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1 대한내과학회지 : 제 84 권제 5 호 특집 (Special Review) - 비만 비만 / 대사수술이체중감소와당뇨병관해를일으키는기전 서울대학교의과대학내과학교실 조영민 Mechanism of Weight Loss and Diabetes Remission after Bariatric/Metabolic Surgery Young Min Cho Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea The greatest achievement in the treatment of obesity and diabetes would be the development of bariatric/metabolic surgery. At the beginning, bariatric surgeries were developed to simply reduce body weight in morbidly obese subjects. Before long, it was discovered that diabetes and other metabolic complications of obesity could be placed in remission. The remission rate of diabetes after bariatric surgery is strikingly high and, in the case of Roux-en-Y gastric bypass surgery, diabetes remission commonly occurs immediately after the surgery, when significant weight loss does not take place. Therefore, the concept of bariatric surgery has evolved into metabolic surgery. Physiologic changes in gastrointestinal endocrine system following the anatomical changes made by bariatric/metabolic surgery are regarded as the major mechanisms of weight loss and diabetes remission. In this regard, the foregut and hindgut hypotheses were suggested as the mechanisms associated with diabetes remission. With the advent of sleeve gastrectomy, which does not bypass the foregut (duodenum and proximal jejunum) but increases the secretion of glucagon-like peptide-1, the foregut hypothesis is currently under attack. However, a single mechanism is not enough to explain the metabolic effect of bariatric/metabolic surgery. Further studies are warranted to elucidate the mechanisms of metabolic improvements after bariatric/metabolic surgery. (Korean J Med 2013;84: ) Keywords: Bariatric surgery; Metabolic surgery; Obesity; Type 2 diabetes; Gastrointestinal hormones 서론비만의치료는매우어렵고비만한당뇨병의치료또한매우어렵다. 식이요법과운동요법으로조절이되는경우가있기는하지만이러한방법으로감량된체중을유지하는것은매우어려움이잘알려져있으며, 약물요법의경우생활 습관개선치료에추가하였을때위약대비고작 3-5% 더체중이감소할뿐이다 [1]. 미국의경우비만환자의 10% 가당뇨병을가진반면당뇨병환자의 80% 가비만하다 [2]. 2012년대한당뇨병학회에서발간한자료에의하면국내의경우는체질량지수 kg/m 2 를과체중, 25 kg/m 2 이상을비만으로정의하였을때, 제2형당뇨병환자의약 50% 가비만이 Correspondence to Young Min Cho, M.D. Department of Internal Medicine, Seoul Nastionl University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul , Korea Tel: , Fax: , ymchomd@snu.ac.kr Copyright c 2013 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 84, No. 5, 며약 25% 가과체중에해당한다. 