Ⅲ. 결 과
3. Rosiglitazone에 대한 반응과 복부지방 분포의 변화 사이의
지 않는 경우로 정의하였다.
표 2는 rosiglitazone 치료 반응에 따라 환자들을 분류하고 rosiglitazone 투여 전에 갖고 있던 생화학적 특성 및 복부 지방 분포를 보여준 것이다. 나이, 성별, 당뇨병 유병기간, 치료 방법, 지질 수치, 공 복 혈청 인슐린 농도는 군간에 통계학적으로 유의한 차이는 없었다. 그러 나, rosiglitazone에 반응이 좋은 군일수록, 치료전에 공복 혈당이나 당화 혈색소 값이 높았고(각각 p<0.001), 더 비만하였다(체중, p for trend=0.062 그리고 체질량 지수, p for trend=0.025). HOMA-IR, 체지방량, 그리고 내장지방 두께는 반응이 좋은 군에서 증가하는 경향을 보였으나 통 계학적 유의성은 없었다.
Rosiglitazone 투여에 대해 반응이 좋은 군들에서 rosiglitazone 투여 후 체중과 피하 지방 두께가 더욱 증가하였다 (표 3). 그러나, 혈청 인슐린의 변화나 C-peptide의 변화, 내장지방 두께 변화나 내장지방 두께/피하지방 두께 비의 변화에 있어서 군간의 차이는 없었다.
표 2. Baseline characteristics according to response of
FPG (mmol/L) 6.68 ± 1.40 7.95±2.43 9.57±2.83 9.29±2.40 <0.001 PP2hr glucose (mmol/L) 10.84±3.06 11.97±4.51 13.75±3.65 13.91±3.78 0.013 HbA1c (%) 7.1 ± 0.8 7.4 ± 1.2 8.3 ± 1.0 8.3 ± 1.2 <0.001 Insulin (pmol/L) 63.9 ± 48.1 63.9± 31.6 67.4±31.6 63.1±48.1 NS C-peptide (ng/mL) 1.67 ± 0.69 1.87±0.75 1.81±0.64 1.65±0.48 NS
HOMA-IR 2.7 ± 2.1 2.9 ± 1.7 3.6 ± 1.7 3.7 ± 3.2 NS
Total cholesterol(mmol/L) 4.60 ± 0.76 4.68±0.87 4.45±0.79 4.69±0.72 NS HDL-cholesterol (mmol/L) 1.23 ± 0.32 1.18±0.31 1.17±0.35 1.09±0.26 NS Triglyceride (mmol/L) 1.87 ± 0.84 1.92±0.94 1.88±1.00 1.75± 0.69 NS Weight (kg) 64.7 ± 7.8 66.7 ± 9.4 70.9 ± 9.8 68.9±11.0 0.062
BMI; body mass index, WHR; waist to hip ration, SFT; soft fat thickness, VFT; visceral fat thickness, HOMA-IR;
homeostasis model assessment of insulin resistance
표 3. Changes of laboratory and anthropometric indexes after rosiglitazone treatment
Response Poor No Good Best pa
Δ FPG (mmol/L) 2.39±2.50 -0.13±0.78c -2.24±1.12c,d -3.19±2.13c,e <0.001 Δ PP2h glucose (mmol/L) 1.93±2.74 -0.76±3.08b -3.53±2.96b -4.60±4.89c,e <0.001 Δ HbA1c (%) 1.07±0.96 -0.03±0.59c -0.81±0.71c -1.53±1.34c,e <0.001 Δ Insulin (pmol/L) -7.5±10.1 -14.4±27.3 -14.6±28.0 -7.5±21.6 NS Δ C-peptide (ng/mL) -0.32±0.45 -0.37±0.47 -0.25±0.49 -0.27±0.40 NS Δ Total cholesterol (mmol/L) 0.51±0.64 0.58±0.58 0.27± .47 -0.01±0.44d 0.002 Δ HDL-cholesterol (mmol/L) 0.08±0.17 0.03±0.21 0.10±0.14 0.04±0.18 NS Δ Triglyceride (mmol/L) 0.32±0.69 0.31±0.88 -0.22±0.75 0.10±0.73 NS Δ Weight (kg) 0.15±1.15 0.65±1.59 1.11±1.45b 1.65±1.71b 0.018
Δ Waist (cm) 0.77±1.20 1.39±2.01 1.02±2.56 2.18±1.71 NS
