quantitative assessment of the degree of hepatic fatty infiltration, which correlates well with liver biopsy results in the same patients. Similarly, in vivo 1H MRS is a fast, safe, non-invasive method forthe quantification of intrahepatocellular lipid (IHCL) levels. Both techniques will be useful tools in future longitudinal clinical studies, either in examining the natural history of conditions causing hepatic steatosis (e.g. non-alcoholic fatty liver disease), or in testing new treatments for these conditions.

Roles of adipocyte derived hormone adiponectin and resistin in insulin resistance of type 2 diabetes

AIM： To detect plasma levels of new adipocyte derived hormone adiponectin and resistin in type 2 diabetes patients and to explore their potential roles in insulin resistance in type 2 diabetes. METHODS： According to the body mass index （BMI）, 60 type 2 diabetes patients were divided into two groups, one group was non-obese diabetes patients with BMI 〈 25Kg/M^2 （30 cases） and the other group was obese diabetes patients with BMI 〉25Kg/M^2 （30 cases）. There were 28 healthy persons in the control group. EUSA technique was employed to determine the plasma adiponectin and resistin concentrations. The fasting blood glucose, insulin and blood lipid were detected respectively by electrocheminescence immunoassay and immunoturbidimetric assay. Insulin resistance index and insulin sensitive index were calculated by the homeostasis model assessment （HOMO）. RESULTS： The levels of plasma adiponectin were decreased significantly in diabetes group compared to that in control group （non-obese： 8.58±0.86, obese： 6.22±1.34 vs 10.53±1.47 P〈0.05）; moreover, adiponectin concentration in obese diabetes group was significantly decreased compared to that in non-obese diabetes group （6.22±1.34 vs 8.58±0.86, P〈 0.05）. The levels of plasma resistin were increased significantly in diabetes group compared to that in control group （obese： 18.64 ± 4.65, non-obese： 24.05±9.07 vs 14.16±5.25, P〈0.05,P〈0.05）; furthermore, the levels of resistin in obese diabetes group were increased significantly compared to that in non-obese diabetes group （P〈 0.05）. Plasma adiponectin was correlated negatively with BMI, blood glucose, insulin resistance index and triglyceride （respectively, r=-0.55, P〈0.01; r=-0.51, P〈0.05; r=-0.52, P〈 0.05： r=-0.39, P〈 0.05）, while it was positively correlated with insulin sensitive index （r=0.45, P〈0.05）. Conversely, plasma resistin correlated positively with BMI, blood glucose, triglyceride and insulin resistance index （respectively, r=0.40, P〈 0.05; r= 0.52, P〈0.05; r= 0.46, P〈 0.01; r= 0.27, P〈 0.05）, and negatively correlated with insulin sensitive index （r=-0.32, P〈 0.05）. CONCLUSION： Plasma adiponectin and resistin are associatecl with the disorder of metabolism of glucose and lipid in diabetes. The relationship between these hormone and insulin sensitivity suggests that they may take part in the development of insulin resistance of type 2 diabetes.

Betaine and nonalcoholic steatohepatitis: Back to the future?

Nonalcoholic steatohepatitis (NASH) is an important indication for liver transplantation in many Western countries. Obesity and insulin resistance are the two most common risk factors for NASH, which can lead to recurrent NASH after liver transplantation. There is currently no approved therapy for NASH, and treatment is directed at risk factor modification and lifestyle changes. Betaine has been used for NASH, with mixed results, and may show promise in conjunction with other agents in clinical trials.

The blind men 'see' the elephant-the many faces of fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a group of diseases with excess fat in liver in the absence of a poorly defined limit of alcohol consumption. Most common variety, a universal public health problem, is associated with insulin resistance caused by a host of genetic and epigenetic defects modulated by life style and environmental factors. In fact the term NAFLD is loose to incorporate so many etiologies except alcoholism and few other etiologies, presenting as fat in liver. However as a sign fatty liver is very important in predicting the risk of diabetes, cardiovascular disease, stroke, cirrhosis and cancer. Abnormal fat accumulation can result from several defects in nuclear receptors associated with lipid sensing, synthesis and oxidation like LXR, FXR, SREBP, ChREBP and PPAR; defects in the lipid influx-efflux channels, insulin signaling, proteins involved in fatty acid catabolism, defects in adipose tissue development and function, inappropriate nutrition and finally defects in neural regulatory mechanisms. The progress of the disease is determined by the basic defects which results in fat accumulation, an individual’s immunological response to the accumulated fat and its derivatives and the oxidant stress response. Congregation of unrelated genetic defects under same diagnosis ‘NAFLD’ can result in inefficient patient management. Further studies are required to understand the molecular basis of fatty liver to enable a personalized management of diseases presenting as fatty liver in the absence of alcohol abuse.

