Endocrinol Metab. 25(2):110-118, June 2010 ORIGINAL ARTICLE 제 2 형당뇨병환자의인슐린요구량에영향을미치는인자에대한고찰 정진욱 조동혁 정동진 정민영 전남대학교의과대학내과학교실 Determining the Factors that Influence the Insulin Requirements in Type 2 Diabetic Patients Jin Ook Chung, Dong Hyeok Cho, Dong Jin Chung, Min Young Chung Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea Background: The initial insulin dose is often determined by clinical experience or with a formula using the body weight. However, it may be difficult to determine the initial insulin dose because various factors such as insulin sensitivity and the glycemic status can influence the insulin requirement. The purpose of this study was to assess the factors that influence the initial insulin requirement in insulin naive patients with type 2 diabetes mellitus. Methods: A total 128 patients who were admitted for glycemic control were investigated. The patients were managed with longacting insulin glargine and rapid-acting insulin lispro. Results: The basal insulin requirement was positively correlated with waist circumference, body mass index (BMI), the HbA1C, AST, ALT, fasting plasma glucose and 2-hour postprandial glucose levels and the homeostasis model assessment of insulin resistance (HOMA-IR), but it was negatively correlated with age and the stimulated C-peptide level. The daily insulin requirement was positively correlated with waist circumference, BMI, the HbA1C, AST, ALT, triglyceride, fasting plasma glucose and 2-hour postprandial glucose level and HOMA-IR, but it was negatively correlated with age. On the multiple linear regression analysis, the basal insulin requirement was independently associated with BMI (β = 0.507, P < 0.001), the 2-hour postprandial glucose level (β = 0.307, P < 0.001), the ALT level (β = 0.214, P = 0.015) and the meal-stimulated C-peptide level (β = -0.209, P = 0.010). The daily insulin requirement was independently associated with BMI (β = 0.508, P < 0.001) and the 2-hour postprandial glucose level (β = 0.404, P < 0.001). Conclusion: Our results show that the BMI and 2-hour postprandial glucose level are useful predictors of the initial insulin requirement in insulin naive type 2 diabetic patients. It may be prudent to consider the other various factors that influence the insulin requirement together when insulin therapy is required. (Endocrinol Metab 25:110-118, 2010) Key Words: Body mass index, Diabetes mellitus, Insulin 서론 제2형당뇨병은췌도베타세포의기능저하에의한인슐린분비감소와인슐린저항성을특징으로하는점진적으로진행하는질환이다 [1]. 이러한병인의특징은혈당조절을하는데있어서질환이경과함에따라다양한치료법이있을수있다는것을시사한다. 대개제2형당뇨병의초기단계에서는식생활의개선을통해혈당조절이 Received: 4 September 2009, Accepted: 27 January 2010 Corresponding author: Min Young Chung Department of Internal Medicine, Chonnam National University Medical School, 8 Hak-dong, Dong-gu, Gwangju 501-757, Korea Tel: +82.62-220-6500, Fax: +82.62-225-8578, E-mail: mychung@chonnam.ac.kr 가능하나시간이지남에따라경구혈당강하제나인슐린치료를필요로하게되며 [2] 최근에는적극적인혈당조절을위해조기에인슐린치료를시작하도록권고하기도한다 [3,4]. 인슐린을투여하고자할때인슐린요구량을결정하는방법으로흔히의사의경험에의하거나체중을이용한방법이사용되고있다 [5]. 하지만제2형당뇨병환자의인슐린요구량에영향을미치는인자는체중뿐만아니라인슐린감수성이나혈당상태등여러요인들이작용할수있다. 또한인슐린을사용하기전에혈당조절을위해복용하던경구혈당강하제의영향도고려되어야할것이다. 이러한점에서제2형당뇨병환자의인슐린요구량에미치는인자들을분석하는것은초기인슐린요구량을결정하는데도움이될것으