Δ Fat mass (kg) 0.16±1.75 0.78±2.50 1.88±2.28 2.71±7.74b NS Δ SFT (mm) 0.78±3.31 1.41±3.38 3.08±2.84b 4.10±3.11b,d 0.001
Δ VFT (mm) 0.01±5.34 0.14±7.16 -0.54 ± 6.31 -0.06±5.8 NS
HOMA-IR; homeostasis model assessment of insulin resistance
4. 체지방 분포의 변화와 rosiglitozone이 혈당과 지질에 미치는 영
있는 상관관계는 보이지 않았다(r=-0.116, r=0.032, p=NS, respectively).총콜레스테롤, 고밀도지단백콜레스테롤, 혹은 중성 지방과 체지방 변화
A B
그림 1. Hypoglycemic effect according to changes in the subcutaneous fat thickness(A) and weight(B).
The p values for trend by ANOVA are as follows; <0.001 and 0.0001 (fasting plasma glucose); 0.045 and 0.007 (postprandial glucose);0.001 and 0.012(HbA1c), repectively.
a
p<0.005 compared to decre
aseA B
C D
그림 2. The linear correlation between the changes of fasting plasma glucose (FPG) or HbA1c and the changes of subcutaneous fat thickness (SFT) and weight
s,
A B
C
그림 3. Relationship between the percent changes of total cholesterol, HDL-cholesterol and triglyceride concentrations and the change of visceral fat thickness (VFT)
5. Rosiglitazone 반응에 영향을 미치는 인자들
다중 회귀분석에서 종속 변수로서 공복혈당이나 당화 혈색소의 변화를 사용한 결과 치료후의 공복혈당의 감소 정도는 기저 공복혈당과 피하지방 두께와 강한 양의 상관 관계를 보였다. 또한 기저 공복혈당이나 당화 혈색 소 그리고 피하지방 두께나 내장지방 두께의 변화는 당화 혈색소의 감소 정도와 유의한 상관 관계가 있었다 (표 4). 그러나 체중, 체질량 지수, 지방량의 기저값과 변화량은 공복혈당이나 당화 혈색소를 독립적으로 개선 시키는데 영향을 미치지 않았다. 또한, rosiglitazone 반응에 영향을 미치 는 독립적인 인자들, 반응군과 비반응군을 알아보고자 다중 로지스틱 회귀 분석을 시행하였는데, 기저 공복혈당(p=0.007), 기저 당화 혈색소 (p=0.018), 내장지방 두께의 변화량(p=0.002), 및 피하지방 두께의 변화량 (p=0.005)이 rosiglitazone 치료 반응에 영향을 주는 중요한 독립 인자임 을 알 수 있었다(표 5).
표 4. Multiple regression analysis of clinical and anthropometric
and HbA1c. The independent variables are the baseline values and change of various clinical and anthropometric indexes. The model r
2are 0.387 and 0.560, respectively.
FPG ; fasting plasma glucose, PP2hr glucose ; 2hr postprandial glucose,
BMI; body mass index, SFT; soft fat thickness, VFT; visceral fat thickness,
HOMA-IR; homeostasis model assessment of insulin resistance
표. 5. Multiple logistic regression analysis of factors to affect the
The dependent variable is the response to rosigltazone, as responder or nonresponder. Responder was defined as groups showing the best and good responses, and nonresponder was defined as groups showing the no and bad response.
