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1 J Korean Diabetes 2016;17:6-10 Vol.17, No.1, 2016 ISSN 성균관대학교의과대학삼성서울병원내분비대사내과 Management of Hypoglycemic Unawareness and the Current Status of Clinical Allogeneic Islet Transplantation Sang-Man Jin Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Abstract Problematic hypoglycemia is defined as a condition in which episodes of severe hypoglycemia are unpredictable and/or cannot be easily explained or prevented, typically associated with impaired awareness of hypoglycemia. The treatment algorithm for patients with type 1 diabetes and problematic hypoglycemia emphasizes the stepwise approach including structured education regarding multiple daily injections of insulin, use of technology such as sensor-augmented pump with low glucose suspension, and islet or pancreas transplantation. Although the prevalence of insulin independence at 5 years is 25~50% in most recent clinical trials of islet transplantation, both islet and pancreas transplantation are equally efficient to cure severe hypoglycemia for more than 5 years in about 70% of the recipients. To date, international cohorts of clinical islet transplantation such as the French-Swiss GRAGIL Network have successfully reproduced the long-term C-peptide positivity initially achieved with the Edmonton protocol, with long-term insulin independence demonstrated in selected cases. Several cases with partial islet graft function have been reported in Korea, with the first case of long-term insulin independence being reported in late Therefore, islet transplantation can offer freedom from life-threatening severe hypoglycemia for type 1 diabetes patients with problematic hypoglycemia, even in non-responders to the latest technology-based treatment. Keywords: Hypoglycemia, Islet transplantation, Type 1 diabetes Corresponding author: Sang-Man Jin Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea, sjin772@gmail.com Received: Jan. 23, 2016; Accepted: Feb. 17, 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright c 2016 Korean Diabetes Association 6 The Journal of Korean Diabetes

2 진상만 서론 최근국내에서처음으로동종췌도이식후 1개월이상인슐린의사용없이목표혈당을유지한사례가언론에발표되면서, 췌도이식이라는치료에대한대중의관심이높아졌다. 췌도이식에대한언론이나일반인들의우선적인관심은흔히 당뇨병의완치시대가열렸다 는기대로요약될수있다. 그러나일반인의기대와달리췌도이식의발전이당뇨병의완치시대가열린것을의미하지는않는다. 췌도이식은에드먼턴프로토콜의등장 [1] 이후 15년여에거친시간동안이루어진적지않은연구들을근거로이제는보다현실적인임상적의의가정립되고있으며, 심한혈당변동성을보이는제1형당뇨병의치료를주된관심사로하는당뇨병전문가들이췌도이식을보는시각은대중들의시각과는차이가있다. 모처럼높아진대중의관심을올바른방향으로이끌기위해, 의료인들은그동안제1 형당뇨병의낮은유병률로인해국내에서사실상잊혀진치료였던췌도이식의현재를올바로이해할필요가있으며, 이를위해먼저췌도이식의대상환자군인저혈당무감지증을가진제1형당뇨병환자의관리에대해알아볼필요가있다. 저혈당무감지증이있는제 1 형당뇨병의관리 최근미국당뇨병학회의 문제있는저혈당 (problematic hypoglycemia) 을동반한제1형당뇨병환자의진료에대한근거기반의추천사항이발표되었다 [2]. 이지침은 문제있는저혈당 을심한저혈당 (severe hypoglycemia, 타인의도움이없이회복될수없는저혈당 ) 이예측할수없고쉽게이유를설명하거나예방할수없이오는상태로정의하였다. 구체적인기준으로최근 12개월간두차례이상의심한저혈당이있던경우, 혹은최근 12개월간저혈당무감지증이나극심한혈당의변동성과연관된심한저혈당이한번이상발생한경우를제시하였다. 저혈당무감지증 (impaired awareness of hypoglycemia) 은제1형당뇨병 의 20~40% 에서나타나며, 이중 66% 의환자에서연간 2 회이상심한저혈당이나타난다 [3,4]. 제1형당뇨병환자의 4~10% 는심한저혈당으로사망하는것으로알려져있다 [5]. 국내에서는역학연구가체계적으로이루어지지않고있지만, 비슷한비율을국내에적용할경우적어도수천명의제1형당뇨병환자가저혈당무감지증을가지고있을것으로예상할수있다. 제1형당뇨병에서인슐린치료의강도와무관하게잔여인슐린분비능이심한저혈당의빈도를결정하는가장중요한인자임은주지의사실이다. 그동안동종췌도이식의성적이꾸준히개선되어왔지만, 췌장이식과췌도이식을받은후 5년이상인슐린없이목표혈당유지가가능한환자의비율은각각약 70% 와 25~50% 로차이가있다 [6-9]. 그러나최근발표된 French-Swiss GRAGIL Network [8] 의결과를비롯한국제다기관연구의결과들에서췌도이식후 5년이상의미있는내인성인슐린분비를유지하는 ( 공복 C-peptide > 0.3 ng/ml) 환자의비율은췌장이식과동일한약 70% 로서, 췌장이식과췌도이식은심한저혈당으로부터의자유를주는목적으로는동등한효과를보인다고할수있다 [7,8]. 이에따라문제있는저혈당의치료에대한미국당뇨병학회의지침은다회인슐린주사에대한체계적인교육, 인슐린펌프, 연속혈당측정을활용하여일정혈당미만에서인슐린주입속도를낮추는인슐린펌프 (sensoraugmented insulin pump with low glucose suspension feature) 혹은 3~4개월간매주방문하여교육을시행하는순서로치료를차례대로시도한후반응하지않는환자에서는췌도또는췌장이식을시행할것을권고하고있다 (Fig. 1). 따라서췌도이식을 당뇨병의완치, 인슐린을끊게해주는치료 로인식하는일반인의관점에서는아직현재의췌도이식의성적이실망스러울지라도, 심한저혈당에자주노출되는제1형환자를많은노력을들여교육하고, 고가의연속혈당측정과인슐린펌프를사용하여치료를시도해왔던의사의관점에서는가장앞선기술을사용한치료로도해결할수없었던저혈당무감지증을동반한환자를개복 7