Determining the Factors that Influence the Insulin Requirements 111 로사료된다. 이에본연구에서는인슐린을사용한병력이없는제 2 형당뇨병환자에게인슐린투여시초기인슐린요구량에미치는 인자에대해서알아보고자하였다. Yes Long-acting insulin (0.2 U/kg) FBS <120 mg/dl No 대상및방법 1. 연구대상 2008년 3월부터 2009년 3월사이에제2형당뇨병으로전남대병원내분비대사내과를방문하여혈당조절을위해입원한환자를대상으로하였다. 인슐린을사용중이거나당대사에영향을미칠수있는심한전신질환이나스테로이드등의약물을복용하고있는환자들은제외하였으며또한 HBs Ag 양성인사람, anti-hcv 항체양성인사람및주 140 g 이상의음주력이있는사람은제외하였다. 2. 신체계측및생화학적검사환자의신체계측을위해신장, 체중, 체질량지수 (kg/m 2 ) 및허리둘레를측정하였다. 혈압은 5분이상안정을취한후앉은상태에서우측상완동맥에서수축기혈압과이완기혈압을측정하였으며 2 회측정하여두값의평균값을사용하였다. 고혈압의진단은각각다른날에 2회이상측정한수축기혈압이 140 mmhg 이상인경우와이완기혈압이 90 mmhg 이상인경우로하였고본원에방문하기전에이미고혈압을진단받고항고혈압제를복용중인환자를고혈압이있는것으로간주하였다. 대상환자를 10시간이상금식시킨후아침공복시에채혈하여혈중포도당, C-펩티드 (RIA법 : Biosource Europe S.A., Nivelles, Belgium), 인슐린농도 (IRMA법 : DAINABOT, Japan), 당화혈색소 (ion exchange liquid chromatography 법 : HLC-723 GHbV, Tosoh, Japan), 총콜레스테롤, 중성지방, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤, 유리지방산 (ACS-ACOD 법 : Wako Pure Chemical Industries Ltd., Japan) 을측정하였다. 또한표준화된당뇨식사 2시간후채혈을하여식후혈중포도당및식후 C-펩티드를측정하였다. 인슐린저항성의지표로서 HOMA-IR (homeostasis model assessment of insulin resistance index) 를이용하였고, 췌장베타세포의인슐린분비능의지표로 HOMA-β를계산하였다 [6]. 계산공식은아래와같다. HOMA-IR = [ Fasting plasma insulin (µiu/ml) fasting plasma glucose (mmol/l)] / 22.5 HOMA-β = [ 20 fasting plasma insulin (µiu/ml)] / [fasting plasma glucose (mmol/l) 3.5] 3. 방법경구혈당강하제를사용중이던환자는경구혈당강하제를중단하였으며혈당조절을위해기저인슐린으로 glargine 인슐린과식전 인슐린으로 lispro 인슐린을피하주사하였다. 인슐린투여방법은 먼저공복혈당을목표로취침전에기저인슐린을피하주사하였으 며공복혈당이조절된이후아침, 점심및저녁식후혈당을목표로 식사 15 분이내에초속효성인슐린을피하주사하였다 (Fig. 1). 공복 혈당 80-120 mg/dl, 식후 2 시간혈당 120-180 mg/dl 로조절될때의 인슐린양을인슐린요구량으로정의하였으며혈당이 70 mg/dl 미 만인경우저혈당으로정의하였다. 표준화된당뇨식사로이상체중 1 kg 당 30 kcal 를공급했으며탄수화물 60%, 단백질 20%, 지방 20% 가포함된식사를섭취하게했으며, 아침, 점심, 저녁식사의칼로리 는 1:1:1 로설정하였다. 4. 통계분석 Maintenance Yes Start rapid-acting insulin (0.05 U/kg) Yes Dosage titration every day 300 mg/dl +4 U 260 mg/dl +3 U 220 mg/dl +2 U 180 mg/l +1 U Maintain rapid-acting insulin dose Postprandial glucose 180 mg/dl Postprandial glucose 180 mg/dl Postprandial glucose <180 mg/dl Dosage titration every day 180 mg/dl +4 U 160 mg/dl +3 U 140 mg/dl +2 U 120 mg/l +1 U FBS <120 mg/dl Maintain long-acting insulin dose 모든결과값들은중앙값 ( 사분위수 ) 또는백분율로나타내었다. 남 녀사이에연속변수의비교는 Mann-Whitney U test 를이용하였고, 범주형변수의비교는카이제곱검정또는피셔의정확성검정을이 용하였다. 또한인슐린용량과변수들간의관계를알아보기위해 No Maintain long-acting insulin dose 120 mg/dl 1 U 100 mg/dl 2 U 80 mg/dl 4 U No Maintain rapid-acting insulin dose Fig. 1. Insulin protocol. The algorithm shows initiation and titration of insulin regimens.
