Clinical Care/Education/Nutrition ORIGINAL ARTICLE

Pharmacokinetics, Prandial Glucose Control, and Safety of Glulisine in Children and Adolescents With Type 1 Diabetes

1 1 THOMAS DANNE, MD CLAUDIA BITTNER, MD meals, particularly with regular human 2 2 REINHARD H. A. BECKER, MD ANNKE D. FRICK, PHD insulin (RHI), which requires administra- 3 3 TIM HEISE, MD KLAUS RAVE, MD tion 30–45 min before mealtime (2). The use of rapid-acting insulin analogs instead of RHI for prandial glycemic control is becoming increasingly accepted, since these can be given much closer to OBJECTIVE — The aim of this study was to investigate the pharmacokinetics, postprandial mealtime (2–4). Thus, rapid-acting insu- blood glucose excursions, and safety of insulin glulisine as compared with regular human insulin lin analogs might offer advantages, partic- (RHI), both administered immediately before meals in pediatric patients with type 1 diabetes. ularly for very young children in whom RESEARCH DESIGN AND METHODS — A total of 10 children (aged 5–11 years) and the actual carbohydrate intake is often dif- 10 adolescents (aged 12–17 years) were enrolled in a randomized, single-center, single-dose, ficult to predict (5). It remains to be double-blind, cross-over study. The blood glucose of fasting patients was stabilized with intra- shown, however, whether the rapid- venous insulin, following which patients received 0.15 IU/kg of subcutaneously injected insulin acting properties of these analogs are pre- glulisine or RHI 2 min before a weight-adjusted standardized liquid meal. served in children. Insulin glulisine ([LysB3, GluB29]- RESULTS — For insulin glulisine versus RHI, maximum insulin concentrations (58 vs. 33 insulin) is a recombinant ␮ Ͻ IU/ml, P 0.05) and initial insulin concentrations (insulin [area under the curve] AUC0–2h designed to provide the same total glu- ␮ Ϫ1 Ϫ1 Ͻ 5,232 vs. 2,994 IU min ml , P 0.05; data are geometric means) were higher after codynamic effect as RHI after subcutane- insulin glulisine than RHI. Both time to maximum insulin concentration (54 vs. 66 min) and ous administration but with a faster onset mean residence time (88 vs. 137 min, P Ͻ 0.05) were shorter with insulin glulisine versus RHI. Postprandial glucose excursions after insulin glulisine were lower than after RHI (glucose and shorter duration of action (6), which Ϫ1 Ϫ1 Ͻ has been demonstrated in adults (7–9). AUC0–6h 641 vs. 801 mg h dl , P 0.05). The pharmacokinetic profile for insulin glulisine was similar for children and adolescents, whereas the pharmacokinetic profile for RHI The altered absorption of insulin glulisine demonstrated a 64% higher concentration in adolescents. Insulin glulisine was safe and well results from the replacement of aspara- tolerated. gine with at position 3 and of lysine by at position 29 on the CONCLUSIONS — The rapid-acting properties of insulin glulisine that have been previ- B-chain of the human insulin molecule. ously demonstrated in adults are also observed in children and adolescents with type 1 diabetes. These substitutions reduce the formation Further, these initial data indicate that insulin glulisine is safe and well tolerated in this patient of oligomers and favor stable monomers, population. enhancing absorption from the subcuta- Diabetes Care 28:2100–2105, 2005 neous tissue (10,11). The objective of this study was to in- vestigate the pharmacokinetic properties of insulin glulisine in comparison to RHI he goal of basal-bolus insulin ther- plications (1). Children and adolescents to confirm the rapid-acting properties of apy in type 1 diabetes is to achieve sometimes encounter difficulties in ad- this novel insulin analog in children and T near to normal glycemic control and justing their daily activities to fixed inter- adolescents with type 1 diabetes. reduce the risk of long-term clinical com- vals between insulin administration and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1Kinderkrankenhaus auf der Bult, Hannover, Germany; 2Aventis Pharma Deutschland, Frankfurt/ RESEARCH DESIGN AND Main, Germany; and the 3Profil Institut fu¨ r Stoffwechselforschung, Neuss, Germany. METHODS — This study compared Address correspondence and reprint requests to Thomas Danne, MD, Kinderkrankenhaus auf der Bult, the pharmacokinetic postprandial glu- Diabetes-Zentrum fu¨ r Kinder und Jugendliche, Janusz-Korczak-Allee 12, 30173 Hannover, Germany. E- cose excursions and safety profile of insu- mail: [email protected]. Received for publication 4 January 2005 and accepted in revised form 9 June 2005. lin glulisine (supplied at 1 ml equimolar T.D. and T.H. have received research grants from Aventis Pharma Deutschland. to 100 units human insulin; Aventis Abbreviations: AUC, area under the curve; MRT, mean residence time; RHI, regular human insulin. Pharma, Frankfurt, Germany) and RHI A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion (Aventis Pharma) in children and adoles- factors for many substances. cents with type 1 diabetes. In this single- © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby center, single-dose, double-blind, two- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. way cross-over trial, pediatric patients

