NO-1886 inhibits size of adipocytes, suppresses plasma levels of tumor necrosis factor-alpha and free fatty acids, improves glucose metabolism in high-fat/high-sucrose-fed miniature pigs.

The synthetic compound NO-1886 is a lipoprotein lipase activator that has been proven to be highly effective in lowering plasma triglycerides and elevating high-density lipoprotein cholesterol. Recently, we found that NO-1886 also had a plasma glucose-reducing action in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study, we investigated the effects of NO-1886 on the morphology of adipocytes, plasma levels of tumor necrosis factor-alpha (TNF-alpha) and free fatty acids (FFA) in miniature pigs fed a high-fat/high-sucrose diet. Our results showed that feeding a high-fat/high-sucrose diet to miniature pigs increased the size of adipocytes, and the plasma levels of TNF-alpha, FFA, and glucose. This diet also induced insulin resistance and impaired the acute insulin response to glucose loading. Supplementing 1% NO-1886 to the high-fat/high-sucrose diet inhibited adipocyte enlargement, and suppressed plasma levels of TNF-alpha, FFA, and glucose. The decrease in plasma TNF-alpha and FFA was simultaneous with the decrease in plasma glucose. We also found an increased whole body glucose clearance and an increased acute insulin response to intravenous glucose loading by NO-1886 supplementation. These data suggest that NO-1886 improves the glucose metabolism in high-fat/high-sucrose diet-induced diabetic minipigs by decreasing fat deposit, and suppressing plasma TNF-alpha and FFA levels. Therefore, NO-1886 is potentially beneficial for the treatment of insulin-resistant syndrome.     

Reversal of glucose intolerance by by pioglitazone in high fat diet-fed rats

The present study was undertaken to determine the effect of pioglitazone (3, 10 and 30 mg/kg p.o.), an insulin sensitizer, on glucose intolerance in high fat diet- (HFD) fed rats (a nongenetic model of insulin resistance). In addition, the effect of pioglitazone (3, 10 and 30 mg/kg p.o.) on diet-induced changes in body weight, plasma glucose, insulin, triglyceride and total cholesterol levels were also determined. The feeding of HFD for 4 weeks produced a significant increase in body weight, total fat pad weight, basal/fasting plasma glucose, insulin, basal triglyceride (TG) and total cholesterol (TC) levels in male rats. Furthermore, the rats fed HFD exhibited fasting hyperglycemia and hyperinsulinemia as well as enhanced glycemic response to exogenously administered glucose (2 g/kg p.o.) during an oral glucose tolerance test (OGTT) at the end of 4 weeks of dietary manipulation, indicating that the rats had developed insulin resistance and glucose intolerance. Treatment with pioglitazone (10 and 30 mg/kg p.o.) once daily for 2 weeks significantly diminished the elevated basal plasma insulin and TG levels in HFD-fed rats. In addition, a statistically significant reduction in TC level was observed only with the high dose of pioglitazone (30 mg/kg p.o.). However, pioglitazone had no significant effect on body weight, total fat pad weight and basal plasma glucose level. Pioglitazone (10 and 30 mg/kg p.o.) significantly reduced fasting hyperglycemia and reversed oral glucose intolerance to normal in HFD-fed rats compared with control normal rats. The above findings suggest that pioglitazone has potent insulin-sensitizing and lipid-lowering properties in a HFD-fed rat model. In conclusion, the present study demonstrates that the adult male rats on a HFD for 4 weeks exhibited the characteristic features of obesity, insulin resistance and glucose intolerance, namely increased body weight, increased total fat pad weight, mild basal/fasting hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and impaired oral glucose tolerance, that closely resemble the human prediabetic obese insulin-resistant and glucose-intolerant state. Further treatment with pioglitazone once daily for 2 weeks significantly ameliorated changes in basal plasma insulin, TG and TC, and reversed oral glucose intolerance to normal in HFD-fed rats, suggesting its potential in the treatment of insulin resistance and glucose intolerance associated with abnormal lipid metabolism.     

