Review Korean J Obes 2015 June;24(2):78-86 pissn 2383-899X eissn 2234-7631 골격근미토콘드리아와인슐린저항성 : 운동의역할 곽효범 * 인하대학교스포츠과학과 Skeletal Muscle Mitochondria and Insulin Resistance: The Role of Exercise Hyo-Bum Kwak* Department of Kinesiology, Inha University, Incheon, Korea Insulin resistance in skeletal muscle, liver, β-cells, fat cells, the gastrointestinal track, α-cells, kidneys, and brain represents the core defect in obesity or type 2 diabetes (T2D). Among them, skeletal muscle insulin resistance due to obesity or T2D is manifested by decreased glucose uptake because skeletal muscle comprises 40-50% of the total human body mass. Many previous reports indicate that T2D patients or obese insulinresistant individuals have less mitochondria in their skeletal muscles than lean control subjects. Whether or not mitochondria in skeletal muscle play a causal role in insulin resistance has been debated. A large number of studies demonstrated that skeletal muscle insulin resistance is associated with mitochondrial deficiency including 1) reduced fatty acid oxidation and increased accumulation of lipid intermediates (e.g., FA-CoA, DAG, ceramide), 2) increased mitochondrial overload and incomplete fatty acid oxidation, and 3) increased mitochondrial oxidative stress (e.g., H2O2) in skeletal muscle. In contrast, some studies demonstrated that mitochondrial dysfunction in skeletal muscle is not responsible for insulin resistance, suggesting that 1) the development of insulin resistance in high-fat diet animals occurs with increased muscle mitochondria, and 2) fatty acid oxidation is higher in T2D patients and obese insulin-resistant individuals compared with lean control subjects. However, various types of exercises (acute vs chronic, aerobic vs resistance) are critical in the treatment and prevention of insulin resistance in obesity and T2D. Key words: Skeletal muscle, Mitochondria, Insulin resistance, Exercise 서론 최근에전세계적으로신체활동의급격한감소와과도한칼로리및지방섭취로인하여과체중및비만인구는기하급수적으로증가하고있다. 한예로세계성인을대상으로 2005년약 13억명 ( 세계성인인구의약 33%) 이었던과체중및비만인구가 2030년에는약 33억명 ( 세계성인인구의약 58%) 까지증가할것으로예상된다. 