The pathophysiology of non-insulin-dependent

Transcription

1 R I G I N A L A R T I C L E Metablic Effects f New ral Hypglycemic Agent CS- 045 in NIPPM Subjects STEPHAN L. SUTER, MD JHN J. NIAN, MD PENNY WALLACE, RN BARRY GUMBINER, MD JERRLD M. LEFSKY, MD BJECTIVE T study the metablic effects f a new ral antidiabetic agent, CS-045, in subjects with nn-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHDS Eleven NIDDM subjects (mean age 59 yr and bdy mass index 32.3) were treated with 400 mg/day CS-045 fr 6-12 wk. Patients were hspitalized befre and at the end f the drug-treatment perid fr metablic studies, including ral glucse tlerance test (GTT), meal tlerance test (MTT), euglycemic glucse-clamp studies, and lipid analyses. RESULTS Eight subjects shwed a marked clinical respnse t the drug, whereas 3 were nnrespnders. The data were analyzed bth fr the ttal grup and fr the respnders. Fasting plasma glucse (FPG) fell frm 12.5 ± 0.7 t 10.7 ± 1.0 mm in the ttal grup but fell mre dramatically frm 12.7 ± 0.5 t 8.3 ± 0.6 mm in the respnder grup. The area under the GTT glucse curve imprved by 17% in the ttal grup and by 29% in the respnders. The area under the MTT glucse curve imprved by 38 and 52%, respectively. MTT levels f insulin, free fatty acids, and glucagn were significantly lwer after treatment. Glucse dispsal rates during glucse-clamp studies were increased in all subjects after CS-045 treatment. Mean increases were 63% at 120 mu m~ 2 min" 1 and 41% at 300 mu m~ 2 min" 1. Basal hepatic glucse prductin fell by 17% in the ttal grup and by 28% in the respnders. CNCLUSINS CS-045 imprves insulin resistance, reduces insulinemia, lwers hepatic glucse prductin, and imprves bth fasting and pstprandial glycemia in NIDDM subjects. CS-045 may represent a new therapeutic ptin fr NIDDM. The pathphysilgy f nn-insulin-dependent diabetes mellitus (NIDDM) is cmplex, cnsisting f peripheral insulin resistance, increased hepatic glucse prductin, and impaired insulin secretin (1-3). Which f these abnrmalities are primary and which are secndary is the subject f intense study and debate (1-4). Hwever, regardless f the etilgical sequence f events, it is quite clear that insulin resistance is a characteristic feature f essentially all NIDDM subjects and cntributes imprtantly t the hyperglycemic diabetic state. Lgically, then, a ratinal therapeutic pharmaclgical apprach shuld invlve interventin in the insulin resistance t allw imprvement in glucse hmestasis. A class f cmpunds has been recently identified that appears t wrk by either mimicking r enhancing insulin actin withut any effects n (J-cell insulin secretin (5). CS-045 is an example f this new (thizlidinline) class f ral hypglycemic agents. Varius in vitr and animal studies have demnstrated that CS-045 enhances insulin actin at bth the receptr and pstreceptr level in bth peripheral and hepatic tissues (5-7). It has als been clearly demnstrated that this agent des nt enhance insulin secretin (5). Fr these reasns, we have been prmpted t examine the effects f CS-045 in NIDDM patients. In this study, we treated a series f NIDDM subjects with CS-045 fr perids f up t 12 wk and examined varius metablic variables befre and after the drug-treatment perid in a clinical research setting. The purpse was t btain infrmatin n the efficacy, therapeutic prfile, and in viv mechanisms f actin f this newly available ral hypglycemic agent. FRM THE DEPARTMENT F MEDICINE, UNIVERSITY F CALIFRNIA, SAN DIEG, LA JLLA; THE VA MEDICAL CENTER, MEDICAL RESEARCH SERVICE, SAN DIEG, CA; AND THE DEPARTMENT F INTERNAL MEDICINE, MEDIZINISHE PLIKLINIK, UNIVERSITY HSPITAL, ZURICH, SWITZERLAND. ADDRESS CRRESPNDENCE AND REPRINT REQUESTS T JERRLD M. LEFSKY, MD, UNIVERSITY F CALIFRNIA, SAN DIEG, DEPARTMENT F MEDICINE (V-111G), LA JLLA, CA RECEIVED FR PUBLICATIN 12 MARCH 1991 AND ACCEPTED IN REVISED FRM 3 JULY RESEARCH DESIGN AND METHDS Eleven NIDDM patients (6 men, 5 wmen), as defined by the criteria f the Natinal Diabetes Data Grup (8), were studied. All subjects exhibited fasting plasma glucse (FPG) lev- DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY

2 Treatment fniddm with CS-045 Table 1 Clinical characteristics f study ppulatin AGE (YR) WEIGHT PRETREATMENT (KG) WEIGHT PSTTREATMENT (KG) FAT-FREE MASS (KG) BDY MASS INDEX (KG/M 2 ) DURATIN F NIDDM (YR) ± ± ± ± ± 1.1 Values are means ± SE except fr age (mean nly). NIDDM, nn-insulin-dependent diabetes mellitus. Fat-free mass was measured by underwater weighing. UJ C 8 20, els >8.4 mm and a bdy mass index (BMI) >27 kg/m 2. Patients with severe diabetic cmplicatins r ther diseases independent f diabetes (e.g., ischemic heart disease, kidney disease, r liver disease) were excluded, as were subjects with significant bichemical abnrmalities n a clinical labratry screening panel. All patients were either untreated r had been treated with diet and/r ral sulfnylureas. In the latter case, ral agents were withdrawn at least 3 wk befre entry int the prtcl. During the entire study perid, subjects were placed n a weight-maintaining diet (28-32 kcal/kg bdy wt) cnsisting f 55% carbhydrate, 30% fat, and 15% prtein. Patients fllwed this diet fr at least 5 wk befre initiatin f drug therapy. All patients were hspitalized n the VA Medical Center's Special Diagnstic and Treatment Unit (SDTU) fr days befre drug treatment fr metablic studies. At the end f this inpatient perid, CS-045 (200 mg twice a day) was started. Patients were then discharged, and drug treatment was cntinued fr 6-12 wk. During the last days f the drug treatment perid, all patients were readmitted t the SDTU fr repeat metablic studies. Fat-free bdy mass (FFM) was determined by underwater weighing (9) befre the start f the drug-treatment phase. Weight was cnstant thrughut the study (Table 1). During the utpatient phase f the drug-treatment perid, B Ttal grup PRE Respnder grup PST Figure 1 A: mean ± SE fasting glucse values befre (pen bars) and during (hatched bars) CS-045 treatment in ttal grup and respnder grup (P < 0.005)., Nnrespnders; #, respnders. B: mean ± SE fasting insulin levels befre (pen bar) and during (hatched bar) CS-045 treatment. Individual data are pltted, and each subject's data befre and during study are cnnected by lines. 194 DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY 1992

3 Suter and Assciates I 15 ' 10- a: X en LU LU cc u a> TIME (hurs) TIME (hurs) (10,11). Glucse turnver was mnitred by a cncmitant infusin f [ 3 H]glucse and Ra was calculated using the Steele equatins in their mdified derivative frm fr nnsteady-state cnditins (12,13). Basal hepatic glucse prductin rates [ 3 H]glucse was given as a primed cntinuus infusin fr a 4-h equilibratin perid as previusly described (12); the cntinuus rate was 0.6 (ici/min. Hepatic glucse prductin rate was then calculated frm the specific activity f samples taken at 10-min intervals fr a subsequent 30 min. Bld samples were cllected in sdium fluride, iced, and centrifuged, then the plasma was separated and frzen at -20 C. Glucse turnver was calculated with the Steele equatin fr steady state cnditins (12,13). GTTs At 0700, a plastic catheter was placed in an arm vein; 30 min later, a fasting bld sample was drawn. ral glucse (75 g) was slubilized in flavred water and cnsumed ver 5 min. Bld samples were taken at 30-min intervals fr 3h. Ttal Respnders all patients were seen twice a week t mnitr bld glucse levels, bdy weight, ptential adverse reactins, and general well-being. During the inpatient perid, ral glucse tlerance tests (GTTs); 7-h meal tlerance tests (MTTs); measurements f basal glucse turnver; euglycemic glucse-clamp studies; and measurements f FPG, insulin, and lipid levels were carried ut. Euglycemic glucse-clamp studies n separate days, clamp studies at insulin infusin rates f 120 r 300 mu m~ 2 min" 1 were perfrmed befre and after treatment. All studies lasted at least 240 min and were cmpleted after the glucse infusin rate had reached steady state fr at least 60 min. The glucse-clamp studies were carried ut as previusly described 7-h MTTs At 0700, a plastic catheter was placed in an arm vein; 30 min later, a fasting Figure 2 Glucse prfiles during 7- h meal tlerance tests. Meals were fed at 0800 and at bld sample was btained. Patients 1200 as utlined in the text. A: glucse