Emodin protects against high-fat diet-induced obesity via regulation of AMP-activated protein kinase pathways in white adipose tissue

Emodin is an active herbal component traditionally used in China for treating a variety of diseases. The aim of this study was to examine the effect of emodin on the reducing lipid accumulation in white adipose tissue of high-fat diet-fed rats, and on the regulation of the expression of the genes involved in lipid metabolism to elucidate the mechanisms. After being fed a high-fat diet for two weeks, rats were dosed orally with emodin (20, 40, 80 mg/kg/day) or pioglitazone (20 mg/kg/day), once daily for eight weeks. Changes in body weight, feeding pattern, serum lipids, coronary artery risk index, and atherogenic index were investigated. Subcutaneous white adipose tissues were isolated for pathology histology and Western blot analyses. Changes of triglyceride accumulation in differentiated 3 T3-L1 adipocytes were also investigated. Emodin exhibited a significant concentration-dependent decrease in the intracellular accumulation of triglyceride in 3 T3-L1 adipocytes. Emodin (80 mg/kg/day) displayed similar characteristics to pioglitazone (20 mg/kg/day) in reducing body weight gain and plasma lipid levels as well as the coronary artery risk and atherogenic indices of high-fat diet-fed rats. Emodin also caused dose related reductions in epididymal white adipose tissue sizes in high-fat diet-fed rats. Emodin and pioglitazone enhanced the phosphorylation of AMP-activated protein kinase and its primary downstream targeting enzyme, acetyl-CoA carboxylase, upregulated gene expression of carnitine palmitoyl transferase 1, and downregulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the epididymal white adipose tissue of high-fat diet-fed rats. Our findings suggest that emodin could attenuate lipid accumulation in white adipose tissue through AMP-activated protein kinase activation.     

替米沙坦对OLETF大鼠脂肪细胞因子网膜素、视黄醇结合蛋白4及内脂素的影响

目的：研究血管紧张素Ⅱl型(AT1)受体阻滞剂替米沙坦对改善OLETF大鼠胰岛素抵抗(IR)的作用及其机制。方法：肥胖自发2型糖尿病雄性OLETF大鼠47只,高脂喂养22周诱导建立胰岛素抵抗大鼠模型。随机分为5组,胰岛素抵抗对照组（OLETF）大鼠给予高脂饮食,替米沙坦组(L)高脂饮食加替米沙坦,二甲双胍组（MET）高脂饮食加二甲双胍,吡格列酮组（P）高脂饮食加吡格列酮,低剂量替米沙坦组(VL) 高脂饮食加低剂量替米沙坦,干预26周后测定空腹血糖、空腹胰岛素、游离脂肪酸、血脂、网膜素、视黄醇结合蛋白4、内脂素水平。结果：替米沙坦具有改善OLETF自发胰岛素抵抗大鼠的胰岛素抵抗和糖、脂代谢的作用,药物干预组与胰岛素抵抗对照组比较,血清网膜素表达水平明显升高(F=6.888,P<0.001), 血清视黄醇结合蛋白4表达水平明显降低(F=7.236,P<0.001),血清内脂素表达水平明显降低(F=4.165,P=0.003),血脂水平和胰岛素抵抗得到明显改善。结论：替米沙坦可能通过提高血清网膜素表达、降低血清视黄醇结合蛋白4及内脂素表达,调节血脂水平,改善胰岛素抵抗。     

Effects of Combination of Thiazolidinediones with Melatonin in Dexamethasone-induced Insulin Resistance in Mice

