J Korean Diabetes 2015;16:108-116 Vol.16, No.2, 2015 ISSN 2233-7431 한경아을지대학교을지병원내과학교실내분비내과 Intensive Insulin Therapy in Type 1 Diabetes Kyung Ah Han Division of Endocrinology, Department of Internal Medicine, Eulji General Hospital, Eulji University, Seoul, Korea Abstract The Epidemiology of Diabetes Interventions and Complications study, a prospective observational follow-up of the Diabetes Control and Complications Trial cohort, reported persistent benefits for micro- and macro-vascular complication in type 1 diabetes mellitus with intensive insulin therapy. It is the standard of care for most patients with type 1 diabetes. There are two modalities: continuous subcutaneous insulin infusion (CSII), so called insulin pump, and multiple dose of insulin. Both shows similar effects in frequency of severe hypoglycemia and progression of microvascular disease, but CSII provides slightly better in glycemic control. An important aspect of intensive insulin therapy is educating patients about basal insulin, and carbohydrate/insulin ratio, sensitivity index, the coordination of meals, activity, stress, and hormonal changes with frequent monitoring of blood glucose levels during pregnancy. It is important to identify and resolve emotional and attitudinal barriers of the patient and family for improving glycemic control during intensive diabetes management. Keywords: Basal insulin, Insulin pump, Intensive insulin therapy, Multiple dose of insulin, Prandial insulin, Type 1 diabetes Corresponding author: Kyung Ah Han Division of Endocrinology, Department of Internal Medicine, Eulji General Hospital, 68 Hangeulbiseok-ro, Nowon-gu, Seoul 139-711, Korea, E-mail: hka114@ gmail.com Received: Apr. 30, 2015; Accepted: May. 6, 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 108 The Journal of Korean Diabetes
한경아 서론 제1형당뇨병환자 1,441명을대상으로적극적인혈당관리의미세혈관합병증예방효과를평가한 Diabetes Control and Complications Trial 연구는 1982년부터 10년간진행됐다 [1,2]. 이연구에서 1일 3회이상인슐린을투여하거나인슐린펌프로혈당을조절하는집중적인슐린치료군과 1일 1~2회인슐린을투여하여조절하는통상적인슐린치료군의효과를비교하였다. 연구종료시집중적인슐린치료군의당화혈색소는 7% 로통상적인슐린치료군의당화혈색소 9% 보다낮았고, 당뇨병성망막병증, 신경병증, 신장병증의위험도도유의하게낮았다. 이후 1994 년부터 Epidemilology of Diabetes Interventions and Complications 연구로연계돼지속적으로두군을추적관찰하였다. 18년추적관찰결과에서양군간당화혈색소수치는차이가없었지만, 당뇨합병증발생률은통상적인슐린치료군대비집중적인슐린치료군에서약 50% 낮게나타났으며모든심혈관사건은 42% 감소했고, 비치명적심근경색, 뇌졸중, 심혈관사망등의위험도는 57% 감소한것으로나타났다. 2012년분석에서도각각모든심혈관합병증의위험도가 33%, 치명적심혈관합병증이 35% 감소한것으로나타나통계적유의성을확보했다. 시간이갈수록당화혈색소감소효과는줄어들었지만여전히유의한심혈 관합병증감소를보이는것으로보아특히 1형당뇨병에서는집중적인슐린치료를되도록빨리시작하는것이유리할것으로보인다 [3]. 