Iron overload and cofactors with special reference to alcohol,hepatitis C virus infection and steatosis/insulin resistance

There are several cofactors which affect body iron metabolism and accelerate iron overload. Alcohol and hepatic viral infections are the most typical examples for clarifying the role of cofactors in iron overload. In these conditions, iron is deposited in hepatocytes and Kupffer cells and reactive oxygen species （ROS） produced through Fenton reaction have key role to facilitate cellular uptake of transferrin-bound iron. Furthermore, hepcidin, antimicrobial peptide produced mainly in the liver is also responsible for intestinal iron absorption and reticuloendothelial iron release. In patients with ceruloplasmin deficiency, anemia and secondary iron overload in liver and neurodegeneration are reported. Furthermore, there is accumulating evidence that fatty acid accumulation without alcohol and obesity itself modifies iron overload states. Ineffective erythropoiesis is also an important factor to accelerate iron overload, which is associated with diseases such as thalassemia and myelodysplastic syndrome. When this condition persists, the dietary iron absorption is increased due to the increment of bone marrow erythropoiesis and tissue iron overload will thereafter occurs. In porphyria cutanea tarda, iron is secondarily accumulated in the liver.

Adiponectin as a protective factor in hepatic steatosis

AIM: Obesity and insulin resistance (IR) are closely related to hepatic steatosis (HS), and adiponectin is a hepatic insulin sensitizer that has important effects in liver function. This study aims at investigating the relationship between serum adiponectin concentration and the presence of HS. METHODS: We carried out a cross-sectional study in a check-up unit of a University Hospital in Mexico City. We enrolled 196 subjects, comprising 98 subjects with HS (27 women, 71 men) and 98 controls (37 women and 61 men). Anthropometric, metabolic and biochemical variables were measured in the two groups. Serum adiponectin and leptin concentrations were determined, their association with grade of HS tested, and concentrations, according to quartiles, compared between cases and controls. X2 analysis for linear trends was used to test for a dose-response relationship and logistic regression analysis was conducted to test for a protective effect of adiponectin. RESULTS: The HS subjects were older and more obese than controls, with a central obesity pattern. In the fourth quartile of adiponectin concentrations, HS was less common and severe. In a multivariate model of the fourth quartile of the adiponectin concentrations, we observed a protective effect (OR = 0.17, 95%CI: 0.04-0.67, P= 0.01). In subjects with more severe HS, we observed higher leptin concentrations, and caloric intakes, total fat and iron consumption were higher than in controls. CONCLUSION: The results of the present study suggest that a high serum concentration of adiponectin is associated with a protective effect against HS.

Metabolic syndrome is associated with erosive esophagitis

AIM： To clarify whether insulin resistance and metabolic syndrome are risk factors for erosive esophagitis.METHODS： A case-control study was performed using the database of the Kangbuk Samsung Hospital Medical Screening Center.RESULTS： A total of 1679 cases of erosive esophagitis and 3358 randomly selected controls were included. Metabolic syndrome was diagnosed in 21% of the cases and 12% of the controls （P 〈 0.001）. Multiple logistic regressions confirmed the association between erosive esophagitis and metabolic syndrome （Odds ratio, 1.25; 95% CI, 1.04-1.49）. Among the components of metabolic syndrome, increased waist circumference, elevated serum triglyceride levels and hypertension were significant risk factors for erosive esophagitis （all P 〈 0.01）. Furthermore, increased insulin resistance （Odds ratio, 0.91; 95% CI, 0.85-0.98） and fatty liver, as diagnosed by ultrasonography （odds ratio, 1.39; 95% CI, 1.20-1.60）, were also related to erosive esophagitis even afl：er adjustment for a series of confounding factors.CONCLUSION： Metabolic syndrome and increased insulin resistance are associated with an increased risk of developing erosive esophagitis.

Adiponectin,a key adipokine in obesity related liver diseases

Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis,non-alcoholic steatohepatitis (NASH),and progressive liver fibrosis is considered the most common liver disease in western countries.Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance.Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients.Besides liver biopsy no diagnostic tools to identify patients with NASH are available,and no effective treatment has been established.Visceral obesity is a main risk factor for NAFLD and inappropriate storage of triglycerides in adipocytes and higher concentrations of free fatty acids may add to increased hepatic lipid storage,insulin resistance,and progressive liver damage.Most of the adipose tissue-derived proteins are elevated in obesity and may contribute to systemic inflammation and liver damage.Adiponectin is highly abundant in human serum but its levels are reduced in obesity and are even lower in patients with hepatic steatosis or NASH.Adiponectin antagonizes excess lipid storage in the liver and protects from inflammation and fibrosis.This review aims to give a short survey on NAFLD and the hepatoprotective effects of adiponectin.