In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o.) or rosiglitazone (5 mg/kg/day, p.o.) with melatonin 10 mg/kg/day p.o. from day 7 to day 22. In the biochemical parameters, the serum glucose, triglyceride levels were significantly lowered (P<0.05) in the combination groups as compared to dexamethasone treated group as well as with individual groups of pioglitazone, rosiglitazone, and melatonin. There was also, significant increased (P<0.05) in the body weight gain in combination treated groups as compared to dexamethasone as well as individual groups. The combination groups proved to be effective in normalizing the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates may be due to antioxidant effects of melatonin and decreased hyperglycemia induced insulin resistance by thiazolidinediones. The glucose uptake in the isolated hemidiaphragm of mice was significantly increased in combination treated groups (PM and RM) than dexamethasone alone treated mice as well as individual (pioglitazone, rosiglitazone, melatonin) treated groups probably via increased in expression of GLUT-4 by melatonin and thiazolidinediones as well as increased in insulin sensitivity by thiazolidinediones. Hence, it can be concluded that combination of pioglitazone and rosiglitazone, thiazolidinediones, with melatonin may reduces the insulin resistance via decreased in oxidative stress and control on hyperglycemia.     

吡格列酮改善高脂饮食导致的大鼠肝脏胰岛素抵抗

目的：观察大鼠肝脏中氧化应激以及胰岛素抵抗的发生并探讨吡咯列酮对高脂饮食导致的大鼠肝脏胰岛素抵抗的改善作用。方法：取4周龄雄性SD大鼠,实验分为4组：对照组,高脂组,吡咯列酮组、吡咯列酮＋高脂组。喂养12周后,称体重后断尾法留取空腹血标本,取血测定空腹血糖浓度、血清胰岛素,并计算胰岛素敏感指数;糖原检测试剂盒检测肝脏组织中糖原含量;DHE染色观察肝脏组织中的活性氧自由基水平。结果：正常大鼠的胰岛素敏感指数为-3.47±0.39,高脂饲料喂养12周后,大鼠空腹血糖水平上升,而胰岛素敏感指数降低为-6.29±0.54,吡咯列酮能降低血糖,增加胰岛素敏感指数为-4.54±0.33。蒽酮法的检测结果显示高脂饲料喂养大鼠肝组织糖原含量显著降低到（13.6±2.7）mg/g,吡咯列酮能促进肝脏糖原合成[（19.62±2.88）mg/g]。DHE染色显示肝组织活性氧自由基水平显著增加,吡咯列酮能降低氧化应激水平。结论：高脂饲料喂养SD大鼠胰岛素敏感指数降低,肝组织中活性氧自由基水平显著增加,糖原含量显著降低,吡咯列酮改善高脂饮食导致的大鼠肝脏胰岛素抵抗。     

NEU-P11, a novel melatonin agonist,inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats

Evidences indicate that a complex relationship exists among sleep disorders, obesity and insulin resistance. NEU-P11 is a novel melatonin agonist used in treatment of psychophysiological insomnia, and in animal studies NEU-P11 showed sleep-promoting effect. In this study, we applied NEU-P11 on obese rats to assess its potential melatoninergic effects in vivo. Obese models were established using high-fat/high-sucrose-fed for 5 months. NEU-P11 (10 mg/kg)/melatonin (4 mg/kg)/vehicle were administered by a daily intraperitoneal injection respectively for 8 weeks. Our results showed that NEU-P11 or melatonin inhibited both body weight gain and deposit of abdominal fat with no influence on food intake. The impaired insulin sensitivity and antioxidative potency were improved and the levels of plasma glucose, total cholesterol (TC), triglycerides (TG) decreased with an increased in HDL-cholesterol (HDL-c) after NEU-P11 or melatonin administration. These data suggest that NEU-P11, like melatonin, decreased body weight gain and improved insulin sensitivity and metabolic profiles in obese rats. We conclude that NEU-P11 has a melatoninergic effect on regulating body weight in obese rats and also improving metabolic profiles and efficiently enhancing insulin sensitivity.     