비만한경우당뇨병이잘발생하는기전은혈중유리지방산의증가, 지방세포에서의비정상적인아디포카인 (adipokine) 분비, 이소성지방축적 (ectopic fat accumulation), 상기열거한요인과관련된인슐린저항성증가, 그리고췌장베타세포의지방독성 (lipotoxicity) 에따른기능장애등으로설명할수있다 [3,4]. 그러면체중을줄이면당뇨병이생기지않을것인가? 미국에서시행된당뇨병예방연구 (Diabetes Prevention Program) 에서는내당능장애를보이는체질량지수약 34 kg/m 2 인사람을대상으로평균 2.8년 ( 년 ) 간생활습관교정요법을시행하였을때, 첫 1년간약 6.5 kg의체중감소가있었으나시간이지나면서체중은다시증가하여 4년추적한환자의경우시작시점대비약 4 kg의체중감소가있었지만, 58% 에서당뇨병으로의진행을억제하는효과를나타내었다 [5]. 또한과체중인제2형당뇨병환자를대상으로 4년간철저한생활습관교정을시행한 Look AHEAD 연구에서는평균 7.9% 의체질량지 수감소를보였고 1년째 11.5% 에서정상내당능혹은전당뇨병 (prediabetes) 로회귀함을보였으며 4년째에는 7.3% 에서정상내당능혹은전당뇨병소견을보였다 [6]. 이처럼내과적영역에서다양한노력이있었지만아주만족스러운결과를얻지못하였으나, 그동안외과적영역에서는실로믿기어려울정도로괄목할결과를보여주었다. 1995년에미국의외과의사 Pories 는 누가생각이라도해봤겠는가? 수술이제2형당뇨병의가장효과적인치료가될것이라는것을 (Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus) 이라는다소선정적인제목의논문을외과학연보에게재하였다 [7]. 당시루와이위우회술 (Roux-en-Y gastric bypass) 을시행받은고도비만환자중에서제2형당뇨병환자 146명중 121명 (82.9%) 그리고 152명의내당능장애환자중 150 (98.7%) 명이정상혈당과정상당화혈색소를유지하는놀라운결과를보였다 [7]. 비만한제2형당뇨병환자를대상으로통상적인 A B Figure 1. Physiologic mechanismof the development and remission of type 2 diabetes. The horizontal axis represents insulin sensitivity and the vertical axis represents pancreatic beta cell function, or insulin secretory capacity. The dotted line represents the relationship between insulin sensitivity and insulin secretory capacity in subjects with normal glucosetolerance. (A) In subjects with normal glucose tolerance, as insulin sensitivity decreases, insulin secretion increases in a compensatory manner (white circles). To the contrary, in subjects who would developtype 2 diabetes, the compensatory insulin secretion in response to the decreasing insulin sensitivity is generally absent, which results in impaired glucose tolerance (black square, I) or overt diabetes (black square, D). (B) Physiologic changes in glucose homeostasis after Roux-en-Y gastric bypass surgery in subjects with morbid obesity. This graph is drawn based on the previously published data [69]. In subjects with normal glucose tolerance, insulin sensitivity dramatically improves with time(white circles). Notably, the improvement in insulin sensitivity is remarkable during the first postoperative week, when there is no significantweight loss takes place. Thereafter, further improvementsin insulin sensitivity could be largely explained by progressive weight loss up to 1 year after the surgery. In subjects with type 2 diabetes, both beta cell function and insulin sensitivity show significant improvement after Roux-en-Y gastric bypass (black squares). The improvements in insulin sensitivity is also prominent during the first postoperative week

