Nelumbinis Semen Reverses a Decrease in $5-HT_{1A}$Receptor Binding Induced by Chronic Mild Stress, a Depression-like Symptom

Jang, Choon-Gon,Kang, Moon-Kyu,Cho, Jae-Han,Lee, Sun-Bok,Kim, Hyun-Taek,Park, Soon-Kwon,Lee, Jin-Woo,Park, Seong-Kyu,Hong, Moo-Chang,Shin, Min-Kyu,Shim, In-Sup,Bae , Hyun-Su The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.10

Depression is associated with a dysfunctional serotonin (5-hydroxytryptamine; 5-HT) system. More recently, several lines of evidence suggest that an important factor in the development of depression may be a deficit in the function and expression of $5-HT_{1A}$ receptors. The present study assessed if Nelumbinis Semen (N. s.) had an anti-depression effect through reversing a decrease in $5-HT_{1A}$receptor binding in rats with depression-like symptoms induced by chronic mild stress. Using a $5-HT_{1A}$ receptor binding assay, with a specific $5-HT_{1A}$receptor agonist, 8- OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin), the mechanism of the anti-depression effect of N. s. on rats was investigated, and the effects compared with two well-known antidepressants, Hyperium Perforatum (St. Johns Wort) and fluoxetine (Prozac). Animals were divided into five groups: the normal (N) group without chronic mild stress (CMS), the control (C) group under CMS for 8 weeks, the Nelumbinis Semen (N. s.) treatment group under CMS for 8 weeks, the Hyperium Perforatum (H. p.) treatment group under CMS for 8 weeks and finally, the fluoxetine (F) treatment group under CMS for 8 weeks. Each treatment was administered to rats during the last 4 weeks of the 8-week CMS. A sucrose intake test was performed to test the anti-depression effect of N. s. The N. s. treatment significantly reversed the decreased sucrose intake under CMS (P<0.05 compared to control group under CMS). In the CA2 and CA3 regions of the hippocampus, both N. s. and H. p. reversed the CMS-induced decrease in $5-HT_{1A}$receptor binding. In the I to II regions of the frontal cortex, N. s. and H. p. also reversed the CMS-induced decrease in$5-HT_{1A}$receptor binding, and even showed a significant increase in $5-HT_{1A}$receptor binding compared to the F treatment group (N. s. vs. P, p<0.05, H. p. vs. P, p<0.05). However, in the hypothalamus, all treatments reversed the CMSinduced decrease in $5-HT_{1A}$receptor binding. This reversal effect of N. s. on the decrease in $5-HT_{1A}$receptor binding in the frontal cortex, hippocampus and hypothalamus of rat brains was very similar to that of H. p, but different from that of F. It is concluded that N. s. presents an anti-depression effect through enhancing $5-HT_{1A}$receptor binding.

