J Korean Diabetes 2015;16:123-129 Vol.16, No.2, 2015 ISSN 2233-7431 양여리, 조재형가톨릭대학교의과대학서울성모병원내분비내과 New Technology for Type 1 Diabetes Yeoree Yang, Jae Hyoung Cho Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea Abstract Type 1 diabetes is an autoimmune disease with insulin deficiency which causes microvascular complications such as retinopathy, nephropathy and neuropathy. There have been some trials to simulate the pancreatic endocrine function of insulin and glucagon for homeostatic equilibration of blood glucose, developing artificial pancreas. There are three major functional components of the modern artificial pancreas, a continuous glucose-monitoring system, an insulin-infusion pump and a control algorithm. There are commercially available continuous glucose monitoring systems with subcutaneous glucose measuring, however, there have been many attempts to develop more efficient glucose monitoring systems, including noninvasive systems. Thanks to technological advances and the miniaturization of electronics, recent advances in the accuracy and performance of these systems have placed research on the threshold of prototype commercial devices and large-scale outpatient feasibility studies. In addition, smartphone technology has created the opportunity for caregivers to receive push notification alerts and makes it possible to provide patients with advisory or decision-support systems. Even though there are still some remaining challenges to develop a successful artificial pancreas, glucose control in type 1 diabetes will be more efficient with its advent. Keywords: Artificial pancreas, Continuous glucose-monitoring system, New technology, Non-invasive, Type 1 diabetes Corresponding author: Jae Hyoung Cho Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul St. Mary s Hospital, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Korea, E-mail: drhopper@ikoob.com Received: May. 4, 2015; Accepted: May. 20, 2015 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. Copyright c 2015 Korean Diabetes Association The Journal of Korean Diabetes 123
