利拉鲁肽对高脂饲养大鼠骨骼肌脂质沉积及骨骼肌超微结构的影响

目的研究胰高血糖素样肽1类似物利拉鲁肽对高脂喂养胰岛素抵抗(IR)大鼠骨骼肌脂质沉积及骨骼肌细胞超微结构的影响。方法雄性Wistar大鼠54只,随机普通饲养16只、高脂饲养38只,饲养8周后,各取5只大鼠判定大鼠IR状态,造模成功后,将高脂饲养大鼠分为高脂组、干预组1[利拉鲁肽100μg/(kg·d)]、干预组2[利拉鲁肽200μg/(kg·d)],每组11只,另11只普通饲养为对照组。药物干预2周后,检测骨骼肌内甘油三酯(mTG)、长链脂肪酰辅酶A(LCACoA),透射电镜观察大鼠骨骼肌细胞超微结构改变。结果与对照组比较,高脂组mTG、LCACoA含量升高[(19.58±1.63)μmol/g vs(9.99±0.90)μmol/g;(6.70±0.18)nmol/g vs(2.51±0.18)nmol/g,P0.01];与高脂组比较,干预组1LCACoA含量下降[(6.10±0.37)nmol/g vs(6.70±0.18)nmol/g,P0.05],干预组2mTG、LCACoA含量明显下降[(13.57±0.66)nmol/g vs(19.58±1.63)nmol/g,(4.73±0.31)nmol/g vs(6.70±0.18)nmol/g,P0.01]。干预组1和干预组2较高脂组和对照组脂滴减少、线粒体肿胀减轻。结论利拉鲁肽可呈浓度依赖性减少高脂喂养大鼠mTG和LCACoA含量,可能是减轻IR的原因之一。     

高脂饮食对老年大鼠骨骼肌脂肪酸含量及乙酰辅酶A羧化酶表达和活性的影响

目的 探讨增龄和高脂饮食对大鼠骨骼肌脂肪酸含量及乙酰辅酶A羧化酶(acetyl-coenzyme A carboxylase,ACC)表达和活性的影响.方法 将22～24月龄雄性Wistar大鼠随机分为老年对照组和高脂组;4～5月龄大鼠作为青年对照组.老年对照组和青年对照组给基础饲料,高脂组给予高脂饲料,喂养8周.用高胰岛素-正葡萄糖钳夹实验评价各组大鼠胰岛素敏感性,用全自动生化分析仪测定骨骼肌三酰甘油,用荧光分光光度计测定骨骼肌总的长链脂酰辅酶A含量,用Western-blot方法测定骨骼肌ACC、和磷酸化ACC(P-ACC)蛋白表达.结果 (1)老年对照组空腹血糖、胰岛索和游离脂肪酸高于青年对照组,高脂组上述几项指标进一步升高,并且出现血清三酰甘油和总胆固醇水平增高;(2)老年对照组葡萄糖输注率(glucose infusion rates,GIR)低于青年对照组,高脂组GIR低于老年对照组,高脂组GIR在8周末低于4周末;(3)老年对照组骨骼肌三酰甘油及长链脂酰辅酶A含量高于青年对照组,高脂组与老年对照组比较进一步升高;(4)老年对照组与青年对照组之间、高脂组与老年对照组之间骨骼肌ACC蛋白表达均无明显变化(P>0.05);骨骼肌P-ACC蛋白水平在老年对照组低于青年对照组,高脂组与老年对照组比较进一步降低(P<0.05或P<0.01).结论 与青年大鼠比较,老年大鼠更易出现脂肪酸代谢异常及胰岛素抵抗;高脂饮食导致老年大鼠骨骼肌脂质积聚更加严重,ACC活性的改变可能在骨骼肌脂质堆积和胰岛素抵抗发生中起了一定作用.     

