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1 대한내과학회지 : 제 87 권제 1 호 특집 (Special Review) - 최신당뇨병치료약제 Dipeptidyl Peptidase-4 (DPP-4) 억제제 원광대학교의과대학내과학교실 이대호 Dipeptidyl Peptidase-4 Inhibitor Dae Ho Lee Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, Iksan, Korea Recent advances in incretin biology have led to the development of a new class of oral anti-diabetic drugs. To date, there are two known incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), of which the former is a more important therapeutic target for type 2 diabetes. GLP-1 is secreted by intestinal L-cells in response to oral nutrient intake, and it stimulates insulin secretion and suppresses glucagon secretion in a glucose-dependent manner. However, both GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), a multifunctional type II transmembrane glycoprotein. Thus, several DPP-4 inhibitors with different pharmacologic features are now available and can be used either as monotherapy or in combination with other anti-diabetic agents for the treatment of type 2 diabetes. In both therapeutic regimens, DPP-4 inhibitors have been shown to reduce hemoglobin A1c levels by approximately %. In clinical trials, DPP-4 inhibitors were generally well-tolerated, posed a low risk of hypoglycemia, and did not increase body weight. Despite some reports of a possible increased risk of pancreatitis with GLP-1 receptor agonists and DPP-4 inhibitors, no causal associations have been found. Recent randomized controlled clinical trials have shown that DPP-4 inhibitors did not increase or decrease the rates of major adverse cardiovascular events in patients with type 2 diabetes at high risk of cardiovascular disease, even though this class of anti-diabetic agents had various salutary effects in many studies involving animals or healthy and diabetic humans. Additional studies will be required to resolve these disparate conclusions. (Korean J Med 2014;87:1-8) Keywords: Incretin; Glucagon-like peptide-1; Glucose-dependent insulinotropic polypeptide; Dipeptidyl peptidase-4 inhibitor; Type 2 diabetes 서 제 2 형당뇨병치료의최근가이드라인들은환자중심적 론 접근을통하여저혈당을최대한피하면서환자의상황에맞게혈당조절최소목표혹은이상적인목표를설정하여생활요법을먼저혹은동시에약물요법을시행하되, 제1차약 Correspondence to Dae Ho Lee, M.D., Ph.D. Department of Internal Medicine, Wonkwang University School of Medicine and Hospital, 895 Muwang-ro, Iksan , Korea Tel: , Fax: , drhormone@naver.com * This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIP) ( ) and by the Basic Science Research Program through the NRF funded by the Ministry of Education ( ). Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 87, No. 1, 물요법은메트포르민을권하고있으며메포르민을사용할수없거나메트포르민요법에도불구하고목표에도달하지못한경우 2번째약제를선택하는데과거에비해약제선택의폭이다양해졌다 [1]. 또한진단당시부터당화혈색소가높은경우 ( 예, 9.0%), 처음부터병합요법을실시할수있기때문에메트포르민과초기부터병합요법을할수있는약제선택도매우중요하다고할수있다. 약제의선택에있어서특히, 저혈당의위험이적고부종이나체중증가가없는새로운약제로서 dipeptidyl peptidase-4 (DPP-4) 억제제인 sitagliptin이 2006년처음으로허가된이후많은 DPP-4 억제제가개발되어사용중에있다. 인크레틴 (incretin) 호르몬과 DPP-4 장점막에는췌장의내분비기능을조절하는물질이존재하여혈당을감소시킬수있다는것이이미 1900년대초부터관찰되었고이후장에서유래하는혈당감소작용을가진물질을 " 인크레틴 " 이라고명명하였으며 1960년대부터면역측정법이개발되면서실험을통하여포도당을정주할때보다경구투여할때췌장의인슐린분비반응이더크게일어나는현상이확인되어이를 " 인크레틴효과 " 라고하였다 [2]. 인크레틴효과에의한인슐린분비반응은경구포도당섭취후에일어나는인슐린분비반응의 50-70% 정도를차지할정도로중요하며당뇨병환자에서는크게감소되어있다 [2]. 현재까지는인크레틴호르몬으로서 glucose-dependent insulinotropic polypeptide (GIP) 와 glucagon-like peptide 1 (GLP-1) 이밝혀졌으며더많은인크레틴호르몬이있을것으로생각하고많은연구가진행되고있다. 제2형당뇨병환자에서는 GIP 농도가정상이거나오히려증가되어있고 GIP에대한인슐린분비반응은크게감소된반면, 식후활성 GLP-1 농도는감소되고 GLP-1 에대한인슐린분비반응은상대적으로거의보존되어 GLP-1 혹은 GLP-1 유도체를제2형당뇨병환자의치료에적용할수있다 [2,3]. GLP-1 의생리적작용은포도당의존적으로인슐린분비증강작용과글루카곤분비억제작용이있고베타세포보호효과가있으며약리적용량투여시에는식욕억제와위배출시간지연등의효과와함께체중감소효과가나타난다 [2,3]. 하지만 GLP-1 수용체작용제는주사제이고 GLP-1 은 DPP-4 (adenosine deaminase complexing protein 2 or CD26) 에의해서빠르게대사되어혈중반감기가 2분이 내이기때문에 DPP-4 효소작용억제를통하여활성 GLP-1 의농도를높일수있는경구당뇨병치료제로서 DPP-4 억제제가개발되었다 [2,3]. DPP-4는다양한기능을가진 type II transmembrane glycoprotein 으로서단백질및펩타이드의아미노말단에서두번째아미노산 [N-terminal penultimate (P 1) position] 이프롤린혹은알라닌인경우그말단에서 2개의아미노산을제거하는단백분해효소이다 [4]. DPP-4의기질은주로아미노산 80개이내의크기인펩타이드가주요기질로서 GLP-1 및 GIP 외에 neuropeptide 와 chemokine 등을포함한 35개이상의기질이존재하며, 대표적인기질로서 neuropeptide Y, peptide YY, substance P 그리고 stromal cell-derived factor 1 등이그기질에속하지만 GLP-1 및 GIP 외다른기질에대한 DPP-4 억제제의영향은아직연구가매우부족한상태이며인체연구는더욱그렇다 [4,5]. DPP-4는상피세포, T 림프구를포함한여러면역세포그리고혈관내피세포등을포함한여러가지세포와신장, 간, 부신, 골격근, 췌장, 폐, 소장, 골수, 비장등을포함한거의모든조직에서발현된다 [4,6,7]. DPP-4의효소활성 homodimer 일때유지되며혈액및체액에서도막단백에서분리된효소활성이있는 soluble DPP-4 가존재한다 [5,8]. 