서론 당뇨병이없는정상인은혈당의변화를인지하고베타세포로부터인슐린을분비하거나알파세포로부터글루카곤을분비하여혈당을정상적으로유지시킨다. 그러나제1형당뇨병환자는베타세포기능의심한장애가발생하여혈당의항상성을유지하는것이어렵게된다. 장기적인고혈당이지속되게되면망막증, 신증그리고신경병증등다양한미세혈관합병증이발생하게되는데미국과유럽및한국에서당뇨병은실명과신질환및발절단의주요원인이되고있다. 제1형당뇨병환자는혈당조절을위하여혈당측정기를이용해혈당을측정하고하루수회인슐린을주사하거나연속피하인슐린주사 ( 인슐린펌프 ) 를통해인슐린을공급하게되는데, 체내의폐루프 (closed-loop) 또는되먹임조절 (feedback regulation) 시스템이없이외부에서인슐린을주입하여조절하는경우저혈당의위험이높아지게된다. 알려진바와같이저혈당은단순한불편한증상을넘어의식저하, 간질및사망에이르기까지다양한위험을내포하고있어제1 형당뇨병환자의치료에서가장염두에두어야하는점이기도하다 [1]. 지난 50년간많은의사, 과학자와공학자들은건강한사람과같은췌장의혈당조절능력을가질수있는복잡한의료기기를개발하기위하여노력해왔다. 1974년 Albisser 등 [2] 은처음으로인공내분비췌장 (artificial endocrine pancreas) 을기술하였는데이는컴퓨터화제어시스템으로췌장의내분비기능을근접하여시뮬레이션할수있도록하는것이었다. 그러나이는당과인슐린또그외요소들을매우복잡한방법을통해혈관내로주입하는것으로입원해있는환자에게서만매우주의깊게사용될수있는것이었다. 그러나제1형당뇨병환자의일상생활에서이용가능하고장기간혈당조절이가능하도록하기위해서는입원상태가아닌외래진료에서도사용가능해야하기때문에이를위한많은노력이있어왔다. 또한제1 형당뇨병을조기에진단하고치료가가능하도록하기위한진단적인방법또한많은발전이이루어져왔다. 인슐린펌 프의사용과더불어연속혈당측정기의개발과상용화는인공췌장의발전에획기적인계기가되었고어느덧인공췌장의상용화는성큼우리앞에다가서고있다. 본글에서는제 1형당뇨병의진단과연속혈당의측정및인슐린치료에있어서발전된기술들을바탕으로제1형당뇨병의관리를위한새로운방안을모색하여보고자한다. 췌도특이자가항체의측정 제1형당뇨병은자가면역질환으로인슐린저항성과베타세포의기능장애를주요병인으로하는제2형당뇨병과는차이가있다. 그러나최근비만유병률의증가와저연령층에서의제2형당뇨병의발병증가로인하여당뇨병형의구분이쉽지않으며상당히중첩되는부분도있다. 최근의연구들에서면역조절 (immune modulation) 과항원특이치료 (antigen-specific therapy) 로제1형당뇨병의자연경과를호전시킨결과들이있어 [3,4] 제1형당뇨병의빠른진단이중요할것으로보인다. 또한제1형당뇨병의빠른진단과치료는생명을위협할수있는급성합병증위험을감소시키고 [5] 내인성인슐린분비기간을연장시킬수있다 [6]. 현재췌도특이자가항체를검사하는방법은느리고가격이비싸며의료가발달하지않은지역에서는검사하기힘들다는단점이있다. 최근에는이러한단점을보완하기위해간단하게자가항체를검사할수있는방법이연구되고있다. 근적외선형광을이용한플라즈모닉금칩 (plasmonic gold chip for near-infrared fluorescence enhanced, NIR-FE) 은나노구조의칩표면에췌도특이항원을코팅한것으로이곳에환자의췌도특이자가항체가결합하면형광시그널이작용하여즉각적으로양성여부를보여준다. 소량의혈액만있어도검사가가능하며빠르고쉬운방법으로민감도, 특이도도높은것으로알려져있어앞으로의개발에많은관심이모이고있다 [7]. 124
양여리외 혈당의측정과모니터링 인슐린치료는인슐린분비능이결핍된제1형당뇨병의치료에서절대적이다. 자가혈당의빈번한측정은혈당조절에필수적으로인슐린용량을조정하면서효과적으로혈당조절목표에도달할수있게해주며저혈당을사전에예측하고예방할수있도록도와준다. 약 27,000명의제1형당뇨병소아청소년들에관한연구에서하루자가혈당을측정하는횟수의증가는당화혈색소의현저한감소와급성합병증을감소시켜주는결과를보여주었다 [8]. 그러나종래의혈당측정방법 (fingertip prick method) 은손가락채혈을위해 32게이지의란셋을이용하는침습적인방법으로채혈부위의통증, 감염의우려가있고매측정시단회의결과만보여주는일회성의단점이있다. 또한자주혈당을측정한다고해도혈당변동폭이큰경우전반적인혈당조절상태를반영하기는힘들다. 따라서이에대한대책으로비침습적이고연속적인혈당측정방법들이개발되고있다. 최근의일련의연구들에서연속혈당측정 (continuous glucose monitoring, CGMS) 은고전적인방법에비해당화혈색소강하효과를보여주었다 [9-11]. 1. 비침습적혈당모니터링 (Non-Invasive Glucose Monitoring) 무채혈혈당기 (pain-free glucose monitoring technology) 는지난수년간혈당측정기개발의주요목표로연구되어왔다. 비침습적혈당측정방법은크게광학적방법 (optical) 과전기적 (electric) 방법으로나눌수있으며그밖에초음파나온도분광학 (thermal spectroscopy) 등을이용하는방법이있다광학적방법으로는적외선분광법 (infrared spectroscopy), 광간섭단층촬영 (optical coherence tomography), 라만분광법 (Raman spectroscopy), 분극 (polarization), 형광 (fluoresence) 등을이용하는방법이있으며전기적방법으 로는임피던스분광법 (impedance spectroscopy), 전자기감지 (electromagnetic sensing), 역이온삼투요법 (reverse iontophoresis) 등을이용한방법이있다 [12]. 