大黄酸和吡格列酮对实验性大鼠非酒精性脂肪性肝炎治疗作用的比较

目的：探讨大黄酸和吡格列酮各自对高脂诱建的大鼠非酒精性脂肪性肝炎（NASH）的影响及其可能的机制。方法：52只清洁级雄性SD大鼠,体重140～160g,随机分成4组：对照组（n=14）、模型组（n=14）、大黄酸组（n=12）、吡格列酮组（n=12）。模型组由高脂高胆固醇饲料（普通饲料＋10％猪油＋2％胆固醇配制）喂养,药物组均在12周高脂饮食后即造模成功后给予干预。大黄酸用生理盐水配成5g／L混悬液,每天固定时间100mg·kg^-1·d^-1灌胃,吡格列酮组8mg·kg^-1·d^-1灌胃。于第20周处死。测定所有动物体重、肝湿重、计算肝指数;测定空腹血糖（FBG）、转氨酶及血脂水平;放射免疫法测空腹胰岛素（FINS）及TNF—α,计算胰岛素抵抗指数;酶法测定肝组织匀浆丙二醛（MDA）、谷胱甘肽过氧物酶（GSH-Px）水平;HE染色肝病理组织切片。结果：与模型组相比,药物组AⅡ、AST、血糖、胰岛素及胰岛素抵抗指数、TNF-α MDA有明显下降;大黄酸组肝脂肪变较吡格列酮组明显（P〈0．05）,但其肝内炎症较吡格列酮组轻。结论：大黄酸和吡格列酮对大鼠NASH均有治疗作用,但在改善肝脂肪变及炎症方面有所不同。     

Piperine, an active principle from Piper nigrum, modulates hormonal and apo lipoprotein profiles in hyperlipidemic rats

PURPOSE: To study the effect of piperine, an alkaloid, on thyroid hormones and apolipoproteins in high-fat-diet (HFD) and antithyroid drug-induced hyperlipidemic rats. EXPERIMENTAL: Male Wistar rats were first divided into two groups, control diet and high-fat diet (HFD) and then subdivided into four subgroups of ten animals each. The animals were treated with the following regimens for 10 weeks: 1% carboxymethyl cellulose; 10 mg carbimazole (CM)/kg body weight; 10 mg CM + 40 mg piperine/kg body weight, and 10 mg CM + 2 mg atorvastatin /ATV//kg body weight. Lipid profiles, hormone levels, and apolipoprotein levels were studied in all groups. RESULTS: HFD and/or CM administration significantly elevated the plasma levels of total cholesterol, VLDL, LDL, triglycerides, free fatty acids, and phospholipids, but significantly reduced the HDL levels. Moreover, CM administration significantly reduced apo A-I levels and T3, T4 and testosterone levels while significantly elevating plasma apo B, thyroid stimulating hormone (TSH) and insulin levels. The simultaneous administration of piperine and HFD significantly reduced plasma lipids and lipoproteins levels, except for HDL, which was significantly elevated. Piperine supplementation also improved the plasma levels of apo A-I, T3, T4, testosterone, and I and significantly reduced apo B, TSH, and insulin to near normal levels. CONCLUSIONS: The data presented here provide evidence that piperine possesses thyrogenic activity, thus modulating apolipoprotein levels and insulin resistance in HFD-fed rats, opening a new view in the management of dyslipidemia by dietary supplementation with nutrients.     

Berberine reducing insulin resistance by up-regulating IRS-2 mRNA expression in nonalcoholic fatty liver disease (NAFLD) rat liver