3 - Young Min Cho. Mechanism of bariatric/metabolic surgery - 내과적치료와대표적인비만수술인루와이위우회술혹은담췌우회술 (biliopancreatic diversion) 을시행하였을때 2년후내과적치료군에서는아무도당뇨병의관해 ( 공복혈장포도당 < 100 mg/dl이면서동시에 HbA1c < 6.5%) 에이르지못하였으나루와이위우회술의경우 75% 에서담췌우회술의경우 95% 에서당뇨병관해에도달함이보고된바있다. 바야흐로체중조절을주목적으로한비만수술 (bariatric surgery) 의개념이대사수술 (metabolic surgery) 이라는개념까지진화하였다. 비만 / 대사수술의효과는단지체중과혈당조절에서끝나지않는다. 스웨덴에서비만환자를대상으로이루어진 SOS (Swedish Obesity Study) 에서비만수술 ( 위밴드술 [gastric banding], 수직밴드위성형술 [vertical banded gastroplasty] 및루와이위우회술 ) 을시행한결과수술후 2년째에현저한체중감소와함께많은사람들이당뇨병, 고혈압, 이상지혈증, 고콜레스테롤혈증, 고요산혈증등으로부터회복되었으며 10 년후까지상당수에서회복된상태를유지함을관찰할수있었다 [8]. 이와더불어 15년추적관찰연구에서당뇨병발병이 83% 에서예방되었다 [9]. 생리학적관점에서볼때, 비만 / 대사수술후에제2형당뇨병환자의인슐린감수성이크게증가하며베타세포의기능역시의미있는증가를보임이일반적으로나타난다 (Fig. 1). 또한비만대사수술의결과앞서언급한바와같이심혈관위험인자가줄어들고 [8], 이에수반하여심혈관사건발생과심혈관사망이줄어들고 [10], 암발생이줄어들고 [11], 연령, 성별, 위험인자보정사망률의감소는 29% 에달했으며 [12], 삶의질또한크게개선되었다 [13]. 즉비만과관련된중대한내과적합병증이모든면에서놀라운수준으로개선됨을알수있다. 이하본종설에서는비만 / 대사수술이어떠한기전으로체중감소와포도당대사개선효과를보이는지에대하여가장대표적인비만 / 대사수술법인루와이위우회술을중심으로위장관내분비시스템에바탕을두고논하고자한다. 위장관내분비시스템개관위장관내분비시스템은뇌하수체, 갑상선, 부신, 성선처럼내분비세포가하나의장기를이루고있지않고위장관전장에걸쳐분포하며위장관상피세포의약 1-2% 를차지하고있다. 이중에서포도당대사와연관하여 glucose-dependent insulinotropic polypeptide (GIP) 를분비하는 K 세포 [14] 와 glucagon-like peptide-1 (GLP-1), GLP-2, peptide YY (PYY), oxyntomodulin을분비하는 L 세포 [15] 가잘알려져있다. 비만 / 대사수술후에 cholecystokinin, serotonin 및 vasoactive intestinal peptide 등의분비는일반적으로변동이없는것으로알려져있으며 [16,17] 위장관호르몬은아니지만식욕조절에핵심적인역할을수행하는 leptin 및 insulin은수술후에그농도가유의하게감소하기때문에 [18,19] 특히위우회수술후에관찰되는식욕감소에는기여하지않을것으로추정된다. 현재수술후의대사개선에서가장주목을끌고있는것은 L-세포에서분비되는 GLP-1, PYY, 그리고 oxyntomodulin 등의호르몬이다. 루와이위우회술의구성요소현재사용하고있는루와이위우회술은 1969년에 Mason 등 [20] 이개발한수술법을기반으로일부변형한것이다. 당시 Mason 은위절제술후에작은용적의잔존위를가진환자들이상당한체중감소를경험하는것을보고이수술을개발하였다고한다. 그림 2A에나타낸것처럼루와이위우회술은전체위용적의약 5% 에해당하는작은용적의근위부위파우치 (pouch) 를만들고나머지위는음식물이지나가지않도록분리한다. 위파우치는근위부공장과루와이형태로문합한다 (gastrojejunal anastomosis in a Roux-en-Y configuration). 위파우치에서부터담즙과췌장의소화효소가흘러나오는길과만나는곳까지를루가지 (Roux limb) 혹은영양가지 (alimentary limb) 라고부른다. 소화효소와담즙은십이지장을거쳐약 cm의근위부공장을지나는데이부위를담췌가지 (biliopancreatic limb) 라고부르며이후영양가지와만나고이결합부위에서부터비로소소화가시작된다. 결국루와이위우회술로인해야기되는해부학적특성은세가지로요약할수있는데첫째, 위용적의감소둘째, 95% 의위와십이지장및상부공장의우회셋째, 음식물이하부소장에빠른속도로도달함이다 (Fig. 2A). 위우회술이제2형당뇨병의관해를가져오는기전은아직명확치않으나 (1) 위용적감소와식욕감소에의한음식섭취량감소, (2) 95% 의위와십이지장및상부공장을우회한효과에기인한다는전장가설 (foregut hypothesis), (3) 음식물이하부소장에빠른속도로도발함으로써촉발되는위장관호르몬분비에의한다는후장가설 (hindgut hypothesis) 등이거론되고있으며지금부터상세히논하겠다

