FRTL-5 세포에서 TSH 수용체를 통한 세포내 신호전달체계에서 cAMP계와 Phosphoinositide계의 상호작용

문병술,박영주,김성연,조보연,이홍규,박도준 대한내분비학회 2003 Endocrinology and metabolism Vol.18 No.4

연구배경 : 갑상선자극호르몬(TSH)는 갑상선세포 표면의 수용체와 결합하면 G 단백을 통해 아데닐릴 사이클라제와 포스포리파제 C를 모두를 활성화한다. 본 연구에서는 이러한 두 시스템이 동시에 자극됨에 따라 서로간에 상호작용이 있는지를 알아보았다. 방법: FRTL-5 갑상선 세포를 6H 배양액에 키운후 자극전 5H 배양액으로 갈아주었다. 이후 mCi/L myo-(2-N-3H) inositol로 표지한 후 갑상선호르몬으로 자극하였다 갑상선호르몬 자극 전에 100 μM Rp-cAMP, 100 μM forskolin, 100 nM PMA, 50 nM staurosprine을 전처치하여 단백질키나제 A와 단백질키나제 C를 각각 자극 및 억제시킨 후 TSH에 의한 inositol phosphates 생성을 측정하였다. 결과: fRTL-5 세포를 100μU/mL의 TSH로 자극하였을 때 IP생성은 1.65배 증가하였다. 두가지 신호전달체계간의 상호작용을 관찰하기 위하여 단백질키나제 A의 억제제인 Rp-cAMP와 자극제인 forskolin을 전처치한 후 TSH에 의한 IP 생성을 측정하였다. 단백질키나제 A를 억제할 수 있는 농도의 Rp-cAMP를 전처치한 경우 TSH에 의한 IP생성은 증가하였곤, 이는 Rp-cAMP 농도에 비례하였다. Forskolin은 반대로TSH에 의한 IP 생성을 억제하였다. 한편 단백질키나제 C의 자극제와 억제제인 PMA와 staurosporine은 TSH에 의한 IP 생성에 별 영향을 주지 못하였다. 결론: TSH에 의해 활성화되는 CAMP 신호전달체계는 단백질키나제 A를 활성화하고, 이렇게 활성화된 단백질키나제 A는 포스포리파제의 작용을 억제하여 IP 생성을 억제한다. 이러한 두 시스템간의 상호작용은 갑상선호르몬 생성과 성장 조절을 정확히 하는데 필요한 요소로 생각된다. Backgroun: TSH stimulates both the adenyl cyclase and phospholipase C(PLC) pathways by binding to a single cell surface receptor that is coupled to G protein, and we examined crosstalk between these two signaling pathways. Methods: FRTL-5 rat thyroid cells were grown in 6H medium, then incubated with 5H medium before the stimulation. Then cells were incubated for 24 hours with 5H mix containing 1 mCi/L myo-(2-N-³H) inositol. After pretreatment of 100μM Rp-cAMP, 100μM forskolin, 50nM staurosporine, or 100nM PMA (phorbol-12-myristate-13-acetate), TSH were added in different expriments. After 30 min at 37℃, cells were disrupted and IP formation was determined. Results: Stimulation with 100 μU/mL TSH resulted in a 1.65 fold increase in IP generation. In pursuing the possibility that the two post-receptor events might be linked in some way, we examined the effect of exogenously administrated Rp-cAMP, protein kinase A antagonist, and forskolin, a direct stimulant of protein kinase A, on IP generation achieved at a dose of 100μU/mL TSH. The pretreatment of 100 M Rp-cAMP at a concentration sufficient to inhibit protein kinase A enhanced TSH-induced IP production. This effect of Rp-cAMP was dose-dependent. Forskolin attenuated TSH-stimulated increases in phosphatidylinositide turnover. PMA, a protein kinase C (PKC) activator and staurosporine, a PKC inhibitor did not affect TSH-induced IP generation. Conclusion: These data suggested that activation of adenylate cyclase/cAMP post-receptor signalling casacde, which results in the protien kinase A activation, has an inhibitory effect on IP turnover activated by TSH (J Kor SOC Endocrinol 18:404-413, 2003).

갑상선 분화암 환자의 경과 관찰에서 혈청 갑상선글로불린 측정의 진단적 유용성

이선화,조보연,이홍규,김원배,박도준,고재준,문병술,김선욱 대한내분비학회 1999 Endocrinology and metabolism Vol.14 No.4