长期脂肪含量较高饲料喂养对大鼠胰岛素抵抗的影响

目的探讨脂肪含量较高饲料长期喂养对大鼠胰岛素抵抗的影响。方法大鼠随机分为两组,对照组以普通饲料喂养16 w,高脂组以脂肪热量比38.5%的饲料喂养12 w,再以脂肪热量比51.3%的饲料喂养4 w。实验结束时,测定空腹血糖(FBG)、空腹血浆胰岛素(FINS)并计算胰岛素敏感指数(ISI)和胰岛素抵抗指数(HOMA-IR);另外进行口服葡萄糖耐量试验(OGTT),计算血糖曲线下面积(AUC)。结果两组大鼠能量摄取相似,体重差别不大。高脂组大鼠FINS显著高于对照组(P<0.01),但FBG无显著差别。高脂组大鼠ISI显著下降(P<0.01),HOMA-IR显著上升(P<0.01),血糖AUC显著升高(P<0.01)。结论脂肪含量较高的饲料喂养大鼠16 w后引起了胰岛素抵抗和糖耐量异常。     

吸烟对大鼠骨骼肌胰岛素受体底物2基因表达的影响

应用RT-PCR和免疫组化检测被动吸烟大鼠骨骼肌胰岛素受体底物2(IRS-2)mRNA和蛋白表达变化,结果显示吸烟使正常组、高脂饲养组大鼠骨骼肌IRS-2 mRNA(0.27±0.02 vs 0.41±0.25,0.40±0.04 vs 0.51±0.02)及蛋白(2.91±0.42 vs 4.90±0.29,2.43 vs 0.36±3.80+0.30)表达显著降低(均P<0.01).糖尿病吸烟组大鼠与对照组则差异无统计学意义(P>0.05),提示IRS-2基因表达的变化可能在吸烟致大鼠胰岛素抵抗发生机制中起一定的作用.     

高脂、高果糖饲料喂养大鼠骨骼肌脂质转运酶类的表达变化

目的观察高脂、高果糖喂养大鼠骨骼肌内甘油三酯含量及脂质转运相关酶类表达变化,探讨两种不同饮食导致肌内脂质沉积的机制。方法 Wistar雄性大鼠分为对照组、高脂组及高果糖组,测定各组大鼠空腹血糖、血胰岛素、血甘油三酯(TG)、骨骼肌TG及肌细胞内长链脂酰辅酶A(LCACoAs)的含量,正常葡萄糖高胰岛素钳夹技术测定葡萄糖输注率(G IR),并测定骨骼肌脂蛋白酯酶(LPL)、脂肪酸转位酶(FAT/CD36)的蛋白表达。结果与对照组相比,高脂组、高果糖组的血葡萄糖、血胰岛素浓度、HOMA指数及GIR明显增高,高脂组骨骼肌TG含量明显增高,高脂组、高果糖组骨骼肌LCACoAs均明显增高,且与HOMA指数呈正相关,高脂组、高果糖组LPL、FAT/CD36表达均增加。结论高脂饮食和高果糖饮食均可引起机体的胰岛素抵抗及骨骼肌内脂质堆积,肌内脂肪堆积与脂质转运相关酶类LPL、FAT/CD36表达增加有关。     

吸烟减少大鼠骨骼肌细胞胰岛素受体基因表达

应用RT-PCR及免疫组化技术分别检测实验大鼠骨骼肌细胞胰岛素受体基因mRNA及蛋白表达.结果显示正常吸烟组、高脂饲养吸烟组及糖尿病吸烟组大鼠骨骼肌细胞胰岛索受体基因mRNA的表达显著低于各自对照组(0.50±0.06对0.84±0.09,0.38±0.01对0.59±0.05,0.37±0.05对0.55±0.05,均P<0.01),蛋白含量亦明显低于各自对照组(6.99±0.53对8.89±0.36,5.17±0.29对7.53±0.53,2.16±0.56对5.03±0.79,均P<0.01),这可能是长期吸烟导致胰岛素抵抗的分子机制之一.     

