成年期追赶生长对大鼠胰岛素敏感性与应激水平的影响

目的 观察成年期追赶生长对大鼠胰岛素敏感性和应激水平的影响,并探讨其胰岛素抵抗形成的可能机制。方法 将7周龄雄性SD大鼠分为6组（共2个时间点）,即4周时间点2组：热卡限制4周组(R4),正常饮食4周组(NC4)作为R4组对照;8周时间点4组：正常饮食追赶生长组(RN4)、高脂饮食追赶生长组(RH4)、持续高脂饮食8周组（HF8）、持续正常饮食8周组(NC8)。通过先热卡限制后恢复饮食的方法建立追赶生长大鼠模型。检测大鼠高胰岛素-正糖钳夹试验过程中葡萄糖输注率和骨骼肌2-脱氧葡萄糖摄取、胰岛素刺激后的骨骼肌胰岛素信号通路、血皮质酮、骨骼肌11β-羟类固醇脱氢酶1(11β-HSD1)表达水平。结果 热卡限制4周时,R4组大鼠血皮质酮和骨骼肌11β-HSD1 mRNA表达水平明显高于NC4组(P＜0.05),骨骼肌蛋白激酶B( Akt) Ser473磷酸化和糖摄取与NC4组相比差异无统计学意义。热卡限制后恢复饮食4周时,血皮质酮和骨骼肌11β-HSD1表达水平RN4组明显高于NC8组,RH4组明显高于NC8和HF8组,而骨骼肌Akt磷酸化和糖摄取RN4组明显低于NC8组,RH4组明显低于NC8组、HF8组和RN4组（均P＜0.05）。结论正常饮食和高脂饮食追赶生长大鼠均可导致整体和骨骼肌应激水平上调及胰岛素抵抗,尤以高脂饮食追赶生长大鼠更为明显。应激和饮食状况的交互作用可能是追赶生长胰岛素抵抗形成的重要原因。     

运动干预对胰岛素抵抗大鼠骨骼肌超微结构的影响及其临床意义

目的 观察胰岛素抵抗(IR)大鼠骨骼肌超微结构变化的特点,探讨高脂饮食及运动对骨骼肌的影响. 方法 健康Wismr雄性大鼠分基础饲料喂养组(NC),高脂饲料喂养组(HF).高脂喂养大鼠10周,构建IR动物模型.HF组再随机分出一半为非运动组,另一半为运动组,游泳运动干预4周.运动前后以钳夹技术评估IR大鼠胰岛素敏感性,检测3组大鼠葡萄糖输注率(GIR)以及股薄肌进行透射电镜观察. 结果 HF组大鼠GIR显著低于NC组(P<0.01),运动组大鼠GIR显著低于非运动组(P<0.01);电镜显示,HF组骨骼肌细胞肌原纤维束排列松散;线粒体数量减少;运动后可明显减轻上述病理改变. 结论 运动可增强骨骼肌的有氧代谢,改变IR大鼠骨骼肌超微结构,并以线粒体改变较为明显.适当的运动能够改善IR机体内胰岛素敏感性,维持骨骼肌细胞的正常形态.     

糖尿病大鼠胰岛脂质分解的变化及意义

目的 观察糖尿病大鼠胰岛中甘油三酯(TG)、脂质分解和激素敏感性脂肪酶(HSL)的变化,探讨胰岛细胞内脂质分解在糖脂毒性中的作用.方法 采用雄性Wistar大鼠,通过高脂饮食+小剂量链脲佐菌素建立糖尿病模型(DM组),同时设立正常对照组(NC组)和单纯高脂饮食组(HF组).成模4周后,检测各组大鼠的血糖、血脂、胰岛素分泌、胰岛中TG含量及HSL mRNA和蛋白的表达;测定胰岛细胞游离脂肪酸的释放以代表脂质分解.结果 与NC组相比,HF组大鼠血糖没有明显变化,但是胰岛素和血脂均明显升高(P＜0.05或P＜0.01);DM组大鼠血糖、血脂水平显著高于NC组(P＜0.05或P＜0.01),而胰岛素水平与NC组相似.HF组大鼠胰岛内TG含量较NC组有明显的增加(P＜0.05),DM组胰岛内脂质积聚更严重,约为NC组的2.15倍.与NC 组相比,HF组和DM组大鼠胰岛脂质分解和HSL表达明显增加(P＜0.05或P＜0.01).结论 糖尿病状态下,胰岛细胞内脂解和HSL的表达明显增加,这既是维持细胞内脂质代谢平衡的重要因素,又体现了机体对脂毒性的保护.     