4 - 대한내과학회지 : 제 84 권제 5 호통권제 633 호 Figure 2. Schematic presentaiotn of Roux-en-Y gastric bypass (A) and duodenal-jejunal bypass (B). The Roux-en-Y gastric bypass surgery is characterized by (1) reduced functional gastric volume, (2) bypassing 95% of the stomach, whole duodenum, and the proximal jejunum, and (3) expedited delivery of undigested nutrientsto the distal small intestine. The duodenal-jejunal bypass is different from the Roux-en-Y gastric bypass only by the absence of reduced functional gastric volume. 루와이위우회술이제 2 형당뇨병의관해를유도하는기전 식사량감소와체중감소루와이위우회술은 35-40% 의체중감소를유도하는데과다체중감소 (excess body weight loss) 는약 50-80% 에달한다 [21]. 위우회술이이처럼현저한체중감소를일으키는주요기전은위용적감소로인한음식섭취량감소와현저한식욕감퇴이다. 그러나식욕이감소하지만음식의맛을달리인식하는것은아니다 [22]. 또한영양소흡수장애및덤핑증후군증상을경험함에따른단순당을많이함유한음식을기피하는음성조건화반응 (negative conditioning response) 등이체중감소에기여할것으로생각해볼수있으나, 덤핑증후군의중증도가체중감량효과와좋은상관관계를보이고있지않으며, 또한알부민혹은프리알부민 (prealbumin) 그리고분변지방 (fecal fat) 검사결과를보면유의미한흡수장애는보이지않는다 [21]. Pories 등 [7] 이 1995년에보고한바와같이루와이위우회술시행후의당뇨병호전은수술직후에바로나타나는것이흔히관찰되는데, 한보고에따르면 89% 의환자가루와이위우회수술후입원기간중당뇨병의관해가관찰되었다 [23]. 이러한사실은매우충격적인데, 일반적으로외과병동에서다양한종류의위장관수술을받은직후의환자들 은각종스트레스호르몬과염증성사이토카인등의영향으로혈당조절이악화됨을경험한다 [21]. 흥미로운점은, 루와이위우회수술후 1주일동안의체중감량이크지않다는점을고려한다면, 체중감소와직접적관련성이없음을알수있다. 더욱재미있는사실은위우회술이나위밴드술의경우모두수술초기에식사량의급격한감소가있지만위우회술의경우에서만수술직후에급격한혈당의호전이나타난다 [7,24]. 따라서루와이위우회술직후에보이는제2형당뇨병의급격한호전은체중과무관한기전에의함을알수있다. 한편일부혈당조절이비교적양호한당뇨병환자를포함한고도비만환자군을대상으로한소규모연구에서수술을하지않고열량제한만시행한군과루와이위우회술을시행한군을비교한결과, 루와이위우회술직후의급격한인슐린감수성개선에는열량제한이필요조건이라고보고된바있다 [25]. 또한고도비만을동반한 10명의제2형당뇨병환자를대상으로수술전 10일간열량제한을하고 6주이상간격을두고같은환자에게루와이위우회술을시행하여열량제한과수술이혈당에미치는영향이비슷함을보임으로써, 수술직후혈당개선에있어서열량제한이중요함을보인바있다 [26]. 그러나이들연구에서는수술을하지않은대조군을이용하였기때문에수술의스트레스가없는상황에서의열량제한효과를관찰하였다는점을고려하여해석할필요가있다. 당뇨병이없는고도비만환자에서위우회술후의말초에서의인슐린감수성개선은체중감소가상당량일어나야관찰되며체중의감소된정도와밀접한관계가있다고보고된바있다 [27]. 체중감소의중요성을뒷받침하는또다른소견으로, 당뇨병을진단받은지 2년미만의비교적경한당뇨병을가진환자에서위밴드술의혈당조절에미치는영향을본결과당뇨병의관해가체중감소와좋은상관관계를보임이알려진바있다 [24]. 당뇨병이없는비만환자를대상으로루와이위우회술과위밴드술을시행하여 20% 체중감소가이루어진시점에인슐린감수성, 베타세포기능등을분석한결과, 두그룹간차이가없었으며지방조직의유전자발현에도차이가없었음이보고된바있는데 [28], 이는결국당뇨병이없는고도비만환자에서는포도당대사호전에있어서체중감소의역할이매우중요하다는것을시사하는소견이다. 그러나당뇨병이있는상황에서는수술전혈당조절정도의차이, 약제의효과, 포도당독성, 베타세포