高脂喂养及罗格列酮干预对老年大鼠骨骼肌线粒体功能的影响

目的 观察高脂饮食和罗格列酮干预对老年大鼠骨骼肌过氧化物酶体增生物激活受体γ共激活因子1α(PGC-1α)和线粒体融合蛋白2(Mfn2)表达的影响. 方法 21～23月龄Wistar大鼠分为老年对照组、高脂组和高脂+罗格列酮干预组(干预组),并设4～5月龄Wistar大鼠作为青年对照组.应用正常葡萄糖高胰岛素钳夹技术评价胰岛素敏感性,高脂喂养第8周时,检测骨骼肌PGC-1α和Mfn2的mRNA及蛋白表达.结果高脂喂养8周后,青年对照组、老年对照组和高脂组空腹血游离脂肪酸[(0.68±0.18)mmol/L、(0.82±0.23)mmol/L和(1.53±0.40)mmol/L],三酰甘油[(0.53±0.13)mmol/L、(0.63±0.17)mmol/L和(1.08±0.30)mmol/L],骨骼肌三酰甘油[(1.09±0.17)mmol/L、(1.34±0.20)mmol/L和(2.07±0.30)mmol/L]均升高,葡萄糖输注率((30.4±4.2)mg·kg~(-1)·min~(-1)、(20.9±2.2)mg·kg~(-1)·min~(-1)和(12.0±1.9)mg·kg~(-1)·min~(-1)]下降;经过罗格列酮干预后游离脂肪酸[(0.93±0.29)mmol/L]、三酰甘油[(0.62±0.12)mmol/L]及骨骼肌三酰甘油[(1.68±0.28)mmol/L)]均明显下降,葡萄糖输注率[(16.7±1.7)mg·kg~(-1)·min~(-1)]升高.与青年对照组比较,老年对照组骨骼肌PGC-1α和Mfn2的表达下降,经高脂喂养后PGc-1α和Mfn2的表达进一步下降,干预组上述基因的表达均显著高于高脂组(P<0.05),但仍比老年对照组降低(P<0.05). 结论 高脂饮食可诱导老年大鼠产生IR,推测可能与骨骼肌PGC-1α和Mfn2的表达下降有关;罗格列酮可通过改变骨骼肌PGC-1α和Mfn2的表达增加胰岛素敏感性.     

罗格列酮对胰岛素抵抗大鼠骨骼肌腺苷酸活化蛋白激酶α表达及活性的影响

目的 探讨罗格列酮对胰岛素抵抗大鼠骨骼肌脂肪酸代谢及腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)α表达和活性的影响.方法 根据随机数字表将40只4～5月龄雄性Wistar大鼠随机分至健康对照组(n=16;给予基础饲料)和高脂喂养组(n=24;给予高脂饲料).喂养4周末,两组各取8只大鼠行高胰岛素.正葡萄糖钳夹实验,评价高脂喂养组胰岛素抵抗状态.造模成功后根据随机数字表将高脂喂养组(n=16)随机分至高脂喂养亚组(n=8)和罗格列酮干预亚组(n=8),继续喂以高脂饲料4周,罗格列酮干预亚组同时给予3 mg·kg-1·d-1罗格列酮灌胃.骨骼肌甘油三酯经氯仿-甲醇抽提后采用全自动生化分析仪测定.运用实时荧光定量逆转录聚合酶链反应方法 测定骨骼肌AMPKα1及AMPKα2 mRNA表达水平;运用聚丙烯酰胺凝胶电泳和Western blot方法 测定骨骼肌AMPKα1、AMPKα2及P-AMPKα蛋白表达水平.组间比较采用完伞随机设计的单因素方差分析.结果 第8周末,高脂喂养亚组葡萄糖输注率低于健康对照组[分别为(19.3±3.7)和(30.4±4.2)mg·kg-1·min-1,P<0.01],罗格列酮干预亚组葡萄糖输注率高于高脂喂养亚组[分别为(25.8±1.6)和(19.3±3.7)mg·kg-1·min-1,P<0.05].高脂喂养亚组骨骼肌甘油三酯含量高于健康对照组[分别为(4.4±1.2)和(2.0±0.5)μmol/g,P<0.01],罗格列酮干预亚组骨骼肌甘油三酯含量低于高脂喂养亚组[分别为(3.3±1.1)和(4.4±1.2)μmol/g,P<0.05].骨骼肌AMPKαl mRNA及蛋白表达无组问差异(P>0.05);骨骼肌AMPKα2 mRNA、蛋白表达和P-AMPKα蛋白表达高脂喂养亚组低于健康对照组,而罗格列酮干预亚组高于高脂喂养亚组(均P<0.05).结论 高脂饮食可导致大鼠骨骼肌脂质堆积及胰岛素抵抗.罗格列酮干预可增加胰岛素抵抗大鼠骨骼肌AMPKα2表达和AMPKα活性,降低骨骼肌脂质含量,提高胰岛素敏感性.     