2100 DIABETES CARE, VOLUME 28, NUMBER 9, SEPTEMBER 2005 Danne and Associates

received subcutaneous injections of 0.15 Assessments and data analysis two insulin treatments. ANOVA for INS IU/kg insulin glulisine or RHI 2 min be- Radioimmunoassays were used for the AUCs, MRT, and Cmax, with adjustments fore a standardized meal. Study days were determination of human insulin and in- for treatment, period, sequence and sub- separated by at least 3 and no more than sulin glulisine concentrations. Unbound, ject-within-sequence effects, were per- 14 days. The study was approved by an free insulin concentrations were mea- formed using natural log–transformed independent ethics committee, and as- sured after polyethylene glycol precipita- values to compare treatments within age- sent and written informed consent were tion to separate the bound from the free- groups. ANOVAs with adjustments for obtained from either the patients’ repre- insulin fraction. Insulin glulisine age-group, period, sequence, and sub- sentative or from the patients themselves concentrations were quantified with a ra- ject-within-sequence effects were also when they were able to understand the dioimmunoassay specific for insulin glu- performed to compare age-groups within informed consent. The trial was con- lisine at a limit of quantification of 5 treatment. Point estimates and 95% CIs ducted in accordance with the principles ␮IU/ml with a working range of 5–200 were calculated for the treatment ratios of Good Clinical Practice and the Decla- ␮IU/ml (sanofi-aventis, data on file). The and for the age-group ratios per treat- ration of Helsinki and its amendments. limit of quantification of human insulin ment. Nonparametric analyses were used ␮ The patients’ usual insulin treatment was 4.3 IU/ml with a working range of to analyze tmax, while 95% nonparametric was suspended from the evening before 4.3–138 ␮IU/ml. CIs for the respective median treatment the study day until the end of the study Blood glucose concentrations were and age-group differences were calcu- day. Patients also fasted from their measured by the glucose oxidase method lated. No adjustment of alpha levels for evening meal on the day before the study with a Glucometer Elite (Bayer, Le- multiple testing or CIs was made. visits until a standardized liquid meal was verkusen, Germany) at the bedside. Postprandial blood glucose concentra- administered on the study day itself. A Pharmacokinetics. The serum insulin tions and excursions. Blood glucose pa- ⌬ variable intravenous infusion of RHI was profile was characterized by the area un- rameters (i.e., BG AUCs, BGmax, BGmax, used to maintain patients’ blood glucose der the insulin concentration–time curve and BGmin) were analyzed using ANO- levels at 100–160 mg/dl (5.6–8.9 at the following times after injection: 1 h VAs. The ANOVAs (with adjustments for mmol/l) before the experiment; this vari- (INS AUC0–1h), 2 h (INS AUC0–2h),4h treatment, period, sequence, and subject- able infusion was discontinued 20 min (INS AUC0–4h), and 6 h (INS AUC0–6h). within-sequence effects included) were before subcutaneous injection of insulin In addition, maximum insulin concentra- performed by age, class, and point esti- glulisine or RHI, respectively. tion (Cmax), the time to maximum insulin mates, and 95% CIs were calculated for After two consecutive blood glucose concentration (tmax), and mean residence the treatment ratios. The time parameters measurements taken 30 min apart were time (MRT) were also calculated. were analyzed by nonparametric analy- within the target range, a subcutaneous Postprandial glucose excursions. Post- ses, and 95% nonparametric CIs for the injection of either insulin at a dose of 0.15 prandial blood glucose was assessed as respective median treatment and age- IU/kg was given in the periumbilical area the area under the baseline subtracted group differences were calculated. of the abdomen. blood glucose concentration–time curve Two minutes after the administration at the following times after injection: 1 h of the study , a standardized (BG AUC0–1h), 2 h (BG AUC0–2h), 4 h RESULTS liquid meal (composition for 8 fl oz: 240 (BG AUC0–4h), and 6 h (BG AUC0–6h), kcal, 4 g fat, 41 g total carbohydrate, and along with the maximum blood glucose Study patients and conduct 10 g protein) (Boost; Novartis Medical concentration (BGmax), maximum blood Twenty pediatric patients (9 male and 11 Nutrition, Mu¨ nchen, Germany) was glucose excursion from baseline female) with type 1 diabetes, disease du- ⌬ Յ given to compensate for the glucose- ( BGmax), and minimum blood glucose ration 1–15 years, HbA1c 11%, and BMI 2 lowering effect of the added exogenous concentration (BGmin). A single baseline 16.4–26.3 kg/m were enrolled. Patients insulin and to prevent hypoglycemic blood glucose concentration was calcu- were stratified according to age into two events. The amount of Boost given was lated as the median glucose concentration groups of 10 patients each: children (aged adjusted according to patients’ weight as from the three measurements (Ϫ60, Ϫ30, 5–11 years, mean 10.1) and adolescents follows: patients who weighed 20–30 kg and 0 min) taken before study medication (aged 12–17 years, 14.7). The mean received 197 ml Boost, those weighing administration. weight for children was 40.0 kg (range 30–40 kg received 296 ml, patients Safety data. Hematology, clinical chem- 26.0–50.0), and the mean weight for ad- weighing 40–50 kg were given 394 ml, istry, human insulin antibodies at base- olescents was 64.2 kg (51.0–82.5). and those patients Ͼ50 kg received 493 line, urinalysis, physical examination, Heights of the children ranged from ml. Patients remained fasted until 6 h after blood pressure, pulse rate, core body tem- 125.0 to 154.0 cm (mean 142.6), while the standardized liquid meal, at which perature, injection site reactions, and ad- the range of heights for the adolescent pa- point a regular meal was given and pa- verse events were collected for the safety tient group was 158.0–180.0 cm (168.7). tients resumed their usual therapy. If analysis. The study test dose was 5.9 Ϯ 2.2 IU for blood glucose fell below 90 mg/dl (50 children and 9.7 Ϯ 3.0 IU for adolescents mmol/l), 10 g carbohydrate was adminis- Statistical analysis (mean Ϯ 2 SD). Mean basal blood glucose tered orally. Samples for pharmacokinetic Pharmacokinetics. The conventional levels were similar in patients immedi- and blood glucose measurements were bioequivalence range of 80–125% for ately before receiving either insulin glu- collected for 6 h after insulin injection in pharmacokinetic variables was used as a lisine (children 130 mg/dl, adolescents all patients. guideline to judge the equivalence of the 135 mg/dl) or RHI (children 133 mg/dl,