Background: Although serum thyroglobulin (Tg) has been proved to be a good tumor marker in the follow-up of the well differentiated thyroid cancer, some patients show low detectable Tg with negative 131I scan. In the present study, we tried to determine the lowest level of serum Tg which suggests requirement of aggressive work-up for the recurrent or metastatic thyroid cancer. Methods: Serum Tg levels were measured in 102 patients with well differentiated thyroid cancer who had underwent thyroidectomy followed by 131I ablative therapy. Of 102 patients, 44 patients had no remnant thyroid tissue, while 58 patients had remnant thyroid. Serum Tg levels were measured while TSH-suppressive dose of T4 was administered (on T4 therapy) and then T4 was discontinued for 4 weeks to increase serum TSH level (off T4 therapy), then serum Tg levels were analyzed in relation to the presence or absence of recurrent or metastatic thyroid cancer, assessed by I scan and operation with reference to the physical examination, chest X-ray and thyroid ultrasonogram. Results: Of 102 patients, 16 patients were found to have recurrent or matastatic thyroid cancer. Among them, 10 patients didnt have any remnant thyroid, while 6 patients had remnant thyroid. Serum Tg was undetectable on T4 therapy in 6 patients, but rose higher than 30 ng/mL off T4 therapy in 2 patients, while Tg remained undetectable in other 4 patients. In all 10 patients whoseTg levels were higher than 1 ng/mL. on T4 therapy, Tg rose higher than 30 ng/mL off T4 therapy. The best cut-off value of serum Tg which suggests recurrent or metastatic disease in patients without remnant thyroid was 3 ng/mL on T therapy (sensitivity 60%, specificity 91%, accuracy 84%) and 30 ng/mL off T4 therapy (sensitivity 80%, specificity 75%, accuracy 77%). In patients with remnant thyroid, cut-off value of serum Tg could not be determined because of the low sensitivity and specificity. Conclusion: In patients with well differentiated thyroid cancer who have no remnant thyroid, serum Tg level lower than 3 ng/mL on T4 therapy can warrant following-up of patients only with such clinical measures only such as physical examination and thyroid ultrasonogram. However, patients with Tg level of 3 ng/mL or more requires Tg measurements off T4 therapy and 131I scan to evaluate the possibility of recurrent or metastatic thyroid cancer (J Kor Soc Endocrinol 14:667-678, 1999).

한국인 산모에서 산후갑상선염의 발생 빈도 및 산후 고요오드식이의 영향

조보연,박경수,김원배,임창훈,이재훈,김성연,이홍규,문병술,전혜원,진호준 대한내분비학회 1998 Endocrinology and metabolism Vol.13 No.3

Background: Postpartum thyroiditis(PPT) is one of syndromes of thyroid dysfunction that occurs in the first year after parturition. Reported incidence of PPT is 3.9-8.2% of postpartum women in several studies from different countries. The fact that 52-100% of patients with PPT have thyroid autoantibodies, and that lymphocytic infiltration of thyroid gland is the characteristic pathological feature of PPT suggest that PPT is an autoimmune disease. High iodine intake in short term period is known to aggrevate the experimental autoimmune thyroiditis. This study was performed to investigate the incidence and clinical features of PPT in Korean postpartum women who usually ingest excessive amount of idine in immediate postpartum period and to investigate the predictive value of thyroid autoantibodies in the development of PPT in them. Method: Between March 1996 and February 1997, 99 women without previous history of any thyroid disease who delivered babies at Boramae hospital were enrolled. Thyroid function parameters(T3, T4, free T4, TSH), thyroid autoantibodies(anti-microsomal antibody, anti-thyroglobulin antibody) and urinary iodine excretion were measured prospectively before and 1, 3 months after delivery. Dietary iodine intake during postpartum period was evaluated by questionnaire, and clinical parameters were followed up. Results: During 3 months of observation, PPT developed in 8.1%(8/99) of postpartum women. Five cases had typical course having thyrotoxic phase and the other 3 cases had hypothyroid phase without toxic phase. However, only one of those required thyroid hormone replacement therapy in the latter group. There were no differences in age, baseline thyroid function parameters, parity, percent cases with family history of thyroid disease between those developed PPT (n=8) and those did not develop PPT(n=91). Duration of high iodine intake(3.8 +- 0.5 wk. vs. 3.7 +- 0.8 wk., p$gt;0.05), total ingested amount of high iodine diet(77 +- 28 vs. 79 +- 24 bowels of miyokguk, p)0.05), and the urinary iodine excretion(1.9 +- 1.4 mg/g creatinine vs. 3.7 +- 3.7mg/g creatinine, p0.05) at 1 month postpartum were not different between two groups. Of 99 total subjects, anti-microsomal antibody(AMA) was present in 13.1%(13/99) before delivery in their sera. Positive predictive value of the presence of AMA before delivery in predicting the development of PPT was 30.8%. Conclusion: The fact that incidence of PPT in normal Korean postpartum women who usually have high iodine intake in immediate postpartum period is not higher than those of other countries, and that there was no difference in the amount of iodine intake between those developed PPT and those did not suggest that high iodine intake in immediate postpartum period do not influence on the incidence of PPT. The presence of AMA before delivery had low specificity in prediction of development of PPT, so the measurement of AMA seems not to be a useful screening test (J Kor Soc Endocrinol 13:339-350, 1998).