시그너스사 (Cygnus, Redwood City, CA, USA) 에서개발한손목시계의형태의 Glucowatch G2 Biographer는역이온삼투요법을이용한최초의상용화무채혈혈당기이다. 시계뒷면의두전극간의전류를이용하여세포간질액을피부로추출하여당을측정하는원리를이용하였으며 1999 년유럽 Conformité Européenne (CE) 승인를받고이어서 2001년미국 Food and Drug Administration (FDA) 승인을받았다. 그러나피부자극문제와칼리브레이션 (calibration), 발한시기계가멈추는문제가대두되었고고혈당에비해저혈당을잘인지하지못하는문제등을해결하지못하고 2007년판매중단되었다 [13]. 그밖에여러나라에서 Pendra, GlucoTrack, OrSense NBM-200G, Symphony, Dispensor 등이개발되었으나대다수의기계들이여러문제로상용화되지못하거나판매가중지된상태이다. 국내에서는역이온삼투요법을이용하여 KMH사 (KMH Co., Ltd., Anyang, Korea) 에서개발한글루콜 (Glu-Call) 이 2008년식품의약품안전청으로부터의료기기품목허가를승인을받았으나상용화되지못하고중지되었다 [14]. 최근구글 (Google) 과노바티스 (Novartis) 사에서공동으로구글콘택트렌즈를개발중이라고발표하였다. 콘택트렌즈센서는눈물을이용한최소한의침습적인센서로하이드로겔층 (hydrogel matrix) 안의초소형전자화학센서가눈물속의당농도를측정하여혈당을예측하게된다. 이렇게읽어들인측정값은무선으로사용자모바일기기를통해전송될수있다. 눈물성분의당농도뿐만아니라젖산, 전해질등과안압을분석하여패혈증, 전해질불균형, 녹내장등의다양한질병을진단할수있을것으로예상된다. 그러나아직상용화까지는수년이소요될것으로예상되며상용화전까지안구자극, 재현성, 민감도등의풀어야할숙제가남아있는실정이다 [15]. 현재까지다양한기술방법으로다양한무채혈혈당기들 www.diabetes.or.kr 125
이개발되었지만혈당측정의정확도, 칼리브레이션의문제, 기구의내구성, 안전성및분석능력등에서기존의혈당기에뒤쳐지지않아야한다는숙제가남아있다. 그밖에빠른반응속도를구현하여연속적인혈당모니터링을가능하게해야할것이다. 2. 연속혈당모니터링연속혈당측정기는메드트로닉사 (Medtronic, Minneapolis, MN, USA) 에서처음개발되어 1999년 6월미국 FDA 승인을받았으며, 혈당변동폭이크고, 저혈당이빈번한당뇨병환자들의치료에도움을주고있다. 연속혈당측정기는당센서, 무선전송기, 수신기의세부분으로구성되어있다. 센서는피하지방에삽입되어세포간질액에서당을측정하게된다. 최근버전의연속혈당측정기는실시간으로혈당측정값을보여주며즉각적으로적절한조치를취할수있게해주고있다. 연속혈당측정기의단점으로는생체불안전성 (bioinstability) 이있다. 센서가염증이나육아종형성, 혈전등으로인하여불안정해지는데 [16] 이를보정하기위해지속적으로기존의혈당기를이용한칼리브레이션이필요하다. 이를해결하기위해서실리콘옥사이드나노입자 (silicon oxide nanoparticles) 를포함하는폴리에틸렌글리콜 (polyethylene glycol) 과같은다양한소재로센서를코팅하는방법이개발되고있으며 [17] 기존의전기화학센서를새로운센서로대체하는기술이개발되고있다. 그중에하나로형광센서를이용하는기술은당이센서에부착시발형광단 (fluorophore) 의밝기가변하는원리를이용하여반영구적이고비침습적인방법으로각광받고있다 [18]. 현재연속혈당측정기로혈당을측정하면서발생하는시간지연 (time lag) 은평균 4~10분정도인데이도해결해야할문제중에하나이다. 정확하고신속한연속적혈당측정은폐루프인슐린전달시스템 (closed-loop insulin delivery system) 구축의필수전제조건으로뒤에서설명할인공췌장의개발과밀접한관련이있다. 인공췌장 인공췌장또는폐루프는연속혈당측정기로부터데이터를받아특정목표혈당값을유지하기위하여필요한적절양의인슐린주입량또는글루카곤주입량을계산하는데이용되는프로그램을의미한다. 이는 2012년 11월미국 FDA의안내에나온인공췌장장치에대한광범위한정의이다 [19]. 그러나인공췌장과폐루프시스템은종종그의미가다를수있는데, 인공췌장은식사시탄수화물양에따른인슐린의개루프전달 (open-loop delivery) 도포함할수있기때문이다. 최근인슐린, 인슐린펌프그리고 CGMS 시스템의발달과더불어이를조정하는알고리즘의발달로인공췌장장치의드라마틱한발전이있어왔고외래환자에서도사용이가능한수준이되었다. 지난 3년만해도인공췌장연구에많은좋은보고들이있어왔다 [20-26]. 가장최근개발된연속혈당측정기의정확성과성능을통해인공췌장은상용화수준에이르렀고대규모의외래환자임상연구에들어갈수있었다. 현재당뇨병환자에서사용할수있는폐루프제어시스템으로크게 2개의방식이소개되고있다. 첫번째는단일호르몬 (unihormonal) 접근방식으로혈당을감소시키기위해인슐린만을이용하는데저혈당의위험을감소시키기위한복잡한안전-완화알고리즘 (safety-mitigation algorithm) 을장치해두었다. 다음으로이중호르몬 (bihormonal) 접근방식은혈당을낮추는데인슐린을사용함과더불어혈당을증가시키기위한글루카곤을같이사용하는것이다. 이또한안전을위해복잡한알고리즘을이용하고있다. 변화하는혈당에따라주입해야하는적절인슐린용량을조절하는주요제어알고리즘들로는 proportionalintegral-derivative 제어, 모델예측제어 (model predictive control), 퍼지논리 (fuzzy logic) 및안전관리설계 (safety supervision design) 등이있다. 이러한알고리즘의발달은연속혈당측정모니터링에서측정한혈당값과실제의혈 126