清肝调脂饮对非酒精性脂肪性肝炎大鼠胰岛素抵抗的影响

目的探讨清肝调脂饮对非酒精性脂肪性肝炎（NASH）大鼠胰岛素抵抗的干预机制。方法建立高脂饲料诱导的Wistar大鼠NASH模型并随机分组,清肝调脂饮低、中、高剂量组和西利宾胺组分别灌胃相应剂量药物治疗。实验12周后,检测各组大鼠血清TG、TC、葡萄糖、瘦素、FFA、INS;肝组织行脂肪染色、糖原染色并作定量分析。结果与模型组比较,各用药组均能不同程度改善以上各指标（P〈0.05,P〈0.01）,其中,在降低TG、葡萄糖、INS、FFA方面,中药高剂量组均明显优于西药对照组（P〈0.05）。结论清肝调脂饮促进游离脂肪酸代谢与肝内TG分解;改善胰岛素抵抗（IR）及瘦素抵抗（LR）。与西利宾胺比较,清肝调脂饮在抑制NASH的IR方面具有明显的疗效优势。     

高脂喂养的胰岛素抵抗大鼠骨骼肌蛋白激酶B mRNA表达的改变

目的研究高脂饮食喂养的胰岛素抵抗(IR)大鼠胰岛素敏感性及骨骼肌中蛋白激酶B(PKB)mRNA表达改变。方法 70只大鼠随机分为正常对照组和高脂饮食组,高脂饮食组采用高脂喂养的方法建立IR大鼠模型,用高胰岛素-正常葡萄糖钳夹实验测定葡萄糖输注率(GIR),同时测定各组大鼠空腹血糖(FPG)、空腹胰岛素(FINS)等指标的水平,实时荧光定量RT-PCR测定大鼠骨骼肌PKB mRNA表达。结果①高脂喂养4 w后,高脂组FPG、FINS、胰岛素抵抗指数(HOMA-IR)均较正常对照组显著升高,而胰岛素敏感指数(ISI)下降(P<0.05),GIR显著低于正常对照组(P<0.01),说明高脂组存在IR,IR模型制造成功。②与正常对照组相比高脂组PKB mRNA表达明显减弱(P<0.05)。结论高脂饮食喂养的IR大鼠IR的产生与骨骼肌胰岛素刺激PKB表达明显降低有关。     

Effect of physical training on glucose tolerance and on glucose metabolism of skeletal muscle in anaesthetized normal rats