한국 일 도시지역 청소년의 우울 증상 유병률과 관련요인에 대한 연구

조성진,전홍진,김무진,김장규,김선욱,류인균,조맹제 大韓神經精神醫學會 2001 신경정신의학 Vol.40 No.4

연구 목적 : 한국의 일 도시지역에 거주하는 청소년의 우울 증상의 유병률과 관련요인을 밝힘으로써 청소년 정신건강 증진을 위한 기초 자료를 수집하기 위하여 실시되었다. 방 법 : 연구 대상은 부천시에 거주하는 중학교나 고등학교에 재학중인 청소년 71,102명 가운데에서 무작위 집락 표본 추출법에 의해 선정된 2,203명이었으며, 이들에 대해서 CES-D(the Center for Epidemiologic Studies Depression Scale)와 사회인구학적 정보에 대한 문항이 들어 있는 설문을 실시하였다. 설문은 직접 학교를 방문하여 수행하였다. 선정된 2,203명의 청소년 가운데에 CES-D문항을 완성한 학생은 1,972명으로 반응률은 89.5%였다. 결 과 : 1) CES-D의 절단점을 16점으로 하여 계산한 '가능한' 우울 증상의 유병률은 중학생의 경우에 남학생 34.6%, 여학생 44.7%였으며, 고등학생의 경우에는 남학생 43.8%, 여학생 49.6%였다. 2) CES-D의 절단점을 25점으로 하여 계산한 '명확한' 우울증 증상의 유별률은 중학생의 경우에 남학생 18.4%, 여학생 20.7%였으며, 고등학생의 경우에는 남학생 21.4%, 여학생 23.9%였다. 3)종교, 인문계와 실업계의 여부에 따라서 우울 증상의 유병률에는 유의한 차이가 없었다. 4) 성,학년, 생활수준에 대한 자신의 평가, 가족의 구조, 성적에 대한 만족도의 다섯 가지 변수에 대해 CES-D점수가 16점 이상인 우울 증상의 유무에 따라서 로지스틱 회귀 분석을 시행하였을 때 성적에 대해 불만적 하는 군에서 매우 만족하는 군에 비해서 8.850배의 상대 위험도를 보였다. 생활 수준을 중하정도라고 대답한 군은 상이라고 대답한 군에 비해서 2.007배의 상대 위험도를 보였다. 여학생은 남학생에 비해서 1.307배의 상대 위험도를 보였다. 5) 우울 증상에 있어서 남학생과 여학생의 비율은 전체 군에서 1:1.38이며 중학생의 경우에는 1:1.88, 고등학생의 경우에는 1:1.13으로 나타났다. 고등학생에 있어 남학생의 우울 증상이 증가하는 것은 학업과 입시에 대한 부담과 관련된 것으로 생각되었다. 결 론 : 한국 일 도시거주 중고등학생에서 CES-D로 측정한 우울 증상은 남학생의 34.3%, 여학생의 47.5%에서 나타날 정도로 흔하다. 특히 학업 성적에 대해 불만족 하는 군에서 높은 우울 증상의 상대 위험률을 보이며, 고등학생에서 남학생의 우울증의 유병률이 높아지는 것은 이 지역 학생들이 학업에 대한 높은 부담을 가지고 있다는 것을 알 수 있었다. 따라서 이들에 대한 특별한 관심이 요구된다. Objective : We tried to see the prevalence and correlates of symptoms of depression in an adolescent population in Korea, and collected the basal data for mental health promotion of adolescents. Method : We sampled 2,203 adolescents among 71,102 adolescents living in Puchon City in Korea by the randomized clustered sampling method. The Center for Epidemiologic Studies Depression scale(CES-D) was used to measure depressive symptoms. The measurements were conducted through visiting schools. Of the 2,203 adolescents(aged 13 to 18) who were sampled, 1,972 persons completed CES-D and sociodemographic questions. The response rate was 89.5%. Result : 1) The prevalence rate of 'probable' depressive symptoms with cutoff point 16 was 34.3% in the boys and 47.5% in the girls. 2) The prevalence rate of 'definite' depression symptoms with cutoff point 25 was 17.4% in the boys and 20.6% in the girls. 3) We could not find any meaningful difference in the average of CES-D from the districts where they live, the course of their education, and their religions. 4) We used the logistic regression analysis to find the risk factor for adolescent depression in these samples. Among the variables degree, it was most important risk factor in adolescent depression to dissatisfy with their school degrees. Compared it with fully satisfied group, the odds ratio was 8.850. The group of mid to low socioeconomic status had the odds ratio 2.007 compared with high socioeconomic status. The girls had the odds ratio 1.307 compared with the boys. 5) The male versus female ratio was 1: 1.38 in the total students and 1 : 1.88 in the middle school students, and 1 : 1.13 in the high school students. The male versus female ratio was relatively low in the high school students. It was the result of the high prevalence of depressive symptoms in the high school boys, and it was due to the large burden to their school degrees. Conclusion : The depressive symptoms checked by CES-D were very common among adolescents in Korean urban area. The prevalence of depressive symptoms was 34.3% in the boys and 47.5% in the girls. The result that male versus female ratio was relatively low in the high school adolescents, and the group that were dissatisfied with the school degrees had high risk of depressive symptoms, revealed that the students had large burden to their school degrees and so they needed special concerns.

