Diabetologia 9 Springer-Verlag 1984

Transcription

1 Diabetlgia (1984) 27:8-12 Diabetlgia 9 Springer-Verlag 1984 Tlbutamide des nt alter insulin requirement in Type 1 (insulin-dependent) diabetes K. P. Ratzmann, B. Schulz, P. Heinke and W. Besch Central Institute f Diabetes "Gerhardt Katsch", Karlsburg, GDR Summary. We examined whether tlbutamide has any acute r shrt-term effects n insulin actin in Type 1 (insulin-dependent) diabetes. A euglycaemic glucse clamp was perfrmed in seven Type 1 diabetic patients withut clinical insulin resistance by infusing glucse at a cnstant rate f.1 mml. kg -1. rain -1 fr 3 h tgether with a simultaneus insulin infusin using an 'artificial pancreas'. The insulin infusin rate required t maintain bld glucse at 6.7 mml/1 at a set lw glucse infusin rate prvides an index f insulin actin in viv. The euglycaemic clamp was perfrmed n 3 separate days in the same patient: (1) in the basal state; (2) during simultaneus intravenus tlbutamide infusin f.5 g/h, and (3) after treatment with 2.5 g tlbutamide/day fr 6 days in additin t insulin. The insulin infusin rate needed t maintain the set bld glucse level did nt differ significantly between the three experimental cnditins ( versus 1.3 _.3 versus 1.2 _.3 U/h). Plasma glucagn, grwth hrmne, nn-esterified fatty acid and glycerl levels did nt differ between cntrl r sulphnylurea treatment studies. The results suggest that tlbutamide des nt exert any acute r shrt-term effects n insulin actin in viv in Type 1 diabetes. Our results d nt prvide supprt fr the idea that this agent is a clinically useful adjunct t insulin in such patients. Key wrds: Tlbutamide, insulin, euglycaemic glucse clamp, [3 cell, Type 1 diabetes. The extra-pancreatic effects f sulphnylureas have been reviewed extensively [1, 2]. Ptentiatin f insulin actin after sulphnylurea treatment has been described in dgs [3] and Type 2 (nn-insulin-dependent) diabetes [4-6]. Cnversely, ther studies in-viv and invitr failed t cnfirm the effect f sulphnylureas n insulin-mediated glucse uptake r insulin receptr binding [7-14]. Resistance t the hypglycaemic effect f insulin in nn-bese, Type 2 diabetic subjects and patients with impaired glucse tlerance has been dcumented with a variety f techniques [15-18]. Mre recently, impaired insulin actin in Type 1 diabetes has been demnstrated, using the smatstatin mdificatin f the quadruple infusin technique [15] r the euglycaemic insulin clamp technique [19]. Bth hepatic and peripheral resistance t the actin f insulin may cntribute t hyperglycaemia in Type i diabetes [2], althugh it is well knwn that insulin receptr binding is either nrmal r smewhat abve nrmal in this cnditin [1, 21]. Since sulphnylurea cmpunds can alter pstreceptr insulin actin [22], this study examined whether tlbutamide exerts any acute r shrt-term effects n insulin actin in Type I diabetes. Subjects and methds Subjects Seven male nn-bese Type 1 diabetic patients, aged 2-46 years were studied (Table 1). All were admitted t the hspital t imprve their diabetic cntrl. They were all ketsis-prne and insulin-dependent since diagnsis. Nne had any ther illness r nephrpathy. Back- grund retinpathy was present in fur patients, and tw had neurpathy. Nne was taking any drugs ther than insulin. Fur patients had n significant endgenus insulin secretin (fasting C-peptide levels <.8 nml/1), whereas three had fasting C-peptide cncentratins between.9 and.41 nml/l (Table 2). Infrmed cnsent was btained after fully explaining the purpse and nature f the study. These studies were apprved by the lcal Ethical Cmmittee. Assessment f insulin sensitivity in viv An euglycaemic glucse clamp was perfrmed by means f a glucse cntrlled insulin infusin system (Bistatr, Life Science Instruments, Elkhart, Indiana, USA). Carbhydrate metablism was well cntrlled by fur injectins f sluble insulin befre the study. On the day