prfiles befre and during CS-045 treatment in 11 were then given a liquid breakfast cn- subjects. B: mean ± SE 7-h glucse prfiles befre and during CS-045 treatment in 8 respnders. taining 33.3% f the daily calries and C: mean ± SE incremental areas under glucse curves in A and B befre (pen bars) and during cnsisting f 50% carbhydrate, 35% (hatched bars) CS- 045 treatment in ttal grup and respnders. fat, and 15% prtein. The rati f plyunsaturated t saturated fat was 1:4. An identical meal was next cnsumed at Bld samples were btained at 0730 and at 60-min intervals fr the next 7 h. Measurements FPG was measured with a YSI autmated glucse analyzer (YSI mdel 23A, Yellw Springs, H). Insulin was measured by radiimmunassay with a DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY

4 Treatment fniddm with CS j " TIME (hurs) Figure 3 Insulin levels during 7- h meal tlerance tests. Data represent mean ± SE insulin values in ttal grup befre () and during ( ) CS-045 treatment. *P < 0.05, **P < duble- antibdy immunprecipitatin technique as previusly described (14). Free-fatty acid (FFA) levels were measured by the methd f Nvak (15). Plasma triglyceride, chlesterl, lwdensity-lipprtein (LDL) chlesterl, and high-density-lipprtein (HDL) chlesterl values were measured accrding t the standardized prcedures f the Lipid Research Clinic (16). Glucagn was measured by radiimmunassay with 40K antibdy (17). CS-045 was prvided in 100-mg capsules by Sanky, Tky, Japan. Unless therwise stated, all data are means ± SE, and differences were analyzed by Student's t test with a Statview sftware package. RESULTS Certain clinical characteristics f the study grup are presented in Table 1. All subjects were bese (BMI >27 kg/m 2 ) and in an age categry typical fr NIDDM. Weight remained stable in all patients thrughut the study. N changes in bld urea nitrgen, creatinine, SGT, SGPT, LDH, r ther rutine clinical labratry tests were nted as a result f CS-045 treatment. FPG and insulin levels The mean FPG during the inpatient perids, befre and after the utpatient treatment phase, was calculated fr each patient. f the 11 patients, 8 shwed a clinical respnse as manifested by lwered FPG values, whereas 3 shwed n reductin in FPG values. Fig. 1A presents the mean ± SE FPG values befre and during CS-045 treatment in the ttal grup and in the 8 respnders. In the ttal grup, FPG fell by 18% (P < 0.005), and in the respnder grup, FPG fell by 35% (P< 0.005) frm 12.7 ± 0.8 t 8.3 ± 0.6 mm. In the 3 nnrespnders, mean FPG was 12.2 and 13.8 mm befre and during treatment, respectively. The time curse f the fall in FPG was quite variable. Significant lwering was generally nt bserved until 2-3 wk f treatment, reaching a maximum effect 2-3 wk later. In sme patients, initial glucse lwering was delayed until 5-6 wk with maximum respnses by wk. Thus, unlike ther frms f antidiabetic therapy, substantial delays (up t several weeks) ccur befre clinical efficacy is realized. A cnsistent decrease in fasting plasma insulin values was bserved, as seen in Fig. IB. Mean values fell frm 30 ± 5 (xu/ml (180 ± 30 pm) t 16 ± 3 xu/ml (96 ± 18 pm) (P < 0.001) and declined in 10 f 11 subjects. The patient whse fasting plasma insulin level did nt fall was a nnrespnder with the lwest initial value. MTTs The mean ± SE 7-h plasma glucse and insulin prfiles befre and during CS-045 in the ttal grup and in the eight respnders are seen in Figs. 2 and 3. Pstprandial glucse levels were imprved by treatment at each time pint (Fig. 2A) and, as expected, were even mre dramatically reduced when the data frm the eight respnders were evaluated (Fig. 2B). Nt nly were the abslute values and ttal areas under the curve lwered, but the pstprandial excursins (i.e., incremental respnses) were als imprved. The incremental area fr the 7-h MTT prfile curve was calculated fr each subject and the results are seen in Fig. 2C. Fr the ttal grup, the mean area fell by 32% (P<0.01); mean area fell by 41% (P< 0.001) fr the respnder grup. This marked fall in daylng glycemia was accmpanied by a substantial decline in pstprandial insulin levels (Fig. 3). Thus, nt nly did CS-045 fail t 196 DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY 1992