In-vitro and In-vivo Anti-hyperglycemic Effects of Nipa palm (Nypa fruticans Wurmb) Extract

Kyung-Tae Kwon,Gi Jung Kim,Tae Yang Kim,Jin-A Yu,Su-Young Lee,Ji-Yoon Hong,Ye Lim Jang,Tessema Haimanot Miticu,Young-In Kwon 한국식품영양과학회 2021 한국식품영양과학회 학술대회발표집 Vol.2021 No.10

In this study, Nipa palm extract by solvent were investigated for their anti-hyperglycemic and using in-vitro, in-vivo animal models. In-vitro study, we investigated the inhibitory activities of Nipa palm stems and flower extracts by solvent against various digestive enzymes such as α-glucosidase, sucrase, maltase, and glucoamylase. In addition, α-amylase inhibitory activity, oxygen radical absorbance capacity, total phenolic and flavonoid content were measured. Among solvent extract, stem water extract (SWE) had the highest α-glucosidase inhibitory activity (3.6 mg/ml of IC50) and high sucrase inhibitory activity (0.28 mg/ml IC50). Furthermore, the extracts were investigated for in-vivo post-prandial blood anti-hyperglycemic effect using Sprague-Dawley(SD) rat model. The maximum blood glucose concentration(Cmax) in SWE-treated SD-rat (0.5 g-ΚBE/kg-bw) was significantly lower than in untreated SD-rats (199.9±10.4 vs. 222.0±15.4 hr·mg/dL, p<0.05). These results indicate that SWE may improve exaggerated post-prandial spikes in blood glucose via inhibition of intestinal α-glucosidase and thus delays carbohydrate absorption in colon.

국소재발된 두경부종양의 무고정틀 정위적 분할방사선치료

김인아(In Ah Kim),최일봉(Ihl Bhong Choi),장지영(Ji Young Jang),강기문(Ki Mun Kang),조승호(Seung Ho Jho),김형태(Hyung Tae Kim),이경진(Kyung Jin Lee),최창락(Chang Rak Choi) 대한두경부종양학회 1998 대한두경부 종양학회지 Vol.14 No.2

Background & Objectives: Frameless fractionated stereotactic radiotherapy(FFSRT) is a modification of stereotactic radiosurgery(SRS) with radiobiologic advantage of fractionation without losing mechanical accuracy of SRS. Local recurrence of head and neck cancer at or near skull base benefit from reirradiation. Main barrier to successful palliation is dose limitation secondary to normal tissue tolerance. We try to evaluate the efficacy and safety of FFSRT as a new modality of reirradaton in these challenging patients. Materials & Methods: Seven patients with recurrent head & neck cancer involving at or near skull base received FFSRT from September 1995 to November 1997. Six patients with nasopharyngeal cancer had received induction chemotherapy and curative radiation therapy. One patient with maxillary sinus cancer had received total maxillectomy and postoperative radiation therapy as a initial treatment. Follow-up ranged from 11 to 32 months with median of 24 months. Three of 7 patients received hyperfractionated radiation therapy(1.1-1.2Gy/fraction, bid, total 19.8-24Gy) just before FFSRT. All patients received FFSRT(3-5Gy/fraction, total 15-30Gy/5-10fractions). Chemotherapy(cis-platin 100mg/m(2)) were given concurrently with FFSRT in four patients. Second course of FFSRT were given in 4 patients with progression or recurrence after initial FFSRT. Because IF(irregularity factor; ratio of surface area of target to the surface area of sphere with same volume as a target) is too big to use conventional stereotactic RT using multiple arc method for protection of radiation damage to critical normal tissue, all patients received FFSRT with conformal method using irregular static ports. Results: Five of 7 patients showed complete remission in follow-up CT &/or MRI. Three of these five patients who developed marginal, in-field, and out-field recurrences, respectively. Another one of complete responders has been dead of G-I bleeding without evidence of local recurrence. One partial responder who showed progressive disease 15 months after initial FFSRT has received additional FFSRT, and then he is well-being with symptomatic improvement. One minmal responder who showed progression of locoregional disease 9 months after 1st FFSRT has received 2nd FFSRT, and then he is alive with stable disease. Five of 7 case had showed direct invasion to skull base and had complaint headache and various symptoms of cranial nerve involvement. Four of these five case showed improvement of neurologic symptoms after FFSRT. No significant neurologic complicaltion related to FFSRT was observed during follow-up periods. Tumor volumes were ranged from 3.9 to 50.7 cc and surface area ranged from 16.1 to 114.9cm(2). IF ranged from 1.21 to 1.74. The average ratio of volume of prescription isodose shell to target volume was 1.02 that indicated the improvement of target coverage and dose distribution with FFSRT with conformal method compared to target coverage with FFSRT with multiple arc method. Conclusion: Our initial experience suggests that FFSRT with conformal method was relatively effective and safe modality in the treatment of recurrent head and neck cancer involving at or near skull base. Treatment benefit included good palliation of symptoms and reasonable radiographic response. However, more experience and additional follow-up are needed to better assess its ultimate role in treating these challenging patients.