112 Chung JO, et al. 왜곡분포를보이는변수들은로그변환을하여분석하였다. 각인슐린용량과요인들간의관계는 Pearson 상관분석을시행하였고인슐린의용량에독립적으로영향을미치는인자를알아보기위해전진단계법 (stepwise) 을이용하여다중선형회귀분석을시행하였다. 통계프로그램은 SPSS (version 17.0) 을이용하였으며통계학적유의수준은 P < 0.05로하였다. 결과 1. 대상환자의임상및생화학적특성전체연구대상자는 128명으로연령은 63세이었으며, 남성과여성 의수는동일했고, 당뇨병유병기간은 7년이었다. 체질량지수는 23.6 kg/m 2, 허리둘레 84 cm, 당화혈색소 7.5%, 공복혈당 132.0 mg/dl, 식후 2시간혈당 207.0 mg/dl 이었다. 또한공복 C-펩티드 2.50 ng/dl, 식후 2시간 C-펩티드 4.85 ng/dl, HOMA-IR은 3.13이었다 (Table 1). 식사조절로혈당을조절중이던환자는 25명 (19.5%) 이었으며 103 명 (80.5%) 은경구혈당강하제를복용하고있었다. 경구혈당강하제를복용중인환자를각각의경구혈당강하제의사용여부로구분하였을때글리메피리드 95명 (74.2%), 메트포르민 73명 (57.0%), 보글리보스 31명 (24.2%), 피오글리타존 6명 (4.7%) 이었다 (Table 1). 글리메피리드를오전에 1회복용한환자는 63명 (66.3%), 오전과오후에 2회복용한환자는 32명 (33.7%) 이었다. 또한경구혈당강하제의병합방법에 Table 1. Clinical characteristics of study population Men (n = 64) Women (n = 64) Total (n = 128) Age (years) 61.9 (16.1) 65.0 (16.5) 63.0 (16.7) DM duration (years) 5.0 (10.5) 9.0 (10.5) 7.0 (9.0) DM family history (n, %) 8 (12.5) 16 (25.0) 24 (18.8) WC (cm) 86.0 (12.6) 83.0 (12.6) 84.0 (12.0) BMI (kg/m 2 ) 23.6 (4.1) 23.6 (4.0) 23.6 (4.0) SBP (mmhg) 130.0 (20.0) 130.0 (20.0) 130.0 (20.0) DBP (mmhg) 80.0 (10.0) 80.0 (20.0) 80.0 (12.0) HbA1C (%) 7.1 (3.6) 8.4 (3.2) 7.5 (3.3) AST (U/L) 23.5 (8.0) 20.0 (7.7)* 22.0 (9.7) ALT (U/L) 24.0 (18.5) 17.0 (13.7)* 21.0 (18.0) TC (mg/dl) 180.5 (77.5) 182.0 (59.0) 181.0 (67.0) HDL-C (mg/dl) 41.0 (14.5) 42.0 (17.0) 42.0 (16.7) LDL-C (mg/dl) 119.0 (51.7) 109.0 (57.0) 114.0 (56.0) TG (mg/dl) 132.0 (107.0) 117.0 (88.0) 124.0 (88.0) FFA (μeq/l) 632.0 (313.7) 683.0 (489.0) 650.0 (383.0) hs-crp (mg/dl) 0.108 (0.253) 0.094 (0.216) 0.096 (0.231) FBS (mg/dl) 129.0 (88.2) 132.5 (66.7) 132.0 (75.5) PP2hr glucose (mg/dl) 207.0 (119.0) 198.0 (121.0) 207.0 (119.0) Fasting insulin (μu/ml) 9.0 (9.1) 11.5 (13.5) 10.3 (11.4) Fasting C-peptide (ng/ml) 2.50 (2.40) 2.45 (2.0) 2.50 (1.90) Meal stimulated C-peptide (ng/ml) 5.30 (3.70) 4.30 (4.30) 4.85 (4.02) HOMA-IR 2.88 (3.02) 3.87 (4.20) 3.13 (3.90) HOMA-β 48.9 (70.2) 62.1 (97.8) 52.1 (77.8) UAE (mg/gcr) 13.5 (73.4) 15.1 (62.4) 14.8 (67.6) Antidiabetic agent (n, %) Diet/OHA Sulfonylurea Biguanide α-glucosidase inhibitor 17 (26.6)/47 (73.4) 42 (65.6) 37 (57.8) 12 (18.8) 8 (12.5)/56 (87.5) 53 (82.8)* 36 (56.2) 19 (29.7) 25 (19.5)/103 (80.5) 95 (74.2) 73 (57.0) 31 (24.2) Antihypertensive (n, %) 22 (34.4) 33 (51.6) 55 (43.0) Antihyperlipidemic (n, %) 23 (35.9) 25 (31.9) 48 (37.5) Data are median (interquartile range). BMI, body mass index; DBP, diastolic blood pressure; DM, diabetes mellitus; FBS, fasting blood glucose; FFA, free fatty acid; HDL-C, high density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment: insulin resistance; hs-crp, high sensitivity C reactive protein; LDL-C, low density lipoprotein cholesterol; OHA, oral hypoglycemic agent; PP2hr glucose, 2-hour postprandial glucose; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; UAE, urinary albumin excretion rate; WC, waist circumference. *P < 0.05, men vs. women.