5 Suter and Assciates 0.6- i.4-3 < 0.2- u. -n A TIME (hurs) enhance insulinemia, but a sharp reductin was bserved. The mean area under the curve fell by 35% ( x 10 3 xu/h) in the ttal grup and by 34% ( X 10 3 p-u/h) in the respnder grup. Fasting and 7-h pstprandial FFA and glucagn levels were als measured. FFA levels were significantly lwer during treatment at mst time pints (Fig. 4A), and the average value declined by 24% (P < 0.01) in the ttal grup and by 25% (P < 0.05) in the respnder grup. Abslute glucagn levels were variable amng ur subjects, but the mean pretreatment fasting value f 241 ± 56 pg/ml was elevated cmpared with that f healthy subjects (152 ± 52 pg/ml). During drug treatment, the values were significantly lwer at several pints, and the area under the 7-h glucagn curve (Fig. 4B) was mdestly (15%) but significantly (P < 0.01) reduced in bth the ttal grup and the respnder grup. 400-i GTTs z B The mean ± SE GTT results fr the respnder grup befre and during treatment are summarized in Fig. 5B Althugh the glucse values were lwer at all time pints (Fig. 5B), the decrease was less marked than the imprvement in the pstprandial glucse prfile during the MTT (Fig. 2B). This was als HI 300- the case fr the ttal grup, in whm a D) 17% decrease in the GTT curve was wcl bserved (Fig. 5A); n change in the 250- GTT results ccurred in the three nnrespnders. a The crrespnding insulin levels a 200 during the GTTs are given in Fig. 5C. As well-described previusly (18,19), insulin secretin during GTTs in NIDDM subjects with this degree f hyperglycemia is quite lw due t the 150 relatively specific defect in glucsestimulated insulin secretin characteriz TIME (hurs) ing this disrder (20). In ur subjects, the GTT insulin levels were nly 20- Figure 4 Plasma glucagn and free fatty acid (FFA) levels during meal tlerance tests. Data40% as high as the levels achieved after represent values fr ttal grup. A: mean ± SE FFA levels befre () and during ( ) CS-045 the MTTs, despite the fact that ambient treatment. B: mean ± SE plasma glucagn levels befre () and during ( ) CS- 045 treatment. DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY

6 Treatment /NIDDM with CS TIME (min) TIME (mln) right-hand bar in Fig. 6 prvides the mean nrmal value fr basal HG in ur labratry; as can be seen, drug treatment led t an imprvement in HG in the respnder grup t nearnrmal values. As expected, n decrease in basal HG ccurred in the three nnrespnders. Figure 7 presents the relatinship between the FPG level and the rate f basal HG in all subjects befre and during CS-045. A highly significant crrelatin was bserved befre (r = 0.77, P < 0.01) and during (r = 0.80, P < 0.005) drug treatment and fr all data cmbined (r = 0.80, P < 0.01). Furthermre, a strng relatinship was bserved between the change in HG and the change in FPG befre and during treatment (r = 0.77, P < 0.01). glucse levels were higher during the GTTs. The relatively lw levels f insulin were nt significantly changed during CS-045 treatment. It is likely that the relatively lw insulin secretry respnse munted during the GTT accunts fr the lesser reductin in the ambient glucse levels during drug treatment cmpared with the MTT glucse prfiles. Hepatic glucse utput (HG) Increased HG is a characteristic feature f NIDDM subjects with fasting hyperglycemia (1-3), therefre, we measured basal HG befre and during CS-045 treatment. A marked reductin in HG ccurred during CS-045 treatment in the ttal grup (P < 0.05), and this effect was even greater in the respnder grup (P < 0.01) (Fig. 6). The Glucse-clamp studies T quantitate insulin resistance, glucseclamp studies were perfrmed at insulin infusin rates f 120 and 300 mu m~ 2 min" 1 befre and during CS-045 treatment. The data in Fig. 8 demnstrate a highly significant increase in glucse dispsal, at bth insulin infusin rates, during drug therapy and represent the data frm the ttal grup. Imprtantly, this drug-induced imprvement in glucse dispsal rates was bserved in every patient at bth insulin infusin rates. At the 120-mU TIME (min) ~ 2 min" 1 insulin infusin, the prem Figure 