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.     

运动对胰岛素抵抗大鼠丝氨酸/酪氨酸磷酸化通路干预效应的研究

目的 观察运动对高脂膳食诱导胰岛素抵抗(IR)大鼠骨骼肌胰岛素受体底物1(IRS-1)丝氨酸307(Ser307)磷酸化和酪氨酸(Tyr)磷酸化通路的影响.方法 Wistar大鼠75只,分为正常对照(NC)组、高脂膳食(HF)组.10周后再将HF组分为高脂膳食运动(HFE)组和高脂膳食非运动(HFNE)组.以钳夹技术观察各组大鼠胰岛素敏感性(IS)变化,Western Blot法检测大鼠骨骼肌IRS-1 Ser307磷酸化和Tyr磷酸化水平.结果 (1) 10周后HF组葡萄糖输注率(GIR60～120)明显低于NC组;与NC组比较,HF组IRS-1 Tyr磷酸化水平降低,IRS-1 Ser307磷酸化水平升高(P均＜0.01).(2) 14周后HFE组GIR60～120明显高于HFNE组;与HFNE组比较,HFE组IRS-1 Tyr磷酸化水平升高,IRS-1 Ser307磷酸化水平降低(P均＜0.01).结论 运动干预改善IR大鼠IS,其机制可能与改善IRS-1 Ser307/Tyr异常磷酸化有关.     

脂联素通过LKB1途径激活腺苷酸活化蛋白激酶

目的 探讨脂联素是否通过LKB1途径激活骨骼肌及肝脏中腺苷酸活化蛋白激酶(AMPK).方法 将28只6周龄雄性Sprague-Dawley大鼠分为普通饮食组(NC组,n=15)和高脂饮食组(HF组,n=13).喂养16 周后,取空腹静脉血测定血清游离脂肪酸(FFA)、甘油三酯(TG)、总胆固醇(TC)、空腹血糖(FPG)、空腹胰岛素(FINS)及脂联素.采用Western印迹法测定各组大鼠骨骼肌及肝脏组织中AMPKα、磷酸化的AMPKcα和LKB1蛋白的表达.将原代培养的骨骼肌细胞及肝细胞分别予以脂联素和根赤壳菌素干预,免疫荧光技术测定各组细胞中AMPKα、磷酸化AMPKα和LKB1蛋白的表达.结果 与NC组比较,HF组大鼠体重、FFA、TG、FPG、FINS均升高(均P＜0.05),脂联素水平降低(P＜0.05).骨骼肌及肝组织巾AMPKα磷酸化和LKB1蛋白表达水平降低(均P＜0.05).原代培养大鼠骨骼肌细胞及肝细胞中脂联素显著增加AMPKα磷酸化及LKB1表达水平(均P＜0.05).加入根赤壳菌素表达明显降低(均P＜0.05).结论 脂联素在大鼠骨骼肌和肝脏组织可能通过LKB1途径激活AMPK.     

N-乙酰半胱氨酸改善高脂饲养大鼠外周胰岛素抵抗的机制

目的 探讨抗氧化剂N-乙酰半胱氨酸(NAC)对高脂饲养大鼠外周胰岛素抵抗的影响及机制.方法 8周龄SD大鼠随机分为正常饲料组(NC组,n=20)、高脂饲料组(HF组,n=20)和高脂+NAC组(NAC组,n=19).饲养20周.(1)测血浆硝基酪氨酸,丙二醛(MDA)和还原型谷胱甘肽(GSH)水平;(2)正常血糖高胰岛素钳夹试验,评价外周组织胰岛素抵抗程度;(3)实时荧光定量PCR方法比较各组大鼠肌肉组织胰岛素受体底物-1(IRS-1)、胰岛素受体底物-2(IRS-2)mRNA表达的变化.结果 (1) HF组血浆硝基酪氨酸,MDA水平明显高于NC组,GSH水平低于NC组,NAC可以改善以上变化;(2) HF组葡萄糖输注率(GIR)比NC组降低(P＜0.01),用NAC后GIR明显改善(P＜0.01);(3)HF组肌肉组织IRS-1、IRS-2mRNA表达比NC组降低52.1%、43.5%(P均<0.01);NAC组肌肉组织IRS-1、IRS-2表达与HF组相比增加73.8%、68.4%(P均<0.01).结论 NAC干预治疗能改善外周组织胰岛素信号传导,逆转高脂饲养导致的大鼠外周胰岛素抵抗,其机制可能与NAC纠正机体氧化及抗氧化失衡有关.     