This study was performed to investigate the molecular mechanism and the therapeutic effect of berberine on nonalcoholic fatty liver disease (NAFLD). Rat models were given a high-fat diet (42% kcal) until they developed NAFLD, then were given normal saline (n = 10), berberine (n− = 10) at 187.5 mg/kg/day, or pioglitazone (n = 10) at 10.0 mg/kg/day intragastrically for 4 weeks, respectively, and evaluated by hyperinsulinemic euglycemic clamping for insulin sensitivity. Serum biochemical markers and liver triglyceride (TG) were analyzed, real-time RT-PCR for mRNA expression and western blotting for protein expression of insulin receptor (IR) and insulin receptor substrate-2 (IRS-2) in liver tissues were performed, and hepatic histopathology in the rat models with NAFLD at the end of treatment was compared with normal controls (n = 10). The NAFLD rats developed insulin resistance, showing increased fasting blood glucose and insulin levels, decreased glucose infusion rate, increased weight of epididymal fat (g/100 g body weight), obvious hepatic steatosis and inflammation, and down-regulated IRS-2 mRNA and protein levels compared with normal controls (all P < 0.05). In comparison with those treated with saline, model rats treated with berberine or pioglitazone underwent significant recovery, including up-regulated IRS-2 mRNA and protein (all P < 0.05). Our results indicate that berberine may improve insulin resistance of NAFLD by up-regulating mRNA and protein levels of IRS-2, a key molecule in the insulin signaling pathway, suggesting that berberine may be used to treat NAFLD.     

脂蛋白酯酶活化剂NO-1886的研究进展

NO 18 8 6可以促进脂肪组织、心肌和骨骼肌内脂蛋白酯酶 (lipoproteinlipase ,LPL)mRNA的表达 ,提高其LPL活性 ,从而提高小鼠的肝素后血浆LPL的活性和数量 ;同时NO 1886也能降低血浆甘油三酯 (triglyceride ,TG) ,升高血浆高密度脂蛋白胆固醇 (high densitylipoproteincholestrol,HDL C)水平 ,此外 ,NO 1886还能降低血糖 ,改善胰岛素抵抗和 β 细胞的功能障碍。因此 ,LPL活化剂NO 1886和其他类似激活LPL的制剂对治疗高TG血症、低HDL C水平、预防AS及降低血糖方面有一定的作用     

吡格列酮对高脂血症大鼠SOD活性和MDA水平的影响

目的观察吡格列酮对高脂血症大鼠血清超氧化物歧化酶(SOD)活性和丙二醛(MDA)水平的影响。方法复制高脂血症大鼠模型,造模成功后随机分为对照组(8只)和治疗组[9只,吡格列酮10 mg/(kg.d)],干预4周后测量各组大鼠的SOD活性和MDA水平。结果高脂饮食喂养12周后,高脂饮食组TG、TC、LDL水平分别为1.74、3.50、0.45 mmol/L,均明显高于正常组(分别为0.93、1.83、0.20 mmol/L),且P值均小于0.01,提示造模成功。干预4周后治疗组的SOD活性为640.72U/m l,较对照组247.40 U/m l明显升高(P<0.01)。治疗组的MDA水平为2.46 nmol/m l,较对照组4.11nmol/m l明显降低(P<0.01)。结论吡格列酮能够提升高脂血症大鼠的SOD活性,降低MDA水平。     

Monoterpene phenolic compound thymol prevents high fat diet induced obesity in murine model

Context: Obesity has become a worldwide health problem. Most of the synthetic anti-obesity drugs have failed to manage the obesity due to either ineffectiveness or adverse effect. The research of prominent chemical constituents from herbal for the management of obesity has greatly increased.

Objective: The main objective of the present study was intended to examine the effects of thymol in high-fat diet (HFD)-induced obesity in murine model.

Methods: Male Wistar rats were fed HFD for 6 weeks to induce obesity. Thymol (14?mg/kg) administered orally twice a day to HFD-fed rats for 4 weeks. Alteration in body weight gain, visceral fat-pads weight and serum biochemical markers were assessed.

Results: At the end of study, rats fed with HFD exhibited significantly (p?p?Discussion and conclusions: Thymol prevents HFD-induced obesity in murine model through several mechanisms including attenuation of visceral fat accumulation, lipid lowering action, improvement of insulin and leptin sensitivity and enhanced antioxidant potential.     

Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening.