5 - 조영민. 비만 / 대사수술이체중감소와당뇨병관해를일으키는기전 - 의양적질적변화 ( 일부비가역적인부분이있음 ) 등등의영향으로인해포도당대사에미치는영향이다를수있을것이므로주의해서해석해야할것이다. 종합하면최근의한리뷰에서자세히소개된바와같이 [29], 당뇨병을동반한고도비만에서루와이위우회수술직후체중감소가얼마일어나지않은시기와그이후현저한체중감소가일어나는시기에포도당대사가호전되는기전이서로다르며, 각각체중과는독립적인기전과체중감소에의존적인기전으로나누어볼수있겠다. 그렐린그렐린 (ghrelin) 은위저부 (fundus) 및십이지장에서분비되는호르몬으로, 위장관에서분비되는호르몬중에서유일하게식욕을촉진시키고식사시간에임박하여공복감을증가시키고식사행위를개시하는데기여한다. 루와이위우회술은위저부와십이지장을음식물이통과하는길에서제외시키기때문에이부위에서생성되는그렐린의분비가감소하게되고따라서식욕이감소할것이라고보고된바있다 [30]. 그러나그렐린이공복상태에서증가하는호르몬이라는점을고려할때, 식사량이줄고특히위저부가음식물이지나가는경로에서분리된상황이라면, 오히려분비가더욱증가해야옳을것이나반대로감소하는것은이해하기가어렵다. 이러한역설적인결과와유사하게, 만성적인자극에의한호르몬의박동성분비억제가다른내분비시스템에알려져있는데, 성선자극호르몬분비호르몬이나성장호르몬분비자극호르몬을지속적으로주입하면이들의작용점이되는성선자극호르몬이나성장호르몬의박동성분비가소실된다 [21]. 또한위저부를제외시키지않는위밴드술이나담췌우회술의경우장기간관찰하였을때그렐린의분비에는변동이없거나증가함이보고된바있다 [21,31]. 그러나이와상반되는결과들도다수보고된바있어서과연루와이위우회술후의식욕감소가그렐린분비감소와관련이있을지의문이있는데, Cummings 등은이러한불일치를보이는결과는위저부를얼마나철저히분리시키는지그리고미주신경을어떻게처리하는지등의수술적기법의차이에기인할것이라고추정하고있다 [21,31]. 루와이위우회술과위소매절제술을 1년간전향적으로비교한연구에서루와이위우회술의경우그렐린이수술직후감소하였다가 1년후수술전수준으로회복하나위소매절제술의경우에는지속적으 로그렐린이감소한결과를보인바있으며 [32], 이는그렐린의감소가위소매절제술의체중감소의하나의기전임을시사한다. 그러나흥미롭게도최근그렐린이결핍된마우스에서위소매절제술을시행한결과식욕, 체중및포도당대사에미치는영향이정상마우스와차이가없음이밝혀져 [33] 그렐린이위우회술후의식욕감소와포도당대사개선에영향을미칠가능성은적거나혹은주된기전은아닌것으로생각한다. 또한그렐린분비를억제하는신호가발생하는곳이위나십이지장이아니라는보고 [34] 는더더욱그렐린분비의변화가식욕의변화를야기하지않을것이라는점을지지한다. 전장가설 (foregut hypothesis) 전장가설은당뇨병에서십이지장과상부공장이기능이상을보이면서이부위에서분비되는소위항인크레틴 (antiincretin) 에의하여포도당대사이상을일으키며이부위를우회함으로써대사적개선을이룰수있다는매우흥미로운이론이다 [35]. 그러면위우회술에서십이지장과상부공장을우회한효과를어떻게검증할수있을까? 그림 2B에서처럼위용적을줄이지않으면서십이지장공장우회술 (duodenal-jejunal bypass, DJB) 을시도해볼수있다 [36]. 그렇지만이러한방법은역시소화흡수되지않은음식물이원위부소장으로빨리도달하게되는성질을그대로지닌다. 전장가설을증명하기위해 Rubino 등 [36,37] 은비만하지않은제2형당뇨병모델인 Goto-Kakizaki 쥐를이용하였다. 비만하지않은당뇨병모델을이용한것은체중감소에따른효과를배제하고순전히대사조절효과만보기위함이었다. 우선그림 3A와같이위공장문합술 (gastrojejunostomy) 를시행하였을때음식물은유문을통과하여십이지장으로도흘러가고동시에문합부위를통해공장으로도직접흘러가지만, 이경우포도당대사의개선은없었다 [37]. 그러나그림 3B와같이위공장문합술을시행한후에유문부와십이지장을분리해줌으로써십이지장과상부공장을우회하였을때포도당대사의개선이관찰되었다 [37]. 또한십이지장공장우회술을시행한결과포도당대사의개선이관찰되었으나분리된십이지장을다시위에연결하게되면포도당대사개선은관찰되지않았다 [37]. 이러한사실은비만하지않은제2형당뇨병모델에서십이지장과상부공장을우회함으로써포도당대사의개선을가져올수있으며, 십이지장과상부공장에서유래하는알

6 - The Korean Journal of Medicine: Vol. 84, No. 5, A B C D Figure 3. Surgical techniques to demonstrate the foregut hypothesis. (A) Gastrojejunostomy, (B) duodenal-jejunal bypass after gastrojejunostomy, (C) duodenal-jejunal bypass, (D) restoration of duodenal nutrient passage after duodenal-jejunal bypass. 려지지않은인자에의해매개될것으로추정하였다 [35]. 그러나십이지장공장우회술을시행한쥐에서십이지장과위를다시문합한실험의경우수술의사망률이높았으므로수술에따른스트레스에의해혈당이상승하였을가능성이있고또한겨우두마리에서관찰된결과이기때문에해석에주의를요한다 [37]. 또한초기에보고된바와달리다른연구에서는 Goto-Kakizaki 쥐에서수술후 3개월까지는혈당조절에유의한차이를보이지않은바있다 [38]. 