Exenatide 对高脂诱导胰岛素抵抗大鼠胰岛素敏感性及糖脂代谢的影响

目的 探讨Exenatide对高脂诱导胰岛素抵抗大鼠胰岛β细胞功能、胰岛素敏感性及糖脂代谢的影响. 方法 高脂诱导胰岛素抵抗大鼠给予Exenatide 6周后,采用静脉葡萄糖耐量(IVGTT)和胰岛素耐量(ITT)试验以及扩展胰岛素钳夹技术测定胰岛素敏感性和糖脂代谢,并观察血浆脂联素水平的变化.结果 高脂大鼠(HF)经Exenatide处理后,Lee′s指数、空腹血浆游离脂肪酸(FFA)、甘油三酯、胆固醇明显降低(均P＜0.01);IVGTT和ITT明显改善,胰岛素分泌水平增高,高剂量组(HFH)较低剂量组(HFL)上述指标改善更为明显.同时,HFH组血浆脂联素水平也明显升高(P＜0.01).在钳夹稳态时,HF组与对照组(NC)相比,血浆FFA、胰岛素水平均明显升高(均P＜0.01),葡萄糖输注率(GIR)、葡萄糖清除率(GRd)明显降低(均P＜0.01),且胰岛素对肝糖输出(HGP)的抑制作用明显障碍(仅抑制26%).经Exenatide(2 μg/kg)处理以后,血浆FFA、胰岛素水平则明显降低(均P＜0.01),GRd、GIR明显升高(均P＜0.01),胰岛素对HGP的抑制作用明显增强(抑制72%).结论 对高脂喂养大鼠用Exenatide预处理可能通过促进β细胞胰岛素分泌和上调血浆脂联素水平,改善糖脂代谢而使机体胰岛素敏感性增加.     

罗格列酮上调高脂饮食老年大鼠骨骼肌GLUT4和PKB的表达

目的 观察高脂饮食对老年大鼠骨骼肌葡萄糖转运蛋白4(GLUT4)和蛋白激酶B(PKB)的表达变化及罗格列酮的干预效果.方法 老年大鼠随机分为对照组、高脂组(HF)、高脂+罗格列酮干预组(RSG),每组20只.应用清醒状态下正常葡萄糖高胰岛素钳夹技术的葡萄糖输注率评价胰岛素抵抗,用荧光定量PCR法和Western印迹技术检测骨骼肌GLUT4和PKB的表达.结果 高脂组骨骼肌长链脂酰辅酶A(LCACoA)升高而葡萄糖输注率明显下降(P＜0.01),骨骼肌GLUT4和PKB的表达明显降低(P＜0.05,P＜0.01),罗格列酮干预组显著缓解高脂组上述变化(P＜0.05,P＜0.01).结论 罗格列酮上调高脂饮食老年大鼠骨骼肌GLUT4和PKB的表达,是改善老年胰岛素抵抗的机制之一.     