The objective of the present study was to develop a rat model that replicates the natural history and metabolic characteristics of human type 2 diabetes and is also suitable for pharmacological screening. Male Sprague-Dawley rats (160-180 g) were divided into two groups and fed with commercially available normal pellet diet (NPD) (12% calories as fat) or in-house prepared high-fat diet (HFD) (58% calories as fat), respectively, for a period of 2 weeks. The HFD-fed rats exhibited significant increase in body weight, basal plasma glucose (PGL), insulin (PI), triglycerides (PTG) and total cholesterol (PTC) levels as compared to NPD-fed control rats. Besides, the HFD rats showed significant reduction in glucose disappearance rate (K-value) on intravenous insulin glucose tolerance test (IVIGTT). Hyperinsulinemia together with reduced glucose disappearance rate (K-value) suggested that the feeding of HFD-induced insulin resistance in rats. After 2 weeks of dietary manipulation, a subset of the rats from both groups was injected intraperitoneally with low dose of streptozotocin (STZ) (35 mg kg(-1)). Insulin-resistant HFD-fed rats developed frank hyperglycemia upon STZ injection that, however, caused only mild elevation in PGL in NPD-fed rats. Though there was significant reduction in PI level after STZ injection in HFD rats, the reduction observed was only to a level that was comparable with NPD-fed control rats. In addition, the levels of PTG and PTC were further accentuated after STZ treatment in HFD-fed rats. In contrast, STZ (35 mg kg(-1), i.p.) failed to significantly alter PI, PTG and PTC levels in NPD-fed rats. Thus, these fat-fed/STZ-treated rats simulate natural disease progression and metabolic characteristics typical of individuals at increased risk of developing type 2 diabetes because of insulin resistance and obesity. Further, the fat-fed/STZ-treated rats were found to be sensitive for glucose lowering effects of insulin sensitizing (pioglitazone) as well as insulinotropic (glipizide) agents. Besides, the effect of pioglitazone and glipizide on the plasma lipid parameters (PTG and PTC) was shown in these diabetic rats. The present study represents that the combination of HFD-fed and low-dose STZ-treated rat serves as an alternative animal model for type 2 diabetes simulating the human syndrome that is also suitable for testing anti-diabetic agents for the treatment of type 2 diabetes.     

Assessment of diabetogenic drug activity in the rat: 5,5-diphenyl-2-thiohydantoin.

The diabetogenic activity of 5,5-diphenyl-2-thiohydantoin (DPTH) via oral administration was assessed in both normal and streptozotocin diabetic rats. Rats were fed powdered chow diet with and without 0.1% (w/w) DPTH. Food consumption and body weight were recorded every other day; whole blood glucose concentrations were determined at the start of the study and at the midpoint. At sacrifice, liver and pancreas were excised and blood samples were collected. Protein and lipid levels were determined in liver; insulin in pancreas; and glucose, insulin, and lipid in blood. DPTH treatment caused decreased food consumption and body weight gain. The drug dose, calculated from the food consumption data, was 76.5 mg/kg/day for the normal rats and 107 mg/kg/day for the diabetic rats. DPTH increased liver weight and liver lipid content in both normal and diabetic rats, and markedly lowered serum triglyceride concentration in normal rats but not in diabetic rats. Serum fatty acid concentration was not altered by DPTH. DPTH produced a significant elevation of blood glucose concentration of the diabetic rats that was not, however, correlated with altered pancreatic insulin concentration. In vitro, DPTH infusion inhibited insulin secretion by the perfused pancreas.     

