Insulin Pump Treatment of Childhood
Type 1 Diabetes
Stuart A. Weinzimer, MDa,T, Kristin A. Sikes, MSNb,
Amy T. Steffen, BSb, William V. Tamborlane, MDa,c
aDepartment of Pediatrics, Yale University School of Medicine, PO Box 208064,
New Haven, CT 06520–8064, USA
bYale Pediatric Diabetes Research Program, Yale School of Medicine, 2 Church Street South,
Suite 312, New Haven, CT 06519, USA
cGeneral Clinical Research Center, Yale University School of Medicine, 333 Cedar Street,
New Haven, CT 06520-8064, USA
Continuous subcutaneous insulin infusion (CSII) pump therapy was intro-
duced to treat patients with type 1 diabetes (T1DM) more than 25 years ago [1,2].
At that time, most children and adolescents were being treated with one or two
daily injections of mixtures of neutral protamine hagedorn (NPH) and regular
insulin of animal origin and treatment was adjusted based on urinary glucose
excretion. With these inadequate methods, it was unsafe to strive for strict meta-
bolic control in young patients, glucose levels often averaged over 300 mg/dL,
and children were at high risk for the later development of the devastating com-
plications of diabetes. With CSII, clinicians could more closely simulate the
patterns of plasma insulin levels seen in normal children. The more predictable
pharmacokinetics of fast-acting versus intermediate-acting insulin  and the
administration of bolus doses immediately before each meal were two obvious
advantages of this approach to insulin replacement. Although not fully rec-
ognized at the time, the basal-bolus regimen offered by CSII and subsequently
applied to multiple daily injection regimens fundamentally changed the diabetes
treatment paradigm from adjusting the patient’s lifestyle to a fixed insulin
regimen to adjusting the insulin regimen to the patient’s lifestyle.
0031-3955/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
Supported by grants from the National Institute of Health (K12 DK063709, RR 06022, U10
HD041906), the Juvenile Diabetes Research Foundation, and the Stephen J. Morse Pediatric Diabetes
T Corresponding author.
E-mail address: firstname.lastname@example.org (S.A. Weinzimer).
Pediatr Clin N Am 52 (2005) 1677–1688
The development of pump therapy in the late 1970s coincided with the
introduction of self-monitoring of blood glucose, hemoglobin (Hb) A1cassays,
and more aggressive approaches to conventional insulin therapy, using multiple
daily insulin injections (MDI). It was suggested that the improved metabolic
control achieved with these intensive therapies might finally provide an answer to
the question of the role of hyperglycemia in the development and progression of
microvascular and neuropathic complications of diabetes . This issue was
finally resolved in 1993 with publication of the results of the Diabetes Control
and Complications Trial (DCCT) . Even in the relatively small subset of
adolescents who were 13 to 17 years of age on entry in the DCCT, intensive
treatment significantly reduced the risk of onset and progression of retinopathy
and microalbuminuria . Subsequent follow-up of adolescents in the DCCT has
shown that the risk of these complications remained reduced many years after
completion of the DCCT, even though HbA1clevels no longer differed between
former intensive and former conventional treatment group patients . It has
been recommended that the goals of treatment in children with diabetes should be
to achieve glucose and HbA1clevels as close to normal as possible and as early in
the course of the disease as possible.
Despite the putative advantages of CSII over conventional insulin injection
regimens, CSII was used in very small numbers of children before publication
of the DCCT results. The advantages of pumped versus injected insulin include
?Uses only rapid-acting insulin
?Bolus doses given before each meal and snack
?Variable basal infusion rate between meals and overnight
?Increased flexibility and improved lifestyle
?One injection every 2 to 3 days
Factors that limited more widespread use of this method of insulin delivery in
children before the DCCTincluded the large size and difficulties in use of early pump
models, psychologic issues about wearing an external device, and the extra costs
of pump therapy . The most important obstacle to use of these devices, however,
was uncertainty regarding the long-term benefits of intensive treatment itself. Results
of the DCCT removed this important obstacle to use of pumps in children and,
as pediatric treatment teams were challenged to find more effective methods to
achieve intensive treatment goals, insulin pump therapy was rediscovered. Con-
sequently, the safety and efficacy of this ‘‘new’’ approach to treatment of childhood
diabetes has been the subject of intense interest over the past few years.
The rediscovery of insulin pump treatment in children coincided with a num-
ber of important improvements in pump technology that have made the devices
safer and easier to use. Advanced pump features include the following:
?Multiple variable basal rates and small increments
?Smaller pumps and better infusion sets
weinzimer et al1678
?Greater safety and reliability
?Wireless link to glucose meter
?Dose calculators that incorporate carbohydrate to insulin ratios and cor-
?Bolus history and other memory functions
The development of pumps with variable basal rate profiles allowed for a
closer match in insulin needs particularly overnight, offering the opportunity to
reduce the risk of nocturnal hypoglycemia. Current devices are small in size, easy
to program, and have a variety of alarms and variable basal rates that can
be adjusted in very small increments. Catheters and infusion sets have also
improved. The most recent advances in pump technology include software
programming of bolus and correction doses based on insulin to carbohydrate
ratios and wireless transmission from meter to pump of blood glucose levels.
The introduction of very rapid-acting insulin analogues has been of benefit to
both CSII and multiple daily injection regimens. In comparison with regular
insulin, rapid-acting insulin analogues have earlier and sharper peaks and less
overshoot hyperinsulinemia, facilitating better control of meal-related hyper-
glycemia with less late postprandial and nocturnal hypoglycemia [8–10]. These
advantages of rapid-acting insulin analogues are of particular importance in
adolescents with diabetes who require relatively large premeal bolus doses to
overcome the peripheral insulin resistance of puberty .
Safety and efficacy of continuous subcutaneous insulin infusion in youth:
clinical outcome studies
When considering the relative benefits and risks of CSII and MDI in children
and adults , most studies before 2000 can be disregarded because both
treatments have changed so dramatically. The initial reports examining the safety
and efficacy of CSII in youth with T1DM in the ‘‘new era’’ were clinical outcome
studies where the patients served as their own controls . Although the results
of these nonrandomized investigations must be interpreted with caution, the
DCCT provides a historical standard by which to judge the usefulness of CSII.
During the course of the DCCT, intensively treated adolescents were able to
lower HbA1c levels to a mean of 8.1% (normal ?6%) versus 9.8% in the
conventional treatment group . Improved diabetes control was achieved at the
cost of a threefold increase in the risk of hypoglycemia, however, compared with
conventional treatment. During the first 12 months of intensive treatment in the
DCCT, the frequency of severe hypoglycemic events requiring the assistance of
another person in adolescents was approximately one event per patient per year
and 39% of these episodes resulted in seizure or coma. Intensive treatment also
increased the risk of excessive weight gain.
The authors’ multidisciplinary treatment team began using CSII in earnest in
1997. Their initial report described clinical outcomes in the first 161 patients
insulin pump treatment
(aged 18 months to 18 years) who were started on CSII in the Yale Children’s
Diabetes Clinic between January, 1997, and March, 2000 . Only patients with
T1DM who had been followed for at least 1 year before the start of pump therapy
were included in the study and clinical data were collected prospectively before
and during pump treatment using standardized case report forms and a database
developed for this purpose. As shown in Fig. 1, before the start of CSII, mean
HbA1clevel was 7.8%, whereas after 12 months of pump therapy it had fallen to
7.1%. This improvement in metabolic control was maintained at the patient’s
end-of-study visit, 26 F 9 months after the start of CSII. Lower HbA1clevels
were achieved with CSII without increasing daily insulin doses or body mass
index (BMI)-z score. Although lower HbA1clevels are expected to be accom-
panied by an increase in the rate of severe hypoglycemia , the frequency of
severe hypoglycemic events fell from 37 to 24 events per 100 patient years after
they switched to pump therapy (Fig. 2). Moreover, preschool children b7 years of
age had the greatest reduction in the risk of severe hypoglycemia. Because these
results were considerably better than the DCCT standards for intensive treatment
in children , it was concluded that CSII is an effective alternative to injection
therapy in a large pediatric diabetes clinic setting and that even very young
patients can use CSII safely to lower HbA1clevels .
The number of children using pump therapy in the authors’ clinic is now more
than 600 youngsters. All are using rapid-acting insulin analogues, and the quar-
terly mean HbA1clevels for this cohort range between 7.2% and 7.4%.
Over the past 4 years, a number of centers have reported their experience in
youngsters who switched from injection to pump treatment [15–24]. As shown
by the representative studies listed in Table 1, most of these investigations in-
volved fairly large cohorts of patients who covered the entire pediatric age range.
In comparison with glycemic control on injection therapy, these studies have
reported decreases in HbA1clevels that ranged between 0.2% and 0.7%, reaching
values that were generally equal to or better than the DCCT standard .
Pre-PumpPump 12mosPump ~26mos
Fig. 1. Reduction in HbA1clevels after switching from injection to pump therapy in the initial Yale
Children’s Diabetes Clinic Study. (Data from Ahern JA, Boland EA, Doane R, et al. Insulin pump
therapy in pediatrics: a therapeutic alternative to safely lower therapy HbA1c levels across all age
groups. Pediatr Diabetes 2002;3:10–5.)
weinzimer et al1680
Although such decreases in HbA1clevels might have been expected to increase
the risk of hypoglycemia , a reduction in the frequency of severe hypogly-
cemia has been consistently observed (see Table 1). Unlike the DCCT, excessive
weight gain has not been a problem after switching from injection to pump
therapy in children even in the face of better control. It should be noted, how-
ever, that in many of these studies mean BMI was already 0.5 to 1 standard
deviations above the mean for age before switching to pump therapy.
One of the last frontiers for pump therapy has been the use of this method of
insulin delivery in infants, toddlers, and preschool children. Because treatment of
very young patients with T1DM provides a special challenge, the authors recently
analyzed long-term outcome data in this age group. Outcomes in 65 children who
were less than 7 years of age at the start of insulin pump therapy were examined
. HbA1clevels fell from 7.4% F 1% to 6.9% F 1%, and this level of control
was sustained for up to 48 months. Even more important for children in this age
group, the frequency of severe hypoglycemic events was reduced by more than
Results of switching from injection to continuous subcutaneous insulin injection therapy in non-
randomized pediatric studies
Author (ref)NAge (y)Hemoglobin A1c(%) Hypoglycemia BMI-z
Ahern et al 
Maniatis et al 
Plotnick et al 
Sulli and Shashaj 
Willi et al 
Mack-Fogg et al 
Weinzimer et al 
Abbreviation: BMI-z, body mass index (z-score).
12 Months Pre-Pump12 Months Pump Rx
Events per 100 patient years
Fig. 2. Reduction in the rate of seizure and coma events during 12 months before and following
switching to pump therapy in the initial Yale Children’s Diabetes Clinic Study. (Data from Ahern JA,
Boland EA, Doane R, et al. Insulin pump therapy in pediatrics: a therapeutic alternative to safely lower
therapy HbA1c levels across all age groups. Pediatr Diabetes 2002;3:10–5.)
insulin pump treatment
50%. Similar improvements in diabetes control were achieved in children with
working mothers and mothers who stayed at home during the day.
Tubiana-Rufi and colleagues  also examined the usefulness of pump
therapy in infants and toddlers. They studied youngsters who were experiencing
recurrent episodes of hypoglycemia while on injection therapy. After switching to
pump treatment, the frequency of severe hypoglycemic events was sharply re-
duced without sacrificing overall diabetes control. Similarly, positive results were
reported in young children who were switched from injection to pump treatment
by Litton and colleagues  and Shehadeh and colleagues .
Safety and efficacy of continuous subcutaneous insulin infusion in youth:
results of randomized clinical trials
The first randomized study in pediatrics that compared the two therapies was
undertaken in newly diagnosed patients. Although b-cell function was not
prolonged, HbA1c levels were significantly lower in the CSII group .
Weintrob and colleagues  used a randomized crossover design to compare
the efficacy of CSII with a four shots per day regimen that used NPH insulin
as basal insulin. Twenty-three children aged 9 to 13 years were studied for
3.5 months on each treatment. The changes in HbA1cwere similar with both
treatments over time and there was a low rate of adverse events with each therapy.
The successful use of NPH insulin in the study by Weintrob and colleagues
 is noteworthy, because it has been suggested that the clinical pharmacology
of NPH insulin poses an important obstacle to safe and effective MDI therapy.
Because NPH is a suspension, there is considerable dose-to-dose variability in the
amount of insulin that is administered and absorbed  and the peaking action
of this insulin makes it less than ideal for basal insulin replacement . These
limitations have been overcome to a great extent by the introduction of glargine
insulin, the first soluble insulin analogue that has a flat and prolonged time-action
profile . Bolus-basal therapy that combines premeal aspart or lispro with
glargine insulin has emerged as the gold standard for intensive MDI therapy in
adults with T1DM.
A practical disadvantage of MDI with glargine in youth with T1DM is the
large number of injections that are required daily. Unlike insulin suspensions,
glargine cannot be mixed with rapid-acting insulin and must be injected sepa-
rately. Because glargine does not peak, injections of rapid-acting insulin are also
required for each meal and large snack to control postprandial hyperglycemia.
Compliance problems with the frequent daily injections may, in part, explain why
randomized pediatric trials have failed to show lower HbA1clevels with glargine
compared with NPH insulin [29,30].
The authors have recently completed a randomized, parallel group clinical trial
comparing the effectiveness of CSII and MDI with glargine in lowering HbA1c
levels in children and adolescents with T1DM. Sixteen conventionally treated
diabetic subjects who were naive to previous treatment with CSII and glargine
weinzimer et al1682
were randomized into each treatment group and changes in HbA1clevels assessed
after 16 weeks of therapy. As shown in Fig. 3, subjects randomized to the
glargine group were able to achieve as effective control of their diabetes as on
conventional injection regimens. In contrast, patients randomized to CSII were
able to significantly lower HbA1cvalues compared with their own baseline levels
and versus the glargine group at 16 weeks . It is noteworthy that 50% of
patients in the CSII group were able to lower HbA1cto 7% or less versus only
12.5% in the MDI group. Two randomized clinical trials in preschool children
with T1DM showed similar or slightly lower HbA1clevels with CSII versus
injection therapy [32,33].
Subjective and other benefits of continuous subcutaneous insulin infusion
A qualitative approach with structured interviews has been used recently to
examine the subjective response of patients and parents to pump treatment .
In that study, parents of very young patients consistently reported that CSII gave
them their former lives back and that they were freed from the slavery of diabetes
management that had previously affected the whole family. Shehadeh and
colleagues  also reported improved diabetes quality of life and treatment
satisfaction in parents of young children treated with CSII . Low and col-
leagues  reported greater satisfaction with CSII in adolescents. Even though
HbA1clevels did not differ, patients in the randomized cross-over study by
Weintrob and colleagues  also reported higher treatment satisfaction with
CSII than with MDI and 16 of the 23 patients elected to use pump rather than
MDI therapy at the end of the study .
Fig. 3. Changes in HbA1clevels in the Yale randomized clinical trial comparing CSII with glargine-
based MDI therapy. The difference in HbA1clevels between the CSII and glargine group at baseline
was not significant. In contrast, at 16 weeks, HbA1clevels in the CSII group were significantly lower
than baseline (P b.02) and versus glargine (P b.05). (Data from Doyle EA, Weinzimer SA, Steffen
AT, et al. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin
infusion with multiple daily injections using insulin glargine. Diabetes Care 2004;27:1554–8.)
insulin pump treatment
One of the less well-publicized advantages of insulin pump therapy is that the
bolus history function of newer models allows clinicians and parents to track the
child’s compliance with administration of premeal bolus doses. Using this
function, Burdick and colleagues  demonstrated that missing boluses is a
common problem in youngsters with rising HbA1clevels on CSII. There is no
similar way to track bolus dose administration by patients on MDI therapy. In
youth with T1DM, the risk of hypoglycemia is increased both during and on the
night following prolonged aerobic exercise . Children and adolescents on
insulin pump therapy can decrease or suspend their rates of basal insulin infu-
sion during exercise and use alternate overnight basal rates to reduce the risk
of hypoglycemia. Acute reductions in the amount of basal insulin to prevent
exercise-induced hypoglycemia are not readily achievable with long-acting in-
sulins like glargine.
Importance of team management
The overriding conclusion from nonrandomized and randomized studies is
that CSII provides an effective method of treatment of children and adolescents
with T1DM across all age groups. It is also clear, however, that no single ap-
proach to treatment is ideal for every patient. The availability of multiple
therapeutic options allows clinicians who care for children with T1DM to choose
the best treatment for that individual patient at that particular time. Indeed, it can
be effectively argued that the dedication, skill, and enthusiasm of the multi-
disciplinary team that cares for these youngsters play a primary role of the
success of diabetes treatment. At the authors’ center, diabetes nurse specialists
(all advanced practice nurses) are the key members of the team who interact most
frequently with the patients and parents . These primary nurse managers
remain in close contact with the families between office visits by telephone,
email, and fax to adjust the treatment regimen and to maintain their commit-
ment to treatment goals. Other members of the team, including the dietitian,
psychologist, social worker, and pediatric endocrinologist, support the nurse man-
agers. One of the major crises that pediatric diabetes care faces at the present
time is that current insurance reimbursement rates cover only a small fraction of
the actual costs of multidisciplinary care of children with this condition .
Toward a brighter future
Self-monitoring of blood glucose in combination with insulin pump therapy
offers the possibility of controlling postprandial hyperglycemia and of reducing
the risk of severe hypoglycemia. Most children and adolescents with T1DM only
measure premeal blood glucose levels during the day, however, and they rarely
measure glucose levels during the night, the time of greatest vulnerability to
hypoglycemia . Marked glycemic excursions from high to low values are
weinzimer et al1684
undoubtedly missed by the brief glimpses into 24-hour glucose profiles provided
by self-monitoring of blood glucose. Consequently, the recent development of
methods for continuous monitoring of interstitial glucose concentrations has the
potential to be one of the most important advances in the management of children
and adolescents with T1DM in the past 20 years. Glucose sensor data regarding
nocturnal glucose profiles should allow clinicians to exploit fully the variable
basal rate capabilities of insulin pumps. Similarly, analysis of postprandial
glycemic excursions can provide a more rational method of dividing daytime
insulin replacement between basal and bolus doses in CSII-treated patients.
The Continuous Glucose Monitoring System (CGMS) developed by Med-
tronic MiniMed (Northridge, California) was the first continuous glucose-
monitoring device approved by the US Food and Drug Administration. The
CGMS sensor is inserted through a needle into the subcutaneous tissue of
the anterior abdominal wall and measures interstitial glucose concentrations. The
other Food and Drug Administration approved glucose sensing system is the
GlucoWatch 2 Biographer (GW2B), developed by Cygnus (Redwood City, Cali-
fornia). It looks like a watch and is worn on the forearm. Glucose is pulled from
the interstitial fluid underneath the skin by reverse iontophoresis.
In comparison with the mature glucose meter technology that has benefited
from 25 years of development, glucose sensor system technology is still in its
infancy. Studies from the Diabetes Research in Children Network have dem-
onstrated some of the limitations of the first-generation systems. As shown in
Fig. 4, both the original CGMS and GW2B lack the accuracy and precision of
current fingerstick blood-glucose meters, especially in the detection of hypo-
glycemia [41–43]. Moreover, in a recent randomized clinical trial involving
0 100200 300400
Reference Blood Glucose (mg/dL)
% Error (median RAD)
Fig. 4. Accuracy of the GlucoWatch G2 Biographer, original and modified CGMS, and One Touch
Ultra meter in 89 children and adolescents with type 1 diabetes. % error (y-axis) represents the median
relative absolute difference (RAD) of sensor and meter glucose levels compared with reference serum
glucose values measured at a central laboratory for the DirecNet Study Group. (Data from references
insulin pump treatment
200 children with T1DM, adding use of the GW2B to conventional glucose meter
monitoring did not lower HbA1c levels or the frequency of hypoglycemia
compared with conventional glucose monitoring alone . By the end of the
6 months of that study, more than 25% of the GW2B group had stopped using
the device altogether and the rest used it very infrequently. The modified CGMS
sensor was shown to be more accurate than the original , however, and a real-
time version of this system and others is on the verge of being introduced.
Although much work still needs to be done, these breakthroughs in continuous
glucose sensing suggest that clinicians may finally be at the threshold of the
development of a practically applicable artificial endocrine pancreas, a prospect
that has been anticipated for more than 30 years .
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