糖尿病大鼠骨骼肌线粒体氧化应激改变及干预治疗

目的 探讨线粒体氧化应激在糖尿病骨骼肌病变发生、发展巾的作用及抗氧化剂的防治效果.方法 雄性Wistar大鼠经链脲佐菌素(STZ,45 mg/kg)诱导建立糖尿病动物模型,随机分为糖尿病未十预(DM)组、胰岛素干预(INS)组、α-硫辛酸干预(α-LA)组,每组24只,同时设正常对照(NC)组(n=24).于4、8、12周时各处死大鼠8只,测定线粒体氧化应激指标谷胱汁肽(GSH)、过氧化氢酶(CAT)、锰一超氧化物歧化酶(Mn-SOD)和丙二醛(MDA).结果 与NC组相比,DM组大鼠4、8、12周时骨骼肌线粒体GSH的含量明显F降(P<0.05),INS组和α-LA组较DM组明显上升.4周时4组间骨骼肌线粒体Mn·SOD活性无差异.8、12周时DM组Mn-SOD的活性比同期NC组明显下降(P<0.05).α-LA组比DM组明显升高(P<0.01).CAT活性的变化与Mn-SOD活性变化相类似.DM组MDA的含量比NC组明显增加,应用α-LA干预后MDA含量下降(P<0.05).NC组从4周到12周骨骼肌线粒体GSH、Mn-SOD活性、CAT活性和MDA含量稳定在同一水平(P>0.05);DM组随着病程的增加骨骼肌线粒体GSH、Mn-SOD活性、CAT活性逐渐下降,MDA含量逐渐上升,12周时与4、8周时比较,差异均有统计学意义(P<0.05);α-LA组各项指标纵向比较差异均有统计学意义(P<0.05).结论 高血糖所致的线粒体氧化应激损伤在糖尿病骨骼肌病变的发生、发展中起重要作用,α-硫辛酸可减弱线粒体氧化应激损伤.     

The protective effect of resveratrol on islet insulin secretion and morphology in mice on a high-fat diet

The aim of this study was to investigate the effect of resveratrol on beta cells in male C57BL/6J mice fed a high-fat diet and the possible mechanisms. Male C57BL/6J mice were randomly divided into three groups: normal control (NC) group, high-fat diet (HF) group and high-fat diet and resveratrol treatment (HFR) group (15 in each group). HFR group was fed with high fat diet for 8 weeks and then orally administered resveratrol at 400mg/kg daily. Twenty-four weeks later, the function of insulin secretion in vivo and in vitro was improved robustly in HFR group compared with HF group. The levels of glucose and lipid metabolism, beta cell mass, lipid content, and oxidative stress were lower in HFR group than in HF group. Simultaneously, resveratrol administration promoted the expression of SIRT1 in islets, while the expression of uncoupling protein 2 (UCP2) was restrained. Resveratrol, as well, also had a beneficial effect on the ratios of expressions of Bcl-2/Bax and levels of malondialdehyde/glutathione peroxidase. Resveratrol can protect islets from abnormal insulin secretion and morphological changes induced by a high-fat diet. The effect might be partly related to activated SIRT1 signal pathway, improved oxidative stress induced damage and incidence of apoptosis.     

Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis

OBJECTIVE: To investigate whether changes in body energy balance induced by long-term high-fat feeding in adult rats could be associated with modifications in energetic behaviour and oxidative stress of skeletal muscle subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations. DESIGN: Adult rats were fed low-fat or high-fat diet for 7 weeks. MEASUREMENTS: Body energy balance and composition analysis together with plasma insulin and glucose level determination in the whole animal. Oxidative capacity, basal and induced proton leaks as well as aconitase and superoxide dismutase activities in SS and IMF mitochondria from skeletal muscle. RESULTS: High-fat fed rats exhibit increased body lipid content, as well as hyperinsulinemia, hyperglycaemia and higher plasma non-esterified fatty acids. In addition, SS mitochondria display lower respiratory capacity and a different behaviour of SS and IMF mitochondria is found in the prevention from oxidative damage. CONCLUSIONS: A deleterious consequence of decreased oxidative capacity in SS mitochondria from rats fed high-fat diet would be a reduced utilization of energy substrates, especially fatty acids, which may lead to intracellular triglyceride accumulation, lipotoxicity and insulin resistance development. Our results thus reveal a possible role for SS mitochondria in the impairment of glucose homeostasis induced by high-fat diet.     