大黄酸对2型糖尿病模型大鼠的保护作用

目的:研究大黄酸对2型糖尿病模型大鼠的保护作用。方法:腹腔注射链脲佐菌素联合高脂饲养以复制大鼠2型糖尿病模型。实验分为正常对照(等容生理盐水)组、模型(等容生理盐水)组、吡格列酮(10 mg/kg)组、大黄酸(100 mg/kg)组。灌胃给药,每天1次,连续8周。测定大鼠尿量(UV)、体质量(BW)、肾质量(KW)、甘油三酯(TG)、总胆固醇(TC)、空腹血糖(FPG)、空腹胰岛素(Fins)、肌酐(Cr)含量,尿蛋白(UPRO)、尿白蛋白(UALB)量,计算肾脏肥大指数(KW/BW)、胰岛素抵抗指数(HOMA-IR)、尿蛋白/肌酐比值(PCR)、尿白蛋白/肌酐比值(ACR)、内生肌酐清除率(Ccr)。结果:与正常对照组比较,模型组大鼠UV、BW、KW、TG、TC、FPG、FINS、Cr、UPRO、UALB量增加,KW/BW、HOMA-IR、PCR、ACR、Ccr升高,差异有统计学意义(P<0.01);与模型组比较,大黄酸组大鼠KW、TG、TC、FPG、Fins、UPRO、UALB、Cr量减少,KW/BW、Ccr升高,HOMA-IR、PCR、ACR降低,差异有统计学意义(P<0.01或P<0.05)。结论:大黄酸具有降低2型糖尿病模型大鼠尿蛋白排泄的作用,其机制可能与改善胰岛素抵抗有关。     

The elucidation of the mechanism of weight gain and glucose tolerance abnormalities induced by chlorpromazine

Antipsychotic drugs induce weight gain and metabolic abnormalities. Recently, the role of adipocytokines secreted from adipocytes in the development of metabolic syndrome has received attention. The aim of this study was to investigate the effects of chlorpromazine (Cp) on body weight, glucose, lipid metabolism, and adipocytokine secretion in rats fed sucrose. Wistar rats received 15% sucrose (Suc group), 15% sucrose and Cp at 7.5 mg/kg per day (Suc + Cp group), or Cp alone (Cp group) in water for 10 weeks. Fasting glucose levels in the Suc and Suc + Cp groups were significantly higher than in the control (Cont) group. Fasting insulin levels in the Suc, Suc + Cp, and Cp groups were also significantly higher than in the Cont group. The adiponectin level in the Suc group was significantly higher than in the Cont group, although the adiponectin level in the Suc + Cp group was not. Furthermore, the plasma tumor necrosis factor (TNF)-alpha level in the Suc + Cp group was significantly higher than in the Suc group. These data suggest that Cp inhibits the compensatory response of adiponectin with respect to obesity due to increased expression of plasma TNF-alpha level. Cp may exert more harmful effects on the glucose level and insulin resistance than on other factors, which may be one of the mechanisms responsible for the metabolic syndrome induced by antipsychotic agents.     

Insulin resistance-reducing effect of a new thiazolidinedione derivative, pioglitazone]

Takeda has a relatively long history in diabetes research. Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models in the 1960s and our chemical research on lipid-lowering agents in the 1970s. Pioglitazone reduced plasma glucose, triglyceride and insulin levels in obese-diabetic animal models with insulin resistance in liver and/or peripheral tissues, but did not decrease normoglycemia in normal rats and aged dogs or hyperglycemia in insulin-deficient streptozocin-induced diabetic rats and impaired-insulin-secretory Goto-Kakizaki rats. The ED50 of plasma glucose-lowering action was 0.5 mg/kg/day in Wistar fatty rats. These findings clearly indicate that pioglitazone works in animals with insulin resistance and has a quite different mechanism from sulfonylureas and insulin itself. Although the exact mechanism of pioglitazone still remains obscure, pioglitazone normalized abnormalities in the cellular signal transduction of insulin. These effects seem to be due to the inhibitory action of pioglitazone on TNF-alpha production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator-activated receptor, (PPAR)-gamma, that is related to differentiation of adipocytes, and the relationship between TNF-alpha production and PPAR-gamma has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-gamma may be involved in the mechanism of reduction of insulin resistance. The clinical data clearly demonstrated that pioglitazone, at clinical doses of 15-45 mg/day, decreased plasma glucose, HbA1c and triglyceride, increased plasma HDL-cholesterol, but did not alter total cholesterol and LDL-cholesterol levels. These findings suggest that pioglitazone has a benefit for prevention of cardiovascular diseases in addition to diabetic complications.     