DIABETES CARE, VOLUME 28, NUMBER 9, SEPTEMBER 2005 2101 Glulisine in children and adolescents

insulin concentration, as assessed by INS AUC0–1h and INS AUC0–2h, was higher for insulin glulisine than for RHI (P Ͻ 0.05), while the overall concentrations (INS AUC0–6h) were comparable. The MRT for insulin glulisine was distinctly shorter at 88 min compared with 137 min for RHI (P Ͻ 0.05), indicating the shorter residence of insulin glulisine in the sys- temic circulation. Children and adolescents presented almost equal pharmacokinetic profiles of insulin glulisine, displayed by point esti- mates close to 100% (Table 1). This was in contrast to the results for RHI, where the ratio of geometric means for INS AUC comparing adolescents (geo- 0–4h Ϫ Ϫ metric mean: 7,367 ␮IU min 1 ml 1) Ϫ Ϫ with children (4,530 ␮IU min 1 ml 1) was 163% (P Ͻ 0.05), compared with 112% for insulin glulisine (children Ϫ Ϫ 7,193 ␮IU min 1 ml 1, adolescents Ϫ Ϫ 8,081 ␮IU min 1 ml 1). Similarly, the ratio of geometric means for Cmax in ado- lescents compared with children was ϳ77% higher with RHI (P Ͻ 0.05) than with insulin glulisine. There were no sig- nificant differences in tmax and MRT be- Figure 1—Serum insulin (A) and postprandial blood glucose (B) after subcutaneous injection of tween age-groups for either study insulin. 0.15 IU/kg insulin glulisine and regular human insulin in children and adolescents.

adolescents 123 mg/dl). In addition, the of RHI due to an inconsistent concentra- Postprandial glucose excursions ⌬ C- data taken 60 min after the tion–time profile. BG AUCs, BGmax, and BGmax were sig- start of the meal showed that concentra- nificantly lower after insulin glulisine ver- tions of insulin in all patients were Ͻ0.2 Pharmacokinetics sus RHI in the pediatric patients for the Ͻ nmol/l (range 0.03–0.2), confirming The Cmax after insulin glulisine compared entire postprandial monitoring period (all severe type 1 diabetes. One subject was with RHI was higher by 71% (P Ͻ 0.05) P Ͻ 0.05) (Fig. 1B; Table 2). This trend excluded from pharmacokinetic analysis (Fig. 1A; Table 1). Likewise, the initial was maintained even when the results

Table 1—Pharmacokinetic results for all patients

Geometric mean Point estimate (95% confidence limits)* All Children Adolescents All Adolescents/children Glu RHI Glu RHI Glu RHI Glu/RHI Glu RHI n 20 19 10 10 10 9 19 10 9

INS AUC(0–1h) 2,287 1,246 2,170 1,023 2,410 1,552 176% (127, 244) 111% (70, 175) 152% (89, 258) (␮IU minϪ1 mlϪ1)

INS AUC(0–2h) 5,232 2,994 4,948 2,383 5,534 3,860 169% (127, 224) 112% (72, 174) 162% (105, 250) (␮IU minϪ1 mlϪ1)

INS AUC(0–4h) 7,624 5,703 7,193 4,530 8,081 7,367 130% (99, 170) 112% (72, 175) 163% (111, 238) (␮IU minϪ1 mlϪ1)

INS AUC(0–6h) 8,361 7,052 7,934 5,581 8,811 9,145 116% (90, 150) 111% (73, 169) 164% (114, 236) (␮IU minϪ1 mlϪ1) ␮ Cmax ( IU/ml) 58 33 55 25 61 44 171% (127, 229) 112% (73, 172) 177% (112, 281) Ϫ Ϫ Ϫ Ϫ Ϫ tmax (min) 54† 66† 55† 59† 52 76† 8 min ( 24, 7)‡ 2 min ( 9, 11) 9 min ( 24, 49) MRT (min) 88 137 87 132 90 144 64% (59, 70) 103% (88, 121) 110% (92, 130) *Point estimates (95% confidence limits) for the ratio of treatment means. †Median; ‡point estimates (95% confidence limits) for the respective median differences from nonparametric data analysis. Glu, glulisine.