1 이러한과체중및비만은각종당뇨병, 고혈압, 심혈관질환, 암등을유발하는데, 이러한질환들의공통적인특징은인체의인슐린저항성과밀접하게관련되어있다. 2 인슐린저항성은인체의혈당이높을때혈당을낮추는역할을하는인슐린이제대로작용하지않아세포가혈액중의포도당 (glucose) 을효과적으로연소하지못하는상태를의미하는데, 인체내간, 골격근및췌장의기능장애로인하여주로유발된다. 3 간 (liver) 에서는인슐린증가를인식하여포도당생성을중지하고포도당의분해를활성화시켜야하지만인슐린저항성으로인하여간에서의포도당생성은증가한다. 4 골격근 (skeletal muscle) 에서는탄수화물의섭취로인하여증가된혈당을골격근으로흡수하여혈당을감소시켜야하는데인슐린신호전달, 포도당전달, 포도당대사등의장애로인해골격근으로의포도당흡수가감소된다. 5 췌장 β-세포 (pancreatic β-cells) 에서는증가된혈당을감소시키기위해더많은인슐린을분비하지만분비된인슐린이제대로작용하지않아결국인슐린분비의장애를유발한다. 6 이외에도인슐린저항성에따른고혈당증 (hyperglycemia) 을유발하는요인들에는지방세포 ( 증가된지방분해 ), 위장 ( 감소된인 Corresponding author Hyo-Bum Kwak Department of Kinesiology, Inha University, 100 Inha-ro, Nam-gu, Incheon 402-751, Korea Tel +82-32-860-8183 Fax +82-32-860-8188 E-mail kwakhb@inha.ac.kr Copyright 2015 Korean Society for the Study of Obesity This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 78 http://www.jksso.org
크레틴효과 ), 췌장 α- 세포 ( 증가된글루카곤분비 ), 신장 ( 증가된포도 당재흡수 ), 뇌 ( 신경전달물질기능장애 ) 를포함하고있다 (Fig. 1). 3 이처럼비만또는당뇨병관련인슐린저항성의유발원인들이많이 보고되고있지만, 이중에서본장에서는골격근내미토콘드리아가 인슐린저항성을유발하는주요원인인지기존선행연구를중심으로 살펴보고, 인슐린저항성의중재로서운동 ( 일회성운동 vs 장기간운 동, 유산소운동 vs 저항성운동 ) 의역할을알아본다. Glucose Production Glucose Secretion Lipolysis Glucose Uptake HYPERGLYCEMIA (INSULIN RESISTANCE) Neurotransmitter Dysfunction Fig. 1. Factors contributing to hyperglycemia (insulin resistance). Insulin Secretion Incretin Effect Glucose Reabsorption 골격근미토콘드리아와인슐린저항성 인체에서약 40-50% 을차지하고있는골격근은에너지대사의중요한원료인포도당과지방을이용하는매우중요한조직이다. 식사후흡수한포도당의약 2/3을인슐린작용을통해골격근안으로흡수한다. 3 식사를통해증가된혈당은췌장 β-세포에서인슐린분비를자극하고분비된인슐린은골격근에서인슐린신호전달과정을통해혈액안에있는포도당을골격근안으로흡수하여에너지원으로사용한다. 7 구체적인인슐린신호전달과정을살펴보면, 정상적인골격근대사작용에서인슐린은 insulin receptor substrate-1 (IRS-1) 을인산화시키고 phosphatidylinositol 3-kinase (PI3K) 를활성화시켜 Akt 인산화를촉진하고, 이는다시 Tre-2/USP6, BUB2, cdc16 domain family member 1 (TBC1D1) 또는 Akt substrate 160 kd (AS160) 인산화를통해 glucose transporter protein 4 (GLUT4) 을세포막으로이동시켜혈액중의포도당을골격근안으로유도한다. 2,8 흡수된포도당은즉시 hexokinase에의해인산화되어글리코겐 (glycogen) 으로저장되거나에너지 (ATP) 생성을위해해당과정 (glycolysis) 을거쳐미토콘드리아로이동하여산화한다 (Fig. 2). 