실제로하루동안인슐린이분비되는양상을도식화하면 Fig. 1과같다. 식사에필요한영양분을이용하는데필요한인슐린이분비되고식사를하지않을때는주로간에서나오는당분을이용하기위한기저인슐린이분비되고있다. 1형당뇨병과같이인슐린의췌장베타세포의자가면역성파괴에의하여인슐린이거의분비되지않는경우에는정상적으로몸에서인슐린이분비가되는패턴으로인슐린을공급해주어야혈당조절을정상에가깝게조절할수있다. 기저인슐린과식사인슐린을공급하여주는집중적인슐린요법에는인슐린펌프와인슐린다회주사요법 (multiple dose of insulin, MDI) 두가지가있다. 인슐린펌프는기저인슐린인초속효성인슐린을카트리지에장착하고플라스틱카테터를통하여피하로 24시간자동주입한다. 새벽에성장호르몬의작용으로혈당이올라가는새벽현상이있는사람이있는데이러한경우새벽 3시경부터주입하는인슐린양을늘려준다. 인슐린다회주사요법에서는인슐린글라진 (glargine), 인슐린디터미어 (determir), 혹은데글루덱 (degludec) 과같은지속형인슐린을기저인슐린으로사용하고, 식사때는식사에있는당분을이용하는데적합한양의초속효성인슐린을추가로주입함으로써공복, 식후혈당모 Fig. 1. Physiologic insulin secretion. www.diabetes.or.kr 109
Table 1. Comparison of insulin pump and multiple daily injection Insulin pump 1. Decreased frequency of injections 2. Prevention of the dawn phenomenon 3. Allows for more flexible lifestyles and activities, and improves nonhealth related quality of life 4. More precise basal rate 5. Reduced complications with hypoglycaemia, particularly for people with hypoglycaemic unawareness, and can possibly prevent cognitive impairment in young children Multiple dose of insulin 1. Less expensive 2. No skin infusion-site infections 3. No need to carry devices 4. No mechanical failure 5. No need for supervision by team 두를정상수준에가깝도록조절하는것이가능하다. 집중적인슐린치료법비교와선택 인슐린펌프와인슐린다회주사요법을비교한몇가지연구에서인슐린펌프로치료하였을때당화혈색소를저하가더뚜렷하였으나, 저혈당과심각한저혈당의빈도는두군사이에의미있는차이가없었다고보고하였다 [4-7]. 그러므로두가지집중적인슐린치료법중각각의장단점을고려하여환자스스로선택하게하는것이좋다. 인슐린펌프만달면합병증이오지않는다거나펌프로당뇨병이나을수있다는생각, 혹은마음껏먹어도기계가다알아서혈당을조절해준다고생각하는인슐린펌프에대한오해는환자스스로노력하고관리해야하는면을간과하여혈당을악화시키거나체중증가로인해비만에따른문제가더생기기도한다. 그밖에도혈당검사를자주하지않으려고하는사람, 식사량에따른인슐린양을계산할수없거나계산하는법을배우려고하지도않는경우, 지나치게다른사람에게인슐린펌프를숨기려고하는경우, 치료의계획이나교육에잘따르지않는경우, 당뇨병이있다는것을다른사람에게알리지않으려고하는경우, 정신적으로불안정하거나인지능력이떨어지는경우에는인슐린펌프치료의대상이되지않는다. 혈당을잘조절하려는의지가강한사람으로서특히여러번의인슐린주사에도불구하고혈당조절이잘되지않는사람, 임신한경우, 저혈당을느끼지못하 는경우, 소량의인슐린에혈당기복이큰경우, 새벽에인슐린의저항성이아주커지는경우 (dawn phenomenon), 식사시간이일정하지않은경우 ( 특히식사시간을예측하기어려운경우 ) 에는인슐린펌프치료를우선적으로고려할수있다. 일반적으로집중적인슐린치료에서당화혈색소를결정하는요소중가장중요한것은혈당검사를자주하고먹을때마다잊지않고인슐린을잘주입하는것이다. 이외혈당과식사등의기록하기, 당질량계산을잘해서정확한양의인슐린양을주사하는것이혈당조절상태와관계가있으며, 치료방법에의한혈당조절의차이는뚜렷하지않다 (Table 1) [8-12]. 1. 기저인슐린의용량결정바람직한기저인슐린양은식사하지않는동안에저혈당없이정상혈당을유지하는데필요한인슐린양으로정의될수있다. 새벽현상이있을때나식사를걸렀을때도혈당이기복없이안정적이되도록정하게기초인슐린이정확하게설정이되어야인슐린보정지수정확하게설정할수있으므로먼저기저인슐린양을설정하고금식을통해확인한후인슐린당분비율과보정지수를정한다 (Table 2). 평소와는다르게심하게운동을한후, 감기몸살등으로아프거나컨디션이나쁠때, 저혈당이있었거나심한고혈당이있을때, 스트레스가있을때, 지방이많은음식을섭취한후에는기저인슐린양을정하는시기로는적절하지않고, 평 110