제2형당뇨병환자, 특히혈당조절이불량한환자에서는혈중 DPP-4 농도가증가되어있고효소활성도높다고보고되었다 [9]. DPP-4는효소활성외에도 fibroblast activation protein α (FAPα), adenosine deaminase, fibronectin, collagen, mannose 6-phosphate/insulin-like growth factor II receptor, CD45, CXCR4, 그리고 plasminogen 2 등과결합하여다양한생리적작용을할수있으며이에대한내용은본고찰에서는생략하기로한다 [4,10]. DPP-4 외에도유사물질이있으며이들을 "DPP-4 activity and/or structure (homologues, DASH)" 라고하며여기에는세포표면에 dipeptidyl peptidase 효소활성을가진 DPP-4 및 FAP-α, 세포질내에서효소활성을가진 DPP-8 및 DPP-9, 그리고효소활성없이세포막에있는 DPP6 및 DPP10 등이있고마지막으로세포내소포체에있으며효소활성이있는 quiescent cell proline dipeptidase (QPP, 혹은 DPP-II) 가여기에속한다 [11]. DASH 에대해서는아직밝혀지지않은것들이더많아서추가연구가필요하며일부 DPP-4 억제제의부작용이 DASH 중에서다른효소에대한비특이적작용때문이라는주장이있으나아직확증이부족하며현재사용중인선택적 DPP-4 억제제들은다른효소들 - 2 -

3 - Dae Ho Lee. Dipeptidyl peptidase-4 - 에비해 DPP-4에대해서수백배이상특이적이기때문에그러한가능성은낮다 [4,12]. DPP-4 억제제 DPP-4 억제제의작용원리와효과를설명요약하면그림 1 과같다. DPP-4 억제제는 DPP-4의효소활성에매우중요한활성포켓의구조분석을통하여선택적으로효소활성을억제하는비교적분자량이적은화학적합성물질로서화학적구조에따라서약간의작용특성이있으며현재국내에서사용중인 DPP-4 억제제들의특성을요약하면표 1과같다 [13,14]. DPP-4 억제제경구투여후대개는 1시간늦어도 4시간내에혈중최고농도에이르고식후활성 GLP-1 농도를 배정도증가시키며통상적인권장투여용량으로혈청 DPP-4 활성억제효과가 80% 이상, 24시간까지유지된다 [13]. Vildagliptin의경우 1일 1회투여시에는 DPP-4 억제효과가 80% 이상유지되지않으므로 2회분할투여가필요하다 [14]. 식사와같이투여해도약제의혈중농도가변하지않거나 15% 이내에서감소하는것으로보여임상적으로효과에별로영향을미치지않는다고판단되어식사와함께투여할수있다 [13]. 제2형당뇨병환자에서 DPP-4 억제제는식후인슐린농도와 C-펩타이드농도를증가시키고글루카곤농도를감소시켜서식후혈당을감소시킬뿐만아니라혈당의변동폭도크게줄이는장점이있다 [15]. 췌장베타세포에대한작용은동물실험에서는비교적잘입증이되었지만제2형당뇨병환자에서는베타세포기능을직접평가하기가곤란하여베타세포기능을평가하는다양한표지자들을대신활용하여평가한많은연구들이베타세포의기능보호효과를보여주고있으며제2형당뇨병환자에서의알파세포의기능이상도개선하여포도당에대한민감도가호전되어혈장글루카곤농도가감소되는결과를보 Figure 1. Incretin hormones and DPP-4 inhibitor. GLP-1 is secreted from entero-endocrine L cells which are distributed mainly in the distal ileum and colon, whereas GIP is from K-cells which are localized to proximal small intestine (duodenum and jejunum. Autonomic nervous system, the neurotransmitters gastrin-releasing peptide and acetylcholine, and GIP can contribute to the rapid release of GLP-1 after nutrient ingestion. To date, only GIP and GLP-1 are known incretin hormones in humans which potentiate glucose-stimulated insulin secretion in an additive manner. DPP-4, which functions as a cell surface serine protease by selectively cleaving dipeptides from peptides and proteins containing proline or alanine in the N-terminal penultimate (P1) position, rapidly converts active GLP-1 (7-36) amide and GIP (1-42) to their