Summary The effect of physical training on glucose tolerance in vivo and skeletal muscle glucose metabolism in vitro was investigated in normal rats. Treadmill running for 10 days up to 240 min/day led to a decrease of basal and glucose-stimulated plasma insulin levels without major alterations of the IV glucose tolerance (1 g/kg body weight). Swim training of two weeks' duration, i. e. exercise up to 2×75 min/ day, which did not induce significant changes in body composition, skeletal muscle glycogen levels or citrate synthase activity, resulted in a significant improvement of IV glucose tolerance and substantial reductions of basal and glucose-stimulated plasma insulin levels. Associated with this apparent improvement of insulin sensitivity in vivo, significant increases of the insulin-stimulated glucose uptake (+ 55%) and lactate oxidation (+ 78%) in vitro were found on perfusion of the isolated hindquarter of swim-trained animals. It is suggested that mild physical training can improve glucose tolerance and insulin sensitivity in normal rats, at least in part, due to an increase of insulin sensitivity of skeletal muscle glucose metabolism.     

坎地沙坦对自发性高血压大鼠骨骼肌胰岛素敏感性的影响

目的探讨血管紧张素Ⅱ(AngⅡ)受体拮抗剂(ARB)坎地沙坦对自发性高血压大鼠(SHR)骨骼肌胰岛素敏感性的影响及其机制。方法 30只SHR随机分为模型组、坎地沙坦高剂量组(Can 1组)及坎地沙坦低剂量组(Can 2组),每组10只,另选10只WKY大鼠作为对照组。均给予果糖喂养,Can 1组(0.8 mg/kg)、Can 2组(0.4mg/kg)分别给予坎地沙坦灌胃干预,观察第8周末各组大鼠胰岛素抵抗指数(HOMA-IR)和AngⅡ的水平,以及骨骼肌蛋白激酶B(Akt)的基因及蛋白表达水平。结果与对照组比较,模型组大鼠AngⅡ、HOMA-IR及血清空腹胰岛素(FINS)明显升高,骨骼肌中Akt mRNA表达及P-Akt蛋白表达显著减少,差异有统计学意义(P<0.05,P<0.01)。与模型组比较,Can 1组大鼠FINS、HOMA-IR明显降低,Can 1组和Can 2组骨骼肌Akt mRNA表达及P-Akt表达显著增加,差异有统计学意义(P<0.05,P<0.01)。结论 AngⅡ通过下调SHR骨骼肌的Akt蛋白表达引起胰岛素抵抗,而坎地沙坦通过抑制AngⅡ的这种作用改善骨骼肌胰岛素抵抗。     

线粒体融合蛋白2改善高脂诱导的骨骼肌细胞胰岛素抵抗机制的研究

目的 探讨线粒体融合蛋白2 （Mfn2）是否通过减轻氧化应激改善大鼠骨骼肌细胞IR.方法 建立高脂诱导骨骼肌细胞IR模型（PA组）,以Mfn2基因重组腺病毒转染细胞（PMfn2组）,观察细胞内葡萄糖摄取率、超氧化物歧化酶总活力（T-SOD）、过氧化氢酶（CAT）、活性氧簇（ROS）及MDA的改变. 结果 （1）与正常对照（NC）组相比,高脂（PA）组葡萄糖摄取率降低（P＜0.01）,T-SOD及CAT活性降低,ROS、MDA含量增加（P＜0.05）;（2）与PA组相比,Mfn2基因重组腺病毒转染（PMfn2）组T-SOD及CAT活力均增加（P＜0.05）;ROS水平、MDA含量降低（P＜0.05）;GSH-Px活力无明显改变. 结论 上调高脂干预后骨骼肌细胞的Mfn2水平可减轻细胞氧化应激,改善IR.     

Curcumin improves insulin resistance in skeletal muscle of rats

Background and aims

Curcumin has been reported to lower plasma lipids and glucose in diabetic rats, and to decrease body weight in obese rats, which may partly be due to increased fatty acid oxidation and utilization in skeletal muscle.