한경아 Table 2. Determination of basal rate Testing overnight basal rate Eat a low fat dinner and no food afterwards Begin basal test 4~5 hours after eating dinner as long as BG is between 100~150 mg/dl Check BG at bedtime, midnight, 3 am and upon waking Testing daytime basal rate Check BG upon waking Start basal testing if BG is between 100~150 mg/dl 1. Skip breakfast and eat no food until lunch for breakfast basal rate 2. Skip lunch and eat no food until dinner for lunch-time basal rate 3. Skip dinner and eat no food until bedtime for dinner-time basal rate Check BG every 1~2 hours from the start of the test for 5 hours Changes in your BG of more than 40 mg/dl during the basal test indicate a need to adjust your basal rates. If your total daily dose of insulin is less than 20 units a day, increase or decrease your basal rate by increments of 0.05 units/hour at a time. If your total daily dose of insulin is over 20 units a day, increase or decrease your basal rate by increments of 0.10 units/hour at a time. Increase or decrease your basal rate about 2 hours before you notice a pattern of high or low blood glucose readings. BG, blood glucose. Table 3. Reassessing basal rate 1. Significant, sustained change in activity 2. Significant change in weight (5~10%) 3. Gastroparesis 4. Pregnancy 5. Menses 6. Illness 7. Medication such as steroid which increase blood glucose 8. Exercise 소와비슷하고편안한상태일때정하는것이좋다. 서양인에서의기저량은하루총인슐린필요량의 50% 로시도해보라권유하고있지만최근 King과 Armstrong [13] 의연구에의하면평상시의활동을하였을때하루총필요량의평균 38% 의용량이기저량으로쓰였다는보고가있다. 일본인을대상으로한연구에서는하루총 32단위의인슐린이필요하였고평균기초량이약 9단위로하루총인슐린필요량의 28% 로보고되었으며한국에서의경험과비슷한결과를보였다 [14,15]. 성장호르몬의야간증가는새벽에인슐린필요량을증가시키는새벽현상이일어난다. 이런현상은모든제1형당뇨병에서생기는것은아니지만어린나이 일수록뚜렷하며, 나이가많을수록이러한현상이더짧은시간에일어나고약하게일어난다 [16]. 인슐린다회주사요법으로치료할때지속형인슐린동족체를기저인슐린으로사용하며자기전에주는것이일반적이다. 인슐린펌프를사용하는환자들도더운여름이나특수한상황에서인슐린펌프를빼야할경우가있다 (pump holiday). 인슐린펌프치료에서인슐린다회주사요법으로변경할때식사인슐린은인슐린다회주사요법이나인슐린펌프나똑같은양을사용하지만, 기저인슐린의양은펌프에서보다글라진을약 10% 증량하여야혈당조절상태가비슷하였다 [8]. 혈당기복이있더라도되도록이면식사인슐린의양을조절하도록교육하지만가끔은기저인슐린의양을변경하여주어야할때가있다 (Table 3). 2. 식사인슐린의결정집중적인슐린치료는섭취하게되는다양한음식에대하여필요한인슐린양과투여방식을결정하는것이필수적이다. 두가지영양분중에서단백질이나지방보다는탄수화물이혈당에가장큰영향을주므로. 인슐린펌프치료에서는당질량계산이필수적이다, 당질량계산을어렵다 www.diabetes.or.kr 111
고생각하는경우가많으므로처음에는접근하기쉬운방법부터시작하고다음에흔히먹거나좋아하는음식, 단백질이나지방이많이함유된음식등으로점차범위를넓혀가면서자세히알아가는것이좋다. 식사인슐린의용량은기본적으로당질량에기초하여결정하지만단백질과지방을고려하여주입할때더정교하게혈당을조절할수있다 [17,18]. 주로단백질의혈당상승효과는논란이있지만식사직후에는혈당에대한영향은미미하나단백질과지방으 로이루어진식사는식후 3~5시간부터혈당이서서히올라가기시작한다 [19-21]. 당질인슐린비의결정은 Fig. 2와같이하게된다. 그러나당질 / 인슐린비도기초량과마찬가지로체중변화에따라변화한다. 3. 