5 ral glucse tlerance tests. Glucse levels befre () and during ( ) CS-045 and psttreatment glucse dispsal treatment in ttal grup (A) and respnders (B). C: insulin levels fr ttal grup befre and during rates were: ttal grup, mg CS-045 treatment. kg" 1 min" 1 (59% increase); respnder grup, mg kg" 1 min" 1 (76% increase); and in the three nnrespnders, mg kg -l mm -l (28% increase). Values at the 300-mU m 2 min" 1 infusin were: ttal grup, mg kg" 1 min" 1 (31% increase); respnder grup, mg-kg" 1 - min" 1 (38% increase); and in the three nnrespnders, mg kg" 1 min" 1 (18% increase). Thus, regardless f the clinical respnse with respect t glycemic imprvement, an effect f CS- 198 DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY 1992

7 Suter and Assciates Q tc Q. LLJ (/> 8 < LU 4- -P 3- TTAL GRUP RESPNDER GRUP NRMAL Figure 6 Hepatic glucse prductin rates. Bars represent mean ± SE hepatic glucse prductin rates befre (pen bars) and during (hatched bars) CS-045 treatment in ttal grup and ilgical cause f fasting hyperglycemia. basal HG is the majr pathphys- respnders. Slid bar, mean ± SE basal hepatic glucse prductin rate in 17 weight-matched Therefre, any treatment that reduces nndiabetic cntrl subjects fr cmparisn. Differences between pretreatment and during treatment with CS-045 results were P< 0.01 (respnders) and P< 0.05 (ttal). Individual data are the rate f basal HG shuld ameli- given in left-hand bars fr respnders ( ) and nnrespnders (). 045 t imprve peripheral insulin actin was bserved in all patients, althugh the effect was greater in the respnders. Lipprtein levels Ttal chlesterl, triglyceride, LDL-chlesterl, and HDL-chlesterl levels were measured befre and during CS- 045 treatment in all patients. The mean values are prvided in Table 2. N significant change in ttal chlesterl r LDL-chlesterl levels was bserved, but a mdest rise in HDL-chlesterl levels ccurred. Althugh the increase in HDL chlesterl was mdest, it was quite cnsistent (10 f 11 patients) and highly significant (P < 0.01). A significant (P < 0.01) fall in ttal triglyceride levels was als bserved. CNCLUSINS Peripheral insulin resistance and increased hepatic glucse prductin rates (21-23) are characteristic metablic abnrmalities in patients with established NIDDM (1-3). Because these abnrmalities cntribute imprtantly t hyperglycemia, ideal therapeutic interventins in this disease shuld have sites f actin that imprve these abnrmalities. CS-045 is a new antidiabetic drug frm the thizlidinline class f cmpunds (5,6). In vitr and animal studies have demnstrated that this agent imprves insulin actin at target tissues but has n effect n p-cell insulin secretin (5,6). Additinally, in liver cells, CS- 045 exerts insulinmimetic effects by itself and augments insulin's actins (5,7). Thus, the sites f actin f CS-045 suggest it may have therapeutic ptential in NIDDM. This study is the first reprt f in viv data n the use f this class f cmpunds in NIDDM patients. ur results shw that, in a small grup f wellstudied diabetic subjects, CS-045 treatment led t substantial imprvement in peripheral insulin resistance, lwering f elevated rates f hepatic glucse prductin, and decreased rates f insulin secretin. This was accmpanied by a striking reductin in glycemia, as manifested by reduced fasting and pstprandial glucse levels. Several previus studies have demnstrated a strng crrelatin between the level f fasting hyperglycemia and the magnitude f the increase in basal hepatic glucse prductin in NIDDM subjects (1,11,21-23). This has led t the cncept that increased rate fasting hyperglycemia, and this is brne ut in the current studies. Thus, HG fell in the grup as a whle, but, mre imprtantly, n analysis f the individual data, HG fell in the eight patients wh shwed imprved FPG levels, whereas, in the three patients whse FPG levels did nt fall, n decline in HG was bserved. Furthermre, significant crrelatins existed between HG and the FPG level bth befre and during CS-045 treatment and between the change in HG and the change in FPG. Abnrmally high pstprandial glycemic excursins are largely due t inadequate rates f insulin-mediated glucse dispsal (1,2). This can be due t insulin resistance, inadequate insulin secretin, r a cmbinatin f bth (1,2). Because insulin levels fell after drug treatment in this study, the imprvement in pstprandial glycemic excursins was prbably due t the imprvement in pe- DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY

8 Treatment fmddm with CS-045 LU (/> si HEPATIC GLUCSE UTPUT (mg/kg/min) est insulin-secretry prfiles f the verall grup. ne culd pstulate that an imprvement in peripheral insulin resistance will manifest itself in lwered glycemia nly if sufficient circulating insulin is present t efficiently stimulate muscle glucse uptake. Further studies will be necessary t determine whether the preexisting magnitude f insulin secretin r sme ther metablic factr can distinguish thse diabetic patients wh will respnd with glucse lwering t CS-045 treatment. Because CS-045 appears t exert its in viv hypglycemic effect by imprving peripheral insulin resistance and reducing HG, the circulating plasma insulin levels fell bth in the fasting and pstprandial state. This is in cntrast t the effects f traditinal sulfnylureas, which lead t increased r Figure 7 Relatinship between basal hepatic glucse prductin rate and fasting glucse level. unchanged plasma insulin levels in Data represent individual values fr all subjects befre () and during ( ) CS- 045 treatment. NIDDM subjects (24,25). Because insu- When all pretreatment and during treatment data are cnsidered tgether, r = 0.80 (P < 0.01); fr pretreatment, r = 0.77, P< 0.01; fr during treatment, r = 0.80, P < ripheral insulin resistance. Indeed, glucse-clamp studies shwed imprved insulin-stimulated glucse dispsal in all patients. The ameliratin f insulin resistance may be due t a direct effect f CS-045 n peripheral tissues. Indeed, in vitr studies have demnstrated that this drug can lead t increased insulin receptrs and increased insulin-stimulated glucse uptake (5,6). Because this agent imprves insulin actin in vitr and because the patients wh shwed n lwering f their FPG levels (nnrespnders) still shwed imprvement in insulin resistance, it seems unlikely that the increased insulin-mediated glucse dispsal rates were simply a cnsequence f the fall in FPG level. Regardless f the precise cellular mechanisms, it is clear that a lwering f bth fasting and pstprandial glycemia resulted frm CS-045 treatment, which is prbably due t the reductin in basal HG and imprvement in peripheral insulin resistance. In ur study grup, eight patients respnded t the drug with reductins in hyperglycemia, whereas three did nt. This is quite typical f ral antidiabetic treatment, in which nt all patients respnd t a particular therapy. It is imprtant t nte that, in the nnrespnders, imprvement in insulin resistance was bserved, albeit nt as great as that which ccurred in the respnders. It wuld be f significant clinical imprtance if the clinical r metablic features that determine whether a given patient will r will nt respnd t drug treatment culd be identified. In analyzing individual data n these subjects, ne distinguishing feature was related t insulin levels. Thus, the nnrespnders had the lw- lin resistance and hyperinsulinemia may be additinal risk factrs fr hypertensin and cardivascular disease (3,30,31), the reductin in insulinemia may represent an additinal clinical benefit f this frm f antidiabetic therapy. A ptentially imprtant finding related t imprvement in cardivascular risk emerged frm ur measurements f plasma lipid levels. CS-045 treatment was assciated with a cnsistent and highly significant increase in HDL-chlesterl levels, and the inverse relatinship between plasma HDL-chlesterl cncentratin and cardivascular risk has been well-described (32). The magnitude f the increase in HDLchlesterl levels bserved in ur study is cmparable t that achieved by treatment f hyperlipidemic patients with standard lipid-lwering drugs (33). We als bserved a highly significant decline in plasma triglyceride levels after 200 DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY 1992