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Table 2—Postprandial glucose for all patients

Arithmetic mean Point estimate (95% confidence limits)* All Children Adolescents All Adolescents/children Glu RHI Glu RHI Glu RHI Glu/RHI Glu RHI n 20 20 10 10 10 10 20 10 10 Ϫ1 Ϫ1 BG AUC(0–1h) (mg h dl ) 57 79 50 75 65 82 73% (59, 90) 131% (69, 287) 108% (70, 171) Ϫ1 Ϫ1 BG AUC(0–2h) (mg h dl ) 179 263 149 258 208 267 68% (56, 82) 140% (82, 269) 103% (74, 144) Ϫ1 Ϫ1 BG AUC(0–4h) (mg h dl ) 419 627 320 590 518 664 67% (55, 80) 162% (87, 395) 113% (81, 159) Ϫ1 Ϫ1 BG AUC(0–6h) (mg h dl ) 641 801 492 729 790 872 80% (67, 95) 161% (88, 369) 120% (82, 179) BGmax (mg/dl) 298 352 273 349 324 355 85% (77, 93) 119% (92, 155) 102% (84, 124) ⌬ BGmax (mg/dl) 166 224 142 216 189 232 74% (64, 86) 133% (84, 226) 107% (81, 143) BGmin (mg/dl) 211 193 180 179 242 207 109% (93, 128) 135% (95, 199) 115% (83, 162) Data are baseline corrected. *Point estimates (95% confidence limits) for the ratio of treatment means according to Fieller’s Theorem. Glu, glulisine. from children and adolescents were ana- demonstrated by lower glucose excur- ited, with respect to the degree of contam- lyzed separately. After insulin glulisine, sions with insulin glulisine compared ination (human insulin was infused but not after RHI injection, blood glucose with RHI. As there were no differences in intravenously at a low dose, compared tended to increase toward the end of the basal blood glucose levels between the with the insulin glulisine injected subcu- 6-h monitoring period. two treatment groups, these results are taneously) and with respect to the time- due to the drug alone and not due to other frame (human insulin intravenous Safety factors such as glucose fluctuations due to infusion was stopped 20 min before the A total of 19 mild adverse events were hormonal adaptations and glucose ab- subcutaneous injection of the study reported in nine patients, of which one sorption effects after a meal. Notably, drug). Therefore, at the time of peak in- (urticaria) was reported to be possibly re- blood glucose levels generally increased sulin absorption following the subcutane- lated to study medication (RHI). There toward the end of the 6-h monitoring pe- ous injection, almost no residual human were no events of severe hypoglycemia or riod in patients treated with insulin glu- insulin would be expected in the intravas- clinically relevant abnormalities in the lisine, reflecting the absence of a basal cular space. physical examinations or in the laboratory insulin. In contrast, the values following In the study presented here, patients variables. There were no injection site RHI administration remained unchanged received RHI immediately before meals, reactions. in this period, reflecting its longer dura- although a 15–30 min interval between tion of action. A very similar pharmaco- injection and ingestion is recommended CONCLUSIONS — This study dem- dynamic picture has been reported for (17). However, it is well known that many onstrates that higher initial concentra- (14), and a similar disparity patients with diabetes inject regular insu- tions of insulin glulisine were seen in between blood glucose levels beyond 4 h lin immediately before or even after the pediatric patients with type 1 diabetes postdosing has also been seen in a study ingestion of food (18). Hence, we decided than with RHI, with a clinically meaning- of insulin glulisine in adults (15). These to include an experiment with RHI in- ful difference in the INS AUC in the first results indicate that when using rapid- jected immediately prior to a meal in the 2 h between the two treatment groups. acting insulin analogs, an adjustment of study to compare postprandial blood glu- Likewise, the maximum serum insulin basal insulin may be required, compared cose excursions following an insulin reg- concentration for insulin glulisine was with RHI, to obtain optimum glycemic imen often practiced by patients with 71% higher compared with RHI. In con- control in the late postprandial period. diabetes (though not recommended). Al- trast to the initial concentrations, the total However, in a separate study in adult pa- though fixed injection–to–meal dosing insulin concentrations over the first 6 h tients with type 1 diabetes using insulin intervals are not advantageous for pa- after injection were similar for insulin glu- glulisine, the basal insulin requirement tients in everyday life (19,20), they were lisine and RHI in the pediatric patients did not increase (16). necessary in the current study where a investigated. The MRT in this study was The use of a radioimmunoassay that predefined, fixed time interval between significantly lower for insulin glulisine was specific for insulin glulisine allowed the injection and the meal was a vital than RHI, indicating a shorter residence insulin glulisine concentrations in the component of the study design, as admin- in the systemic circulation. Hence, in this presence of human insulin to be deter- istering insulin glulisine 30–45 min be- study investigating pediatric patients with mined precisely. According to the study fore the meal may have caused type 1 diabetes, pharmacokinetic proper- protocol, patients had to be treated with hypoglycemia. However, in acknowledg- ties, which are characteristic of rapid- an intravenous infusion of human insulin ment of the limitations of fixed injection– acting insulin analogs, are demonstrated before injection of the study medication; meal dosing, a subsequent clinical study with the use of insulin glulisine (12,13). hence contamination a priori, in principle with glucose control as the primary objec- The pharmacokinetic results are re- at least, could not be excluded. However, tive has incorporated a more flexible dos- flected in postprandial glucose profiles, as contamination with human insulin is lim- ing–meal regimen.