이러한전장가설을지지하는매우흥미로운증례보고가있는데, 제2형당뇨병이있는 51세남자비만환자가위우회술을받은후위공장문합 (gastro-jejunostomy) 부위의누출 (leakage) 이의심되어경피적위튜브 (percutaneous gastric tube) 를설치하여이를통해 3주간경장영양을시행하고이후 2주간경구로음식을섭취하였다. 5주째에각각의경로로음식물을투여하고혈당과호르몬변화를관찰한바, 경피적위튜브를통해음식을섭취할때보다경구로음식을섭취하여변경된해부학적구조를통해위와십이지장을우회하고음식물이장으로전달될때에 GLP-1 분비가더욱높고인슐린분비가증가되며이에따라혈당이낮게유지됨이보고된바있다 [39]. 그러나이러한실험을하기전 2주간은경구로음식을섭취하였고위와십이지장은우회되어음식물의소화흡수에서제외된상태였기때문에이부위의상피세포위축과내분비세포의변화가나타났을가능성을배제할수없다. 아직미흡한부분은많으나, 이러한전장가설에힘입어내시경을이용하여영양소가투과되지않는튜브형태의구 조물을십이지장구부 (bulb) 에고정하여십이지장과상부공장에서음식물의소화흡수를막는 내강소매 (endoluminal sleeve) 가개발된바있으며, 동물실험과임상시험에서체중감소와혈당개선이보고된바있다 [40-42]. 그러나사람에서실험적으로십이지장공장우회술을시행하였을때 ( 대부분이대조군이없이시행되었거나 [43-45] 제대로무작위배정이되지않았음 [46]) 그효과가만족스럽지못하였다. 전장가설과관련하여주의할점으로, 십이지장공장우회술자체가전장가설을설명하는것처럼생각하는경우가많은데, 사실이경우에도원위부소장으로소화흡수되지않은영양소가빨리도달할수있도록하는특성이있음을간과해서는안된다. 즉, 후장가설 (hindgut hypothesis) 로부터자유롭지못하다는것이다. 실제로 Goto-Kakizaki 쥐에서십이지장공장우회술을시행한후 GLP-1 이증가하였으며 GLP-1 수용체에대한길항제인 exendin 9-39 를투여하면포도당대사의개선이소실됨이알려진바, 대표적인후장호르몬인 GLP-1 이십이지장공장우회술의포도당대사개선기전에서핵심적역할을담당함을시사한다 [47]. 따라서전장가설을시험하는연구결과를해석할때그실험결과가정말전장가설로해석할수있는것인지, 아니면후장가설의요소로도설명할수있는지를주의깊게살펴야할것이다. 또한흥미롭게도최근한연구에의해서십이지장공장우회술의한기전으로공장의영양소센서를통해장-뇌- 간축 (gut-brain-liver axis) 를거쳐혈당을낮출수있음이보고된바있다 [48]. 이러한결과는십이지장공장우회술의작용기전이매우복합적임을시사한다. 그러나최근전장가설이매우강력한반박

7 - Young Min Cho. Mechanism of bariatric/metabolic surgery - 에부딪히고있다. 즉, 위소매절제술의경우십이지장과상부공장과위장과의해부학적관계가정상으로유지됨에도불구하고위우회술과유사한수준의체중감량과혈당의호전을보인다는사실때문이다 [49-51]. 따라서위소매절제술의놀라운당뇨병관해효과를통해현재전장가설은위기에봉착해있다 [32]. 후장가설 (hindgut hypothesis) 위우회술을시행하면소화흡수되지않은영양소가원위부소장에빨리도달하게된다. 원위부소장은 GLP-1, PYY, oxyntomodulin을생산하는 L-세포가풍부하게위치하는곳이다 [15]. GLP-1 이식욕과인슐린분비에중요한작용을하고 PYY가식욕조절에중요한작용을하는점을감안하면이러한후장효과 (hindgut effect) 가위우회술의대사개선의주요기전일가능성이있다. 원위부소장으로소화흡수되지않은음식물이지나가게되면우리몸은위배출속도를늦추고위장관운동속도를떨어뜨리고자노력한다. 이것을회장브레이크 (ileal brake) 라고부르는데 GLP-1 이주된작용을나타낸다 [52]. 이와함께식욕을감소시키는호르몬인 PYY 가동시에많이분비되는것도일맥상통하는현상이라고볼수있다. 실제로제2형당뇨병을동반한비만환자에서위우회술 1개월후에 L-세포에서분비되는세가지호르몬인 GLP-1, PYY, oxyntomodulin이경구포도당부하후에모두증가하였으며, 식이요법으로비슷한정도의감량을이룬환자에서는이러한소견이관찰되지않았다 [53]. 또한루와이위우회술그룹에서위밴드수술을받은그룹에비하여포도당흡수속도가빠르고 GLP-1 상승이빠르며초기인슐린분비가급속히일어난다 [28]. 흥미롭게도위우회술을받고제2형당뇨병의관해가온환자에게 GLP-1 수용체길항제인 exendin 9-39 을투여해도당대사의악화가뚜렷이나타나지않는다는사실은 GLP-1 이외에도다른요소가혈당개선에기여함을시사한다 [54]. 루와이위우회술에서 GLP-1 이증가하는것과마찬가지로담췌우회술에서도원위부소장으로소화흡수되지않은영양소가많이도달하여 GLP-1이증가한다 [55]. 그러나제한적술식 (restrictive procedure) 인위밴드술에서는 GLP-1의증가가관찰되지않는다 [56]. 