Determining the Factors that Influence the Insulin Requirements 113 따라구분하였을때단독요법 24.3% (25명 ), 이제병합요법 54.4% (56명), 삼제병합요법 21.4% (22명 ) 이었으며이중글리메피리드와메트포르민병합요법의빈도가 40.8% (42명 ) 로가장높았다. 복용중인경구혈당강하제의평균 1일용량은글리메피리드 3.0 mg, 메트포르민 543.6 mg, 보글리보스 1.10 mg이었다. 항고혈압제를복용하고있는사람은 55명 (43.0%) 이었으며지질강하제를복용중인사람은 48명 (37.5%) 이었다. 전체대상환자를남녀로구분하였을때, 여성에비해남성에게서 AST와 ALT가유의하게높았으며그외당뇨병유병기간, 당화혈색소, 공복혈당, 체질량지수등의차이는관찰되지않았다 (Table 1). 여성의경우남성에비해글리메피리드복용의빈도가유의하게높았으나그외다른경구혈당제의빈도의차이는없었다. 2. 인슐린요구량공복혈당 120 mg/dl 이하가될때 1일기저인슐린요구량은 20 U이었으며평균소요시간은 6.1일이었다. 식후 2시간혈당이 180 mg/dl가될때의아침식전인슐린양은 6 U, 점심식전인슐린양 6 U, 저녁식전인슐린양 6 U, 일일인슐린요구량 37 U이었다. 하지만남녀간의인슐린요구량의유의한차이는관찰되지않았다 (Table 2). 매식후 2시간혈당을조절하기위해소요된평균시간은각각 2.8일, 2.6일, 2.5일이었다. 전체환자중 24명 (18.8%) 의환자에서저혈당이발생하였으며이중 6명 (4.7%) 의환자에서는 2회이상의저혈당이발생하였다. 전체대상환자의기저인슐린요구량대일일인슐린요구량의비는 0.543 (0.157) 이었으며남성 0.527 (0.121), 여성 0.567 (0.250) 로기저인슐린요구량대일일인슐린요구량비에있어서남녀사이에유의한차이는없었다. 3. 인슐린요구량과관련된인자들과의관계기저인슐린요구량은허리둘레 (r = 0.298, P = 0.003), 체질량지수 (r = 0.423, P < 0.001), 당화혈색소 (r = 0.496, P < 0.001), AST (r = 0.222, P = 0.012), ALT (r = 0.407, P < 0.001), 공복혈당 (r = 0.340, P < 0.001), 식후 2시간혈당 (r = 0.434, P < 0.001) 및 HOMA-IR (r = 0.239, P = 0.007) 과양의상관관계를보였으며연령 (r = -0.421, P < 0.001) 및식후 C-펩티드 (r = -0.188, P = 0.035) 와음의상관관계를보였다. 식사인슐린요구량은체질량지수 (r = 0.318, P < 0.001), 당화혈색소 (r = 0.249, P = 0.005), AST (r = 0.252, P = 0.004), ALT (r = 0.391, P < 0.001), 중성지방 (r = 0.204, P = 0.022), 유리지방산 (r = 0.207, P = 0.040), 식후 2시간혈당 (r = 0.279, P = 0.004) 및 HOMA- IR (r = 0.241, P = 0.006) 과양의상관관계를보였다. 일일인슐린요구량은허리둘레 (r = 0.237, P = 0.021), 체질량지수 (r = 0.427, P < 0.001), 당화혈색소 (r = 0.422, P < 0.001), AST (r = 0.231, P = 0.009), ALT (r = 0.418, P < 0.001), 중성지방 (r = 0.198, P = 0.027), 공복혈당 (r = 0.254, P = 0.004), 식후 2시간혈당 (r = 0.400, P < 0.001) 및 HOMA-IR (r = 0.294, P = 0.001) 과유의한양의상관관계가있었으며연령 (r = -0.318, P < 0.001) 과는음의상관관계를보였다 (Table 3). 유의한관계를보이는변수들을다중선형회귀분석을통해분석한결과기저인슐린요구량에독립적으로영향을미치는인자는체질량지수 (β = 0.507, P < 0.001), 식후 2시간혈당 (β = 0.307, P < 0.001), ALT (β = 0.214, P = 0.015) 및식후 C-펩티드 (β = -0.209, P = 0.010) 이었다 (Table 4). 식사인슐린요구량에독립적으로영향을미치는인자는 ALT (β = 0.353, P = 0.001), HOMA-IR (β = 0.211, P = 0.032) 및식후 2시간혈당 (β = 0.0226, P = 0.033) 이었다 (Table 5). 또한일일인슐린요구량에독립적으로영향을미치는인자는체질량지수 (β = 0.508, P < 0.001) 와식후 2시간혈당 (β = 0.404, P < 0.001) 이었다 (Table 6). 고찰본연구에서제2형당뇨병환자의혈당조절을위한인슐린요구량에미치는인자들을분석하였을때기저인슐린요구량에영향을미치는독립적인인자는체질량지수, 식후 2시간혈당, ALT 및식후 C-펩티드이었으며일일인슐린요구량에영향을미치는독립적인인자는체질량지수와식후 2시간혈당이었다. 제2형당뇨병환자에게경구혈당강하제가혈당을조절하는데효과적일지라도공복혈당이나당화혈색소가매우높은환자의경우 Table 2. Insulin requirements for plasma glucose control in type 2 diabetic patients Men Women Total Basal insulin (U/day) 20.0 (11.0) 20.0 (11.7) 20.0 (12.0) Prandial insulin BB (U/day) 6.0 (4.0) 6.0 (7.2) 6.0 (4.0) Prandial insulin BL (U/day) 6.0 (4.0) 5.5 (8.0) 6.0 (5.0) Prandial insulin BS (U/day) 6.0 (4.7) 5.0 (8) 6.0 (5.0) Total insulin (U/day) 38.0 (17.5) 34.5 (28.7) 37.0 (21.5) Total insulin (U/kg/day) 0.59 (0.30) 0.64 (0.53) 0.60 (0.39) Data are median (interquartile range). BB, before breakfast; BL, before lunch; BS, before supper. Data were analyzed by Mann-Whitney U-test. There were no significant difference between men and women.