이에반해, 금식상태에서는골격근안으로의포도당흡수가감소되고혈액의자유지방산 (free fatty acid, Glucose Exercise Insulin Fatty Acids Glycogen Glucose Glycolysis GLUT4 AMPK Ca 2+ /Calmodulin ROS PKC IRS-1 Akt CD36 FABP Fatty Acids FA-CoA ACSL Skeletal Muscle Membrane TAG TBC1D1, AS160 CPT-I CPT-II TCA β-oxidation FA-CoA NADH I ADP ATP O2 H2O FADH2 II III IV V Mitochondrion Fig. 2. Insulin signaling, fatty acid signaling, and exercise effects on glucose uptake in skeletal muscle. IRS-1, insulin-receptor substrate-1; Akt, protein kinase B; AS160, Akt substrate of 160 kda; TBC1D1, Tre-2/USP6, BUB2, cdc16 domain family member 1; GLUT4, glucose transporter protein 4; CD36, cluster of differentiation 36; FABP, fatty acid binding protein; ACSL, long-chain acyl-coa synthethase; FA-CoA, fatty acyl-coa; TAG, triacylglycerol; CPT-I, carnitine palmitoyl transferase 1; CPT-II, carnitine palmitoyl transferase 2; AMPK, AMP-activated protein kinase; ROS, reactive oxygen species; PKC, protein kinase C; TCA, tricarboxylic acid; NADH, nicotinamide adenine dinucleotide; FADH2, flavin adenine dinucleotide. http://www.jksso.org 79
FFA) 이증가하여골격근은에너지대사를위해대부분지방에의존 하게된다. 즉, 혈액중의 FFA 은 cluster of differentiation 36 (CD36)/ fatty acid translocase (FAT) 와 fatty acid binding protein (FABP) 을 통해골격근안으로들어오고 long-chain acyl-coa synthethase (ACSL) 이라는효소에의해 fatty acyl-coa (FA-CoA) 로활성화된다. 9 활성화된 FA-CoA 는골격근내지방으로저장되거나미토콘드리아 로이동하여산화하게된다 (Fig. 2). 9 위에서와같이포도당과지방의 대사작용에서골격근내미토콘드리아는에너지산화를위해매우 중요한역할을한다. 그러나선행연구들에서는인체의인슐린저항성 은골격근내미토콘드리아에의해영향을받는다고보고하고있지 만, 반면에골격근의미토콘드리아는인슐린저항성을유발하지않는 다는상반된결과들을보고하고있다. 따라서본장에서는두가지상 반된연구결과를중심으로논의하고자한다. 골격근미토콘드리아는인슐린저항성과관련있다 인슐린저항성은비만 ( 특히복부비만 ) 과간과골격근에서의지나친 지방축적그리고신체비활동과밀접하게관련되어있다. 특히골격 근내미토콘드리아의구조및기능장애는인슐린저항성유발의주 요요인이라하겠다. 제 2 형당뇨병또는인슐린저항성이있는비만한 사람들은정상적인사람들에비해골격근내미토콘드리아의모양이 변하고미토콘드리아의양이감소된다. 10,11 또한, 장시간동안고지방 섭취를한동물의골격근내미토콘드리아는부풀어오르고미토콘 드리아의구성성분인 cristae 의정렬에이상이생긴다. 12 이처럼제 2 형 당뇨병또는인슐린저항성이있는비만한사람들의골격근이나고지 방섭취에의해인슐린저항성을보이는골격근내미토콘드리아는지방산산화의감소 ( 지방형성중간물질의증가 ), 미토콘드리아의과부하 ( 불완전한지방산산화 ), 그리고미토콘드리아의산화적스트레스를통해인슐린저항성을유발한다 (Fig. 3). 1. 미토콘드리아의지방산산화의감소 ( 지방형성중간물질의증가 ) 골격근안으로유입된자유지방산은신체의항상성유지관련에너지생성을위해미토콘드리아로들어가산화하게된다. 그러나비만이나고지방섭취또는제2형당뇨병으로인해발생된미토콘드리아의양또는기능감소는정상적으로지방산을산화하지못하고지방산산화의감소를초래한다. 