f the experiment, the patients received their last injectin f sluble insulin at 2. h. After an vernight fast, patients were cnnected t the Bistatr at 7. h. After a 3 min cntrl perid, the cmputer was prgrammed t achieve a bld glucse level f 6.7 mml/1 (static plus dynamic cntrl f insulin infusin). Fasting hyperglycaemia (ranging frm 8-12 retl/l) was rendered nrmal by the glucse-cntrlled insulin infusin and the pre-prgrammed bld glucse cncentratin f 6.7 mml/l was achieved within 2h. After an additinal 3min perid in which the pre-prgrammed bld glucse level f 6.7 mml/l was maintained, an intravenus glucse infusin f.1 mrnl.kg bdy weight-~.min -~ was given fr 3 h. The plasma glucse cncentratin was determined every minute and the mean steady-state glucse cncentratin was calculated fr every hur f the glucse insulin infusin. Using the euglycaemic glucse-clamp technique, the rate f exgenus insulin infusin was adjusted by the Bistatr t maintain nrmglycaemia with a set lw glucse infusin rate. The insulin infusin rate needed t maintain the pre-prgrammed steady-state plasma glucse level prvides a measure f insulin actin in viv. We have assumed that the insulin requirement reflects tissue sensitivity t insulin. We have cnsidered the steady-state glucse cncentratin during the last hur f the study in rder t calculate the insulin requirement. Bld samples were btained simultaneusly fr the measurement f C-peptide, grwth hrmne, pancreatic glucagn, nn-esterified fatty acid and glycerl cncentratins.

2 K.R Ratzmann et al.: Effect f tlbutamide n insulin requirement Table/. Clinical characteristics f the patients studied Patients Age (years) Duratin f Bdy weight Relative bdy Insulin requirement diabetes (years) (kg) weight (%) (U/day) (U. kg- 1. day -1) Mean _ Table 2. C-peptide values during an infusin f glucse (.1 retl, kg -1- rain -I) cntrlled by the "Bistatr' in six Type 1 diabetic patients C-peptide (nml/l) at time (rain) Patients Cntrl study , ,2.1.2, , ~ Mean_+.12_+.6.13_+.8.13_+.8.15_ _ ,16_+.1 Intravenus infusin f 1, ,1.1.5 g tlbutamide/h fr 3 h ,21, Mean_+.7_+.3.7_+.3.8_+.4.9_+.4.12_+.5.12_+.6.12_+.6.13_+.6.12_+.6 Oral treatment with 1.2, ,1 2.5 g tlbutamide/day in additin t insulin A 9 therapy fr 6 days 4.3 (3) (4) Mean _+.6.12_+.6.12_ _+.6.11_ Results expressed as mean +. a The C-peptide values f ne patient were belw the detectin limit f the methd used In each patient, insulin sensitivity was studied accrding t the fllwing prtcl n three ccasins n 3 separate days: (1) insulin sensitivity was evaluated in the fasting state; (2) after 3 days, the study was repeated with a tlbutamide infusin (.5g/h) simultaneusly with the glucse infusin; (3) all patients were treated with 2.5 g tlbutamide/day fr 6 days in additin t their insulin. The patients received the last dse f 1. g tlbutamide befre they were cnnected t the Bistatr. The studies were always perfrmed in the same sequence. Each patient served as his wn cntrl. The daily treatment schedule, i.e. diet, insulin and physical activity remained unchanged during the entire study. Tile diet f calries was divided int three meals and three snacks, each cntaining 5% carbhydrate, 3% fat and 2% prtein f energy cnsumptin. The bdy weight did nt change during the study. Analytical methds The plasma glucse cncentratin was measured enzymatically (Bistatr). C-peptide levels were measured after the remval f prinsu- lin and alchlic extractin [23]. Grwth hrmne cncentratin was determined by radiimmunassay [24]. Pancreatic glucagn was measured with specific antiserum R4 which did nt crss-react with prcine gut glucagn-like immunreactivity in the physilgical range [25]. Nn-esterified fatty acids (NEFA) were estimated accrding t Duncmbe [26] and glycerl cncentratins accrding t Eggstein and Kreutz [27], Results are presented as mean _+, and the paired t-test was used fr statistical analysis. Results Treatment with tlbutamide in additin t insulin fr 6days failed t imprve glycaemic cntrl in these ~l~r 1 diabetic patients. The ttal daily insulin dse re- mained unchanged (41 U r.6 U/kg bdy weight), and the mean bld glucse values (mean f nine measurements in the curse f 24 h) taken I day befre

3 1 K.P. Ratzmann et al.: Effect f tlbutamide n insulin requirement Table3. Steady-state plasma glucse cncentratins during an infusin f glucse (.1 retl, kg -1. min -1) cntrlled by the 'Bistatr' in the cntrl and tlbutamide treatment studies in seven Type I diabetic patients Cntrl study Intravenus infusin f.5 g tlbutamide/h fr 3 h Oral treatment with 2.5 g tlbutamide/day in additin t insulin therapy fr 6 days Results expressed as mean_+ 1- E E m g c 2- El Steady-state plasma glucse cncentratin (mml/l) at: 6 min rain rain Stedy stre p[srnct glucse cncentrtin Insulin applied by the Bicstatr Fig. 1. Steady-state plasma glucse cncentratin (12 18 rain) and insulin requirement during a cntinuus infusin f glucse (.1 mml- kg -1 bdy weight-min-1) cntrlled by the 'Bistatr' in seven Type 1 diabetic patients. ["]= cntrl study withut tlbutamide; [] = cmbined infusin f glucse and tlbutamide (.5 g/h); [] = study after treatment with 2.5 g tlbutamide/day in additin t insulin fr 6 days (7.7 mml/1; range mml/1) and 6days after sulphnylurea treatment (7.7mml/1; range mml/1) were cmparable. During the euglycaemic glucse clamp, the glucse cncentratin was held clse t the pre-prgrammed level. The mean steady-state plasma glucse cncentratin f the entire study perid (3 h) was identical in all the three experimental cnditins (Table 3). We used the steady-state glucse cncentratin during the last hur f the study t calculate the insulin requirement. The stability f the plasma glucse cncentratin during the last hur f the euglycaemic glucse clamp (![2-18 rain) is indicated by the cefficient f variatin which averaged 3.5_.5%, 4.4.8% and % n the three ccasins, respectively. The rate f insulin infusin needed t maintain euglycaemia with the set lw glucse infusin was nt significantly altered by acute r shrt-term tlbutamide treatment (Fig. 1). The mean rates f insulin infused by the Bistatr during the glucse clamp were t , and U/h, respectively. Endgenus insulin secretin was nt significantly altered under the experimental cnditins in the cntrl and sulphnylurea treatment studies as indicated by C-peptide measurement (Table 2). There were n significant differences in the fasting glucagn levels at the beginning f the experiment n three separate days (Table 4). In additin, glucagn respnse patterns did nt differ significantly between cntrl and sulphnylurea treated patients. There were majr individual variatins amng patients in grwth hrmne respnse as shwn by the large standard deviatins (Table 4). During the perid f steady-state plasma glucse cncentratin, i.e. during the last hur f the glucse clamp, grwth hrmne cncentratin did nt differ significantly between the cntrl and the tlbutamide-treated patients (Table 4). Mean plasma NEFA and glycerl cncentratins were nt significantly altered during either the glucse infusin alne r during acute r shrt-term tlbutamide treatment. In additin, the plasma NEFA and glycerl levels did nt differ between the cntrl and the sulphnylurea treatment studies (Table 4). Discussin Over the past 15 years, several studies have dealt with the questin f whether sulphnylureas exert an extrapancreatic effect. Ptentiatin f insulin actin n varius tissues by sulphnylureas has been described [22, 28-33]. Several reprts indicate that these drugs increase the number and/r affinity f insulin receptrs [4, 34-36]. Cnversely, ther wrkers have been unable t demnstrate the effectiveness f sulphnylureas in vitr n insulin receptr binding in rat adipcytes [22], human fibrblasts, lymphcytes, mammary carcinma cells, and rat hepatcytes [37, 38]. In additin, ther authrs have shwn that varius sulphnylureas have n acute r shrt-term effects n insulin actin in vitr [8, 9, 11, 12, 37]. Our shrt-term study with tlbutamide in additin t insulin demnstrated neither imprved glycemic cntrl nr altered insulin requirement in Type 1 diabetes. Thus, we were unable t shw that this agent is a dinically useful adjunct t insulin in this cnditin. In agreement with ur findings, Grunberger et al. [1] and Ward et al. [13] failed t demnstrate any additive effect f sulphnylurea treatment t insulin n the cntrl f bld glucse in Type I diabetic patients. In accrdance with these clinical bservatins, ur findings demnstrate that tlbutamide des nt exert any acute r shrt-term effects in augmenting the efficacy f insulin actin in viv in Type I diabetes. In the present study, we cmpared the insulin requirement fr a pre-prgrammed lw glucse infusin rate with a eu-

4 K.P. Ratzmann et al.: Effect ftlbutamide n insulin requirement 11,.. c~ 2.~, ~ 9 ~ eel ~D e~ % Z ~ l l +1 d ~ ~ d dm ~ d d~ l i +l I l [ +l 41 +l ~ glycaemic glucse clamp befre and during acute and shrt-term tlbutamide treatment. We assumed that the insulin infusin rate under the experimental cnditins reflected insulin sensitivity. Thus, the insulin requirement needed t maintain a pre-prgrammed steadystate plasma glucse cncentratin was used as a rugh index f the bdy's sensitivity t insulin. Studies using a priming-cnstant 3-H3-glucse tracer infusin have shwn that hepatic glucse prductin is markedly, but nt ttally, suppressed during a superimpsed lw glucse infusin f.1 mml.kg -1. rain-t in healthy subjects and patients with diminished insulin respnse [39]. Our previus studies [6, 4, 41] and ther investigatins [42-44] have shwn that an insulin infusin in the range used in the present study resulted in a mild degree f physilgical hyperinsulinaemia. Since the peripheral utilizatin f glucse is augmented during the lw glucse lad [39], we assume that insulin acts bth n hepatic glucse prductin and peripheral glucse uptake under the current experimental cnditins. The present experiments d nt differentiate whether tlbutamide exerts any effect n insulin-mediated suppressin f hepatic glucse prductin r tissue glucse uptake. Hwever, ur apprach prvides a means f cmparing the efficacy f insulin actin in viv befre and after tlbutamide treatment. Endgenus insulin secretin, and hrmnal and metablic insulin antagnist levels, such as pancreatic glucagn, grwth hrmne and NEFA, were nt significantly altered by acute r shrt-term tlbutamide treatment under these experimental cnditins. The failure t demnstrate any acute r shrt-term extra-pancreatic effects f tlbutamide in Type 1 diabetic patients is in agreement with reprts n frearm insulin-mediated glucse uptake in nrmal and diabetic man [7, 14]. Grunberger et al. [1] demnstrated similar results. Shrt-term treatment with sulphnylureas in additin t insulin in Type 1 diabetic patients did nt alter insulin binding t circulating mncytes r erythrcytes. We cnclude that tlbutamide des nt exert any acute r shrt-term effect n the efficacy f insulin actin in viv in Type 1 diabetes. Our results d nt prvide supprt that this agent is a clinically useful adjunct t insulin in Type 1 diabetes.,xz 41 Acknwledgements9 Investigatins have been carried ut in the medical research prject "Diabetes mellitus and disturbances f lipid metablism" supprted by the Ministry f Health, GDR. Presented, in part, at the 18th Annual Meeting f EASD, Budapest, 1-4 September % c~ e~ L) -= i References 1. LebvitzHE, FeinglsMN (1978) Sulfnylurea drugs: mechanism f antidiabetic actin and therapeutic usefulness9 Diabetes Care 1: Ratzmann KP (1983) Neue Aspekte in der Therapie des Diabetes mellitus mit Sulfnylhamstffen? Dtsch Gesundheitswes 38:

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Ratzmann Centre fr Diabetes and Metablic Disrders KlsterstraBe Berlin, GDR