114 Chung JO, et al. Table 3. Simple correlation between insulin dosage and other parameters in type 2 diabetic patients Basal insulin Prandial insulin Total insulin r r r Age -0.421-0.173-0.318 DM duration 0.045 0.024 0.055 WC 0.298 0.119 0.237* BMI 0.423 0.318 0.427 SBP -0.119-0.066-0.087 DBP -0.039-0.037-0.034 HbA1C 0.496 0.249 0.422 AST 0.222* 0.252 0.231 ALT 0.407 0.391 0.418 TC 0.018 0.103 0.063 HDL-C -0.101-0.157-0.158 LDL-C 0.069 0.160 0.123 TG 0.171 0.204* 0.198* FFA 0.143 0.207* 0.167 hs-crp -0.106-0.079-0.075 FBS 0.340 0.155 0.254 PP2hr glucose 0.434 0.279 0.400 Fasting insulin 0.102 0.153 0.177* Fasting C-peptide -0.008-0.025-0.014 Meal stimulated C-peptide -0.188* -0.121-0.170 HOMA-IR 0.239 0.241 0.294 HOMA-β -0.105 0.062 0.008 UAE -0.126-0.050-0.110 Sulfonylurea 0.041 0.151 0.133 Biguanide 0.012 0.149 0.085 α-glucosidase inhibitor 0.040 0.047 0.048 *P < 0.05, P < 0.01, P < 0.001, Prandial insulin before breakfast. BMI, body mass index; BW, body weight; DBP, diastolic blood pressure; DM, diabetes mellitus; FBS, fasting blood glucose; FFA, free fatty acid; HDL-C, high density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment: insulin resistance; hs-crp, high sensitivity C reactive protein; LDL-C, low density lipoprotein cholesterol; PP2hr glucose, 2-hour postprandial glucose; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; UAE, urinary albumin excretion rate; WC, waist circumference; NS, not significant. Table 4. Multivariate linear regression analysis with basal insulin dose as the dependent variable Basal insulin dose per day β P-value Partial F R 2 (adjusted R 2 ) BMI 0.507 < 0.001 ALT 0.214 0.015 PP2hr glucose 0.379 < 0.001 Meal stimulated C-peptide -0.209 0.010 24.954 0.558 (0.536) The log transformed variables were used for analysis. BMI, body mass index; PP2hr glucose, 2-hour postprandial glucose. 는종종동반된대사장애와베타세포의기능부전에의해정상혈당상태를도달하고유지하는데어려움을겪는다 [1]. 또한경구혈당강하제는일정기간동안에는혈당조절에효과적이나시간이지남에따라혈당조절의실패율이증가하는것으로알려져있다 [7]. 이러한 단계에서는대개인슐린치료가필요하며되며최근에는제2형당뇨병환자의혈당조절을위해조기인슐린치료가강조되고있다 [3]. 제2형당뇨병환자에게인슐린을사용하고자할때기존의연구들은대개체중을기준으로하여초기인슐린용량을결정하였다
Determining the Factors that Influence the Insulin Requirements 115 Table 5. Multivariate linear regression analysis with prandial insulin does as the dependent variable Prandial insulin* β P-value Partial F R 2 (adjusted R 2 ) ALT 0.353 0.001 HOMA-IR 0.211 0.032 PP2hr glucose 0.226 0.033 8.225 0.297 (0.261) *Prandial insulin before breakfast. The log transformed variables were used for analysis. HOMA-IR, homeostasis model assessment: insulin resistance; PP2hr glucose, 2-hour postprandial glucose. Table 6. Multivariable linear regression analysis with total daily insulin dose as the dependent variable Total insulin dose per day β P-value Partial F R 2 (adjusted R 2 ) BMI 0.508 < 0.001 PP2hr glucose 0.404 < 0.001 27.646 0.406 (0.391) The log transformed variables were used for analysis. BMI, body mass index; PP2hr glucose, 2-hour postprandial glucose. [8,9]. 또한 Biesenbach 등 [10] 도경구혈당강하제에이차실패를보인제2형당뇨병환자를대상으로한후향적연구에서체중이높은경우에초기혈당조절을위한인슐린요구량이더높은경향을보였으며정상및과체중환자모두에게서체중증가와함께인슐린요구량이증가되었다고보고하였다. 본연구에서도기저인슐린양이나일일인슐린요구량은체중과양의상관관계를보였다. 하지만체중보다는체질량지수가더높은상관관계를보였으며다중회귀분석에서체질량지수가인슐린요구량에가장영향을미치는독립적인인자인것으로분석되었다. 이러한결과는기저인슐린양이나일일인슐린양결정시체중보다는체질량지수가더유용한척도가될수있음을시사한다. ALT는최근비만정도와관련없이제2형당뇨병의발생과관련이있는간효소로알려지고있으며 [11], 간에서의지방축적과밀접한연관이있기때문에비알코올지방간의표지자로인식되고있다 [12]. O Brien 등 [13] 은인슐린은포도당신합성에관여하는유전자를억제하는데 ALT는포도당신합성에관여하는효소이기때문에 ALT 증가는손상된인슐린신호전달체계를반영한다고보고하였다. Vozarova 등 [11] 은 ALT의상승은간에서의인슐린저항성과관련이있다고보고하였다. 