9 Suter and Assciates LLJ 10, 8- g 6- Q. E 22 ) in ) 4- (0 E w 3 2- Befre After Befre After Figure 8 Glucse-clamp studies. Bars represent mean ± SE glucse dispsal rates befre (pen due t a nnspecific r placeb effect. bars) and during (hatched bars) CS-045 treatment during 120-mU m~ 2 mtn~ J insulin-infusin Thus, weight and diet were rigrusly studies (left side) and 300-mU m~ 2 min~* insulin-infusin studies (right side). Differences maintained cnstant thrughut the between pre- and pst-cs-045 results were P< 0.01 at each insulin dse. Mean ± SE steadystate glucse and insulin values befre and during CS-045 treatment were 90 ± 1 vs. 95 ± 2 mmcian supervisin were initiated 5 wk study (Table 1), and dietary and physi- and M8 ± 29 vs. 359 ± 25 pm fr the 120-mU m~ 2 min' 1 infusin and 92 ± 1 vs. 92 ± 1 befre the start f drug treatment. mm and 2220 ±170 vs ± 86 pm fr the 300-mU m~ 2 min~* insulin infusin, respec-bltively. Individual data represent respnders ( ) and nnrespnders glucse levels were stable in the (). drug treatment. The psttreatment increase in HDL-chlesterl levels and decrease in triglyceride levels in the face f n change in ttal chlesterl and LDL-chlesterl cncentratins represents a lipprtein pattern that might have a lng-term beneficial effect n cardivascular disease, which is a well-knwn, frequently assciated cmplicatin f NIDDM. Table 2 Plasmid lipid levels (mg/dl) befre and during CS-045 treatment TTAL CHLESTERL LDL CHLESTERL HDL CHLESTERL TTAL TRIGLYCERIDES BEFRE 210 ± ±8 38 ± ± 28 LDL, lw-density lipprtein; HDL, high-density lipprtein. DURING 225 ± ±8 42 ± ± 18 NS NS An interesting aspect f this frm f antidiabetic drug treatment is the issue f hypglycemia. It culd be argued that, n a physilgical basis, hypglycemia shuld nt be a ptential side effect f this frm f therapy, and, indeed, n hypglycemic episdes were bserved in any f the subjects. Because the predminant mde f actin f this drug is t imprve peripheral and hepatic insulin resistance, the nrmal (3-cell feedback mechanisms are maintained. Indeed, this was manifested by the striking reductin in plasma insulin levels bserved after CS-045 treatment. Thus, as insulin sensitivity increases, plasma insulin wrks mre effectively and glucse levels fall, leading t a negative feedback mechanism that shuld prevent excessive insulin actin and result in avidance f hypglycemia. Althugh this study was nt placeb cntrlled, it seems unlikely that the imprvement in glycemia and in the ther metablic events culd be study grup during the last 2-3 wk f this pretreatment perid. Additinally, glycemic lwering ccurred 2-3 wk after nset f treatment. Therefre, after entry int the study (with the start f physician and dietitian supervisin, glucse mnitring, and frequent hspital visits) all patients had at least 4 wk f stable glycemic values. In summary, this study has demnstrated that treatment f NIDDM subjects with a new ral antidiabetic agent, CS-045, leads t enhanced insulin sensitivity, reduced rates f hepatic glucse prductin, lwered circulating insulin levels, and clinically significant imprvement in bth fasting and pstprandial hyperglycemia. Because these are the first reprted clinical studies with this new agent, it is quite pssible DIABETES CARE, VLUME 15, NUMBER 2, FEBRUARY

10 Treatment f NIDDM with CS-045 that therapy might be made mre effective by using higher dses, lnger treatment perids, r, pssibly, cmbinatins f CS-045 with either sulfnylureas r small dses f insulin. In any event, this agent may prve t be a ptentially imprtant new treatment fr NIDDM that will eventually add t the clinician's armamentarium fr the treatment f this disease. Acknwledgments This wrk was supprted in part by Natinal Institutes f Health Research Grant DK-33649; the Department f Veteran Affairs, VA Medical Center, San Dieg; Natinal Institutes f Health General Clinical Research Center Grant RR-00827; and a grant frm the Sanky Cmpany, Ltd., Tky, Japan. S.L.S. was the recipient f a research fellwship grant frm the Schweizerischer Natinalfnds zur Frderung der Wissenschaftlichen Frschung, Switzerland. We thank Elizbeth Martinez fr excellent wrk in preparatin f this manuscript and Tim Ditzler fr preparatin f the figures. 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