이처럼미토콘드리아의감소또는미토콘드리아의지방산산화장애는골격근내지방축적을초래한다. Hulver 등 13 은정상인 (BMI 24 kg/m 2 ), 과체중인 (BMI 30 kg/m 2 ) 그리고고도비만인 (BMI 38 kg/m 2 ) 간골격근의지방산산화능력을비교했는데, 고도비만인의골격근지방산화가정상인과과체중인에비해각각 58% 와 83% 감소하였다. 또한, Abu-Elheiga 등 14 은유전적조작동물을이용하여감소된미토콘드리아의지방산산화가인슐린저항성을유발하는중요한역할을한다고강조하였다. 이전선행연구들 15 에서는골격근내축적된지방이인슐린저항성을유발하는원인이라고보고하였지만이와상반된연구들 16 도보고되고있어최근에는골격근내지방축적이인슐린저항성을유발한다고단정할수없다. 하지만골격근내미토콘드리아의기능약화로발생된골격근내지방형성의중간물질들인 FA-CoA, diacylglycerol (DAG) 또는 ceramide가골격근내인슐린저항성을유발하는주요요인들이라보고되고있다. 17,18 Skeletal Muscle Mitochondria Reduced FAO & Increased Lipid Intermediates (FA-CoA, DAG, ceramide) Mitochondrial Overload & Incomplete FAO (Acylcarnitine Production) Mitochondrial Oxidative Stress (ROS) & Redox State Alteration Insulin Resistance Fig. 3. Potential mechanisms by which skeletal muscle mitochondria induce insulin resistance. FAO, fatty acid oxidation; FA-CoA, fatty acyl-coa; DAG, diacylglycerol; ROS, reactive oxygen species; Redox, reduction and oxidation. 80 http://www.jksso.org
2. 미토콘드리아의과부하 ( 불완전지방산산화 ) 지나친영양섭취에의해야기되는인슐린저항성발생초기에골격근내미토콘드리아에서어떤일이발생하는가? 정상적인미토콘드리아에서지방산은미토콘드리아로유입하여 β-산화를통해 acetyl- CoA를생성하고 Krebs 사이클과전자전달계를거쳐에너지를생성한다. 그러나비만이나고지방섭취등에의해지나치게많은지방산이미토콘드리아의수용능력을넘어미토콘드리아로유입되면미토콘드리아의과부하 (mitochondrial overload) 가발생하고결국미토콘드리아는지방산을완전히산화하지못하고불완전하게지방산을산화하여 acylcarnitine 등을생성한다. 19 이러한 acylcarnitine 축적과불완전한 β-산화는비만이나제2형당뇨병환자들에서보고되고있다. 20 이처럼골격근의인슐린저항성은미토콘드리아의산화능력보다는비만, 고지방섭취또는제2형당뇨병에의해미토콘드리아가얼마만큼부하 (load) 를받고있는가에의해결정되어진다하겠다. 하지만미토콘드리아의 β-산화에의한에너지공급이미토콘드리아의에너지요구와균형을맞추면골격근내인슐린감수성은유지되거나향상될것이다. 한예로, 골격근내미토콘드리아의 β-산화를유전적으로제한한쥐에서고지방섭취가골격근, 간, 지방조직의지방축적은증가하였지만인슐린감수성은그대로유지되었다. 21 3. 미토콘드리아의산화적스트레스미토콘드리아에서생성되는산화적스트레스 ( 예, reactive oxygen species, ROS) 는인슐린저항성유발과관련된 serine kinases나 transcription factors ( 예, c-jun amino-terminal kinases, JNK; IkB kinase catalytic subunit β, IKK-β; NF-kappa B transcription factor, NF-kB; protein kinase C, PKC) 를활성화시킨다. 22 또한유전적으로조작한비만및당뇨병쥐에게항산화음식을처치했을때인슐린작용과포도당항상성이향상되었다. 23 Anderson 등 24 은비만쥐와사람을대상으로미토콘드리아에서생성되는산화적스트레스가인슐린저항성을유발한반면에미토콘드리아의항산화제단백질이고지방섭취에의한골격근의인슐린저항성을억제시켰다고보고하였다. 