EXPERIMENTAL AND THERAPEUTIC MEDICINE 8: , 2014

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1 EXPERIMENTAL AND THERAPEUTIC MEDICINE 8: , 2014 Comprison of continuous subcutneous insulin infusion nd insulin glrgine-bsed multiple dily insulin sprt injections with preferentil djustment of bsl insulin in ptients with type 2 dibetes GUAN-QI GAO 1, XUE-YUAN HENG 2, YUE-LI WANG 1, WEN-XIA LI 1, QING YU DONG 1, CUI GE LIANG 1, WEN-HUA DU 1 nd XIAO-MENG LIU 1 Deprtments of 1 Endocrinology nd 2 Clinicl Medicine, Linyi People's Hospitl, Linyi, Shndong , P.R. Chin Received November 21, 2013; Accepted My 2, 2014 DOI: /etm Abstrct. The purpose of this study ws to evlute nd compre multiple dily injection (MDI) therpy of bolus insulin sprt nd bsl insulin glrgine with continuous subcutneous insulin infusion (CSII) with sprt in ptients with type 2 dibetes mellitus (T2DM). It ws ssessed whether MDI ws cpble of controlling glycemic index with higher efficcy thn CSII by preferentil djustment of bsl insulin with lower totl dily insulin dosge in T2DM. Two hundred ptients with T2DM were enrolled in the study nd rndomly ssigned to CSII (n=100) nd MDI (n=100; sprt immeditely prior to ech mel nd glrgine t bedtime) groups for 12 weeks of therpy. During the lst week of ech tretment period, the subjects wore continuous glucose monitoring system for 2 3 dys. The dosge of bsl insulin ws preferentilly djusted to control prior mel blood glucose levels, nd the chrcteristics of insulin dosge were nlyzed. No sttisticlly significnt differences were observed between the two groups in hemoglobin A1c (HbA1c), which dropped from 10 11% prior to therpy to 7 7.5% fter 12 weeks. After 12 weeks, good glycemic level control ws chieved in ll ptients in the MDI nd CSII groups. A sttisticlly significnt difference in the dose of insulin between the CSII nd MDI groups ws observed (P<0.001). In conclusion, no significnt differences were found between the two therpies in the incidence of hypoglycemi nd HbA1c for the 12 weeks. The bsl insulin dosge ws significntly decresed in the MDI group compred with tht in the CSII group, but the CSII group ws superior to MDI group in decresing fsting blood glucose Correspondence to: Dr Gun Qi Go, Deprtment of Endocrinology, Linyi People's Hospitl, 27 Jiefng Rod, Linyi, Shndong , P.R. Chin E mil: [email protected] Key words: type 2 dibetes, insulin sprt, glrgine insulin, hypoglycemi nd shortening the time required for hypoglycemi to meet the trgeted level. Introduction Continuous subcutneous insulin infusion (CSII) therpy with n externl pump nd multiple dily injection (MDI) therpy re two of the currently selected methods of insulin tretment for dibetes. MDI therpy for dibetes requires bolus injections of rpid or short cting insulin prior to ech mel nd long cting insulin injection once or twice per dy for bsl insulin coverge. Control of postprndil glycemi with rpid cting insulin hs been shown to be more effective thn tht with norml humn insulin (1,2). Long cting insulin, such s insulin glrgine, is suitble s bsl insulin therpy in dibetes (3,4). CSII therpy produces higher efficcy thn MDI nd improvements in insulin pump technology hve resulted in n increse in ptient preference (5 10). However, occsionlly ptients my hve to temporrily discontinue CSII therpy due to skin problems, pump mlfunction or physicl ctivity. It hs been shown tht MDI therpy is t lest equivlent in its ction to CSII (10). Type 2 dibetes mellitus (T2DM) is chrcterized by progressive reduction in β cell secretion of insulin nd mss together with insulin resistnce (11). The incidence rte of T2DM hs been reported to be 9.7 % in Chin (12) nd Chinese ptients with T2DM hve shown more significnt β cell deteriortion thn ptients of other genelogies (13). Insulin preprtion nd mediction hve undergone rpid progress; however, the mount of insulin injected flls short of wht is physiologiclly secreted in individuls without T2DM. Furthermore, insulin therpy my cuse weight increses, hypoglycemi nd itrogenic hyperinsulinemi, which cn increse insulin resistnce nd the potentil risks of vsculr disese (14). High doses of insulin cn induce insulin resistnce in dibetic rts, whilst intermedite doses cn mximlly improve insulin sensitivity (10); therefore, studies investigting the optiml insulin dosge re required. Numerous investigtions in ptients with type 1 dibetes mellitus (T1DM) hve shown tht CSII therpy ws more efficcious thn MDI therpy (15,16), since CSII decresed the dose of insulin required to greter

2 1192 GAO et l: TYPE 2 DIABETES CONTROL BY PREFERENTIAL ADJUSTMENT OF BASAL INSULIN degree (17 19). Phillip et l (20) demonstrted tht the higher dose of insulin required with MDI in ptients with T1DM, the more mrked the insulin decrese subsequent to switching to CSII. Conversely, Monmi et l (21) showed by met nlysis of insulin replcement in ptients with T2DM tht the dily dose of insulin with CSII ws not significntly different from tht with MDI therpy. Similrly, study of Indin ptients with T2DM showed no significnt differences in the totl dily dose of insulin when therpy ws trnsitioned from MDI to CSII for six months (22). The dysfunction of β cells hs been found to be mjor contributing fctor in Chinese ptients with T2DM (13); therefore, insulin remins the first choice of therpy. However, s previously discussed, this tretment my result in weight increse, hypoglycemi nd itrogenic hyperinsulinemi, thus incresing the potentil risks of insulin resistnce, vsculr disese nd sleep pne syndrome (14,23 26). Bruttomesso et l (15,17) nd Hoogm et l (27) found tht ptients with T1DM using CSII required lower insulin dosge, s compred with those using MDIs. In the present study, it ws hypothesized tht insulin dosge djustment my lso improve therpy for ptients with T2DM. In Chin, MDI therpy of bolus insulin sprt nd bsl insulin glrgine nd CSII re minly used for glycemic control nd tretment of T2DM in hospitlized ptients with T2DM. There currently hve not been enough relevnt investigtions demonstrting the optiml insulin dosge in Chinese ptients with T2DM. In this study, the insulin dosge chrcteristics of 200 hospitlized ptients with T2DM who were treted with CSII nd MDI therpy were investigted. Ptients nd methods Subjects. Two hundred ptients with T2DM (80 femles nd 120 mles) were recruited for this study. All subjects were hospitlized between Jnury 2011 nd July 2013 in the Deprtment of Endocrinology t Linyi People's Hospitl (Linyi, Chin). The dignosis of T2DM ws estblished on the bsis of the 1999 Dibetes Dignostic Criteri of the World Helth Orgniztion. Subjects hospitlized for insulin tretment due to poor glycemic control nd newly dignosed ptients with high blood glucose were enrolled. Subjects prescribed other orl hypoglycemi gents, with the exception of metformin, were excluded nd none of the subjects received bsl insulin regimen intensifiction prior the ntidibetic tretment. Subjects with impired renl or heptic function nd those who were pregnnt or brest feeding, hd mlignncies, impired crdic function, hypoglycemi unwreness, cute infection or cute complictions (such s dibetic nonketotic hyperosmolr com, dibetic ketocidosis nd dibetic lctic cidosis) were excluded from the study. Investigtors nd ptients were blinded to the therpy sequence up to the point of subject rndomiztion. Subjects were rndomly divided into CSII or MDI group, ccording to their hospitliztion number. One hundred subjects (60 mles nd 40 femles) were rndomly ssigned to continued therpy with CSII nd 100 subjects (60 mles nd 40 femles) to therpy with MDI for 12 weeks. Subjects in the MDI group were dministered insulin sprt immeditely prior to ech mel nd then insulin glrgine before bed. In the CSII group, ll ptients received insulin; 32 hd peripherl neuropthy, 18 hd retinopthy nd six hd lrge vessel diseses. In the MDI group, ll ptients received insulin; 31 subjects hd peripherl neuropthy, 18 hd retinopthy nd seven hd lrge vessel diseses. Ethics sttement. The investigtion ws pproved by the Medicl Ethics Committee of Linyi People's Hospitl. All subjects were ptients dmitted to the Deprtment of Endocrinology nd ll ptients signed consent form llowing their informtion to be stored in the hospitl dtbse nd used for this study. The consent form ws pproved by the Medicl Ethics Committee of Linyi People's Hospitl. Investigtion design nd method. No orl hypoglycemic drugs, with the exception of metformin, were used during the insulin tretment in the present study. The initil dosge for ll subjects ws IU/kg/dy. The MDI group ws treted with insulin sprt (Novo Nordisk, Bgsværd, Denmrk) injected subcutneously prior to ech of the three mels in the dy, s well s single bsl bedtime injection of insulin glrgine (Lntus, Snofi Aventis Phrmceuticls, Mumbi, Indi) dily, for 12 weeks. The initil glrgine bsed insulin injections ccounted for 60% of the totl dily dose nd the insulin sprt ccounted for 40%. The CSII group ws treted with insulin sprt using insulin pumps (Medtronic, Northridge, CA, USA). In the CSII group, the initil bsl dose, which ccounted for 60% of the totl dily mount, ws divided into the following four periods of the dy: midnight 4:00.m., 4:00 9:00.m., 9:00.m. 9:00 p.m. nd 9:00 p.m. midnight. The three pre mel doses together ccounted for 40% of the totl dily dose nd were dministered for 12 weeks. Blood glucose levels were monitored using stble blood glucose monitoring device from LifeScn (Johnson & Johnson Compny, Milpits, CA, USA). Blood glucose levels were mesured from finger stick blood smples eight times per dy (before ech of the three mels, 2 h lter nd t 10:00 pm nd 3:00 m). The diet of ll subjects ws regulted ccording to the Chin Guideline for T2DM. The bsl insulin dose ws preferentilly djusted to control the blood glucose when the pre mel blood glucose level ws >9 mmol/l or the postprndil glucose (PBG) ws <6 mmol/l ccording to the fetures of the PBG stte in ptients with T2DM (15,26). Pre mel doses were distributed evenly mong the three mels. Bsl insulin doses were titrted to trget fsting glucose between 4.0 nd 7.0 mmol/l. Pre mel insulin doses were djusted ccording to 2 h PBG levels to chieve the trget of 11.0 mmol/l. If the subject chieved two consecutive dys t this level, the length of time required to chieve the trget, totl dily insulin doses, dily bsl insulin doses, blood glucose fluctutions nd hypoglycemic episodes were clculted. Hypoglycemic episodes were clssified s severe hypoglycemi when ptients were not ble to tret the episode themselves nd blood glucose ws 3.9 mmol/l, symptomtic hypoglycemi when ptients were ble to tret the episode nd blood glucose ws 3.9 mmol/l, nd reltive hypoglycemi when ptients exhibited symptoms of hypoglycemi but blood glucose ws either >3.9 mmol/l or not mesured (28). Hypoglycemic episodes were evluted s ll events (ll episodes occurring over 24 h period) nd nocturnl events (episodes occurring between 11:00 p.m. nd 6:00.m.). Once glycemic control ws stbilized for 3 dys, the dily insulin dose ws clculted when the pre mel glucose nd

3 EXPERIMENTAL AND THERAPEUTIC MEDICINE 8: , PBG were <7.01 nd mmol/l, respectively. The stte of hypoglycemi ws defined s blood glucose levels 3.9 mmol/l or where symptoms of hypoglycemi resolved with dministrtion of orl crbohydrtes, nd decrese in bsl insulin or regulr insulin dose ccording to pre mel glucose nd PBG. Sttisticl nlysis. All sttisticl dt nlyses were performed using SPSS version 13. (SPSS, Inc., Chicgo, IL, USA). Descriptive dt nlyses of the qulittive vribles were performed with proportions nd percentges. Quntittive vribles re presented s the men ± stndrd devition. The vribles were nlyzed with the independent smples t test between the CSII nd MDI groups. A vlue of P<0.05 ws considered to be sttisticlly significnt. Results Clinicl dt. No sttisticlly significnt differences were observed between the CSII nd MDI groups in gender, ge, hemoglobin A1c (HbA1c), fsting serum C peptide, body mss index, fsting blood glucose (FBG) or other clinicl dt (P>0.05) (Tble I). Insulin doses nd incidence of hypoglycemi. Neither the MDI nor the CSII groups hd severe hypoglycemic episodes during the tretment durtion, nd no sttisticlly significnt differences were observed in nocturnl hypoglycemic episodes. Good glycemic level control ws chieved in the 100 subjects in the MDI group fter 6.88±2.31 dys. The men totl dily dosge of insulin ws 37.12±10.18 IU (0.58±0.17 IU/kg/dy), nd the totl dily bsl nd bolus doses were 19.35±7.84 nd 17.55±3.52 IU (50.80±8.32 nd 49.11±8.32% of the totl dily dose), respectively. Good glycemic level control ws chieved in the 100 subjects in the CSII group fter 5.43±2.30 dys. The decrese in HbA1c in the two groups ws reched erlier in ptients in the CSII group compred with those in the MDI group. The men totl dily insulin dose in the CSII group ws 31.68±8.88 IU (0.48±0.16 IU/kg/dy), nd the totl dily bsl nd bolus doses were 22.77±7.65 nd 9.78±2.74 IU (69.13±6.99 nd 30.87±6.99% of the totl dily dose), respectively (Tble II). A significnt difference in the dose of insulin ws observed between the CSII nd MDI groups (P<0.001). Insulin requirements decresed 19.12±2.3% fter 12 weeks for good glycemic level control in the two groups. Significnt differences were found between the two groups in the totl dose of insulin nd the bsl nd bolus doses of insulin per dy (P<0.001) (Fig. 1 nd Tble II). The incidence of hypoglycemi ws 5.93% in the MDI group nd 1.62% in the CSII group (P<0.01) (Tble II). Tretment efficcy. The men HbA1c showed sttisticlly significnt decrese during the course of the experiment for the MDI nd CSII groups (Tble III). In the MDI group, men HbA1c decresed from 10.79±1.42 to 7.51±1.28%. In the CSII group, men HbA1c decresed from 10.86±1.36 to 7.11±1.32%. No significnt differences were identified between the groups. The men FBG levels in the two groups showed sttisticlly significnt bseline to end point decreses, from 8.61±3.12 to 6.76±1.13 mmol/l in the CSII group nd from 8.68±3.32 to 6.85±1.26 mmol/l in the MDI group (P<0.005 for both). No Tble I. Demogrphic chrcteristics of the subjects. - - Prmeter MDI CSII Mle/femle (n/n) 60/40 60/40 Newly dignosed ptients (n) Durtion of dibetes (yers) 6.78± ±5.79 Age (yers) 51.38± ±12.67 BMI (kg/m 2 ) 24.41± ±3.47 HbAlc (%) 10.86± ±1.42 FBG (mmol/l) 7.61± ± h PBG (mmol/l) 15.42± ±5.71 FCP (ng/ml) 0.71± ±0.45 Descriptive dt re expressed s the men ± stndrd devition. P>0.05 versus MDI group. HbA1c, hemoglobin A1c; BMI, body mss index; FBG, fsting blood glucose; PBG, postprndil blood glucose; FCP, fsting C peptide; MDI, multiple dily injection; CSII, continuous subcutneous insulin infusion. Figure 1. Insulin dose distribution of the MDI nd CSII groups. * P<0.05 versus MDI group. MDI, multiple dily injection; CSII, continuous subcutneous insulin infusion. sttisticlly significnt differences in bseline to end point FBG level decreses were observed between the two groups (P>0.05) (Tble III). The men 2 h PBG level decresed significntly from 15.42±4.78 mmol/l t bseline to 9.87±2.63 mmol/l t the end point in the CSII group nd from 15.60±5.71 to 9.95±2.16 mmol/l in the MDI group (P<0.005 for both). No sttisticlly significnt differences in bseline to end point 2 h PBG level decreses were observed between the two groups (P>0.05) (Tble III). Chnges in insulin doses. The totl dily insulin dose in the CSII group decresed from 0.48±0.16 to 0.39±0.23 IU/kg/dy fter 12 weeks ( 0.09±0.22 IU/kg/dy), nd from 0.58±0.17 to 0.47±0.19 IU/kg/dy fter 12 weeks in the MDI group ( 0.11±0.21 IU/kg/dy); however, the bsl nd bolus insulin doses s percentges of the totl dily dose remined unchnged t the end of the 12 week period (Tble IV). Blood glucose levels. Blood glucose levels in the CSII group were lower thn those in the MDI group (P>0.05) t ech time point;

4 1194 GAO et l: TYPE 2 DIABETES CONTROL BY PREFERENTIAL ADJUSTMENT OF BASAL INSULIN Tble II. Comprison of insulin doses upon chievement of good blood glucose control t the strt of the 12 weeks of therpy. n Rte (IU/kg/dy) Bsl insulin dose (%) Bolus insulin dose (%) Incidence of hypoglycemi (%) CSII ± ± ± b MDI ± ± ± Descriptive dt re expressed s the men ± stndrd devition. P<0.001 nd b P<0.01 versus MDI group. CSII, continuous subcutneous insulin infusion; MDI, multiple dily injection. Tble III. Comprison of efficcy between the CSII nd MDI groups for 12 weeks Prmeter MDI CSII HbAlc Bseline (%) 10.79± ±1.36 End point (%) 7.51± ±1.32 Chnge (%) 3.47± ±1.48 P vlue <0.005 <0.005 FBG Bseline (mmol/l) 8.68± ±3.12 End point (mmol/l) 6.85± ±1.13 Chnge (mmol/l) 1.83± ±2.36 P vlue <0.005 < h PBG Bseline (mmol/l) 15.60± ±4.78 End point (mmol/l) 9.95± ±2.63 Chnge (mmol/l) 5.65± ±4.15 P vlue <0.005 <0.005 Descriptive dt re expressed s the men ± stndrd devition. P>0.05 versus MDI group. PBG, postprndil blood glucose; FBG, fsting blood glucose; CSII, continuous subcutneous insulin infusion; MDI, multiple dily injection. Tble IV. Comprison of insulin doses upon chievement of good blood glucose control fter 12 weeks Prmeter MDI CSII Rte (IU/kg/dy) 0.47± ±0.23 Bsl insulin dose (%) 50.88± ±6.89 Bolus insulin dose (%) 49.12± ±6.99 Descriptive dt re expressed s the men ± stndrd devition. P<0.001 versus MDI group. CSII, continuous subcutneous insulin infusion; MDI, multiple dily injection. however, good glycemic control ws reched in both groups nd no sttisticl differences were observed in FBG levels, 2 h Tble V. Comprison of blood glucose levels t different times nd blood glucose fluctutions fter 12 weeks. Prmeter MDI CSII Rte (IU/kg/dy) 0.47± ±0.23 Bsl insulin dose (%) Bolus insulin dose (%) post brekfst, 2 h post lunch or 2 h post supper blood glucose levels or blood glucose levels t 3:00.m. between the two groups (Tble V). Blood glucose fluctutions for the CSII group were lower thn those for the MDI group (P<0.001) (Tble V). Insulin requirements decresed 19.12±2.3% fter 12 weeks for good glycemic level control in the two groups. Discussion 50.88± ± ± ±6.99 Blood glucose levels (mmol/l) Fsting 6.17± ± h fter brekfst 8.96± ± h fter lunch 9.23± ± h fter supper 8.59± ±0.89 3:00.m. 6.26± ±0.61 Blood glucose fluctution (mmol/l) 0.23± ±0.04 b Descriptive dt re expressed s the men ± stndrd devition. P<0.001 nd b P<0.01 versus MDI group. Blood glucose dily fluctutions contribute to oxidtive stress, which cn cuse long term complictions in ptients with dibetes (29). Avoiding glucose fluctutions in ptients with dibetes is n emerging chllenge (30). The dt presented indicte tht fluctutions in dily blood glucose were nrrower for ptients undergoing CSII therpy thn for those undergoing MDI therpy. The results were consistent with the theory tht bsl insulin djustment using CSII therpy in ptients with dibetes provides less vrible blood glucose levels thn long cting insulin (31). The vribility in blood glucose control ppers to be prticulrly significnt with regrd to long cting insulin. However, no difference ws detected in dily blood fluctutions between CSII nd MDI therpies in previous study of ptients with T2DM (32). Hypoglycemi is one of the min fctors for ptients with dibetes requiring insulin to chieve tight glycemic control

5 EXPERIMENTAL AND THERAPEUTIC MEDICINE 8: , nd reduced likelihood of complictions. No sttisticlly significnt differences in nocturnl hypoglycemic episodes nd hypoglycemi were detected between the two groups in the present study (P>0.05), suggesting tht the sfety of the MDI therpy my be comprble to tht of CSII therpy in subjects with T2DM. The dt presented in this study showed tht, in ptients with T2DM treted with insulin therpy for 12 weeks, the totl dily dose of insulin in the MDI group ws significntly greter thn tht in the CSII group. The bsl dose regultion in the MDI group ws not convenient nd the muttion vrition rtes of subcutneous bsorption of bolus insulin sprt nd bsl insulin glrgine were considerbly greter in the MDI group thn those in the CSII group. Three fctors contribute to PBG in dibetes: Increses in glycogen output, FBG nd bsorption of intestinl glucose. In generl, incresing the rnge of 2 h PBG depends upon incresing the gstrointestinl glucose bsorption nd glycogen output. However, gstrointestinl glucose bsorption is the sme in ptients with T2DM nd helthy subjects (31) Bsl insulin my restrict the glycogen output (33) by decresing both pre mel blood glucose nd FBG levels nd prtilly restrining postprndil hyperglycemi. Although decresing PBG my be treted using bsl insulin, lower pre mel insulin dose is still required s supplement to control PBG. The pre mel insulin dose my only restrin the bsorption relted increse in glucose nd some of the output of glycogen. A lower pre mel dose my decrese the dditive effect of the bsl dose, therefore voiding the requirement for djustments to be mde the bsl dose. The study by Suzuki et l (33) indicted tht n increse in bsl insulin dose my be n effective method to control HbA1c nd FBG in ptients with T2DM nd showed the dominnce of bsl insulin tretment. Due to the djustment therpy method used in the present study, the totl dily bolus insulin dose of the CSII group ws 30.87±6.99%; this contrsted with the totl dily bolus dose used in the tretment of Koren ptients (64.11±12.10%) (34). In the present study, the men totl dily dose of insulin ws 31.68±8.88 IU (0.48±0.11 IU/kg/dy) for the 100 ptients in the CSII group, while in study of 46 Indin ptients with T2DM the dily insulin dose ws 44.0±23.7 IU/dy (18). In the present study, the totl dily bolus dose (17.55±3.52 IU) of the MDI group subjects comprised 49.11±8.32% of the totl dily dose, nd the men totl dily dose of insulin ws 37.12±10.18 IU/dy (0.58±0.17 IU/kg/dy); these vlues were both higher thn those of the CSII group subjects. In ll subjects, the men totl dily dose of insulin ws 34.86±9.76 IU nd the dose of insulin per unit body weight ws 0.53±0.17 IU/kg/dy. The totl dily bolus nd bsl insulin doses were 13.75±5.01 nd 21.12±7.91 IU (40.07±11.88 nd 59.93±11.88% of totl dily dose), respectively. These vlues differed from those in previous report where the bsl/totl dily rtio of insulin ws 0.23±0.08 nd the men dily dose of insulin ws 38.22±14.92 IU/dy (35). From studying 200 ptients with T2DM nd other relted reserch reports (21,22,34), pre mel nd bsl dose proportions hve been shown to be ssocited with the totl insulin dose. Pre mel blood glucose levels cn be controlled by preferentilly regulting bsl insulin, mking the required totl dily dose of insulin lower. After 12 weeks of ppliction, MDI treted ptients with T2DM hd higher totl insulin dose requirement nd hypoglycemi incidence nd took longer to chieve the trgeted glycemic control compred with the CSII treted ptients. Following CSII tretment in ptients with T2DM, decreses in bolus dose nd increses in bsl insulin dose cn form n effective method to chieve good glycemic control with lower totl dily dose. However, where fctors exist to prevent the use of therpy with insulin pumps, once dily glrgine t bedtime combined with sprt dministrtion t ech of the three mels should be n effective lterntive. Acknowledgements This study ws supported by the Shndong Province Science nd Technology Development Pln (2012YD18019). The uthors would like to thnk ll the stff working t the Deprtments of Endocrinology nd Clinicl Medicine in the Linyi People's Hospitl. References 1. Lindholm A, McEwen J nd Riis AP: Improved postprndil glycemic control with insulin sprt. A rndomized double blind cross over tril in type 1 dibetes. Dibetes Cre 22: , Anderson JH Jr, Brunelle RL, Koivisto VA, et l: Reduction of postprndil hyperglycemi nd frequency in hypoglycemi in IDDM ptients on insulin nlog tretment. Multicenter Insulin Lispro Study. Dibetes 46: , Rskin P, Klff L, Bergenstl R, et l: A 16 week comprison of the novel insulin nlog insulin glrgine (HOE901) nd NPH humn insulin used with insulin lispro in ptients with type 1 dibetes. Dibetes Cre 23: , Lepore M, Pmpnelli S, Fnelli C, et l: Phrmcokinetics nd phrmcodynmics of subcutneous injection of long cting humn insulin nlog glrgine, NPH insulin, nd ultrlente humn insulin nd continuous subcutneous infusion of insulin lispro. Dibetes 49: , Pickup J nd Keen H: Continuous subcutneous insulin infusion t 25 yers: evidence bse for the expnding use of insulin pump therpy in type 1 dibetes. Dibetes Cre 25: , Reynolds LR: Reemergence of insulin pump therpy in the 1990s. South Med J. 93: , Bode BW, Steed RD nd Dvidson PC: Reduction in severe hypoglycemi with long term continuous subcutneous insulin infusion in type 1 dibetes. 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