당뇨병 환자에서 혈청 8-hydroxy-Guanine 농도의 증가

박수진,이홍규,신찬수,김성연,박경수,문병술,이윤용,정명희 대한당뇨병학회 1997 Diabetes and Metabolism Journal Vol.21 No.3

설폰요소제로 치료받던 인슐린비의존형 당뇨병 환자에서 아카보즈 병합치료의 효과

김진성,이홍규,신찬수,김성연,박도준,박건상,이윤용,문병술,박경수 대한당뇨병학회 1997 Diabetes and Metabolism Journal Vol.21 No.4

갑상선중독증 환자에서 폐환기 기능의 변화

정현경(Hyun Kyung Chung),김원배(Won Bae Kim),이선화(Sun Hwa Lee),문병술(Byung Sool Moon),이재호(Jae Ho Lee),박도준(Do Joon Park),조보연(Bo Youn Cho),정희순(Hee Sooh Chung) 대한내과학회 1999 대한내과학회지 Vol.56 No.6

N/A Objective : Dyspnea is a common symptom in patients with thyrotoxicosis, which may be caused by several mechanisms including pulmonary ventilatory dysfunction. There have been controversies among studies on changes in pulmonary ventilatory function in thyrotoxicosis. We were to evaluate the changes in pulmonary ventilatory function in patients with thyrotoxicosis. Methods : We measured the pulmonary ventilatory function with spirometry in 32 thyrotoxic patients with Graves' disease and in 22 age, sex-matched euthyroid control subjects. The changes in ventilatory function after treatment were evaluated in 18 thyrotoxic patients who became euthyroid with antithyroid drug treatment. Results : 1) Forced vital capacity(FVC) was significantly lower in thyrotoxic patients compared to control subjects(3.06±0.68 L and 3.35±0.55 L, respectively, p<0.05). Percent predicted values of FVC showed similar results; 82±16 % in patients and 95±11 % in control subjects(p<0.05).2) Forced expiratory volume for 1 sec.(FEV1.0), forced expiratory flow 25-75(FEF 25-75) and FEF 50 were not different between patients and control subjects. FEV1.0/ FVC ratio were higher in thyrotoxic patient than in control(88±7 % vs. 84±8 %, p<0.05). 3) Serum thyrotropin binding inhibitor immunoglobulin (TBII) activities were significantly correlated with pretreatment FVC values(R=-0.45, p<0.05) and with FEV1.0 values(R=-0.41, p<0.05) in thyrotoxic patients. However, serum thyroid hormone concentrations had no correlations with FVC or with FEV1.0 values. 4) FVC, FEV1.0 of thyrotoxic patients increased, and FEV1.0/FVC ratio decreased sifnificantly after treatment of thyrotoxicosis in patient group. Numbers of patients with normal, mild, moderate, severe restrictive disease were 10, 4, 3, 1, respectively before treatment, which became 14, 2, 2, 0 after treatment of thyrotoxicosis in patient group. Conclusion : Ventilatory disturbances of restrictive pattern were common in thyrotoxic patients that were partially reversible after treatment of thyrotoxicosis. Such changes may be one of mechanisms causing dyspnea in thyrotoxic patients. The fact that decrease in FVC were significantly associated with serum TBII activities (thyroid autoantibody), but not with degree of thyrotoxicosis suggests that autoimmune process itself is involved in the development of pulmonary function abnormalities observed in those patients.

뇌하수체 미세선종에 의한 쿠싱병의 접형골경유 수술의 치료성적

이윤용(Yun Yong Lee),김진성(Jin Seong Kim),문병술(Byeong Sul Mun),신찬수(Chan Soo Shin),김성연(Seong Yeon Kim),조보연(Bo Youn Cho),이홍규(Hong Kyu Lee),고창순(Chang Soon Koh),정희원(Hee Won Joeng),한대희(Dae Hee Han),한문희(Moom Hee 대한내과학회 1997 대한내과학회지 Vol.53 No.6

N/A Background: Cushing's disease is a hypercortisolic state attributable to hypersecretion of ACTH at pituitary gland Most of these diseases are due to pituitary microadenoma. Selective removal of adenoma by transsphenoidal microsurgery is the treatment of choice for Cushing's disease. We evaluated 25 cases to analyze results of transsphenoidal microsurgery and to identify prognostic factors that may predict successful outcome. Methods: From 1989 to 1995, 25 patients were diagnosed as having Cushing's disease in Seoul National University Hospital. They were underwent pituitary microsurgery and confirmed to have pituitary microadenoma radiologically and pathologically. About these patients. retrospective evaluation was done. Results: The patients consist of 21 females and 4 males and the age was ranged from 23 to 49 years. 19 patients (76%) were judged as immediate remission. The preoperative clinical, hormonal, and radiological characteristics of the remission and failure groups were similiar The patients who were immediate remission were followed from 3 months to 72 months. 3 patients had recurrences(15.8%) at 4, 8, 49 months after operation. The pre and postoperative clinical, hormonal, and radiological characteristics of the long-term remission and recurrence groups were similiar. We could not find any predictable factors of surgical outcome. Conclusion: The first line trearment of Cushing's disease is transsphenoidal microsurgery. However considering relative late and high rate of recurrence of Cushing's disease following curative surgery, careful longterm follow up is mandatory.

당뇨병성 말초 신경병증에 대한 PGE1의 효과

김민선,조보연,이홍규,신찬수,고창순,김성연,박경수,박건상,김진성,박형규,김현규,문병술 대한당뇨병학회 1995 Diabetes and Metabolism Journal Vol.19 No.4