이연구를통해인슐린저항성은골격근의미토콘드리아에서생성되는증가된 H 2O 2 와감소된 glutathione과밀접하게관련되어있음을알수있다. Lee 등 25 은미토콘드리아의항산화제인 catalase를유전적으로과발현시킨쥐에서지방형성중간물질인 DAG를감소시켰고노화에의한인슐린저항성을억제하였다고보고하였다. 이처럼미토콘드리아에서생성되는산화적스트레스및산화환원상태변화는비만및제 2형당뇨병에의해야기되는인슐린저항성의중요한원인이라하겠다. 골격근미토콘드리아는인슐린저항성과관련없다 기존선행연구들 10,11 에의하면제 2 형당뇨병또는인슐린저항성이 있는비만한사람들은정상적인사람들에비해골격근내미토콘드리 아의양이약 30% 정도적다고보고되고있다. 특히, 제 2 형당뇨병또 는인슐린저항성이있는비만한사람들은정상적인건강한사람들에 비해미토콘드리아의활동마커효소들인 citrate synthase 26, cytochrome oxidase 27, succinate dehydrogenase 28 의활동수준이 20-40% 정도낮다고보고되었다. 위와같은연구들의주장에의하면당뇨병 환자의골격근내미토콘드리아의감소는지방산을산화하는골격근 의능력을저하시키고골격근내지방축적을유발하여결국인슐린 저항성을유발한다는것이다. 즉, 골격근내미토콘드리아의기능저하 가인슐린저항성과관련되어있음을강조하는것이다. 18,29 하지만이 러한가설은골격근내미토콘드리아와인슐린저항성간의상관관계 를보여주었을뿐이가설에대한과학적인근거를제시하고있지는 않다. 이에대해다음과같은과학적인근거들을통해미토콘드리아 의감소가인슐린저항성을유발하지않는다는주장을강조한다. 1. 미토콘드리아증가와인슐린저항성유발 만약미토콘드리아의기능저하가인슐린저항성을유발한다면미 토콘드리아의기능저하는인슐린저항성이전에발생해야한다. 하지 만현실적으로제 2 형당뇨병및인슐린저항성이있는비만한사람들 은장시간에걸쳐발생하는관계로실험연구에서는사람을대상으로 한연구보다는동물을대상으로고지방섭취에의한비만및인슐린 저항성유발모델연구를진행한다. 30,31 많은선행연구들에의하면 동물대상고지방섭취는골격근의인슐린저항성유발뿐만아니라골 격근내미토콘드리아관련효소 32, 지방산산화능력 33 그리고합성인 자 34 를증가시킨다고보고하고있다. 이처럼고지방섭취는근육미토 콘드리아의증가와동시에인슐린저항성을유발한다. 또한, Nair 등 35 의연구에의하면제 2 형당뇨병과인슐린저항성이있는아시안인디 언들은정상적인인디언들과비교했을때골격근에서비슷한수준의 ATP 를생성하는미토콘드리아능력을나타냈고, 건강한북미사람 들에비해서는높은수준의미토콘드리아능력을보였다. 이상과같 은과학적인연구결과에의해미토콘드리아의기능저하가인슐린저 항성을유발한다고단정할수없다. 또한, 기존많은선행연구들은유전적조작동물들을이용하여골 격근내미토콘드리아의기능저하가인슐린저항성을유발하지않는다 고보고하고있다. Wredenberg 등 36 은골격근내 Tfam (mitochondrial transcription factor A) 을유전적으로제거한쥐 (knockout mice) 를이 용하였는데, Tfam 은중요한미토콘드리아호흡관련단백질을포함 http://www.jksso.org 81
하고있다. Tfam knockout 쥐의골격근에서심각한호흡관련기능의장애를보였지만오히려인슐린작용이증가하였고인슐린에의한골격근안으로의포도당흡수가향상되었다. Pospisilik 등 37 은미토콘드리아의호흡기능유지에필요한 apoptosis-inducing factor (AIF) 에대한유전적제거쥐를연구하였다. 이연구에서 AIF knockout 쥐의골격근은미토콘드리아의호흡관련단백질들 (complex I and IV) 수준을감소시켰지만인슐린감수성과포도당내성을향상시켰고인슐린자극에의한골격근의포도당흡수활동을증가시켰다. 그리고최근에 Zechner 등 38 의연구에의하면미토콘드리아재합성마커인 peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) knockout 쥐에서미토콘드리아효소수준과지방산화능력이급격하게감소하였지만포도당감수성은향상되었다. 이상의유전적조작쥐를이용한선행연구들을종합하면골격근의지방산화를제한하는미토콘드리아의기능저하가인슐린반응을향상시키고인슐린저항성을유발하지않는다고할수있다. 2. 제2형당뇨병및인슐린저항성이있는비만환자들의지방산화증가일부이전연구들은골격근내지방산화가제2형당뇨병및인슐린저항성이있는비만환자에서감소된다고보고하였다. 한예로 Kelley 등 39 에의하면제2형당뇨병환자가정상인에비해골격근에서의지방산화가감소하고포도당산화는증가한다고하였다. 