하지만놀랍게도, 제한적술식으로애당초개발되었던위소매절제술의경우루와이위우회술에견줄만한 GLP-1 상승이일어나며 [50,57], 그기전으로는 Figure 4. The ileal transposition procedure, an experimental surgical technique to demonstrate the hindgut hypothesis. 위산분비역할을맡은부위를대부분잘라냄으로인해위산분비가감소하고이에대한피드백으로가스트린유리펩티드 (gastrin- releasing peptide) 가분비되며이것이자극이되어 GLP-1이분비된다는소위위장가설 (gastric hypothesis) 이있고 [58] 또위소매절제술이후위배출시간이빨라지기때문일것이라는가설이있다 [59]. 아직이것은가설의수준에머무르고있기때문에향후메커니즘에대한연구가필요하다. 루와이위우회술은매우복합적인기전에의해체중감소와대사개선을일으키기때문에후장효과를증명하기는쉽지않다. 회장전치술 (ileal transposition) 은이러한목적으로개발된실험적술식으로원위부회장을상부공장으로혈관과신경이연결된장간막과함께위치를옮기는것이다 [60-62] (Fig. 4). 따라서기타위장관의해부학적구조에전혀영향을전혀주지않으면서원위부회장이근위부로옮겨져서소화흡수되지않은영양소가다량으로이부위와접촉하게된다 [60-62]. 동물실험결과를종합하면체중변화는없거나약간줄어들며, 정상쥐에서는혈당변화가없으나당뇨병쥐모델에서는혈당이개선되며, 전반적으로인슐린감수성이증가한다 [60-65]. 이러한변화는 GLP-1 분비및 PYY 분비의증가와연관되어있다 [61-65]. 동물실험에서회장전치술후의체중감소는뚜렷치않으며 [60] 특히비만한

8 - 대한내과학회지 : 제 84 권제 5 호통권제 633 호 쥐모델에서시행한수술의경우체중에유의한변화가관찰되지않았다 [63,64]. 사람에서는회장전치술과위소매절제술을병행하여 87% 에서당뇨병관해와함께 23% 의체중감소효과가나타난바있다 [66]. 그러나사람에서각각의수술을따로했을때와비교한연구는없으며, 또한장기간의체중조절에대한연구도현재로서는없는실정이다. 결국후장가설이중요하게작용할것으로생각되나그단독만으로는루와이위우회술에서나타나는체중감소와다양한대사개선효과를설명할수는없다. 결론본종설에서살펴본것처럼비만 / 대사수술을통해체중감소가일어나고대사이상이개선되는것은매우다양한기전의복합적인상호작용에의해서일어난다. 각각의기전에대해서는좀더연구가필요하며, 이러한기전을밝힘으로써수술을하지않고내과적치료만으로비슷한효과를얻을수있는시대가곧다가올것으로믿어의심치않는다. 그러나수술과는달리평생약을복용해야할가능성이있기때문에일회성의치료로식행동까지바꾸어놓는비만 / 대사수술은여전히유용한치료수단으로남을것으로전망된다. 무수한미해결과제가산재해있지만, 대한민국의의사로서가장궁금한점은 과연우리나라환자들에게도비만대사수술이유용할것인가? 라는질문일것이다. 최근한연구에서 22명의체질량지수 32 kg/m 2 정도인비만한제2형당뇨병환자를대상으로루와이위우회술을시행한결과 16 명 (73%) 에서수술후 1년째검사에서당뇨병의관해가확인되었으며 ( 공복혈당 < 126 mg/dl 이면서 HbA1c < 6.5% 를기준으로함 ), 수술전내장지방이많은경우관해가잘일어나지않았고관해가일어난환자들은수술후 1년째인슐린분비능에는차이가없었으나인슐린감수성이우수한특징을보였다 [67]. 전국적으로이루어진연구에서 2008년부터 2011년까지비만 / 대사수술 (27.6% 가위밴드술, 28.0% 가루와이위우회술, 44.4% 가위소매절제술 ) 을받은 261명의환자와생활습관교정과약물치료등의내과적치료를받은 224명을후향적으로분석한결과, 치료후 18개월경과시점에치료시작시점대비수술군에서 22.6% 대조군에서 6.7% 의체중감소가있었고, 당뇨병, 고혈압, 이상지혈증으로부터각각 57%, 47%, 84% 에서회복이되어대조군의 10%, 20%, 24% 보다유의하게우수한성적을보임을알수있었다 [68]. 체중감소는큰차이는없었으나루와이위우회술에서수술전체중대비 26.6% 의감소가있었고, 위밴드술에서 20.8%, 위소매절제술에서 22.3% 의체중감소를보였다 [68]. 수술군에서 1명이 30일이내에흡인성폐렴으로사망하여수술관련사망률은 0.38% 이었으며, 위소매절제술의경우수술직후및그이후의합병증이가장낮았다 [68]. 그러나수술군이대조군에비해유의하게체질량지수가높았고 (39.0 ± 6.2 kg/m 2 vs ± 3.8 kg/m 2 ) 당뇨병유병률도수술군이대조군에비해유의하게높은 (39.1% vs. 12.9%) 등, 두그룹간의차이가있었기때문에정확한비교가이루어졌다고볼수없다. 그럼에도불구하고수술군에서현저한체중감소와대사합병증의호전이있었으므로국내비만환자에게도비만 / 대사수술은중요한치료방법의하나이며어쩌면가장우수한치료법이라고할수있을것이다. 이러한점에서대사합병증을동반한비만환자의경우비만 / 대사수술이하루빨리건강보험의혜택을받아야할것이다. 앞으로여러진료과의의사들이협력하여비만대사수술을받는환자를관리해야할것이며, 또한이분야의미해결과제를풀기위해함께노력해야할것이다. 