양여리외 당값의시간차이를보정할뿐만아니라, 섭취한탄수화물의양이나혈당변화의속도를계산하여적절한인슐린용량을조절함으로써혈당을낮춤과동시에저혈당의발생을최소화하는데일조하고있다. 이러한인공췌장의발전은무엇보다도혁신적인컴퓨터의발전과전자기기제품크기의축소화에기인한다. 그리고또하나의커다란새로운기술혁신은바로스마트폰의소개이다. 2007년아이폰이처음소개되면서스마트폰을이용하여자체적으로동작하는펌프조절장치에조절알고리즘을접목할수있게되었다. 최근에는스마트폰의발달과더불어또하나의방안이마련되었는데인공췌장의가장중요한핵심엔지니어링기술로스마트폰기술을이용하는것이다. 이는 Diabetes Assistant 플랫폼으로버지니아대학교에서이용되었다 [27]. 이러한스마트폰의발전에힘입어현재크게두가지의새로운방법이이용되고있는데바로원격모니터링 (remote monitoring) 과자문시스템 (advisor system) 이다. 연속혈당측정시스템과스마트폰을연결함으로써환자의혈당이미리정해둔적절한범위이상또는이하로벗어날때의료팀이푸쉬알람을받을수있도록하는것 [28] 과, 원격모니터링에더하여환자에게자문이나의사결정-지원시스템 (decision-support system) 을제공하는것이가능하게되었다 [29]. 그러나이러한눈부신발전에도불구하고성공적인폐루프제어시스템이되기위해서는아직해결해야할다섯가지의문제가남아있다. 운동, 다른질환의영향, 고탄수화물음식, 부적당한인슐린의약동학그리고각각다른상업적영역의연속혈당모니터와인슐린펌프, 폐루프알고리즘을잘연결시켜야하는상업적인이슈등이다. 결론 제1형당뇨병환자의혈당조절을위해의사, 과학자, 공학자들의많은노력이있었다. 인슐린주사의종류와효과에도많은발전이이루어졌으나이것만으로는충분한혈당조절을하기에아직어려운부분이많다. 인슐린펌프의소 개와함께연속혈당측정기의개발로인공췌장의연구가매우활발이진행되었다. 그리고여기에측정된혈당에따라인슐린주입용량을조절하는폐루프제어시스템기능의향상으로저혈당을최소화하면서혈당을조절하는기술이확대되고있다. 이제외래환자를대상으로한대규모임상연구가진행되고있으며상업적으로이용될수있을수준으로발달되고있는것이다. 더불어연속혈당측정을좀더효과적으로하기위한비침습적혈당측정시스템또한다각도로이루어지고있어가까운미래에좀더실시간으로불편하지않고쉽게혈당을연속적으로측정할수있는시스템이소개될수있을것으로기대된다. 여기에스마트폰기술의발달과함께환자의혈당데이터를실시간으로모니터링하고이를분석하는프로그램이함께접목됨으로써환자개개인에맞는정보를제공해줄수있게된것도큰기술적발전이라할수있다. 이렇듯다양한분야에서기술이발전되고이것이제1형당뇨병환자를위한혈당관리시스템에함께이용됨으로써제1형당뇨병환자의치료에밝은미래가있을것으로기대된다. REFERENCES 1. Cryer PE. Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes 1994;43:1378-89. 2. Albisser AM, Leibel BS, Ewart TG, Davidovac Z, Botz CK, Zingg W. An artificial endocrine pancreas. Diabetes 1974;23:389-96. 3. Greenbaum CJ, Schatz DA, Haller MJ, Sanda S. Through the fog: recent clinical trials to preserve β-cell function in type 1 diabetes. Diabetes 2012;61:1323-30. 4. Michels AW, Eisenbarth GS. Immune intervention in type 1 diabetes. Semin Immunol 2011;23:214-9. 5. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, Winkler C, Ilonen J, Veijola R, Knip M, Bonifacio E, Eisenbarth GS. Seroconversion to multiple www.diabetes.or.kr 127