또한비만한사람은정상인에비해골격근의지방산화가낮다고보고하였다. 40 그러나이와상반된연구결과들도보고되고있다. Colberg 등 41 의연구에의하면제2형당뇨병이나인슐린저항성이있는비만한환자들에서지방산화가감소하지않는다고하였다. 그리고인슐린저항성이있는비만환자들에서혈액의지방산화는감소하였지만골격근의지방산화는증가하여결국전체적인지방산화능력은인슐린저항성이있는비만환자와정상인간에차이가없다고보고하였다. 42 또한대부분의다른최근선행연구들에의해서도제2형당뇨병이나인슐린저항성이있는비만한환자들이정상인에비해골격근의산화능력이높다고보고하였다. 43 인슐린저항성은지방산화증가와관련되어있다는가설은 Randle 의포도당및지방산싸이클 (glucose fatty acid cycle) 이론에근거하고있다. 44 이이론은포도당과지방산의산화신호전달이미토콘드리아내 acetyl-coa에서집결됨에따라지방산화가포도당흡수를억제한다는것이다. 이이론에대해 Felber 등 45 은인슐린저항성이있는사람을대상으로그근거를제공하였다. 즉, 제2형당뇨병과인슐린저항성이있는비만한환자들은정상인에비해더높은지방산화능력을보였다. 이처럼기존많은선행연구들에의해알수있듯이제2형당뇨병이나인슐린저항성이있는비만한환자들은정상적인사람들에비 해골격근의지방산화능력이감소하는것이아니라오히려증가하였다. 따라서골격근의미토콘드리아는인슐린저항성을유발하지않는다고할수있다. 운동과골격근의인슐린저항성 인슐린저항성에대한미토콘드리아의역할과상관없이기존많은선행연구들에의하면운동은인슐린저항성을억제하고인슐린감수성을향상시키는데매우효과가있다고보고되고있다. 즉비만또는제2형당뇨병환자에서운동에의한대사적건강을향상시키는가장잘검증된기전들중의하나는골격근의인슐린저항성을감소시키는골격근의적응이라하겠다. 특히, 운동에의한인슐린감수성향상은전통적인인슐린신호전달과는다른독립적인신호전달과정을통해달성된다고한다. 46 이이론에의하면운동 ( 근육수축 ) 은 AMP/ATP 증가에의한 AMP-activated protein kinase (AMPK), 세포내 Ca 2+ 농도, ROS 및 PKC를활성화시키고, 이는다시 TBC1D1 또는 AS160를인산화시켜 GLUT4 이동을통해골격근안으로의포도당흡수를향상시킨다 (Fig. 2). 그리고골격근내미토콘드리아는에너지소비에의해조절되기때문에에너지요구 ( 예, 운동, 신체활동등 ) 의증가는미토콘드리아에가해지는부하나스트레스를감소시키고미토콘드리아의 ROS 생성을감소시켜인슐린감수성을향상시키는중요한기전이된다. 이에관련하여운동 ( 일회성운동 vs 장기간운동 ) 에따른골격근의인슐린감수성향상에대한구체적인내용을살펴보면다음과같다. 일반적으로일회성유산소운동에서도인슐린작용은향상된다고보고되고있는데, 저강도또는중강도로운동을하였을때혈당수준이감소되고, 그효과는 2-72시간지속된다고한다. 47 또한유산소운동의효과는한번운동을하는것과여러번동일시간을나누어하는것과비교했을때큰차이를보이지않는다고한다. 48 일회성저항성운동도비슷한효과를보이는데, 내당능장애 (impaired fasting glucose) 를보이는사람의경우일회저항성운동을통해혈당수준이감소하였고, 이수준은저항성운동의양과강도에의해비례하였다. 49 그리고일회성운동들에의해골격근으로의포도당흡수를촉진하는 AMPK와 AS160의인산화수준이증가하였다. 50,51 장기간저항성운동은골격근의근육량을증가시키는반면에장기간유산소운동은골격근내미토콘드리아의구조와기능을향상시킨다. 하지만유산소운동과저항성운동모두제2형당뇨병환자의골격근내 GLUT4 을증가시키고혈당수준을낮춰인슐린감수성을향상시킨다 (Table 1). 규칙적인운동훈련은골격근의산화적능력을향상시키고 GLUT4의증가를통해자유지방산의수준을낮추고포도당흡수를증가시켜인슐린저항성과당뇨병의위험을낮춘다. 예를들어, 82 http://www.jksso.org