2003년 국내 중증급성호흡기증후군 진료 현황 및 문제점 분석

이진수,김은실,정문현,백제중,정선화,안주희,최영화,이선희,고철우,김성범,김민자,박승철,기현균,송재훈,최상호,김양수,이상오,조용균,박영훈,정숙인,김연숙,이흥범,손창희,장성희,정희진,김우주 대한감염학회 2004 감염과 화학요법 Vol.36 No.3

목적 : 2002년 말 중국에서 SARS가 발생한 이후 국내에서도 2003년 10월까지 총 3명의 추정환자, 17명의 의심환자가 보고되었다. 향후 추가적인 SARS의 유행이 우려되는 상황에서, 그간의 SARS 환자 진료에 있어서의 실질적인 준비사항, 진료 현황 등에 대한 조사를 통해 문제점을 파악하여, 향후 더 나은 대비가 될 수 있도록 개선점을 제시하고자 하였다. 재료 및 방법 : SARS로 의심되는 환자를 진료 경험이 있는 병원의료진을 대상으로 2003년 10월에 설문조사를 실시하였다. 설문에는 SARS 환자 진료 시의 실질적인 조치, 진료 현황, 병실, 응급실 및 외래에서의 격리 시설과 준비사항, 보건당국의 관리와 지원에 관한 사항을 포함하였다. 결과 : 대상이 되는 22개 병원 중 17개(17/22, 77.2%) 병원이 설문에 응하였다. SARS 환자를 위한 격리실은 응급실, 외래, 일반병실 및 중환자실에서 각각 9개(9/17, 52.9%), 5개(5/17, 29.4%), 15개(15/16, 93.7%), 4개(4/16, 25%) 병원에서 음압처리가 되어있지 않은 일인실 혹은 다인실이 사용되었고, 1개(1/16, 6.3%) 병원에서만 일반병실에서 음압격리실이 운영되었다. 입원환자의 진찰 시 개인보호구의 착용은 거의 모든 의료기관에서 이루어졌다. 보건당국에서 SARS지정병원의 시설 등을 사전에 확인한 곳은 1곳(1/12, 8.3%)이였고, 14개 병원(14/15, 93.3%)에서는 보건당국에 의뢰한 검사결과를 통하 받지 못하였다. 결론 : 의료기관에서 SARS 환자용 격리실뿐만 아니라 기존의 격리실 설비 등이 미흡하였으며, 특히 중환자실 및 외래의 준비가 더욱 부족하였다. 보건당국의 의료기관에 대한 종합적인 지원이 부족하였고, 병원과의 원활한 연계가 잘 이루어지지 않았다. SARS 만이 아닌 격리를 필요로 하는 질환의 적절한 진료를 위해 향후 병원 시설의 정비와 정부차원에서의 보다 구체적이고 실질적인 대책마련이 필요하다. Background : There was an worldwide outbreak of the Severe Acute Respiratory Syndrome (SARS) originated from China in late 2002. During that period three cases of suspected SARS and 17 cases of probable SARS were reported in Korea. With the concerns about the reemergence of SARS-coV transmission, it is important to be prepared for any possibility. So, this study is aimed to analysis the past measures in managing SARS and propose the amendatory plans to improve the preparedness. Materials & Methods : Questionnaires were collected among clinicians with any experience in managing the probable or suspected SARS cases in Oct. 2003. 17 out of 22 hospitals responded to the questionnaire. The contents in the questionnaire were practical activities, personal equipments, response plans, isolation facilities in emergency centers, outpatient clinics, general wards and intensive care units, and relationship with the public health department. Results : The dedicated isolation rooms in emergency centers, outpatient clinics, general wards, and intensive care units were prepared in 9 (9/17, 52.9%), 5 (5/17, 29.4%), 15 (15/16, 93.7%), and 4 (4/16, 25.0%) hospitals, respectively. Except for one hospital that newly made negative pressure room for SARS, single or multi-bed rooms without airborne infection control were used in all the other hospitals. The personal precaution principles were kept quite well in general wards. Before the designation of SARS hospital by the public health department prior evalution to see if the hospital was suitable for managing SARS was conducted in only 1 (1/12, 8.3%) hospital. The results of laboratory diagnosis were reported back in 1 (1/15, 6.6%) hospital. Conclusions : The isolation facilities which can control airborne infection were almost deficient not only for SARS but also for other respiratory transmissible diseases. For the infection control of transmissible diseases including SARS, more investment is needed on medical facilities and comprehensive support from the public health department required.