islet autoantibodies and risk of progression to diabetes in children. JAMA 2013;309:2473-9. 6. Sørensen JS, Johannesen J, Pociot F, Kristensen K, Thomsen J, Hertel NT, Kjaersgaard P, Brorsson C, Birkebaek NH; Danish Society for Diabetes in Childhood and Adolescence. Residual β-cell function 3-6 years after onset of type 1 diabetes reduces risk of severe hypoglycemia in children and adolescents. Diabetes Care 2013;36:3454-9. 7. Zhang B, Kumar RB, Dai H, Feldman BJ. A plasmonic chip for biomarker discovery and diagnosis of type 1 diabetes. Nat Med 2014;20:948-53. 8. Ziegler R, Heidtmann B, Hilgard D, Hofer S, Rosenbauer J, Holl R; DPV-Wiss-Initiative. Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatr Diabetes 2011;12:11-7. 9. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, Fiallo-Scharer R, Fox LA, Gilliam LK, Hirsch IB, Huang ES, Kollman C, Kowalski AJ, Laffel L, Lawrence JM, Lee J, Mauras N, O'Grady M, Ruedy KJ, Tansey M, Tsalikian E, Weinzimer S, Wilson DM, Wolpert H, Wysocki T, Xing D. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med 2008;359:1464-76. 10. Wong JC, Foster NC, Maahs DM, Raghinaru D, Bergenstal RM, Ahmann AJ, Peters AL, Bode BW, Aleppo G, Hirsch IB, Kleis L, Chase HP, DuBose SN, Miller KM, Beck RW, Adi S; T1D Exchange Clinic Network. Realtime continuous glucose monitoring among participants in the T1D Exchange clinic registry. Diabetes Care 2014;37:2702-9. 11. Yeh HC, Brown TT, Maruthur N, Ranasinghe P, Berger Z, Suh YD, Wilson LM, Haberl EB, Brick J, Bass EB, Golden SH. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med 2012;157:336-47. 12. Tura A. Noninvasive glycaemia monitoring: background, traditional findings, and novelties in the recent clinical trials. Curr Opin Clin Nutr Metab Care 2008;11:607-12. 13. Diabetes Research in Children Network (DirecNet) Study Group. Accuracy of the GlucoWatch G2 Biographer and the continuous glucose monitoring system during hypoglycemia: experience of the Diabetes Research in Children Network. Diabetes Care 2004;27:722-6. 14. Vashist SK. Non-invasive glucose monitoring technology in diabetes management: a review. Anal Chim Acta 2012;750:16-27. 15. Farandos NM, Yetisen AK, Monteiro MJ, Lowe CR, Yun SH. Contact lens sensors in ocular diagnostics. Adv Healthc Mater 2015;4:792-810. 16. Klueh U, Liu Z, Feldman B, Henning TP, Cho B, Ouyang T, Kreutzer D. Metabolic biofouling of glucose sensors in vivo: role of tissue microhemorrhages. J Diabetes Sci Technol 2011;5:583-95. 