중심단어 : 비만 ; 당뇨병 ; 비만수술 ; 신진대사수술 ; 위장호르몬 REFERENCES 1. Eckel RH. Clinical practice: nonsurgical management of obesity in adults. N Engl J Med 2008;358: Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged yr. Diabetes 1987;36: Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006;444: Unger RH, Scherer PE. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol Metab 2010;21: Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346: Gregg EW, Chen H, Wagenknecht LE, et al. Association of an intensive lifestyle intervention with remission of type

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11 - Young Min Cho. Mechanism of bariatric/metabolic surgery Patriti A, Aisa MC, Annetti C, et al. How the hindgut can cure type 2 diabetes. Ileal transposition improves glucose metabolism and beta-cell function in Goto-kakizaki rats through an enhanced Proglucagon gene expression and L-cell number. Surgery 2007;142: Strader AD, Vahl TP, Jandacek RJ, Woods SC, D'Alessio DA, Seeley RJ. Weight loss through ileal transposition is accompanied by increased ileal hormone secretion and synthesis in rats. Am J Physiol Endocrinol Metab 2005; 288:E Wang TT, Hu SY, Gao HD, et al. Ileal transposition controls diabetes as well as modified duodenal jejunal bypass with better lipid lowering in a nonobese rat model of type II diabetes by increasing GLP-1. Ann Surg 2008;247: Culnan DM, Albaugh V, Sun M, Lynch CJ, Lang CH, Cooney RN. Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat. Am J Physiol Gastrointest Liver Physiol 2010;299:G Ikezawa F, Shibata C, Kikuchi D, et al. Effects of ileal interposition on glucose metabolism in obese rats with diabetes. Surgery 2012;151: Strader AD. Ileal transposition provides insight into the effectiveness of gastric bypass surgery. Physiol Behav 2006;88: DePaula AL, Macedo AL, Rassi N, et al. Laparoscopic treatment of metabolic syndrome in patients with type 2 diabetes mellitus. Surg Endosc 2008;22: Kim MK, Lee HC, Lee SH, et al. The difference of glucostatic parameters according to the remission of diabetes after Roux-en-Y gastric bypass. Diabetes Metab Res Rev 2012;28: Heo YS, Park JM, Kim YJ, et al. Bariatric surgery versus conventional therapy in obese Korea patients: a multicenter retrospective cohort study. J Korean Surg Soc 2012;83: Jørgensen NB, Jacobsen SH, Dirksen C, et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with Type 2 diabetes and normal glucose tolerance. Am J Physiol Endocrinol Metab 2012; 303:E