Table 1. Comparison of the effects of aerobic exercise and resistance exercise on insulin resistance Variables Aerobic exercise Resistance exercise Insulin response to glucose challenge Basal insulin levels Basal glucose levels GLUT4 levels Insulin sensitivity Basal metabolism GLUT4, glucose transporter protein 4. = decrease; = increase; The more arrows, the greater the change. 중강도및고강도유산소운동은노인또는제 2 형당뇨병환자의인슐 린감수성을향상시켰고 52,53, 골격근내 GLUT4 단백질발현을증가시 켰다. 54 또한, 유산소운동훈련은근육내지방축적을증가시키고지 방산화능력을향상시켰다. 55 유산소운동과마찬가지로장기간저항 성운동도제 2 형당뇨병환자의혈당조절과인슐린작용을향상시킨다 고보고되었다. 56-58 결론 기존많은선행연구들에의하면골격근의인슐린저항성은미토콘 드리아의기능과밀접하게관련되어있다. 즉, 제 2 형당뇨병이나인슐 린저항성이있는비만한환자들은미토콘드리아의지방산산화능력 이감소되고이에따른골격근내지방형성중간물질들이증가하여 골격근의인슐린저항성을유발한다. 또한비만및고지방섭취에의해 미토콘드리아에지나치게많은부하나스트레스가가해지면미토콘 드리아는불완전한지방산을산화하거나산화적스트레스를생성하 여인슐린저항성을유발한다. 이에반해골격근의미토콘드리아는인 슐린저항성을유발하지않는다는상반된연구들도있다. 즉, 고지방 섭취에의한동물모델에서골격근내인슐린저항성은유발하였지만 동시에골격근내미토콘드리아도증가하였고또한제 2 형당뇨병이나 인슐린저항성이있는비만환자들에서정상적인사람에비해골격근 의지방산화능력이증가하였다. 그러나여러가지형태의운동 ( 일회 성 vs 장시간, 유산소 vs 저항성 ) 은비만또는제 2 형당뇨병환자들의 혈당수준을낮추고골격근내인슐린저항성을억제하는요인들을 증가시킴으로써인슐린저항성이나제 2 형당뇨병을예방하는데매우 중요한역할을한다. 요약 골격근, 간, β- 세포, 지방세포, 위장, α- 세포, 신장그리고뇌에서의 인슐린저항성은비만및제 2 형당뇨병유발의중요한요인들이다. 이 중에서체중의 40-50% 를차지하고있는골격근의인슐린저항성은골 격근안으로의포도당흡수를감소시킨다. 많은선행연구들에의하면제2형당뇨병환자나인슐린저항성이있는비만한환자들은정상인에비해골격근내적은미토콘드리아가존재한다고보고되고있다. 하지만골격근내미토콘드리아가인슐린저항성을유발하는원인인지에대해서는많은논쟁이되고있다. 먼저골격근의인슐린저항성이미토콘드리아의기능장애와관련되어있다는주장은다음과같은가설에근거하고있다. 1) 비만또는제2형당뇨병은골격근의지방산화능력을감소시키고인슐린저항성을유발하는지방형성중간물질들 ( 예, FA-CoA, DAG, ceramide) 의축적을증가시킨다. 2) 비만또는고지방섭취에의한인슐린저항성은골격근내미토콘드리아의과부하와불완전한지방산화에의해야기된다. 3) 골격근내미토콘드리아에서생성된산화적스트레스 ( 예, H 2O 2) 가비만및고지방섭취에의한인슐린저항성을유발한다. 하지만골격근내미토콘드리아의기능장애는인슐린저항성을유발하지않는다는상반된주장도다음과같은이유로제기되고있다. 1) 고지방섭취동물은인슐린저항성유발뿐만아니라골격근내미토콘드리아의증가도야기한다. 2) 제2형당뇨병과인슐린저항성이있는비만한환자들은정상인에비해높은골격근지방산화능력을나타낸다. 그러나여러가지형태의운동 ( 일회성 vs. 장기간, 유산소 vs. 저항성 ) 은비만과제2형당뇨병에의해야기되는인슐린저항성을처치하고예방하는데매우중요한역할을한다. 중심단어 : 골격근, 미토콘드리아, 인슐린저항성, 운동 Conflicts of Interest The author have no conflicts of interest to declare. Acknowledgments This work was supported by Inha University Research Grant. References 1. Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 2008; 32:1431-7. 2. Abdul-Ghani MA, DeFronzo RA. Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol 2010;2010:476279. 3. Defronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95. 4. DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglyce- http://www.jksso.org 83
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