스키 리조트 이용자의 여가갈등에 관한 연구

한우진(Woo Jin Han),이장희(Jang Hee Lee),여인성(In Sung Yeo) 한국여가레크리에이션학회 2005 한국여가레크리에이션학회지 Vol.29 No.-

Although various studies concerning leisure conflict have been conducted in the U.S, there is little research in this area for Korean. There are many both unasked and unanswered questions in the experience of leisure conflict between or among various leisure activity group. Therefore, an attempt to understand the experience of leisure conflict in ski resort between skier and snowboarder may provide new insights into the nature of leisure conflict of Korean. The purpose of this study was to examine differences of leisure conflict by demographic variables and investigated effect of user’s characteristics in leisure conflict between skier and snowboarder.For this study, 482 participants were selected from 2 ski resorts located in Kangwon Province for one month from January 15th to February 15, 2005, using the convenience sampling method. For the data analysis SPSS 12.0 for Windows version was utilized. The hypothesis tests were conducted with independent t-test, one-way ANOVA, and Multiple Linear Regression to solve problems of the study. On the basis of the results, the conclusions were drawn as follows; 1. There are differences in leisure conflict between or among skier and snowboarder’ demographic characteristics(gender and age group) 2. Leisure conflicts of skier are effected by user’s background in both in-group and out-group. 3. Leisure conflicts of snowboarder are effected by user’s background in both in-group and out-group.

정상인 및 신기능장애환자에서 Carumonam(AMA-1080)의 약동학

임동석,이경훈,엄재호,한진석,김성권,장인진,신상구 大韓臨床藥理學會 1994 臨床藥理學會誌 Vol.2 No.1

서방형 Diltiazem제제의 개발을 위한 약동학/약력학적 특성 검토

유경상,배균섭,조주연,장인진,신상구 大韓臨床藥理學會 1998 臨床藥理學會誌 Vol.6 No.2

Functional characterization of MATE2-K genetic variants and their effects on metformin pharmacokinetics

Chung, Jae-Yong,Cho, Sung Kweon,Kim, Tae Hee,Kim, Kyoung Hee,Jang, Geun Hye,Kim, Choon Ok,Park, Eun-Mi,Cho, Joo-Youn,Jang, In-Jin,Choi, Ji Ha Wolters Kluwer Health | Lippincott Williams Wilkin 2013 Pharmacogenetics and genomics Vol.23 No.7

OBJECTIVE: Human multidrug and toxin extrusion member 2 (MATE2-K, SLC47A2) plays an important role in the renal elimination of various clinical drugs including the antidiabetic drug metformin. The goal of this study was to characterize genetic variants of MATE2-K and determine their association with the pharmacokinetics of metformin. METHODS: We screened DNA samples from 48 healthy Koreans for variants in the promoter and coding regions of MATE2-K and examined the function of common haplotypes in the promoter region using in-vitro luciferase assays. Then, the metformin pharmacokinetic study was carried out to determine the association between MATE2-K promoter haplotypes and metformin pharmacokinetics. RESULTS: Nine variants in the promoter region of MATE2-K and one nonsynonymous variant, p.G211V, were identified. The MATE2-K promoter haplotype 1 containing a known functional polymorphism, g.−130G>A and haplotype 2 containing two polymorphisms, g.−609G>A and g.−396G>A showed a significant increase in reporter activity. Among the 45 individuals who participated in the metformin pharmacokinetic study, 12 healthy Koreans who were homozygous for haplotype 1 or 2 showed a significant increase in renal clearance [539±76 (reference group) vs. 633±102 (variant group) ml/min; P=0.006] and secretion clearance [439±81 (reference group) vs. 531±102 (variant group) ml/min; P=0.007] of metformin compared with that shown by the reference group. CONCLUSION: Our study suggests that common promoter haplotypes of MATE2-K are associated with the pharmacokinetics of metformin.