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Of particular interest in the current RHI in pediatric and adolescent patients versus (IL) and regular hu- study is the lack of meaningful differences with type 1 diabetes. Thus, insulin glu- man insulin (RHI) in patients with type 1 between children and adolescents with lisine displays pharmacokinetic and phar- diabetes (Abstract). Diabetes 53 (Suppl. regard to pharmacokinetic properties for macodynamic properties in pediatric 2):557, 2004 insulin glulisine. In contrast, for RHI, patients with type 1 diabetes that classify 9. Becker RHA, Frick AD, Kapitza C, Heise T, Rave K: Pharmacodynamics (PD) and Cmax in this study was 77% higher and it as a rapid-acting insulin analog in this pharmacokinetics (PK) of insulin glu- overall concentrations of insulin were population. lisine (GLU) versus insulin lispro (IL) and 64% higher for adolescents compared regular human insulin (RHI) in patients with children. These findings with RHI with type 2 diabetes. Diabetes 53 (Suppl. are in line with a separate study compar- Acknowledgments— This study was partly 2):503, 2004 ing a rapid-acting insulin analog, insulin supported by a research grant from Aventis 10. Brange J, Ribel U, Hansen JF, Dodson G, aspart, with RHI. In this study, for which Pharma, Frankfurt/Main, Germany. Hansen MT, Havelund S, Melberg SG, The results of this study have been previ- there is detailed pediatric pharmacoki- Norris F, Norris K, Snel L: Monomeric ously published as an abstract at the European insulins obtained by protein engineering netic information, Mortensen et al. (14) Association for the Study of Diabetes 2004 An- describe higher C both for insulin as- and their medical implications. Nature max nual Meeting (26). 333:679–682, 1988 part and for RHI in adolescents compared The authors thank the study participants 11. Kang S, Brange J, Burch A, Volund A, with children. In the study presented and their families, the diabetes team and study Owens DR: Subcutaneous insulin absorp- here, treatment with RHI resulted in sig- staff at the Kinderkrankenhaus auf der Bult, tion explained by insulin’s physicochem- nificantly higher insulin concentrations and the excellent technical assistance of Uta ical properties: evidence from absorption in adolescents compared with children; Eckers. studies of soluble human insulin and in- however, the insulin concentrations in sulin analogues in humans. Diabetes Care adolescents treated with insulin glulisine 14:942–948, 1991 were not statistically higher than in chil- References 12. Heinemann L, Woodworth J: Pharmaco- dren receiving the same treatment. In 1. White NH, Cleary PA, Dahms W, Gold- kinetics and glucodynamics of insulin lis- both studies, there were no discrepancies stein D, Malone J, Tamborlane WV: Ben- pro. Drugs Today 34:23–36, 1998 eficial effects of intensive therapy of 13. Heinemann L, Starke AAR, Heding L, between adolescents and children in post- diabetes during adolescence: outcomes Jensen I, Berger M: Action profiles of fast prandial blood glucose excursions. after the conclusion of the Diabetes Con- onset insulin analogues. Diabetologia 33: Therefore, in the study presented here, trol and Complications Trial (DCCT). 