민감지수의결정집중인슐린치료를받는환자가꼭알아야할것중에하 Make sure BG is in target range before doing an evaluation Choose a low-fat meal with a carb count that s easy to estimate Now just bolus and eat Monitor your BG every 1~2 hours for the next 4 hours At 2 hours after meal, your BG is usually 40~80 mg/dl higher than before meal Aim for BG to return to target range by about 4 hours after meal Reevaluate at different times of the day Fig. 2. Determination of carbohydrate/insulin ratio. BG, blood glucose. Start evaluation at least 3 hours after a bolus when BG is high at least 180 mg/dl using initial SF Take correction bolus for BG to return to target range by about 4 hours after meal Monitor your BG every 1~2 hours for the next 4 hours New SF Change of BG Correction bolus Fig. 3. Evaluation of sensitivity factor (SF). BG, blood glucose. 112
한경아 나가민감지수 (sensitivity factor) 이다. 인슐린 1단위가내리는혈당정도를말하며, 교정지수 (correction factor) 라고도한다. 혈당혈당목표범위를벗어난경우 (out-of-range glucose values) 에이지표를이용하여목표혈당으로돌리는데필요한인슐린의용량을계산한다. 민감지수는확실하게정하지는않았지만경험적으로예측할수있다. 1,800 을하루에필요한총인슐린양으로나누어나온값을인슐린 1단위가내리는혈당값 (mg/dl) 으로한다. 그렇지만이방법은정확하지않으므로다음과같이확실하게결정할수있다 (Fig. 3). 4. 집중적인슐린치료법에서운동제1형당뇨병환자에서환자는운동으로인한저혈당을피하기위해서개개인의경험을기초로하여인슐린치료방법을조정할필요가있다. 혈당조정상태를잘유지하면서운동과게임에효과적이고안전하게참여하기위해서는자가혈당측정이가장중요하다. 집중적인슐린치료법중 30분이내의운동을할때는인슐린양을조정하지않아도되는것으로알려져있으나더긴시간의운동을할때는조절하여주어야한다. 기저인슐린의양의몇퍼센트를감소시켜야할지는운동시간과강도, 그리고이에따른환자의개개인의혈당반응에따라개별화하여야한다. 일반적으로처음으로운동을시작할때는인슐린용량을 50% 로줄이고운동을하고스스로자가혈당을자주측정하면서경험을통하여터득하게된다. 운동을하는시간에따라기저인슐린을줄이기도하고식사인슐린을줄이기도한다. 식사후 1~3시간에한시간이상의운동을계획한다면식사전주입하는식사인슐린의용량을기존의 50% 정도로줄여서주입하고아침식사전에운동을하거나. 식사인슐린주입후 4~6시간정도에는기저인슐린주입속도를조절하는것이좋다. 단, 인슐린다회주사요법은그때그때인슐린양의조절이어려우므로간식을추가로섭취하는것이좋다. 장시간운동을할수록환자는신체적으로더잘훈련되고 운동에더잘적응하며, 따라서인슐린필요량을더많이줄일수있다. 그러나, 평소에운동을하지않던사람이갑작 스럽게강도높고스트레스가많은경쟁적인운동을할때 혈당이오히려올라갈수있다. J Korean Diabetes 2015;16:117-122 5. 임신중집중인슐린 http://dx.doi.org/10.4093/jkd.2015.16.2.117 요법 2014년미국당뇨병학회는전혈기준으로식전혈당을 95 mg/dl 이하, 식후 1시간 140 mg/dl 이하, 식후 2시간 120 mg/dl 이하로조절하도록권고하였다 [22]. 가임기의제1형당뇨병여성에서혈당은월경주기에따라프로제스테론, 에스트로겐과같은성호르몬에의해혈당이오르내린다. 임신중에도역시태반에서분비되는 lactogen, somatomammotropin, cortisol, estrogen과 progesterone 과호르몬에의해혈당이올라가게된다. 특히프로게스테론은췌장에서인슐린분비능과인슐린감수성을모두저하시키는것으로보고되었다 [23]. 임신중인슐린양의조절은하루 4회검사한혈당수치와산모와태아의체중, 뇨중케톤수치를고려하여정하게된다. 제1 형당뇨병임산부에서임신이지속될수록필요한인슐린의양이점점더늘어간다. 2010년 American Association of Clinical Endocrinologists consensus statement에서는임신초기부터분만까지기저인슐린과식사인슐린모두같은비율로인슐린투여량을서서히증량하여임신전대비 60~70% 정도증량하는스케쥴을제시한바있었다 [24]. 인슐린다회주사요법과인슐린펌프등의치료방법에따른임산부의혈당조절상태, 태아의건상상태는차이가없었다 [25-27]. 결론 제1형당뇨병환자에서집중적인슐린치료는발병초기부터도입하는것이좋다는것은잘알려져있다. 이러한치료법의장점을극대화하기위해서는환자개개인에맞춘정확한기저인슐린설정, 당질 / 인슐린비. 민감지수를결정하고이것을기반으로교육을하여야한다. 한번결정된단위 www.diabetes.or.kr 113
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