본연구에서 ALT는기저인슐린요구량및일일인슐린요구량과유의한상관관계를보였으며특히기저인슐린요구량에독립적인영향을미치는유의한인자인것으로분석되었다. 대상성간경변증이동반된경우인슐린저항성이더높으며혈당조절을위한인슐린요구량이증가될수있다고보고되었으나비알코올성지방간질환에서 ALT가인슐린요구량에미치는영향에대해서는아직알려진바가많지않다 [14,15]. 본연구의결과는제2형당뇨병환자의경우간기능상태가인슐린요구량에영향을줄수있음 을시사하며향후이에대하여더많은환자를대상으로한전향적인추가연구가필요하겠다. 공복혈당은일차적으로간에서의당생성기전에의해조절되며 [16] 문맥순환에있는인슐린은간에서의글리코겐분해및포도당신합성을억제하고말초혈액인슐린은지방분해를억제하여유리지방산유입에의한포도당신합성을억제한다 [17,18]. 제2형당뇨병환자의경우공복상태에서간으로의기저포도당섭취 (basal glucose uptake) 는인슐린비의존성으로약 70% 를차지하며인슐린의존성을보이는근육에의한기저포도당섭취는약 10-20% 를차지하는것으로알려져있다 [19]. 따라서제2형당뇨병에서공복고혈당은주로간에서의포도당생성의부적절한증가에의해발생하며 [20,21], 근육에의한인슐린의존성당섭취장애가미치는영향은상대적으로적다. 제2형당뇨병에서간에서의당생성증가의원인으로간에서의인슐린감수성의둔화, 글루카곤의증가, 말초조직에서유리지방산과같은포도당신합성전구물질유입의증가등여러요인들이알려지고있다 [22]. 이러한점들은공복혈당이인슐린요구량에영향을미칠수있음을시사하며 Nelson 등 [5] 은공복혈당을토대로초기기저인슐린요구량을결정할수있는계산식을제시하였다. 섭취된탄수화물은대부분간을우회하여말초순환으로유입되며탄수화물섭취후 2-3시간동안간에서의당생성은 60-90% 정도가빠르게억제된다 [23]. 제2형당뇨병환자의경우섭취된당의전신순환으로의유입은정상이나간에서의당생성억제는손상되어있는것으로알려져있다 [23]. 따라서제2형당뇨병에서관찰되는식후고혈당은섭취된탄수화물의양과흡수율 [24], 조기인슐린분비반응의소실 [25], 글루카곤분비율 [24], 인슐린에의한근육에서당섭취율및간에서의당생성억제 [26] 등의요인들이관여됨이보
116 Chung JO, et al. 고되고있다. 이러한점들은식후혈당이식사인슐린뿐만아니라기저인슐린에도영향을받을수있음을시사한다. 본연구에서공복혈당과식후혈당은기저인슐린요구량및일일인슐린요구량과유의한상관관계가있음을보여주었으나다중회귀분석에서식후혈당만이기저인슐린과일일인슐린요구량에독립적으로영향을미치는인자로확인되었다. 본연구에서환자의공복혈당이나당화혈색소수치가비교적높지않았던점이공복혈당보다식후혈당이인슐린요구량과더관련성을나타내는데부분적으로영향을미쳤을것으로사료된다 [27]. 혈중 C-펩티드농도는췌도베타세포기능을평가하는지표로이용되며 [28], 공복및자극후 C-펩티드농도는당뇨병환자의인슐린치료필요성을예측하는데도움이되는것으로알려져있다 [29,30]. 특히공복 C-펩티드가낮거나경구포도당부하, 글루카곤자극및식후 C-펩티드농도가낮은경우인슐린치료가요구된다고보고되었다 [31,32]. 본연구에서공복 C-펩티드농도는인슐린요구량과유의한상관관계를보이지않았으며식후 C-펩티드농도가기저및일일인슐린요구량과역의상관관계를보였다. 따라서본연구결과는식후 C-펩티드농도가초기혈당조절을위한인슐린요구량에영향을미칠수있으며인슐린분비자극에대한베타세포의반응이낮을수록인슐린요구량이증가될수있다는것을시사하였다. 최근에 Biesenbach 등 [33] 은술포닐우레아에대한이차실패를보인제2형당뇨병환자를대상으로한연구에서공복 C-펩티드농도가낮은경우인슐린요구량이더높다고보고하였다. 하지만본연구와달리대상군이술포닐우레아에이차실패를보인환자들로서베타세포의기능부전이본연구보다더컸으며자극후 C-펩티드반응에대한분석은없었다. 따라서베타세포의기능부전의진행정도나인종적인차이가다른영향을주는지에대해서추가연구가필요하겠다. 기저인슐린요구량은일일인슐린요구량의 40-50% 를차지한다고알려져있으며 [34], 본연구에서도기저인슐린요구량대일일인슐린요구량은 54.3% 를보였다. 국내연구를보면이등 [35] 은제1형당뇨병환자를대상으로한연구에서기저인슐린요구량이일일인슐린요구량의 33.7% 를차지한다고보고하였다. 본연구에서일일인슐린요구량중기저인슐린요구량의비율이높은요인으로는기저인슐린으로공복혈당의조절후에식후혈당을조절했던방식의차이와식후혈당의목표치의차이가부분적으로관여했을것으로생각된다. 제2형당뇨병환자에게인슐린을사용하는방법으로경구혈당강하제에인슐린을추가하는방식뿐만아니라경구혈당강하제에서인슐린단독요법으로전환하거나경구혈당강하제의일부를인슐린으로변경하는방법이사용되기도한다. 따라서본연구에서는경구혈당강하제의일부또는전부를인슐린으로변경할때에인슐린요구량과관련이있는지를분석하였으며각경구혈당강하제의사용량 은기저인슐린요구량이나일일인슐린요구량과유의한관계를보이지않았다. 이러한결과는기존경구혈당강하제의일부나전체를인슐린으로변경하고자할때경구혈당강하제의사용량이기저인슐린요구량이나일일인슐린요구량에영향을미치지는않는다는것을시사한다. 본연구에서기저인슐린용량과일일인슐린요구량을결정하는식을다중회귀분석에서얻어진식을통해관계식을구해보면기저인슐린양은 log (basal insulin dosage) = -1.545 + 1.307 log (BMI) + 0.155 log (ALT) + 0.409 log (pp2hr glucose) 0.118 log (stimulated C-peptide) 와일일인슐린투여량은 log (total insulin dosage) = -2.147 + 1.736 log (BMI) + 0.589 log (pp2hr glucose) 를얻을수있었다. 하지만인슐린치료는말초조직에서의인슐린감수성을 17-75% 정도개선시킬수있으며 [36,37] 인슐린분비능을개선시킬수있다고알려져있다 [36]. 또한 Garvey 등 [38] 은인슐린치료에의해말초조직에서인슐린저항성과인슐린분비능이완전히개선되기는어려우나인슐린치료후에간에서의기저당생성은완전히정상화될수있음을보고하였다. 따라서인슐린치료후에고혈당에의한포도당독성의감소와인슐린감수성변화및인슐린분비능의변화등이있을수있어본연구에서얻은관계식을제2형당뇨병환자에서초기인슐린용량을결정하는데바로적용하기에는어려움이있을것으로사료된다 [39]. 결론적으로본연구는처음인슐린치료를시행받는제2형당뇨병환자의인슐린요구량을예측하는데체질량지수와식후 2시간혈중포도당농도가유용한인자임을보여주었다. 초기인슐린용량을결정할때인슐린요구량에영향을미치는여러인자들을함께고려하여인슐린양을정하는것이환자가고혈당에노출되는시간을최소화할수있을것으로사료된다. 향후더많은환자를대상으로하여일일인슐린투여량이나기저인슐린양을임상에서쉽게결정할수있는방법을만들기위한추가연구가필요하겠다. 요약배경 : 인슐린을투여하고자할때인슐린요구량을결정하는방법으로흔히의사의경험에의하거나체중을이용한방법이사용되고있다. 하지만제2형당뇨병환자의인슐린요구량에영향을미치는인자는체중뿐만아니라인슐린감수성이나혈당상태등여러요인들이작용할수있으며기존에복용중인경구혈당강하제의영향도고려될수있을것이다. 따라서제2형당뇨병환자의인슐린요구량에미치는인자들을분석하는것은초기인슐린요구량을결정하는데도움이될것으로사료된다. 이에본연구에서는인슐린을사용한병력이없는제2형당뇨병환자를대상으로인슐린투여시초기인슐린요구량에미치는인자에대해서알아보고자하였다. 방법 : 혈당조절을위해입원한 128명의제2형당뇨병환자를대