肥胖大鼠非酒精性脂肪肝与血清脂联素和肿瘤坏死因子α的关系及吡格列酮干预

目的观察营养性肥胖大鼠非酒精性脂肪肝(NAFLD)与血清脂联素和肿瘤坏死因子α(TNF-α)的关系,以及吡格列酮干预后的变化。方法45只SD♂大鼠随机分为3组:吡格列酮组(P)、高脂对照组(HF)和普通饮食组(NC),各15只。P、HF组给予高脂饮食,NC组给予普通饲料;12wk后,P组行吡格列酮10mg·kg-1.d-1灌胃,HF组和NC组用相应溶剂灌胃,均灌胃4wk。检测血清脂联素、TNF-α、游离脂肪酸(FFA)水平和其他生化指标等,计算Lee′s指数、HOMA-IR指数和肝脏指数,行肝脏病理切片和HE染色。结果与NC组相比,HF组大鼠体重、肝脏指数、FPG、FINS、ALT、HOMA-IR和血清TNF-α水平均明显增高,血清脂联素水平降低(P<0.05),肝细胞出现脂肪变性。与HF组比较,P组大鼠肝脏指数、HOMA-IR、FFA、TNF-α均降低,脂联素水平升高(P<0.05),肝细胞脂肪变性明显改善。HF组大鼠血清FFA、TNF-α与HOMA-IR、肝脏指数正相关,脂联素与之负相关(P<0.05)。结论高脂饮食可引起大鼠营养性肥胖、胰岛素抵抗和NAFLD;吡格列酮能提高胰岛素敏感性,改善脂肪细胞变性,可能与降低TNF-α、升高脂联素有关。     

Pioglitazone attenuates prostatic enlargement in diet-induced insulin-resistant rats by altering lipid distribution and hyperinsulinaemia

BACKGROUND AND PURPOSE

Increased incidence of benign prostatic hyperplasia among insulin-resistant individuals suggests a role for hyperinsulinaemia in prostatic enlargement. We have already reported increased cell proliferation and enlargement of prostate gland in insulin-resistant rats. The present study aimed to elucidate the molecular mechanisms underlying the reversal of prostatic enlargement in insulin-resistant rats by the peroxisome proliferator-activated receptor γ agonist pioglitazone.

EXPERIMENTAL APPROACH

Sprague–Dawley rats were fed a normal pellet or a high-fat diet for 12 weeks with or without pioglitazone (20 mg·kg⁻¹). Subgroups of animals fed different diets were castrated. Effects of dietary manipulation and pioglitazone were measured on insulin sensitivity, lipid distribution, cell proliferation and apoptosis.

KEY RESULTS

A high-fat diet led to the accumulation of fat in non-adipose tissues, insulin resistance, compensatory hyperinsulinaemia and prostatic enlargement in rats. Pioglitazone treatment altered fat distribution, improved insulin sensitivity and normalized lipid and insulin level in rats on the high-fat diet. The improved metabolic parameters led to decreased cellular proliferation and increased apoptosis in the prostate gland. High-fat diet feeding and pioglitazone treatment did not change plasma testosterone levels. However, significant prostatic atrophy was observed in castrated rats irrespective of dietary intervention.

CONCLUSIONS AND IMPLICATIONS

Our results show a previously unexplored therapeutic potential of pioglitazone for prostatic enlargement under insulin-resistant condition and further suggest that targeting distribution of lipid from non-adipose tissue to adipose tissue and insulin signalling could be new strategies for the treatment of benign prostatic hyperplasia.