3 Fig. 1. Proposed treatment algorithm for patients with type 1 diabetes and problematic hypoglycemia. Data from the article of Choudhary et al. (Diabetes Care 2015;38: )[2] with original copyright holder s permission. MDI, multiple daily injection; SMBG, self-monitoring of blood glucose; CSII, continuous subcutaneous insulin infusion; SAP, sensor-augmented pump; LGS, low-glucose suspension, RT-CGM, real-time continuous glucose monitoring. 수술의위험부담없이도심한저혈당으로부터해방시켜줄수있는중요한치료로생각할수있다. 국내의췌도이식 국내에서는 1999년말삼성서울병원에서아시아최초로동종췌도이식을시행하였다. 첫췌도이식후공복 C-peptide는이식전 0.6 g/ml로부터 2.1 ng/ml로상승하였고, 인슐린요구량은하루 80단위에서 36단위로감소하였다. 그러나이식후 70일째에췌도이식편의기능이소실되었고, 두번째공여자로부터재이식을시행하였다. 재이식후혈당의변동성이호전되었고빈번하게나타났던저혈당이발생하지않게되었으며신경병증에의한통증이극적으로호전되었다 [10]. 또한같은기관에서양성췌장종 양으로인한췌장부분절제후자가췌도이식을 30예이상시행하였고, 이중 50~60% 의췌장절제범위를가진 20예에서췌도분리효율에따른임상경과를보고하기도하였다 [11]. 췌도이식은일반적으로 2~3명의공여자에서얻은췌도를이식하여야인슐린의사용없이목표혈당을유지할수있는상태에이르나 2000년대중반이후일부해외기관에서보다적극적인면역억제요법을사용하여 1명의공여자에서얻은췌도를이식하고도장기간인슐린없이목표혈당을유지한사례들이보고되었다 [9]. 국내에서는 2013 년서울성모병원에서한명의뇌사자만으로부터얻은췌도를이식하여저혈당무감지증을교정한사례를보고했고 [12], 2015년 1명의뇌사자로부터분리된췌도로동종췌도이식후인슐린을중지한상태에서도 1개월이상목표혈당을유지한사례를언론에소개하였다. 8