inactive metabolites GLP-1 (9-36) and GIP (3-42). DPP-4 inhibition causes an increase in the plasma active GLP-1 level by 2-3 folds, thereby enhancing incretin action. Because this is not that high level as seen in pharmacological treatment with GLP-1, DPP-4 inhibitor therapy in patients with type 2 diabetes does not affect appetite and gastric motility [3-7]

4 - 대한내과학회지 : 제 87 권제 1 호통권제 647 호 Table 1. Main features of DPP-4 inhibitors approved for clinical use [13-15,36] Drugs (daily dosage) Sitagliptin 100 mg od Active metabolite (activity vs parent drug, %) Demethylated, acetylated (3-6%) Excretion a 87% renal (80% unchanged) 13% biliary Vildagliptin 50 mg bid Negligible 85% renal (21% unchanged) 15% biliary Saxagliptin 5 mg od BMS (50%) 75% renal (24% unchanged; 36% BMS ) 22% biliary Linagliptin 5 mg od Negligible 6.3% renal > 85% biliary (mostly unchanged) Alogliptin 25 mg od Negligible 76% renal (95% unchanged) 13% biliary Gemigliptin 50 mg od Yes 63% renal (39% unchanged) 27% biliary (11% unchanged) b Dosage adjustment in renal impairment (per day) Moderate: 50 mg Severe: 25 mg Moderate to severe: 50 mg Moderate to severe: 2.5 mg No adjustment Moderate: 12.5 mg Severe: 6.25 mg No adjustment bid, twice daily; od, once daily. a Unchanged: percentage of % of an administered dose that is eliminated unchanged in the urine or feces. b Creatinine clearance in renal impairment: mild, 50 ml/min; moderate, 30 to < 50 ml/min); severe, < 30 ml/min) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis. 고하였다 [16]. 하지만인간의췌장을직접대상으로한연구보고는매우드물고, 한연구에서는베타세포의증식뿐만아니라알파세포의기능억제때문에상대적으로알파세포역시세포증식을보인다고보고되었으나향후추가연구가필요하다 [17]. DPP-4 억제제의효능통상적으로 DPP-4 억제제의치료효과는단독요법환자에서당화혈색소의감소량이 % 로보고되었고다른항당뇨병약제와병합요법시에도추가적으로 % 정도감소되는것으로보고되었다 [15]. 현재까지임상경험이가장많이축적된 sitagliptin의예를들어설명하면제2형당뇨병환자에서단독요법시에당화혈색소 7% 미만에도달하는환자는위약군 (5-17%) 에비해유의하게높으며 (21-58%), 위약군에비해당화혈색소는 %, 공복혈당은 mg/dl, 식후 2시간혈당은 mg/dl 정도더낮게조절된다 [15]. 아직까지 DPP-4 억제제들을직접비교를통해서어떤한약제가다른약제에비해더우월하다는보고는없으며다른 DPP-4 억제제들도이와비슷한효능을보일것으로생각할수있다 [14,15,18]. 또한장기간투여시에도효과가잘유지 되고당뇨병유병기간이 5년이상인환자에서나치료전당화혈색소가비교적높은환자에서도효과가차이없이잘나타난다는장점이있다 [14]. 뿐만아니라메트포르민과병합요법시에추가적인 GLP-1 분비증가가보고되어병합요법의장점을살릴수있으며 [19] 최근에일본에서시행된연구에서는비교적효과가약하다고여겨져서잘사용하지않던 α-glucosidase 억제제도단독요법에비해 DPP-4 억제제와병합요법시에당화혈색소의개선 (-0.91~-0.96%) 이다른항당뇨병약제와 DPP-4 억제제의병합요법효과와비슷할정도로효능을보이고이러한상가작용혹은상승작용의기전으로는 α-glucosidase 억제제에의해서추가적으로발생하는혈중 GLP-1 증가가기여할것이라는보고가있다 [20]. 