Methods and results

Diabetic rats induced by high-fat diet plus streptozotocin (STZ, 30 mg/kg BW) were fed a diet containing 50, 150, or 250 mg/kg BW curcumin for 7 wk. Curcumin dose-dependently decreased plasma lipids and glucose and the dose 150 mg/kg BW appeared to be adequate to produce a significant effect. Curcumin supplementation reduced glucose and insulin tolerance measured as areas under the curve. L6 myotubes were treated with palmitate (0.25 mmol/L) in the presence of different levels of curcumin for 24 h in our in vitro experiment. Curcumin at 10 μmol/L was adequate to cause a significant increase in 2-deoxy-[³H]d-glucose uptake by L6 myotubes. Curcumin up-regulated expression of phosphorylated AMP-activated protein kinase (AMPK), CD36, and carnitine palmitoyl transferase 1, but down-regulated expression of pyruvate dehydrogenase 4 and phosphorylated glycogen synthase (GS) in both in vivo and in vitro studies. Moreover, curcumin increased phosphorylated acetyl COA carboxylase in L6 myotubes. The effects of curcumin on these enzymes except for GS were suppressed by AMPK inhibitor, Compound C. LKB1, an upstream kinase of AMPK, was activated by curcumin and inhibited by radicicol, an LKB1 destabilizer.

Conclusion

Curcumin improves muscular insulin resistance by increasing oxidation of fatty acid and glucose, which is, at least in part, mediated through LKB1-AMPK pathway.     

Effects of glycaemia on glucose transport in isolated skeletal muscle from patients with NIDDM: in vitro reversal of muscular insulin resistance

Summary We investigated the influence of altered glucose levels on insulin-stimulated 3-0-methylglucose transport in isolated skeletal muscle obtained from NIDDM patients (n=13) and non-diabetic subjects (n=23). Whole body insulin sensitivity was 71% lower in the NIDDM patients compared to the non-diabetic subjects (p <0.05), whereas, insulin-mediated peripheral glucose utilization in the NIDDM patients under hyperglycaemic conditions was comparable to that of the non-diabetic subjects at euglycaemia. Following a 30-min in vitro exposure to 4 mmol/l glucose, insulin-stimulated 3-0-methylglucose transport (600 pmol/l insulin) was 40% lower in isolated skeletal muscle strips from the NIDDM patients when compared to muscle strips from the non-diabetic subjects. The impaired capacity for insulin-stimulated 3-0-methylglucose transport in the NIDDM skeletal muscle was normalized following prolonged (2 h) exposure to 4 mmol/l, but not to 8 mmol/l glucose. Insulin-stimulated 3-0-methylglucose transport in the NIDDM skeletal muscle exposed to 8 mmol/l glucose was similar to that of the non-diabetic muscle exposed to 5 mmol/l glucose, but was decreased by 43% (p <0.01) when compared to non-diabetic muscle exposed to 8 mmol/l glucose. Despite the impaired insulin-stimulated 3-0-methylglucose transport capacity demonstrated by skeletal muscle from the NIDDM patients, skeletal muscle glycogen content was similar to that of the non-diabetic subjects. Kinetic studies revel a K_m for 3-0-methylglucose transport of 9.7 and 8.8 mmol/l glucose for basal and insulin-stimulated conditions, respectively. In conclusion, the impaired capacity for insulinstimulated glucose transport in skeletal muscle from patients with NIDDM appears to protect the cell from excessive glucose uptake under hyperglycaemic conditions. Furthermore, the in vitro normalization of the decreased insulin-stimulated glucose transport in NIDDM skeletal muscle following exposure to 4 mmol/l glucose suggests that glycaemia per se has a profound effect on the regulation of muscular glucose transport.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - KHB Krebs-Henseleit bicarbonate buffer - BSA bovine serum albumin - ANOVA analysis of variance - GLUT 4 insulin regulated glucose transporter     

Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle

Melatonin has a number of beneficial metabolic actions and reduced levels of melatonin may contribute to type 2 diabetes. The present study investigated the metabolic pathways involved in the effects of melatonin on mitochondrial function and insulin resistance in rat skeletal muscle. The effect of melatonin was tested both in vitro in isolated rats skeletal muscle cells and in vivo using pinealectomized rats (PNX). Insulin resistance was induced in vitro by treating primary rat skeletal muscle cells with palmitic acid for 24 hr. Insulin‐stimulated glucose uptake was reduced by palmitic acid followed by decreased phosphorylation of AKT which was prevented my melatonin. Palmitic acid reduced mitochondrial respiration, genes involved in mitochondrial biogenesis and the levels of tricarboxylic acid cycle intermediates whereas melatonin counteracted all these parameters in insulin‐resistant cells. Melatonin treatment increases CAMKII and p‐CREB but had no effect on p‐AMPK. Silencing of CREB protein by siRNA reduced mitochondrial respiration mimicking the effect of palmitic acid and prevented melatonin‐induced increase in p‐AKT in palmitic acid‐treated cells. PNX rats exhibited mild glucose intolerance, decreased energy expenditure and decreased p‐AKT, mitochondrial respiration, and p‐CREB and PGC‐1 alpha levels in skeletal muscle which were restored by melatonin treatment in PNX rats. In summary, we showed that melatonin could prevent mitochondrial dysfunction and insulin resistance via activation of CREB‐PGC‐1 alpha pathway. Thus, the present work shows that melatonin play an important role in skeletal muscle mitochondrial function which could explain some of the beneficial effects of melatonin in insulin resistance states.     

The lipoprotein lipase activator, NO-1886, suppresses fat accumulation and insulin resistance in rats fed a high-fat diet

Abstract Aims/hypothesis. Fat balance is critical in the aetiology of obesity and related diseases. Lipoprotein lipase is of major importance in lipid metabolism. The aim of this study was to investigate the long-term effects of the lipoprotein lipase activator, NO-1886, on substrate utilisation, adiposity and insulin action in rats fed a high-fat diet.?Methods. Male, Sprague-Dawley rats were fed for 10 weeks on a chow diet or a high-fat diet with, or without, NO-1886 (50 mg · kg^–1· day^–1). Weight gain, fat accumulation and both hormone-sensitive and lipoprotein, lipase activities were measured. Insulin action was assessed by the euglycaemic hyperinsulinaemic clamp and metabolic rate/substrate utilisation by open-circuit respirometry.?Results. Compared with chow-fed controls, a high-fat diet increased weight gain, an effect lessened by NO-1886 [weight gain (g): chow, 37 ± 3, high-fat, 222 ± 9; high-fat + NO-1886, 109 ± 6, all groups differed p < 0.001]. A similar pattern existed for fat accumulation [visceral fat (g): chow, 35.9 ± 3.2; high-fat, 81.9 ± 6.6; high-fat + NO-1886, 52.3 ± 4.7, p < 0.01 high-fat vs the other groups]. A high-fat diet induced whole-body insulin resistance (clamp glucose infusion rate: 4.8 ± 1.3 mg · kg^–1· min^–1 vs 10.6 ± 1.1 for the chow group, p < 0.01) with NO-1886 lessening this effect (8.3 ± 0.5, p < 0.05 vs high-fat). The 24-h respiratory quotient was lower in the high-fat + NO-1886 group (0.825 ± 0.010) compared with high-fat alone (0.849 ± 0.004, p < 0.05). A high-fat diet increased lipoprotein and hormone-sensitive, lipase activities in epididymal fat, an effect not altered by NO-1886. In myocardium and skeletal muscle a high-fat diet lowered lipoprotein lipase activity, an effect lessened by NO-1886.?Conclusion/interpretation: Lipoprotein lipase activators could have potential benefits for the treatment of obesity by increasing fat utilisation. [Diabetologia (2000) 43: 875–880] Received: 11 January 2000 and in final revised form: 4 April 2000     

The effect of acarbose on insulin resistance in obese hypertensive subjects with normal glucose tolerance: a randomized controlled study

