The Korean J ournal of Inte rnal Medicine Vol. 16, No. 2, J une , 2001 T h e Eff e ct o f C ilo s t a z o l o n G lu c o s e T o le r a n c e a n d In s u lin Re s is t a n c e in a Ra t M o d e l o f N o n - in s u lin De p e n d e nt Dia b e t e s M e llit u s S a n g A h C h a n g , M . D. , Bo n g Yu n C h a , M .D.*, S o o n J ib Yo o , M .D. , Yo o Ba e A h n , M .D., Ki Ho S o n g , M .D. , J e Ho Ha n , M .D., J o n g M in Le e , M .D. , Hy u n S ik S o n , M .D. , Ku n Ho Yo o n , M . D. , M o o IL Ka n g , M .D. , Kw a n g W o o Le e , M .D. , Ho Yo u n g S o n , M .D. , a n d S u n g Ku Ka n g , M .D. De p a rt m e nt of Inte rna l M e d ic ine , Cat ho lic Un iv e rs ity Me d ica l Co lle g e , S e o u l, Ko re a B a c kg ro u n d : It h as b e e n re p o rt e d t h at m a ny p e rip he ra l v a s o d ilat ing d rug s m ig ht im p ro v e ins u lin re s is t a n ce . C ilo s t az o l, a a nt it h ro m b o t ic ag e nt , in c re as e s p e rip h e ra l b lo o d f lo w in no n - ins u lin d e p e nd e nt d ia b e t ic p at ie nt s . T h e e f f e ct o f c ilo st azo l t re at m e nt o n ins u lin re s is ta nce in s t re p to zoto c in (S T Z ) - ind uce d no n - ins u lin d e p e nd e nt d ia be t ic W is ta r rat s w as e x a m ine d . M e t h o d s : A b o ut a h a lf o f tw o -d ay o ld ne o nat e s ib ling s w e re inj e ct e d int ra p e rito ne a lly w it h S T Z a nd m a int a in e d f o r s ix m o nt h s , at w h ic h t im e t he y w e re c o m p a re d w it h ag e - m at c h e d c o nt ro l rats f o r int ra p e rito ne a l g luc o s e t o le ra n ce t e s t ( IPGT T ) a nd f o r g luc o s e inf us io n rat e (G IN F) in a e ug ly ce m ic hy p e rins u line m ic g luc o s e -c la m p s t udy . A f t e r t h at , t he s e s t ud ie s w e re a ls o p e rf o rm e d af t e r f e e d ing rat c ho w c o nt a in ing c ilo s t az o l ( 10 0 m g/ kg/ d ay ) t o rats w it h S T Z - ind u ce d no n - in s u lin d e p e n d e nt d ia b e te s m e llit u s f o r f o u r-w e e ks a nd c o m p a re d w it h t ho s e o f ag e - m at c he d c o nt ro l rat s . R e s u lt s : In t h e int ra p e rit o n e a l g lu co s e to le ra nc e te s t s t ud ie s , p las m a g lu co s e le v e ls o f S T Z - ind u ce d no n - in s u lin d e p e nd e nt d ia b e t ic rat s w e re s ig n if ic a nt ly h ig he r a nd p las m a ins u lin le v e ls s ig n if ica nt ly lo w e r t ha n t ho s e o f ag e - m atc he d c o nt ro l rat s in t h e ag e o f s ix m o nt hs . G luc o s e inf u s io n rat e w as lo w e r in S T Z - ind u ce d no n - in s u lin d e p e n d e nt d ia b e t ic rat s t h a n t ho s e o f ag e - m atc he d c o nt ro l rat s . Ho w e v e r, af t e r a f o u r-w e e k c ilo s ta zo l t re at m e nt , g luc o s e inf u s io n rat e o f S T Z - in d uc e d no n - ins u lin d e p e nd e nt d ia b e t ic rat s w a s no t s ig n if ica nt ly d if f e re nt f ro m t hat o f co nt ro l rat s . C o n c lu s io n : T he s e f in d ing s s ug g e s t e d t hat c ilo s ta zo l m ay im p ro v e in s u lin re s is t a nc e in S T Z - in d uc e d no n - in s u lin d e p e nd e nt d ia b e t ic rat s . Ke y W o rd s : Cilostaz ol; Insulin resistance; Streptoz otocin-induced non-insulin dependent diabetic rat; Euglycemic hyperinsulinemic clamp technique; Glucose tolerance test INT RO D UCT IO N diabetes mellitus. It is well known that insulin resistance accompanies increased peripheral vascular resistance. Insulin resistance is one of the major pathophysiologic In addition, increased peripheral vascular resistance may findings in non- insulin dependent diabetes mellitus. exacerbate insulin resistance by inhibiting the access of Improvement of insulin resistance is one of the major insulin and glucose to skeletal muscle cells. These goals in the management of non- insulin dependent findings have recently been supported by observations that peripheral vasodilating drugs, such as angiotensin Address reprint requests to : Bong Yun Cha, M.D., converting enzyme inhibitors and alpha- 1- adreno- Department of Internal Medicine, Catholic University Medical College, # 505 Banpo-dong Seocho-ku, Seoul 137-040, receptor antagonists, improve insulin resistance by Korea increasing insulin mediated glucose disposal1 , 2 ) . 87 S.A. Chang, B.Y. Cha, S.J. Yoo, Y.B. Ahn, K.H. Song, J.H. Han, J.M. Lee, H.S. Son, K.H. Yoon, M.I. Kang, K.W. Lee, H.Y. Son, S.K. Kang Cilostazol (6- [4- (1- cyclohexyl- 1- H-tetrazol-5-yl)butoxyl]- 2. Glucose Tolerance Test with Measurement of 3,4-dihydro-2(1H) quinolinone), a novel synthetic anti- Insulin and Free Fatty Acid Levels thrombotic drug, has been shown to have potent in vitro Intraperitoneal glucose tolerance tests (IPGTT) (2 g/kg and in vivo inhibitory effects on platelet aggregation body weight) were performed under pentobarbital induced by almost all physiological aggregator sub- anesthesia (4 mg/100 g body weight IP). Control and stances, including adenosine diphosphate (ADP), col- STZ- induced non- insulin dependent diabetic rats were lagen, epinephrine, platelet activating factor (PAF) and fasted for 16 hr after which time they were given an IP thromboxane A2 (TXA2)3 ) . In addition, this drug has been injection of 20% glucose solution. Blood samples were shown to increase blood flow and to ameliorate the drawn from the eyeball capillary plexus before and 15, hypertriglyceridemia in insulin- resistant non- insulin dependent 60 and 120 minutes after the glucose challenge. Blood diabetes mellitus4 - 8 ) . Thus, it is possible that cilostazol samples were immediately centrifuged at 4℃ and may improve insulin resistance by increasing peripheral plasmas were stored at -20℃ until assayed.