모델동물의 병태.생리 유발 유전자 기능 연구 : 당뇨모델동물의 췌장 β-세포를 이용한 비만발생에 관한 연구 Effect of development of diabetes by fatty acid in animal model

황대연,김용규,강태석,황진희,임채형,강현구,이주은,허영범,장인석,조정식,채갑용 식품의약품안전청 2001 식품의약품안전청 연보 Vol.5 No.-

체장 β세포에 지방이 축적되는 lopotoricity 현상은 인슬린 비의존성 당뇨 (Non InsuBin Dependent Diabetes Mellitus :NIDDM)의 발생과 상당히 밀접한 관계가 있으며, 췌장 β세포의 lipoapoptosis는 세포막형성에 관여하는 sphingomyelin의 전군체안 ceramide의 과생산에 의해 유도된다는 보고가 있다. 그러나, 지방산 종류에 따른 췌장 β세포에서의 세포사멸 (apoptosis)유발 기작에 대해서는 야직까지 보고된 바가 없파. 또한, 지방세포에서 생성되며, 지질대사, 음식섭취 및 체중조절에 관여하는 렙틴 (leptin)과 렙틴 수용체와의 관계 역시 체장 세포에서 명착하게 밝혀져 있지 않다. 따라서 본 연구에서는 6주령 53와 Zucker rat의 췌장으로부터 췌도를 분리하는 기술을 확립하고, 배양된 췌장 췌도 세포와 MS-1세포주에 불포차즌방산 (n-3 linolenic acid; n-6 :linoleic acid), 포화지방산 (stearic acid), conjugated linoleic acid (CLA)를 포함하는 4 가지의 지방산을 처리한 후 이들이 췌장 』세포의 사멸에 미치는 영향을 다양한 apoptosis 관련 유전자의 발현을 분석함으로써 확인하고자 하였다. 그 결과 SD rat으로부터 마리 당 평균 약 500개의 췌장 췌도를 분리하는데 성공하였으며, 4 종류의 지방산 중 포화지방산인 stearic acid를 처리하여 ONA fragmentation 증가를 관찰하였다. 또한 RT-PCR 방법을 이용하여 분리된 췌도 세포에사의 Bcl-2, Bax, iNOS가 지방산의 종류에 따라 서료 다른 발현양상을 나타낸다는 」라실을 관귿하였다. 이러한 떤구 결과는 지방산의 종류에 따라 췌장 췌도 세포에서의 세포사멸 유발 효과를 겋증하였으며, 이러한 연구결과는 복잡한 당뇨발병 원인 규명에 중요한 정보를 제공할 것으로 사료된다. Fat contents within the pancreatic islets are closely related to lipotoxicity which induces apoptosis, resulting in non insulin dependent mellituse(NIDDM). High level of fat may contribute to both insulin resistance and obesity in rodent and humans but the evidence is limited. To determine whether dietary fatty acids affect pancreatic cell function, the INS-1 cells and the pancreatic islets isolated from SD and Zucker obese(fa/fa) rats(6 wk, prediabetic stage) were cultured with stearic acid and CLA. As a result, DNA fragmentation laddering was substantially decreased in the INS-1 cells and the isolated pancreatic islets cultured with 2mM CLA compared with those with stearic aced. To investigate the mechanism by which CLA alleviates cell apoptosis as indicated by DNA fragmentation assay, we examined mRNA expressions of apoptosis-related proteins including Bax and Bcl-2 associated with cell death agonist and antagonist, respectively in the both INS-1 cells and islets cultured with 2 mM fatty acids. Bax mRNA expression was not markedly altered by either stearic acid or CLA, whereas Bcl-2 mRNA expression was noticeably enhanced by CLA compared with stearic acid. However, there were no changes in cell apoptosis and cell apoptotic-regulating gene products in the both INS-1 cells and isolated islets treated without or with 2 mM CLA. It is concluded that CLA may have a beneficial effect for maintenance of cell viability via increased Bcl-2 protein expression compared with steraic aced, which lead to delay or prevent, at least somewhat, the onset of NIDDM in the physiological status.