Resveratrol attenuates high-fat diet-induced insulin resistance by influencing skeletal muscle lipid transport and subsarcolemmal mitochondrial β-oxidation

Although resveratrol (RES) is implicated in the regulation of insulin sensitivity in rodents, the exact mechanism underlying this effect remains unclear. Therefore, we sought to investigate how RES affects skeletal muscle lipid transportation and lipid oxidation of subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial populations in high-fat diet (HFD)-induced insulin resistance (IR) rats. Systemic and skeletal muscle insulin sensitivity together with expressions of several genes related to mitochondrial biogenesis and skeletal muscle lipid transportation was studied in rats fed a normal diet, an HFD, and an HFD with intervention of RES for 8 weeks. Citrate synthase (CS), electron transport chain (ETC) activities, and several enzymes for mitochondrial β-oxidation were assessed in SS and IMF mitochondria from tibialis anterior muscle. The HFD-fed rats exhibited obvious systemic and skeletal muscle IR as well as intramuscular lipid accumulation. SIRT1 activity and expression of genes related to mitochondrial biogenesis were greatly declined, whereas the gene for lipid transportation, FAT/CD36, was upregulated (P < .05). Subsarcolemmal but not IMF mitochondria displayed lower CS, ETC, and β-oxidation activities. By contrast, RES treatment protected rats against diet-induced intramuscular lipid accumulation and IR, increased SIRT1 activity and mitochondrial biogenesis, and reverted the decline in SS mitochondrial CS and ETC activities. Importantly, although expression of FAT/CD36 was increased (11%, P < .05), activities of SS mitochondrial β-oxidation enzymes were largely enhanced (41%∼67%, P < .05). This study suggests that RES ameliorates insulin sensitivity consistent with an improved balance between skeletal muscle lipid transportation and SS mitochondrial β-oxidation in HFD rats.     

Resveratrol improves insulin resistance of catch-up growth by increasing mitochondrial complexes and antioxidant function in skeletal muscle

Caloric restriction followed by refeeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We investigated the potential of resveratrol (RES) in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. Rats (8 weeks of age) were divided into 3 groups: normal chow, CUG, and CUG with RES intervention. Skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed. Catch-up growth-induced IR resulted in significant reductions in both average glucose infusion rate(60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase activity was lower; and the activity of complexes I to IV in the intermyofibrillar and subsarcolemmal (SS) mitochondria were reduced by 20% to 40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species levels were significantly higher in intermyofibrillar and SS mitochondria, whereas activities of antioxidant enzymes were decreased. Oral administration of RES, however, increased silent information regulator 1 activity and improved mitochondrial number and insulin sensitivity. Resveratrol treatment decreased levels of reactive oxygen species and restored activities of antioxidant enzymes. This study demonstrates that RES protects insulin sensitivity of skeletal muscle by improving activities of mitochondrial complexes and antioxidant defense status in CUG rats. Thus, RES has therapeutic potential for preventing CUG-related metabolic disorders.     

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.     

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice

Aims/hypothesis  

High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function.     

Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity

This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake.     

Skeletal muscle oxidative capacity in rats fed high-fat diet.

OBJECTIVE: To investigate whether young rats respond to high-fat feeding through changes in energy efficiency and fuel partitioning at the level of skeletal muscle, to avoid obesity development. In addition, to establish whether the two mitochondrial subpopulations, which exist in skeletal muscle, ie subsarcolemmal and intermyofibrillar, are differently affected by high-fat feeding. DESIGN: Weaning rats were fed a low-fat or a high-fat diet for 15 days. MEASUREMENTS: Energy balance and lipid partitioning in the whole animal. State 3 and state 4 oxygen consumption rates in whole skeletal muscle homogenate. State 3 and state 4 oxygen consumption rates, membrane potential and uncoupling effect of palmitate in subsarcolemmal and intermyofibrillar mitochondria from skeletal muscle. RESULTS: Rats fed a high-fat diet showed an increased whole body lipid utilization. Skeletal muscle NAD-linked and lipid oxidative capacity significantly increased at the whole-tissue level, due to an increase in lipid oxidative capacity in subsarcolemmal and intermyofibrillar mitochondria and in NAD-linked activity only in intermyofibrillar ones. In addition, rats fed a high-fat diet showed an increase in the uncoupling effect of palmitate in both the mitochondrial populations. CONCLUSIONS: In young rats fed a high-fat diet, skeletal muscle contributes to enhanced whole body lipid oxidation through an increased mitochondrial capacity to use lipids as metabolic fuels, associated with a decrease in energy coupling.     

Cardioprotective effects of metformin and vildagliptin in adult rats with insulin resistance induced by a high-fat diet

Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.