Aim:  Acarbose, a glucose oxidase inhibitor, delays the absorption of glucose thus reducing post-prandial blood glucose level, haemoglobin A1c (HbA1c) and insulin resistance in patients with diabetes mellitus and in subjects with impaired glucose tolerance. The effect of acarbose in subjects with normal glucose tolerance (NGT) has hitherto not been examined. The aim of the present study was to examine the effect of acarbose in obese hypertensive subjects with NGT.
Methods:  A double-blinded, parallel group study was performed on 56 male subjects with hypertension, body mass index (BMI) 27–35 kg/m², fasting blood glucose ≤ 6 mmol/l and a normal oral glucose tolerance test. Blood pressure, HbA1c, lipid profile and insulin resistance [homeostasis model assessment (HOMA) index] were determined initially and following 24 weeks of acarbose, 150 mg/day or placebo. The primary end point was the change in insulin resistance. Anti-hypertensive treatment and diet were kept constant during the study.
Results:  Insulin resistance decreased in acarbose users but not on placebo. HOMA index declined from 5.36 ± 1.7 to 4.10 ± 1.6 (p = 0.001) on acarbose, the corresponding values on placebo were 5.44 ± 1.9 and 5.53 ± 1.7. A decrease in serum triglyceride values (2.16 ± 0.16 mmol/l to 1.76 ± 0.15 mmol/l, p = 0.02) took place on acarbose with no change on placebo. There was no change in BMI, low-density lipoprotein or high-density lipoprotein values in either group. Blood pressure declined equally in both the groups, probably due to better patient compliance.
Conclusions:  Acarbose may reduce insulin resistance and triglycerides also in obese hypertensive subjects with normal glucose tolerance.     

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

Aims/hypothesis To study the secondary consequences of impaired suppression of endogenous glucose production (EGP) we have created a transgenic rat overexpressing the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in the kidney. The aim of this study was to determine whether peripheral insulin resistance develops in these transgenic rats.Methods Whole body rate of glucose disappearance (R_d) and endogenous glucose production were measured basally and during a euglycaemic/hyperinsulinaemic clamp in phosphoenolpyruvate carboxykinase transgenic and control rats using [6-³H]-glucose. Glucose uptake into individual tissues was measured in vivo using 2-[1-¹⁴C]-deoxyglucose.Results Phosphoenolpyruvate carboxykinase transgenic rats were heavier and had increased gonadal and infrarenal fat pad weights. Under basal conditions, endogenous glucose production was similar in phosphoenolpyruvate carboxykinase transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min). Moderate hyperinsulinaemia (810 pmol/l) completely suppressed EGP in control rats (–0.6±5.5 µmol/kg/min, p<0.05) while there was no suppression in phosphoenolpyruvate carboxykinase rats (45.2±7.9 µmol/kg/min). Basal R_d was comparable between PEPCK transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min) but under insulin-stimulated conditions the increase in R_d was greater in control compared to phosphoenolpyruvate carboxykinase transgenic rats indicative of insulin resistance (73.4±11.2 vs 112.0±8.0 µmol/kg/min, p<0.05). Basal glucose uptake was reduced in white and brown adipose tissue, heart and soleus while insulin-stimulated transport was reduced in white and brown adipose tissue, white quadriceps, white gastrocnemius and soleus in phosphoenolpyruvate carboxykinase transgenic compared to control rats. The impairment in both white and brown adipose tissue glucose uptake in phosphoenolpyruvate carboxykinase transgenic rats was associated with a decrease in GLUT4 protein content. In contrast, muscle GLUT4 protein, triglyceride and long-chain acylCoA levels were comparable between PEPCK transgenic and control rats.Conclusions/interpretation A primary defect in suppression of EGP caused adipose tissue and muscle insulin resistance.Abbreviations EGP endogenous glucose production - R_d rate of glucose disappearance - LCACoA long chain acyl CoA - TG triglycerides - MCR metabolic clearance rate