이러한혈당조절개선이체중증가없이달성될수있으므로추가적인 DPP-4의장점이라할수있다. 기존메트포르민요법에추가하는요법 (add-on to metformin therapy) 에있어서설폰요소제, 피오글리타존, 기저인슐린, 혹은 exenatide 등다양한병합을시도할수있으며특히메트포르민은 GLP-1 분비를증가시키므로 DPP-4 억제제와병합요법시에활성 GLP-1 의증가를기대할수있고실제메트포르민과 sitagliptin의병합요법에서당화혈색소의감소 (-2.4%) 가크게나타날수있다 [15,21]

5 - 이대호. Dipeptidyl peptidase-4 (DPP-4) 억제제 - DPP-4 억제제와타약제들과의비교에서는각각설폰요소제및피오글리타존에비해서는동등한효과를, 기저인슐린혹은 GLP-1 수용체작용제인 exenatide 혹은 liraglutide 주사치료효과에비해서는열등한치료효과를보였다 [15,18]. DPP-4 억제제가베타세포보호효과를가지고있는데병합요법시에서는 DPP4 억제제와메트포르민 (sitagliptin과메트포르민 ) 병합요법이다른병합요법 (sitagliptin + 피오글리타존, 혹은피오글리타존 + 메트포르민 ) 에비해서베타세포보호효과가더우월하다는보고가있다 [16]. DPP-4 억제제의치료효과가한국인을포함한아시아인에서서구인에비해당화혈색소감소효과가더뛰어나다는보고가있는데, 특히체질량지수가 30 kg/m 2 미만인환자들에서이러한현상이더저명하였는데한국인에서도역시 DPP-4 억제제치료가크게도움이될수있음을시사한다 [22]. DPP-4 억제제중에서효능비교아직약제간에혈당조절에있어서당화혈색소의변화를직접비교한연구는별로없으며또한통계적으로약제간에유의한차이를보이는경우도없었다 [18]. 하지만 sitagliptin 과 vildagliptin의 3개월치료효과를비교한연구에서당화혈색소는두치료군사이에차이가없었지만 vildagliptin 투여환자군에서식후혈당의변이와변동폭이더작고식간에혈장 GLP-1 의농도가유의하게더높을뿐만아니라식간에혈장글루카곤억제효과도더좋은경향을보였으며산화스트레스와일부염증싸이토카인의유의한감소를보여서향후추가적인관심이필요해보인다 [23]. 약물상호작용약제간의약물상호작용은주로 CYP 효소계의활성을유도하거나억제하는약제들간에발생하는경우가많은데 DPP-4 억제제는 saxagliptin을제외하고는 CYP에의해서대사되지않아서임상적으로문제가되는약물상호작용은별로없다 [14]. Saxagliptin은체내흡수된양의 50% 정도가 CYP3A4/5에의해서 5-hydroxy saxagliptin (BMS ) 로대사되며이대사체역시활성을지니므로 saxagliptin 과강력한 CYP3A4/5 억제제 (ketoconazole, atazanvir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) 와병합투여하는경우는용량감량이필요하다 [13]. 국내에서개발한 gemigliptin 역시 CYP3A4에의해서일부대사되나 saxagliptin에비해서는정도가더적으며용량조절이필요없다. Sitagliptin의경우일부대사 (16%) 에 CYP3A4와 CYP2C8가관여하므로신기능감소환자에서강력한 CYP3A4 억제제와같이사용시에는용량조절을염두에두어야한다 [14]. P-glycoprotein 과작용때문에 vildagliptin, sitagliptin, saxagliptin이혈청 digoxin 농도를약간올릴수있으나임상적으로고려해야할정도는아니다 [14]. 특정환자에서의약제사용주의사항중등도이상의신장질환자에서는 linagliptin과 gemigliptin 을제외하고는모두약제용량의감량이필요하며, 간질환환자에서의약제용량조절은대개의 DPP-4 억제제의경우필요하지않으나심한간손상환자에서는 vildagliptin 사용이금지되어있으며, 특히간손상과신장질환이같이있는환자에서는 vildagliptin 축적이더저명하므로더욱주의가필요하다 [13,14]. 심혈관계기대효과및임상연구결과작지만통계적으로유의한혈압강하효과가자주보고되었지만안지오텐신전환효소억제제인 enalapril과병합투여하는경우 10 mg 이상의용량에서는이러한효과가사라짐을보고한연구가있어서향후기전과함께추가연구가필요하며고용량의안지오텐신전환효소억제제와 DPP-4 억제제를같이투여하는경우혈압에대한관찰이필요해보인다 [24]. 그외에도 DPP-4 억제제는심혈관계위험인자나병태생리와관련된다양한효과를보인다고보고되었지만이러한효과가실제심혈관계질환의발생을줄이는데기여하는지는아직대규모임상연구등을통해서입증된바는없다. 혈당강하효과외에 DPP-4 억제제의효과는혈압강하효과, 식후고지혈증의개선, 염증표지자의감소, 산화스트레스의감소, 혈관내피세포의기능개선, 단백뇨의감소등을들수있다 [25-27]. 최근의메타분석에서는 DPP-4 억제제치료군에서타약제치료군이나위약군에비해사망률이나심혈관질환의발생이차이가없다는결과들이나오고있으나소그룹분석에 - 5 -