384–386, 1990 with the exception of the results for insu- J Pediatr 139:804–812, 2001 14. Mortensen HB, Lindholm A, Olsen BS, lin glulisine, results suggest that higher 2. Danne T, Deiss D, Hopfenmuller W, von Hylleberg B: Rapid appearance and onset insulin concentrations are observed with Schutz W, Kordonouri O: Experience of action of insulin aspart in paediatric comparable postprandial blood glucose with insulin analogues in children. Horm subjects with type 1 diabetes. Eur J Pediatr profiles in adolescents compared with Res 57 (Suppl 1):46–53, 2002 159:483–488, 2000 children. Any differences may be partially 3. Owens DR, Zinman B, Bolli GB: Insulins 15. Nosek L, Becker R, Frick A, Kapitza C, due to disparities in residual endogenous today and beyond. Lancet 358:739–746, Heise T, Rave K: Prandial blood glucose 2001 control with pre- and post-meal insulin insulin secretion between adolescents 4. Martin D, Licha-Muntz G, Grasset E, Gre- glulisine versus regular human insulin and children or as a consequence of the neche MO, Nouet D, Francois L, Legrand (Abstract). Diabetes 53:A139, 2004 size of the Boost meal given, as the ado- C, Polak M, Augendre-Ferrante B, Tubi- 16. Dreyer M, Prager R, Robinson A, Busch K, lescents received a larger meal bolus than ana-Rufi N, Robert JJ: Efficacy of Huma- Souhami E: Efficacy and safety of insulin the children yet received virtually the log injections before an afternoon meal glulisine and insulin lispro, combined same amount of insulin per gram of car- and their acceptance by children and ad- with in patients with type bohydrate. However, the results are in olescents with type 1 diabetes. Diabet Med 1 diabetes. Diabetes 53: A520, 2004 line with the relatively impaired insulin 19:1026–1031, 2002 17. American Diabetes Association: Insulin sensitivity and higher insulin concentra- 5. Powers SW, Byars KC, Mitchell MJ, Pat- administration (Position Statement). Dia- tions reported in healthy adolescents ton SR, Standiford DA, Dolan LM: Parent betes Care 27 (Suppl. 1):S106–S109, report of mealtime behavior and parent- 2004 (21,22). ing stress in young children with type 1 18. Heinemann L: Do insulin-treated diabetic Since meal management in children is diabetes and in healthy control subjects. patients use an injection-meal-interval in difficult, therapy given immediately after Diabetes Care 25:313–318, 2002 daily life? Diabet Med 12:449–450, 1995 a meal to balance the actual carbohydrate 6. Becker RHA, Frick A, Wessels D, Scholtz 19. Scheen AJ, Letiexhe MR, Lefebvre PJ: intake may be of significant advantage. H: Evaluation of the pharmacodynamic Minimal influence of the time interval be- Optimum management of pediatric pa- and pharmacokinetic profiles of insulin tween injection of and tients with diabetes should consider post- glulisine-a novel, rapid-acting, human in- food intake on blood glucose control of prandial administration of insulin sulin analogue (Abstract). Diabetologia 46: type 1 diabetic patients on a basal-bolus in- glulisine. This has been demonstrated to 775, 2003 sulin scheme. Diabetes Metab 25:157–162, be safe and effective in adults but still re- 7. Becker RHA, Burger F, Scholtz H, Frick A: 1999 Bioefficacy of insulin glulisine versus reg- 20. Overmann H, Heinemann L: Injection– quires further investigation in pediatric ular human insulin (Abstract). Diabetes meal interval: recommendations of diabe- patients (15,23–25). 53 (Suppl. 2):557, 2004 tologists and how patients handle it. In conclusion, insulin glulisine was 8. 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