4 진상만 그러나국내연구진들의적지않은노력에도불구하고국내에서췌장 / 췌도이식은서구의선진국들에비해활발히이루어지지못해왔으며, 이는제1형당뇨병의낮은유병률과부족한사회의인지도, 저혈당무감지증에대한체계적인치료를어렵게하는왜곡된의료체계등이복합적으로작용한결과로생각한다. 이로인해췌장 / 췌도이식의공급이수요보다훨씬부족한외국과달리국내에서는오히려뇌사자가기증한췌장의대부분이사용되지않고폐기되는독특한상황이계속되고있다. 현재국내에서연속혈당측정, 인슐린펌프에대한보험적용이전무한실정이고 sensor-augmented insulin pump 등기술기반치료의영역에서도국내기술및관련교육수준이서구에비해훨씬뒤처진것을생각하면, 국내에서최소한수천명이존재할것으로보이는저혈당무감지증환자의치료를위해췌장 / 췌도이식을적절히사용하는것은오히려서구의국가에서보다도높은중요성을가진다고생각할수있다. 결론 췌도이식은비록당뇨병의완치라는대중의기대와는차이가있지만저혈당무감지증을동반한환자를개복수술의위험부담없이도심한저혈당으로부터해방시켜줄수있는임상적의의가큰치료이다. 국내동종췌도이식이의미있는성과를거두기시작하면서높아진췌도이식이라는기술에대한대중의관심을이제는저혈당무감지증으로인해잦은생명의위협에빠지는환자들에대한관심으로승화시킬필요가있다. 이러한환자군에대한집중적인인슐린치료에대한교육, 급격히발전하고있는기술기반의치료, 췌장 / 췌도이식등다양한치료가이루어질수있도록의료환경을개선하는것이당뇨병전문가사회에맡겨진중요한과제라할수있다. REFERENCES 1. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343: Choudhary P, Rickels MR, Senior PA, Vantyghem MC, Maffi P, Kay TW, Keymeulen B, Inagaki N, Saudek F, Lehmann R, Hering BJ. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care 2015;38: Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994;17: Geddes J, Schopman JE, Zammitt NN, Frier BM. Prevalence of impaired awareness of hypoglycaemia in adults with type 1 diabetes. Diabet Med 2008;25: Skrivarhaug T, Bangstad HJ, Stene LC, Sandvik L, Hanssen KF, Joner G. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia 2006;49: Dunn TB, Kirchner V, Bellin MD. Beta-cell replacement therapy: current outcomes and future landscape. Curr Opin Organ Transplant 2015;20: Hering BJ, Bellin MD. Transplantation: sustained benefits of islet transplants for T1DM. Nat Rev Endocrinol 2015;11: Lablanche S, Borot S, Wojtusciszyn A, Bayle F, Tétaz R, Badet L, Thivolet C, Morelon E, Frimat L, Penfornis A, Kessler L, Brault C, Colin C, Tauveron I, Bosco D, Berney T, Benhamou PY; GRAGIL Network. Five-year metabolic, functional, and safety results of patients with type 1 diabetes transplanted with allogenic islets within the Swiss-French GRAGIL network. Diabetes Care 2015;38:

5 9. Bellin MD, Barton FB, Heitman A, Harmon JV, Kandaswamy R, Balamurugan AN, Sutherland DE, Alejandro R, Hering BJ. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 2012;12: Yang TY, Oh SH, Jeong IK, Seo IA, Oh EY, Kim SJ, Chung JH, Min YK, Lee MS, Lee MK, Kim KW, Do YS, Choo SW. First human trial of pancreatic islet allotransplantation in Korea: focus on re-transplantation. Diabetes Res Clin Pract 2002;56: Jin SM, Oh SH, Kim SK, Jung HS, Choi SH, Jang KT, Lee KT, Kim JH, Lee MS, Lee MK, Kim KW. Diabetes-free survival in patients who underwent islet autotransplantation after 50% to 60% distal partial pancreatectomy for benign pancreatic tumors. Transplantation 2013;95: Yang HK, Ham DS, Park HS, Rhee M, You YH, Kim MJ, Kim JW, Lee SH, Hong TH, Choi BG, Cho JH, Yoon KH. Reversal of hypoglycemia unawareness with a singledonor, marginal dose allogeneic islet transplantation in Korea: a case report. J Korean Med Sci 2015;30:

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R