FPG ; fasting plasma glucose, PP2hr glucose ; 2hr postprandial glucose,
BMI; body mass index, SFT; soft fat thickness, VFT; visceral fat thickness,
HOMA-IR; homeostasis model assessment of insulin resistance
Ⅳ. 고 찰
주지는 않았다. 하지만, rosiglitazone을 3개월 투여한 후에 공복 혈당과
회귀분석을 통하여, rosiglitazone 투여 후 내장 지방량의 감소뿐만
포함되어있었기 때문에 TZD 이외의 약물들이 줄 수 있는 영향들을 완전히 배제하지 않았던 점이다. 비록 서로 다른 치료군 간에 차이는 거의 없었지만, 다양한 약물들을 사용한 것이 결과에 영향을 미쳤을 수도 있다.
둘째, 본 연구가 non-controlled, 그리고 비교적 소수 집단을 대상으로 이루어졌다는 것이다. 따라서, placebo-controlled, 그리고 최소한의 변수를 갖는 대규모 연구가 필요할 것으로 보인다. 마지막으로, 대상 환자들이 본 연구에 앞서 최소한 6개월 이상 당화 혈색소가 큰 변동 없이 안정적으로 적절한 양의 경구 혈당 강하제나 인슐린을 사용하고 있었지만, rosiglitazone에 대한 반응에 따라 분류한 군간에는 당지수가 의미 있게 차이가 있었다. 왜냐하면 rosiglitazone에 대한 반응을 혈당 강하 정도에 따라 분류하였기 때문에, 공복혈당이나 당화 혈색소가 높은 환자일수록 rosiglitazone에 반응이 더 좋은 것처럼 보였을 가능성도 있다. 따라서, 이러한 가능성들을 배제하기 위해서 추가적인 작업이 필요할 것으로 보인다.
V. 결 론
결론적으로, rosiglitazone이 혈당 조절과 인슐린 저항성을 개선시키고 체지방량, 특히 피하 지방량을 증가시키는데, 피하 지방량의 증가가 혈당 조절과 관련이 있고 rosiglitazone의 효과를 판단하는 독립적인 인자라고 생각된다. 반면 지질 대사 장애의 개선은 내장 지방량의 감소와 관련이 있음을 알게 되었다.
참고 문헌
1. Taylor SI, Accili D, Imai Y. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes 1994;
43: 735-740
2. Chaour M, Theroux P, Gilfix BM. True fasting serum insulin level, insulin resistance syndrome and coronary artery disease. Coron Artery Dis 1997; 8: 683-688
3. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17α activity and serum androgens. J Clin Endocrinol Metab 1997; 82: 4075-4079
4. Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 1996; 45: 1661-1669
5. Maggs DG, Buchanan TA, Burant CF, cline G, Gumbiner B, hsuesh WA, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128 :176-185
6. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shieta Y, Kaneko T. A
new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996; 19: 151-156
7. Suter SL, Nolan JJ, Wallace P, Gumbiner B, Olefsky JM. Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects.
Diabetes Care 1992; 15: 193-203
8. Mudaliar S, Henry RR. PPAR agonists in health and disease: a pathophysiologic and clinical overview. Curr Opin Endocrinol Diabetes 2002; 9: 285-302
9. Spiegelman BM. PPAR-γ: adipogenic regulator and thiazolidinedione receptor.
Diabetes 1998; 47: 507-514
10. Fonseca V, Eoyt HL, Shen K, Whitcomb R. Long-term effects of troglitazone. Diabetes Care 2000; 23: 354-359
11. Mori Y, Murakawa Y, Okada K, Horokoshi H, Yokoyama J, Tajima N, et al. Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 1999; 22: 908-912
12. Miyazaki Y, Mahankali A, Matsuda M, Mahankai S, Hardies J, Cusi K, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002; 87: 2784-2791
13. Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards JC, Biswas N, et
al. Efect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res 2002; 10: 1008-1015 14. Lukaski HC, Bolonchuk WW, Hall CB, Siders WA. Validation of
tetrapolar bioelectrical impedence method to assess human body composition. J Appl Physiol 1986; 60:1327-1322
15. Suzuki R, Watanabe S, Hirai Y. Abdominal wall fat index, estimated by ultrasonography, for assessment of the ratio of visceral fat to subcutaneous fat in the abdomen. Am J Med 1993;
95: 309-314
16. Armellini F, Zamboni M, Rigo L. Sonography detection of small intra-abdominal fat variations. Int J Obes 1991; 15: 847-852 17. Sears IB, MacGinnitie MA, Kovacs LG, Graves RA.
Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor gamma. Mol Cell Biol 1996; 16: 3410-3419
18. Adams M, Montague CT, Prins JB, Holder JC, Smith SA, Sanders L, et al. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation. J Clin Invest 1997; 100: 3149-3153
19. Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, et al.
Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998; 101: 1354-1361
20. Katoh S, Hata S, Matsushima M, Ikemoto S, Inoue Y, Yokoyama J, et al. Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy-A randomized controlled trial. Metabolism 2001; 50: 414-417
21. Fujioka S, Matsuzawa Y, Tokunaga K, Tauri S. Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism1987; 36: 54-59 22. Virtanen KA, Hällsten K, Parkkola R, Janatuinen T, Lönnqvist F,
Viljanen T, et al. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. Diabetes 2003; 52: 283-290
23. Rossner S, Bo WJ, Hiltbrandt E. Adipose tissue determinations in cadavers: a comparison between cross-sectional planimetry and computed tomography. Int J Obes Relat Metab Disord 1990; 14: 893-902
24. Ribeiro-Filho FF, Faria AN, Kohlmann O Jr, Ajzen S, Ribeiro AB, Zanella MT, et al. Ultrasonography for the evaluation of visceral fat and cardiovascular risk. Hypertension 2001; 38: 713-717
Abstract
Relation between the changes in abdominal fat distribution and the efficacy of rosiglitazone
Kyu Yeon Hur
Department of Medicine
The Graduate School, Yonsei University
(Directed by Professor Hyun Chul Lee)We investigated the inter-relation between the hypoglycemic effects of peroxisome proliferator-activated receptor (PPAR)-γ ligand and the changes of regional adiposity in type 2 diabetic patients.
We added rosiglitazone (4 mg/day) to 173 diabetic patients (111 males and 62 females) already taking a stable dose of conventional antidiabetic medication except PPAR-γ lignads. Distribution of body fat was assessed by ultrasonography at baseline and repeated after 12 weeks. On ultrasonographic images, subcutaneous fat and visceral fat thickness (SFT and VFT, respectively) were measured.
Rosiglitazone treatment significantly improved glycemic control and insulin sensitivity, and resulted in weight gain. In ultrasonographic findings, rosiglitazone treatment increased SFT by 9.6% and decreased VFT/SFT ratio, but did not alter VFT. The percent changes in fasting plasma glucose (FPG) and HbA1c concentrations after treatment were inversely correlated with the increase in SFT(r=-0.327 and r=-0.353, p<0.001, respectively) and/or body weight(0.316, p<0.001 and r=-0.327, p<0.001). The group with the greater increase in SFT or body weight showed better glycemic control after treatment. By multiple regression analysis, the change in SFT was related with improvements of fasting plasma glucose (p=0.019) and HbA1c(p=0.010). Multiple logistic regression analysis revealed that baseline fasting plasma glucose(p=0.007) and HbA1c(p=0.018), baseline VFT(p=0.002), and the changes of SFT (p=0.005) andVFT (p=0.008) were independent predictors of response to rosiglitazone treatment.
The present findings suggest that PPAR-γ agonist significantly increased subcutaneous fat mass, but did not alter visceral fat mass, and that the hypoglycemic effect of PPAR-γ agonist was closely correlated with the increase in body weight, especially subcutaneous fat mass.
In contrast, the reduction in the visceral fat mass may be the prime determinant to improve dyslipidemia.
Key words : rosiglitazone, subcutaneous fat thickness, visceral fat thickness, type 2 diabetes