17. van den Bosch EE, de Bont NH, Qiu J, Gelling OJ. A promising solution to enhance the sensocompatibility of biosensors in continuous glucose monitoring systems. J Diabetes Sci Technol 2013;7:455-64. 18. Peyser T, Zisser H, Khan U, Jovanovič L, Bevier W, Romey M, Suri J, Strasma P, Tiaden S, Gamsey S. Use of a novel fluorescent glucose sensor in volunteer subjects with type 1 diabetes mellitus. J Diabetes Sci Technol 2011;5:687-93. 19. Guidance for Industry and Food and Drug Administration Staff: The Content of Investigational Device Exemption (IDE) and Premarket Approval (PMA) Applications for Artificial Pancreas Device Systems. Available from: 128
양여리외 http://www.fda.gov/downloads/medicaldevices/ deviceregulationandguidance/guidancedocuments/ ucm259305.pdf (updated 2012 Nov 9). 20. Cobelli C, Renard E, Kovatchev B. Artificial pancreas: past, present, future. Diabetes 2011;60:2672-82. 21. Renard E, Cobelli C, Kovatchev BP. Closed loop developments to improve glucose control at home. Diabetes Res Clin Pract 2013;102:79-85. 22. Elleri D, Dunger DB, Hovorka R. Closed-loop insulin delivery for treatment of type 1 diabetes. BMC Med 2011;9:120. 23. Thabit H, Hovorka R. Closed-loop insulin delivery in type 1 diabetes. Endocrinol Metab Clin North Am 2012;41:105-17. 24. Hovorka R. Closed-loop insulin delivery: from bench to clinical practice. Nat Rev Endocrinol 2011;7:385-95. 25. Kumareswaran K, Evans ML, Hovorka R. Closed-loop insulin delivery: towards improved diabetes care. Discov Med 2012;13:159-70. 26. McCall AL, Farhy LS. Treating type 1 diabetes: from strategies for insulin delivery to dual hormonal control. Minerva Endocrinol 2013;38:145-63. 27. Keith-Hynes P, Guerlain S, Mize B, Hughes-Karvetski C, Khan M, McElwee-Malloy M, Kovatchev BP. DiAs user interface: a patient-centric interface for mobile artificial pancreas systems. J Diabetes Sci Technol 2013;7:1416-26. 28. Dassau E, Jovanovic L, Doyle FJ 3rd, Zisser HC. Enhanced 911/global position system wizard: a telemedicine application for the prevention of severe hypoglycemia--monitor, alert, and locate. J Diabetes Sci Technol 2009;3:1501-6. 29. Rigla M, Hernando ME, Gómez EJ, Brugués E, García- Sáez G, Torralba V, Prados A, Erdozain L, Vilaverde J, de Leiva A. A telemedicine system that includes a personal assistant improves glycemic control in pump-treated patients with type 1 diabetes. J Diabetes Sci Technol 2007;1:505-10. www.diabetes.or.kr 129