6 - The Korean Journal of Medicine: Vol. 87, No. 1, 서는 DPP-4 억제제치료가특히설폰요소제에비해서심혈관질환의위험도가더낮다는메타분석결과가있다 [28-30]. 하지만이러한기대에도불구하고최근에종결된대규모임상연구결과는고위험환자군에서사망률, 심근경색증, 뇌졸중의감소를보여주지못했다. 급성심근경색증혹은불안정형협심증으로입원한제2형당뇨병환자에서입원 15-90일이내에 alogliptin 투여군과위약투여군을비교한 Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) 연구에서는 median 18개월후에두군간에사망률, 심근경색증, 뇌졸중의발생에차이가없었다 [31]. 또한동맥경화성심혈관질환을이미가진환자혹은고위험환자에대하여 saxagliptin과위약을비교한 The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 연구에서는심혈관질환에의한사망, 심근경색증, 뇌경색증의발생에는차이가없었으나심부전에의한입원가능성이 saxagliptin 치료군에서위약군에비해 27% 증가하는결과를보였다 [32]. 따라서현재진행중인 DPP-4 억제제의심혈관질환에대한대규모임상연구들의결과들을기다려보아야하겠지만현재시점에서는 DPP-4 억제제치료에의해서심혈관질환의발생이증가하지는않는것으로생각할수있다. 부작용및안전성전반적으로부작용이거의없는약제이며현재까지축적된자료에근거한분석들에서도 DPP-4 억제제투여환자군에서전체사망률역시증가하지않는다 [15]. Angioedema 를포함한심한과민반응이매우드물게시판후보고된바있다 [15]. 인크레틴호르몬작용이포도당의존적으로인슐린분비를일으키기때문에저혈당환자에서는인슐린분비증강이일어나지않고저혈당에대한글루카곤반응은그대로유지되기때문에 DPP-4 억제제투여시에심한저혈당의위험은거의없다 [33]. 하지만설폰요소제나인슐린치료와병합시에는메트포르민혹은기타약제와병합할때보다저혈당위험이증가하므로주의가필요하다. Vildagliptin의경우허가를위한초기연구에서드물게간기능이상을초래하는경우가있어초기투여시첫 1년간은 매 3개월마다간기능검사를권고하고있으나제2상및 3상임상연구분석결과들에서는간손상의증거가없으므로실제임상에서는당뇨병에대한정기적인채혈검사시에만확인하는경우가대부분인것같다 [14]. 췌장암을비롯하여암발생과의관련성은근거가없는상태이다. DPP-4 억제제를포함한인크레틴기반치료시췌장염의위험이높을가능성이제기되었으나제2상및 3상임상연구결과나보험회사데이터에대한후향적분석, 그리고신약도입시기에증가하는자발적보고자료등을이용한분석의한계점때문에결론이쉽지않다. 최근 3상임상연구데이터를모아서분석한연구결과, 환자천명- 년 (1000 patientyear) 당췌장염발생빈도가 DPP-4 억제제치료군 1.0, 대조군환자군에서 1.2로서췌장염발생이차이가없다는보고가있으며여기에 SAVOR-TIMI53 및 EXAMINE 연구데이터를추가하여분석하면각각 DPP-4 억제제치료군 1.3, 대조군환자군에서 1.2로서역시차이가없었다 [34]. 인크레틴기반치료에대한 60개의임상연구 (n = 353,639) 에대한최근의메타분석에서도췌장염발생의빈도가차이가없었다 [35]. 과거췌장염의병력이있는환자에서도췌장염의발생을증가시키는지는불확실하다. 하지만 DPP-4 억제제투여중에췌장염의심증상이있으면약제를즉시중단해야한다. 결론 DPP-4 억제제는비교적안전하게저혈당이나체중증가위험없이메트포르민과초기부터병합요법을할수있는약제이며심혈관질환의위험을증가시키지않는다. 인슐린이나설폰요소제와병합시에는저혈당에대한주의가필요하다. 경도의혈압강하효과와식후고지혈증의개선등을포함한심혈관질환위험인자에대한이로운효과등이혈당조절효과외에자주관찰되었지만더장기적인치료경험과현재진행중인대규모임상연구결과등이더나오면심혈관질환에대한영향이더명확해질것이다. 또한그외에도 DPP-4 및 DASH의작용과 DPP-4 억제제의영향에대한추가연구가필요할것이다. 중심단어 : 인크레틴 ; Glucagon-like peptide-1; Glucose-dependent insulinotropic polypeptide; Dipeptidyl peptidase-4 억제제 ; 제2형당뇨병 - 6 -

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract