Diabetologia 9 Springer-Verlag 1993

Transcription

1 Diabetlgia (1993) 36: Diabetlgia 9 Springer-Verlag 1993 Impact f injectin sites fr sluble insulin n glycaemic cntrl in Type 1 (insulin-dependent) diabetic patients treated with a multiple insulin injectin regimen J. E. Henrikscn l, M. S. Djurhuus 2, A. Vaag I, P. Thye-Rnn 1, D. Knudsen 3, O. Hther-Nielsen t, H. Beck-Nielsen 1 Diabetes Research Centre, Odense University and Department f Endcrinlgy and Internal Medicine M, Odense University Hspital, Odense, Denmark 2 Department f Clinical Chemistry, Odense University Hspital, Odense, Denmark 3 Department f Radilgy, Odense University Hspital,Odense, Denmark Summary. The absrptin rate f rapid acting (sluble) insulin is slw frm the subcutaneus tissue f the thigh cmpared t intramuscular injectin int the thigh and s. c. injectin int the abdminal wall. The aim f the study was t evaluate the impact f sluble insulin injected either intramuscularly int the thigh (IMT), s. c. int the abdminal wall (SCA) r s.c. int the thigh (SCT) n glycaemic cntrl in Type 1 (insulin-dependent) diabetic utpatients treated with the basal blus insulin delivery regimen. Fifty-five, C-peptide negative Type 1 diabetic utpatients were included in a randmised 3-mnth interventin study. The insulin dses were adjusted frequently by blinded bservers based n the patients' self-mnitred bld glucse values and reprted hypglycaemic episdes. The serum fructsamine value was within nrmal limits in three patients in the IMT grup, in six patients in the SCA grup and in nne f the patients in the SCT grup fllwing the interventin perid (p < 0.01). Hwever, the difference in mean serum fructsamine values did nt reach statistical significance (IMT: 1.24 retl/1 (95 % cnfidence interval; 1.17 t 1.31), SCA: 1.25 mml/1 (1.18 t 1.32), SCT: 1.34 mml/1 (1.26 t 1.41), (p = 0.09)). Bld glucse excursins were larger in the SCT grup than in the SCA and IMT grup frm pst-lunch t pre-dinner measurements and frm pre- t pst-dinner measurements. A higher number f measured lw ncturnal bld glucse values (less than 4 mml/1) was bserved in the SCT grup (34 f 85) than in the IMT (14 f 64) and SCA (21 f 81) grup (p < 0.05). Three patients in the IMT grup, tw in the SCA grup, and seven in the SCT grup experienced severe hypglycaemic episdes (p = 0.14). In cnclusin s. c. injectin f sluble insulin int the abdminal wall is preferable cmpared t s. c. injectin int the thigh in the basal blus insulin delivery regimen. Furthermre, sluble insulin injectin s. c. int the thigh during daytime has imprtant clinical implicatins fr the develpment f ncturnal hypglycaemia independently f the NPH insulin injectin at bedtime. Key wrds: Insulin pharmackinetics, intramuscular insulin injectin, subcutaneus insulin injectin, bld glucse cntrl, ncturnal hypglycaemia. The multiple insulin injectin regimen (basal blus insulin delivery regimen) is based n injectins f sluble (rapid acting) insulin at mealtimes and injectins f NPH (intermediate acting) insulin at bedtime. The purpse f this insulin regimen is t mimic the nrmal diurnal plasma insulin prfile [1]. Thus, the purpse f the blus cmpnent is t prvide insulin delivery adequately timed t the absrptin f the meal, whereas the purpse f the basal cmpnent is t prvide adequate insulinisatin during the night time and between meals. Obviusly, insulin delivery depends n the absrptin rate f the injected insulin and this has been demnstrated t vary cnsiderably between different anatmical regins [2-12]. It has been shwn, that the preferred injectin site fr NPH insulin is the subcutaneus (s.c.) tissue f the thigh [8, 10-12]. Thus, this injectin site prduces the mst cn- stant insulin absrptin rate with the smallest peak in plasma insulin [8, 10-12]. Furthermre, the subcutaneus tissue f the thigh is the injectin site with the lwest intrapatient cefficient f variatin f absrptin [10]. Hwever, the absrptin rate f sluble insulin frm the subcutaneus tissue f the thigh is t slw t adequately mimic the nrmal spikes in plasma insulin fllwing the meals [2]. Thus, apprximately 50 % f the s.c. injected insulin is absrbed after 5 h cmpared t 2 h after intramuscular (i.m.) injectin int the thigh [2, 4]. The absrptin rate f sluble insulin frm the abdminal wall is as fast as i.m. injected insulin int the thigh [4, 8, 13] and the absrptin rate is faster than seen after s.c. injectin int the thigh [6-8]. The cnsequence f a slw absrptin rate f sluble insulin is relative hypinsulinaemia after a meal and relative hyperinsulinaemia befre the next meal. In turn, this enhances pst-prandial hyperglycaemia

2 J. E. Henriksen et al.: Sluble insulin injectin and glycaemic cntrl 753 Table 1. Clinical characteristics, at randmisatin, f 49 Type 1 diabetic patients randmly assigned fr use f either the intramuscular tissue f the thigh (IMT), the subcutaneus tissue f the abdminal wall (SCA) r the subcutaneus tissue f the thigh (SCT) fr injectin f sluble insulin Grup IMT SCA SCT n 14 Sex (male/female) 9/5 Age (years) 30.4 (1848) Duratin f diabetes (years) 12.6 (5-22) Number f patients with retinpathy nn-prliferative prliferative Number f patients with micralbuminuria BMI (kg/m 2) Weight (kg) Glycated haemglbin (%) Serum fructsamine (mml/1) Patients with se-fructsamine value within nrmal range number f patient 0 % (95% CI) 0% (0t23) Values are mean (range r 95 % cnfidence interval) /7 12/ (18-56) 34.7 (18-57) 16.5 (~29) 14.4 (1-28) (22.0 t 24.7) 23.8 (22.7 t 24.9) 24.6 (23.3 t 24.9) 71.9 (66.4 t 77.4) 70.5 (65.7 t 75.4) 74.5 (69.2 t 79.9) 8.1 (7.4 t 8.8) 8.3 (7.6 t 9.1) 8.7 (8.0 t 9.3) 1.40 (1.29 t 1.51) 1.39 (1.29 t 1.48) 1.48 (1.37 t 1.59) 1 2 6% (0t 29) 11% (1 t 35) and causes an increased risk fr pre-prandial hypglycaemia. We previusly demnstrated in an inpatient crss-ver study that i.m. injectin f sluble insulin int the thigh clearly generates an insulin prfile with meal-related peaks in plasma insulin whereas the peaks btained after s. c. injectin int the thigh were blunted [2]. Cnsequently, the cefficient f variatin f bld glucse cncentratins during the study perid was significantly higher fllwing s. c. injectins int the thigh cmpared t the perid with i.m. injectins. Therefre, ur previus study indicated that i.m. injectin f sluble insulin in the basal blus insulin delivery regimen may be beneficial cmpared t s.c. injectin int the thigh. On the ther hand, ther investigatrs have warned against an increased risk fr exercise-induced hypglycaemia fllwing i.m. injectin f sluble insulin [3,14]. Therefre, studies have been requested [14] t evaluate the impact f insulin injectin site fr lng-term metablic cntrl, risk fr hypglycaemic episdes and acceptability t patients. The present study was designed t answer these questins in a single blinded 3-mnth utpatient setting, where patients were randmly assigned t injectin f sluble insulin int either the intramuscular tissue f the thigh (IMT), the subcutaneus tissue f the abdminal wall (SCA) r the subcutaneus tissue f thigh (SCT). NPH insulin was injected s. c. int the thigh in all patients. Patients and methds Patients Type i diabetic patients, attending the utpatient clinic at Odense University Hspital, Department f Endcrinlgy, were invited t participate in the study. Fifty-five patients gave infrmed cnsent and were included. All patients were withut endgenus insulin secretin (C-peptide < 0.06 nml/l). Patients were treated with sluble insulin (Actrapid HM r Velsulin HM; Nv-Nrdisk, Bagsvaerd, Denmark) befre breakfast, lunch and dinner and intermediate acting insulin (Prtaphane HM r Insulatard HM; Nv-Nrdisk) at bedtime. Six patients were later excluded frm the study due t insufficient cmpliance (i.e. perfrmed less than 25 % f requested bld glucse measurements). Three patients were frm the IMT grup, tw frm the SCA grup and ne frm the SCT grup. Clinical characteristics are given in Table 1. All patients were carefully infrmed abut the nature and purpse f the study befre their cnsent t participate was btained. The prtcl f the study was reviewed and apprved by the reginal ethical cmmittee. Prtcl and methds After a 1 mnth run-in perid patients were randmized t three different injectin sites fr sluble insulin fr 3 mnths using either i. m. injectin int the thigh (IMT), s. c. injectin int the abdminal wall (SCA) r s. c. injectin int the thigh (SCT). In all three grups intermediate acting insulin at bedtime was taken s. c. int the thigh. Patients visited the utpatient clinic at the start f the run-in perid, at randmisatin and 1 -, and 3 mnths after randmisatin. In additin t the scheduled visits t the utpatient clinic frequent cntacts were made t the patients by telephne and letter t achieve r imprve cmpliance. At the end f the study patients were asked t answer a questinnaire regarding the injectin site and technique they had used befre and during the study. The patients were als asked abut their physical activity level during the study perid. Subcutaneus thickness and injectin technique. In patients randmized t thigh injectin fr sluble insulin the thickness f the subcutaneus tissue was determined with an ultrasund scanner (Picker 9500; Hitachi, Tky, Japan) using a linear transducer (5 MHZ R40). Thickness f the subcutaneus tissue was measured at nine different sites in the anterlateral area n each thigh and nted in a diagram. Using this diagram patients in the SCT and IMT grups were instructed t use apprpriate areas f the thigh t ensure either

3 754 J. E. Henriksen et al.: Sluble insulin injectin and glycaemic cntrl Table 2. Metablic cntrl at the end f interventin, severe hypglycaemic episdes during the interventin perid and mild hypglycaemic episdes in the last 14 days perid f the study in 49 Type i diabetic patients wh used different injectin sites fr sluble insulin (IMT, intramuscular tissue f the thigh; S CA, subcutaneus tissue f the abdminal wall; S CT, subcutaneus tissue f the thigh) Grup IMT SCA SCT Mean bld glucse (mml/1) Mean glucse prfiles CV (%) Mean bld glucse at hurs (mml/1) Number f ncturnal bld glucse measurements belw 4 mml/1 Glycated haemglbin (%) Serum fructsamine (mml/l) Patients with se-fructsamine value within nrmal range number f patient % (95 % CI) Weight (kg) Severe hypglycaemic episdes number f patients % (95 % CI) ttal number f episdes Mild hypglycaemic episdes, events/ patient/14 days 8.5 (7.6 t 9.3) 8.4 (7.7 t 9.2) 8.2 (7.5 t 8.8) 27 (21 t 33) 27 (23 t 32) 29 (26 t 33) 8.2 (6.5 t 9.8) 8.0 (6.8 t 9.2) 6.1 (5.0 t 7.1) a 14/64 21/81 34/85 ~ 7.8 (7.3 t 8.3) 7.8 (7.3 t 8.3) 8.2 (7.6 t 8.8) 1.25 (1.18 t 1.32) 1.24 (1.17 t 1.31) 1.34 (1.26 t 1.41) b 21% (5t51) 35% (14t62) 0% (0t19%) 71.9 (66.1 t 77.6) 70.8 (66.1 t 75.6) 74.2 (69.2 t 79.2) % (5 t 51) 12 % (1 t 36) 39 % (17 t 64) (2.1 t 6.0) 2.4 (0.9 t 3.8) 2.8 (1.6 t 4.1) a p < 0.05, b p < 0.01, vs IMT, SCA by ne-way ANOVA. Values are mean and 95 % cnfidence interval r prprtin and 95 % cnfidence interval. CV, Cefficient f variatin f the mean daily bld glucse prfile true s. c. r true i. m. placement f insulin. Mean thickness f the subcutaneus tissue was 10.6 mm (range 5.5 t 18.4) and was larger in the medial and prximal part f the thigh than in the lateral and distal part f the thigh (11.9 _+ 0.6 mm vs mm). Nne f the patients had any lipdystrphy at the injectin sites either at the thigh r at the abdmen. The SCA grup was instructed t use the area frm 10 cm abve t 10 cm belw the umbilicus and up t 15 cm lateral t each side. Fr s. c. injectins 12.5 mm needles were used and injectin given int an elevated skin fld at an angle f 45 ~ Fr i. m. injectin 16 mm needles were used with perpendicular injectin withut elevatin f the skin. The patients injected sluble insulin immediately after bld glucse measurements befre meals. NPH insulin was injected at hurs. Intermediate acting insulin was injected s. c. int the thigh in all three grups. Bld samples. Three times during the study perid (at run-in, randmisatin and at the end f the study) bld was sampled fr measurements f HbA1 c (HPLC, nrmal range 5.4 t 7.4 %), and serum (se) fructsamine (crrected fr variatin in se-albumin (nrmal range 0.86 t 1.14 mml/1 [15,16]). Equipment. At the start f the run-in perid each patient received a glycmeter (Refllux S; Behringer Mannheim GmbH Diagnstica, Mannheim, FRG) tgether with a cnnectable memry device (CAMIT EL; Behringer Mannheim GmbH Diagnstica). All glycmeters were tested and certified as errr-free by a specially trained technician. Test strips (Haemglyctest 1-44 R) were all frm the same batch. Patients were carefully instructed in bth thery and practice f the use f the glycmeter and memry device. Bld glucse measurement. During the first mnth f the interventin perid bld glucse was measured daily fur times per day i. e. befre meals and at bedtime. After that bld glucse was measured twice per week with measurements befre and 1.5 h after meals and at bedtime. During the last 2 weeks f the study perid bld glucse was measured befre and after meals, at bedtime and at hurs. The latter measurements were used in the cmparisn f the three different injectin sites. Insulin dse adjustment. During the adjustment perid (0-2.5 mnths) insufin dses were adjusted by trained diabetlgists wh were unaware f the injectin site n each individual. Thus adjustments were made each week during the first mnth and after that every secnd week. Adjustments were made based n bld glucse prfiles and reprted hypglycaemic episdes. The aim f these adjustments was t achieve "near nrmal" pre-meal bld glucse values. Thus, the target was 4-7 mml/l fr pre-meal bld glucse values and 7-10 mml/l fr glucse values measured 1.5 h after meals and at bedtime. Hypglycaemia. Tw categries f hypglycaemic episdes were defined in the prtcl. Mild hypglycaemic attacks were defined as episdes which the patient culd handle himself by intake f glucse. If the patient became dependent n help frm ther persns the attack was defined as "severe". Only three mild hypglycaemic episdes were allwed per week. Fr higher frequencies insulin dses were reduced r redistributed. Statistical analys& Differences between values befre and after the interventin perid were evaluated using Student's t-test fr paired data. Differences between grups were determined by ne-way analysis f variance. Differences in distributins between the grups were assessed with the G-test [17]. Fr each patient a mean diurnal bld glucse prfile was calculated frm the final 6 days f the study. The cefficient f variatin (CV) and changes in bld glucse values during the day were thereafter calculated frm this prfile. Differences between the grups in CV, in bld glucse cncentratins and in changes in bld glucse cncentratins were then cmpared using ne-way ANOVA. Data are presented as mean and 95 % cnfidence limits. Differences with p-values less than 0.05 were cnsidered significant.

4 J. E. Henriksen et al.: Sluble insulin injectin and glycaemic cntrl 755 Table 3. Ttal daily insulin dse, sluble insulin dse at mealtime and NPH insulin dse at bedtime in 49 Type 1 diabetic patients after 3 mnths f intensified insulin treatment and difference between insulin dses at randmisatin and after 3 mnths. Sluble insulin was injected: IMT, i. m. int the thigh; SCA, s. c. int the abdminal wall; SCT. s. c. int the thigh Grup IMT SCA SCT Insulin dse (IU) Ttal Difference Ttal Difference Ttal Difference Breakfast 9.0(6.5t11.5) -1.7(-3.7t0.3) 11.1(8.3t13.8) 0.4(-1.4t2.1) 10.2(8.6t11.9) 1.0(-0.2t2.2) Lunch 10.1 (8.1 t 12.1) 2.0 (0.1 t 3.9) 9.5 (7.1 t 11.9) 1.1 ( t 3.0) 8.4 (6.7 t 10.2) 1.6 (0.3 t 2.8) Dinner 13.6 (11.5 t 15.7) 0.6 ( t 2.0) 12.5 (10.1 t 14.8) 0.6 ( t 2.0) 10.8 (9.2 t 12.4) 0.0 ( t 1.5) Bedtime 24.0 (18.9 t 29.1) 3.4 (1.6 t 5.3) 21.2 (17.3 t 25.1) 3.8 (2.3 t 5.3) 17.4 (13.4 t 21.5) 0.2 ( t 1.5)" Ttal 56.7 (46.7 t 66.7) 4.3 (0.7 t 7.9) 54.2 (44.1 t 64.4) 5.8 (2.1 t 9.4) 46.9 (40.0 t 53.8) 2.8 ( t 6.1) ap < vs IMT, SCA by ne-way ANOVA. Values are mean and 95 % cnfidence interval Results Overall metablic cntrl Metablic cntrl was similar in the three grups at the start f the study and remained unchanged during the runin perid (Table 1). Fllwing the interventin perid bth HbAlc value (8.39 % (95 % CI, 8.00 t 8.78) t 7.94 % (7.64 t 8.24), (p < 0.002)) and se-fructsamine value (1.42 mml/1 (1.37 t 1.48) t 1.27 mml/1 (1.23 t 1.32),(p < )) were reduced cmpared t befre the study. There was n difference between the grups in HbAlc value r in se-fructsamine value at the end f the study althugh there was a tendency twards a higher se-fructsamine value in the SCT grup (Table 2, p = 0.09). Hwever, fllwing interventin se-fructsamine values were nrmal in three patients in the IMT grup, in six patients in the SCA grup and in nne f the patients in the SCT grup (Table 2). This was in cntrast t befre interventin where se-fructsamine values were nrmal in nne f the patients in the IMT grup, ne patient in the SCA grup and tw patients in the SCT grup (Table 1). Glycaemic cntrl during the last2 weeks Figure 1 shws the mean diurnal bld glucse values fr the three grups. The prfiles fr the IMT and the SCA grups lk similar, whereas the prfile fr the SCT grup has anther appearance with larger fluctuatins in bld glucse values at the end f the day, althugh there was n difference in the CV (Table 2, NS). Hwever, bld glucse cncentratins frm pst-lunch measurement t predinner measurement decreased 1.2 mml/1 (-2.6 t 0.3) in the SCT grup cmpared t an increase in the IMT and the SCA grups (0.9 mml/1 (-0.8 t 2.5) and 1.0 mml/1 (0.0 t 2.0), (p < 0.04)). Als the increase in bld glucse cncentratin frm pre- t pst-dinner measurements was higher in the SCT grup than in the SCA and IMT grup (IMT: 1.5 mml/1 (0.4 t 2.6), SCA: 1.1 mml/1 (-0.1 t 2.3), SCT: 2.7 mml/1 (2.0 t 3.5), (p < 0.05)). Bld glucse cncentratin frm bedtime t hurs decreased 2.9 mml/1 (1.6 t 4.3) in the SCT grup cmpared t nly 0.5 mml/1 (-0.6 t 1.5) in the IMT grup and 0.1 mml/1 (-1.7 t 1.8) in the SCA grup (p < 0.008). All ther changes in bld glucse cncentratins during the day were similar between the grups. Mean bld glucse value at night was significantly lwer in the SCT grup than in the ther tw grups (Fig. 1 and Table 2). This was due t a statistically significant larger number f measured bld glucse values belw 4 mml/1 in the SCT grup (Fig. i and Table 2). Hypglycaemia There was a tendency twards a higher prprtin f patients with severe hypglycaemic episdes in the SCT grup (Table 2, p = 0.16) and a tendency twards mre episdes (Table2, Kruskal-Wallis ne-way ANOVA, p = 0.14). Seven hypglycaemic episdes were with lss f cnsciusness. One patient in the IMT grup experienced tw episdes, three patients in the SCT experienced fur episdes and ne patient in the SCA grup experienced ne episde. lnsulin dse Ttal daily insulin dse was increased in all but the SCT grup during the interventin perid (Table 3). Hwever, the difference between the grups did nt attain statistical significance. On the ther hand, a clear difference between the grups was nted in the bedtime NPH insulin dse (Table 3). Thus, in the SCA and IMT grups the NPH insulin dse increased whereas in the SCT grup there was n increase (Table 3). Despite the increase in insulin dse, bdy weight remained unchanged (Table 2). Physical activity level and acceptability f injectin site There was n difference in the level f physical activity between the grups either in the level during the wrking hurs (ttal hurs per week f walking and f mderate t hard physical activity: IMT: 19.0 (9.5 t 28.5), SCA: 18.3 (9.8 t 26.7), SCT: 21.8 (10.6 t 33.0), (NS)) r during the leisure time (ttal hurs per week f biking, jgging, running r ther frms f sprt: IMT: 5.3 (0.3 t 10.4), SCA: 7.9 (4.1 t 11.6), SCT: 4.3 (2.3 t 6.3), (NS)). Of the patients wh injected sluble insulin int the abdminal wall befre the study and wh were randmly assigned t the SCT grup (16 patients), 7 patients claimed that they had equal pain at the new injectin site, 7 pa-

5 756 J. E. Henriksen et al.: Sluble insulin injectin and glycaemic cntrl 12- E E m 4- I I I I I I I I I Pre Pst Pre Pst Pre Pst Bedtime Pre Breakfast Lunch Dinner hurs Fig. 1. Diurnal bld glucse values in three grups f Type i diabetic patients randmized t injectin f siuble insulin either i. m. int the thigh (/x ), s. c. int the abdminal wall ( O ) r s. c. int the thigh ( 9 ) at mealtimes. Intermediate acting insulin at bedtime was taken s.c. int the thigh in all patients. Values represent mean ( + SEM) frm six bld glucse prfiles (eight measurements per day) per patient measured during the last 2-week perid f the 3-mnth interventin perid. * p < "~ 16- E ") " n"t & ~ 080 = ii AA ~ :i: " '" AA O,,,!I,,,;i;, A~AA AAAA AA 0 0 e@ e AA IMT grup SCA grve SCT grup Fig.2. Ncturnal bld glucse values measured during the last 2 weeks f the 3-mnth interventin perid in three grups f Type 1 diabetic patients randmized t injectin f sluble insulin either i.m. int the thigh (IMT), s.c. int the abdminal wall (SCA) r s.c. int the thigh (SCT) at mealtimes. The SCT grup had a higher number f bld glucse values belw 4 mml/l (p < 0.05) tients had greater pain and 2 had less pain. In the IMT grup (13 patients) 7 had equal pain, 5 had mre pain and i had less pain. The patients were als asked if they wuld use the injectin site they had used in the study in the future if we culd recmmend it. All patients wh used the SCA wuld accept it and 9 f 14 patients in the IMT grup and 13 f 18 patients in the SCT grup wuld accept the used injectin site. Given a free chice mst patients preferred the abdminal wall as the site fr sluble insulin injectins. Thus, 36 patients wuld prefer the abdminal wall, 2 patients the subcutaneus tissue f the thigh, 3 patients the intramuscular tissue f the thigh and 8 patients wuld prefer t alternate between injectin sites (p < 0.001). Discussin The present study demnstrates that sluble insulin injectin int the subcutaneus tissue f the abdminal wall and int the intramuscular tissue f the thigh prduces equal glycaemic cntrl, whereas use f the subcutaneus tissue f the thigh is fllwed by larger bld glucse excursins including a higher risk f ncturnal hypglycaemia. In ur utpatient clinic we aim fr patients t have HbAlc values belw 8.0 %. At the end f the 3-mnth intensified insulin treatment perid, the IMT and SCA grup had mean values belw this value but nt the SCT grup. Hwever, the HbAI value was nt different between the grups. HbAlc and se-fructsamine are assumed t reflect glycaemic cntrl during the preceding 2-3 mnths and 4-6 weeks, respectively [18] and in this way se-fructsamine can be assumed t reflect glycaemic cntrl mre precisely at the end f interventin. There was a tendency twards a lwer se-fructsamine value in the SCA and IMT grups, althugh this did nt reach statistical significance. Hwever, mre patients in the IMT and SCA grups than in the SCT grup had a nrmal sefructsamine value fllwing interventin. Bld glucse cncentratins increased mre after the meal and decreased mre after the pstprandial bld glucse peak arund lunch and dinner in the SCT grup. This is in agreement with ur previus findings [2]. Due t the slw absrptin rate f sluble insulin frm the subcutaneus tissue f the thigh, bld glucse cncentratins wuld increase mre after meals and due t the prlnged actin f the injected insulin bld glucse cncentratins wuld decline mre frm the pstprandial bld glucse peak t the next meal. Thus, in ur previus inpatient study we fund a significantly lwer CV f diurnal bld glucse cncentratins after i.m. injectin f sluble insulin int the thigh than after s. c. injectin int the thigh [2] An imprtant finding in the present study was the marked decrease in bld glucse cncentratins frm bedtime t hurs in the SCT grup The lwer nc turnal bld glucse cncentratin in the SCT grup was due t a higher incidence f bld glucse values belw 4 mml/1. Ncturnal hypglycaemia is a majr prblem in the treatment f the diabetic patient [19-25]; several risk factrs have been identified [23-25]. The present study indicates a frmerly unknwn risk factr. An increased risk fr ncturnal hypglycaemia was demnstrated when sluble insulin was injected s. c. int the thigh during the day. It is imprtant t realise that the increased number f ncturnal lw bld glucse values in the SCT grup was nt due t an increased NPH insulin dse at bedtime. In fact, the bedtime NPH insulin dse remained unchanged in the SCT grup, whereas the NPH insulin dse in the SCA and IMT grup was increased by abut 4 units during the interventin perid by the single blinded diabetes treatment team. Therefre, if the NPH insulin dse in the SCT grup had been increased as in the SCA and IMT grup it seems reasnable t assume an even higher number f lw bld glucse values at night in the SCT grup.

6 J. E. Henriksen et al.: Sluble insulin injectin and glycaemic cntrl Anther risk factr fr ncturnal hypglycaemia is bld glucse cncentratin at bedtime, thus the lwer the bld glucse cncentratin the higher the risk fr develping ncturnal hypglycaemia [23-25]. Hwever, bld glucse cncentratin at bedtime was similar in the three grups. Als, the injectin site fr NPH insulin at bedtime was the same in the three grups. It thus seems unlikely that differences in the absrptin rate f NPH insulin between the grups culd have been respnsible fr the higher number f lw bld glucse values in the S CT grup. The finding that the injectin site fr sluble insulin during the day markedly influences the bld glucse cncentratins at night has imprtant clinical implicatins. Thus, a lw bld glucse cncentratin at night is usually prevented by a reductin f the bedtime NPH insulin dse [26]. Hwever, this study demnstrates that the insulin injectin site and, thereby als the insulin dses f sluble insulin during the day has a great influence n the nighttime bld glucse cncentratins. This means that the day time insulin injectin technique and the insulin dse shuld be cnsidered in the future if a lw ncturnal bld glucse cncentratin is inadequately cntrlled by a reductin f the NPH insulin dse. In this cntext it shuld be nted that the pre-dinner sluble insulin injectin in particular may be the prime candidate t influence nighttime bld glucse cncentratin. It has been suggested that i.m. injectin f sluble insulin might be dangerus due t an elevated risk f exercise-induced hypglycaemic episdes and fr this reasn that i.m. injectin shuld be avided [4]. During ur 3- mnth study there was n evidence f such an elevated risk fr severe hypglycaemic episdes in the IMT grup. In cntrast, mre patients in SCT grup experienced severe hypglycaemic episdes althugh this did nt attain statistical significance. The difference culd nt be explained by a difference in the level f physical activity as this was cmparable between the grups. Severe hypglycaemic attacks in the SCT grup culd be due t the delayed insulin absrptin frm the subcutaneus tissue f the thigh resulting in inapprpriate hyperinsulinaemia hurs after the meal. This, tgether with exercise culd be ptentially dangerus regarding the develpment f severe hypglycaemic episdes. If a patient refuses t use the abdminal wall fr injectin f sluble insulin he shuld be advised t use the intramuscular tissue f the thigh. Amng ur patients the acceptability f this injectin site was as high as the acceptability f the s. c. injectin site f the thigh. Als the pain after i. m. injectin was cmparable t that seen after s. c. injectin int the thigh. This is cnsistent with the findings f Wynne et al. [27], wh have demnstrated that i. m. injectin f insulin with a thin needle is n mre painful than s.c. injectin. Imprtantly, the thickness f the subcutaneus tissue is thinner n the lateral and distal aspects f the thigh. Therefre, this is the mst apprpriate area t recmmend, if it is nt pssible t assess the precise subcutaneus thickness using ultrasund measurement. Furthermre, a 16 mm lng needle shuld be used with injectin given perpendicular t the skin. Hwever, mst f ur patients preferred the abdminal wall as injectin site fr sluble insulin. Obviusly, this in- 757 jectin site is mre cnvenient at mealtime than the injectin sites f the thigh. The abdminal wall is ften easily accessible als in public places whereas thigh injectin mst ften must be preceded by remval f mre clthing. On the ther hand, frm a pharmackinetic pint f view the best injectin site fr NPH insulin is the thigh and als frm a practical pint f view thigh injectin at bedtime is acceptable. In cnclusin we have demnstrated that an equal glycaemic cntrl can be btained with i.m. injectin f sluble insulin int the thigh as with s.c. injectin int the abdminal wall and that i.m. injectin is nt assciated with an increased risk f severe hypglycaemia. Injectin f sluble insulin int the thigh s. c. at mealtime is fllwed by a nn-favurable glycaemic cntrl with larger bld glucse excursins and an enhanced risk fr ncturnal hypglycaemia. We therefre recmmend that sluble insulin in the basal blus insulin regimen shuld be injected s.c. int the abdminal wall r alternatively i. m. int the thigh, whereas s.c. injectin f sluble insulin int the thigh shuld be avided. Acknwledgements. We acknwledge the financial supprt frm Nv Nrdisk Farmaka Denmark and Behringer Mannheim, Mannheim, FRG fr supplying the patients with Refllux S and CAMIT EL. We als wuld like t thank Mr. I. Jhansen fr measuring ~uctsamine and Mr. B.Pedersen fr testing the glycmeters prir t the study. References 1. 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