Determining the Factors that Influence the Insulin Requirements 117 상으로표준화된당뇨식사를제공하였으며기저인슐린으로 glargine 인슐린과식전인슐린으로 lispro 인슐린을피하주사하였 다. 공복혈당 80-120 mg/dl, 식후 2 시간혈당 120-180 mg/dl 로조 절될때의인슐린양을인슐린요구량으로정의하였다. 결과 : 전체대상환자의 1 일기저인슐린요구량은 20 U, 아침식전 인슐린양 6 U, 점심식전인슐린양 6 U, 저녁식전인슐린양 6 U 및 일일인슐린요구량은 37 U 이었다. 기저인슐린요구량은허리둘레, 체질량지수, 당화혈색소, AST, ALT, 공복혈당, 식후 2 시간혈당및 HOMA-IR 과양의상관관계를보였으며연령및식후 C- 펩티드와음 의상관관계를보였다. 일일인슐린요구량은허리둘레, 체질량지수, 당화혈색소, AST, ALT, 중성지방, 공복혈당, 식후 2 시간혈당및 HOMA-IR 과유의한양의상관관계가있었으며연령과는음의상관 관계를보였다. 유의한관계를보이는변수들을다중선형회귀분석 을통해분석한결과기저인슐린요구량에독립적으로영향을미 치는인자는체질량지수 (β = 0.507, P < 0.001), 식후 2 시간혈당 (β = 0.307, P < 0.001), ALT (β = 0.214, P = 0.015) 및식후 C- 펩티드 (β = -0.209, P = 0.010) 이었다. 또한일일인슐린요구량에독립적으로영 향을미치는인자는체질량지수 (β = 0.508, P < 0.001) 와식후 2 시간 혈당 (β = 0.404, P < 0.001) 이었다. 결론 : 본연구는처음인슐린치료를시행받는제 2 형당뇨병환자 의인슐린요구량을예측하는데체질량지수와식후 2 시간혈중포 도당농도가유용한인자임을보여주었다. 초기인슐린용량을결 정할때인슐린요구량에영향을미치는여러인자들을함께고려 하여인슐린양을정하는것이환자가고혈당에노출되는시간을 최소화할수있을것으로사료된다. 향후더많은환자를대상으로 하여일일인슐린투여량이나기저인슐린양을임상에서쉽게결정 할수있는방법을만들기위한추가연구가필요하겠다. 참고문헌 1. Nathan DM: Clinical practice. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 347:1342-1349, 2002 2. Koski RR: Practical review of oral antihyperglycemic agents for type 2 diabetes mellitus. Diabetes Educ 32:869-876, 2006 3. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B; American Diabetes Association; European Association for Study of Diabetes: Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32:193-203, 2009 4. Campbell RK, White JR Jr: Insulin therapy in type 2 diabetes. J Am Pharm Assoc (Wash) 42:602-611, 2002 5. Nelson SE, Palumbo PJ: Addition of insulin to oral therapy in patients with type 2 diabetes. Am J Med Sci 331:257-263, 2006 6. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412-419, 1985 7. U.K. prospective diabetes study 16. Overview of 6 years therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 44:1249-1258, 1995 8. Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, Hirsch IB; American Diabetes Association Diabetes in Hospitals Writing Committee: Management of diabetes and hyperglycemia in hospitals. Diabetes Care 27:553-591, 2004 9. Trence DL, Kelly JL, Hirsch IB: The rationale and management of hyperglycemia for in-patients with cardiovascular disease: time for change. J Clin Endocrinol Metab 88:2430-2437, 2003 10. Biesenbach G, Raml A, Alsaraji N: Weight gain and insulin requirement in type 2 diabetic patients during the first year after initiating insulin therapy dependent on baseline BMI. Diabetes Obes Metab 8:669-673, 2006 11. Vozarova B, Stefan N, Lindsay RS, Saremi A, Pratley RE, Bogardus C, Tataranni PA: High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 51:1889-1895, 2002 12. Westerbacka J, Cornér A, Tiikkainen M, Tamminen M, Vehkavaara S, Häkkinen AM, Fredriksson J, Yki-Järvinen H: Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women: implications for sex differences in markers of cardiovascular risk. Diabetologia 47:1360-1369, 2004 13. O Brien RM, Granner DK: Regulation of gene expression by insulin. Biochem J 278:609-619, 1991 14. Kim MG, Choi WC: Differential diagnosis of diabetes mellitus caused by liver cirrhosis and other type 2 diabetes mellitus. Korean J Hepatol 12:524-529, 2006 15. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, Maldonado-Garza H: Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol 15:280-288, 2009 16. Inzucchi SE: Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287:360-372, 2002 17. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh WA, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI: Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 128:176-185, 1998 18. DeFronzo RA, Goodman AM: Efficacy of metformin in patients with noninsulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 333:541-549, 1995 19. Baron AD, Kolterman OG, Bell J, Mandarino LJ, Olefsky JM: Rates of noninsulin-mediated glucose uptake are elevated in type II diabetic subjects. J Clin Invest 76:1782-1788, 1985 20. Basu R, Schwenk WF, Rizza RA: Both fasting glucose production and disappearance are abnormal in people with mild and severe type 2 diabetes. Am J Physiol Endocrinol Metab 287:E55-E62, 2004 21. DeFronzo RA, Ferrannini E, Simonson DC: Fasting hyperglycemia in noninsulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38:387-395, 1989
118 Chung JO, et al. 22. Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA: Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84:205-213, 1989 23. Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J: Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39:1381-1390, 1990 24. Riddle MC, Drucker DJ: Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1. Diabetes Care 29:435-449, 2006 25. Weyer C, Bogardus C, Mott DM, Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104:787-794, 1999 26. DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 131:281-303, 1999 27. Monnier L, Lapinski H, Colette C: Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26:881-885, 2003 28. Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, Karrison T, Frank B: Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. J Clin Invest 77:98-105, 1986 29. Rendell M: C-peptide levels as a criterion in treatment of maturity-onset diabetes. J Clin Endocrinol Metab 57:1198-1206, 1983 30. Turkington RW, Estkowski A, Link M: Secretion of insulin or connecting peptide: a predictor of insulin dependence of obese diabetics. Arch Intern Med 142:1102-1105, 1982 31. Lee A, Bray GA, Morley JE: Stimulated C-peptide and glucose levels as metabolic criteria to use insulin treatment in adult-onset type II diabetes. Endocr Pract 2:183-190, 1996 32. Laakso M, Sarlund H, Korhonen T, Voutilainen E, Majander H, Hakala P, Uusitupa M, Pyörälä K: Stopping insulin treatment in middle-aged diabetic patients with high postglucagon plasma C-peptide. Effect on glycaemic control, serum lipids and lipoproteins. Acta Med Scand 223:61-68, 1988 33. Biesenbach G, Bodlaj G, Pieringer H, Raml A: Insulin requirement after one year of insulin therapy in type 2 diabetic patients dependent on fasting C-peptide. Neth J Med 66:259-260, 2008 34. Holman RR, Turner RC: A practical guide to basal and prandial insulin therapy. Diabet Med 2:45-53, 1985 35. Lee HJ, Kim KB, Han KA, Min KW, Kim EJ: Insulin requirement for Korean type I diabetics using continuous insulin infusion with portable external pumps. J Korean Diabetes Assoc 28:538-546, 2004 36. Scarlett JA, Gray RS, Griffin J, Olefsky JM, Kolterman OG: Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care 5:353-363, 1982 37. Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber HS: Intensive conventional insulin therapy for type II diabetes. Metabolic effects during a 6-mo outpatient trial. Diabetes Care 16:21-31, 1993 38. Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG: The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34:222-234, 1985 39. Won KC, Yoon JS: Glucose toxicity and pancreatic beta cell dysfunction in type 2 diabetes. Korean Diabetes J 32:175-181, 2008