Cindy Sihotang

September 2014
Integrative Pharmacology
Type I Diabetes Mellitus Insulin Therapy in Pediatric Patients:
Then, Now, and in the Future either
Type 1 Diabetes Mellitus (T1DM) is one of the most common chronic diseases in the
pediatric population. In the US, there are approximately 1.54 cases for every 1,000 youth (age
<20 years). The incidence of TIDM is about 19 cases for every 100,000 persons per year and its
incidence has been increasing annually approximately 2.3% each year. (8)
Most patients are diagnosed as children with a peak diagnostic age at early to midpubertal ages. There is a strong genetic component to the disease. Those with certain
mutations of the major histocompatibility component on chromosome 6 have shown to either
increase the risk of T1DM or are actually protective. In addition, there seems to be increased
risk in those with a close family relative with T1DM. However, only about 10-20% of those with
TIDM actually have a close family relative with T1DM. Ultimately, T1DM is caused by
autoimmune destruction of the pancreatic islet cells. Autoantibodies to many different cellular
components have been associated with T1DM. Interestingly, the more types of antibodies found
within one patient, the increased risk of T1DM. However, there are many with the
autoantibodies who dont develop T1DM. This limitation is part of the reasoning for why
screening of T1DM is not recommended at this time. After months to years, when there is less
than eighty percent left of the pancreatic islet cells, the patient then begins to develop
symptoms of T1DM including polyphagia, polydypsia, weight loss, frequency often manifesting
as children wetting their beds. Once patients are diagnosed and treated, there is a period of
time, lasting usually several months, called the honeymoon period. Treatment lowers the
glucose levels and the remaining islet cells have improved insulin production. This leads to
interesting changes in insulin management which will be mentioned later. After this
honeymoon period, there is usually no pancreatic islet cells that remain which leads to an
absolute insulin deficiency.
Therefore, the gold standard of treatment for T1DM is insulin. There are short term and
long term goals for insulin therapy. Short-term goals include preventing hypoglycemic events
often defined as glucose <70mg/dL and preventing Diabetic Ketoacidosis (DKA). Mild
hypoglycemia can lead to sweating, anxiety, and tremors while severe hypoglycemia can lead to

seizures and mortality. DKA also has high mortality. Long term, the goal is to have tight
glycemic control, which includes having glucose within the target range of about 80-100 mg/dL
and about a HgA1c of about 7%. Studies have shown that tighter glycemic control leads to
reduced risk of microvascular and microvascular complications such as retinopathy,
nephropathy, and neuropathy. (8) However with tighter glycemic control comes the risk of
increased hypoglycemic events.
There are now many types of insulin therapies available which can be categorized by
their onset of action: rapid, short, intermediate, and long acting. Aspart (Novolog), glulisine
(Apidra), lispro (Humalog) are rapid acting insulin; their time to onset is 15-30 minutes with a
peak at 30-90 minutes and lasting 3-5 hours. Short acting insulin includes regular insulin; it
starts working 30-60 minutes after administration peaking at 2-5 hours and lasting for 5-8 hours.
NPH is the intermediate acting insulin; its time to onset is 1-2 hours peaking at 4-12 hours and
lasting 18-24 hours. Glargine (Lantus) and Levemir are the long acting insulin, which start
working 1-2 hours after administration and lasts approximately 24 hours. Levemir peaks at 6-8
hours; however, glargine maintains its concentration resulting in no peak.
Most patients will require about .5-1 units/kg of insulin to manage their T1DM; this is
often referred to as the total daily dose (TDD). During the honeymoon period, while
endogenous insulin continues to be produced by the remaining islet cells, the TDD may actually
decrease below 0.5units/kg. As patients grow older and/or enter puberty, insulin requirements
usually increase.
There are two main regimens for insulin: mixed-split and basal-bolus. The mixed-split
regimen usually includes administering 1/3 of the TDD as rapid or short acting insulin such as
regular and the other 2/3 of the TDD as intermediate insulin such as NPH. 2/3 of that
combination is given in the morning and the other 1/3 is given at bedtime. It is possible to
provide euglycemia; however, it requires patients to eat their meals at the same time each day
and to eat the same amount of carbohydrates at each meal.
An alternative method is the basal-bolus regimen. The basal insulin covers the fasting
states in-between meals. The bolus insulin is given before each meal covering the meal and also
correcting for hyperglycemia. This requires the use of correction factor/sensitivity and
insulin:carbohydrate (I:C) ratio calculations. The correction factor/insulin sensitivity is used for
correction of hyperglycemia. For example, a patient may have a correction factor of 50. If the
patients preprandial glucose level is 300 mg/dL and he/she has a target goal of 100mg/dL, the

patient needs to correct his/her glucose by 200mg/dL. The correction factor means that for
each 1 unit of insulin, his/her sugar will decrease by 50 gm/dL. So to correct for his/her
hyperglycemia, this patient will require 4 units of insulin. Correction factors vary among
patients and may even vary between meals for one single patient. However, a good rule for a
newly diagnosed patient is correction factor = 1800/TDD. The I:C ratio is used to cover the
meals; a value such as 8 means that each unit of insulin will cover about 8 gm of carbohydrates.
For example, if a patient is going to eat 50gm of carbohydrates for his/her next meal, he/she
needs about 6 units of insulin. So in total for this patient, he/she will need 10 units before the
meal: 4 units for correction and 6 for coverage. Again, the I:C ratio may vary between patients
and may even vary among meals within one patient. A good rule of thumb for an initial I:C ratio
is 500/TDD. There are several benefits of the basal-bolus regimen, the main being its allowance
for flexibility. Patients have the freedom to choose how many carbohydrates they will eat and
what time they will eat. Overall, this regiment also provides better glycemic control than the
mixed-split.
The basal-bolus regimen can be administered either through multiple daily injections
(MDI), done with a pen or syringe, or through continuous subcutaneous insulin infusions (CSII),
also known as the insulin pump. With MDI, a long acting insulin is given either once or twice a
day and a rapid acting insulin is given as boluses. The CSII or insulin pumps utilizes only rapid
acting insulin and administers continuous amounts of basal insulin with bolus amounts before
meals. Basal insulin infusions can be manually adjusted so that they vary at certain times of the
day. For example, patient who display the Dawn Phenomenon, which is the natural
physiological morning hyperglycemia, can have higher basal insulin infusions during the night to
counter it. The CSII provides insulin in a manner closer to the true pancreas. Several studies have
also suggested that there is improved glycemic control in the CSII group compared to the MDI
group which included lower HgA1c, lower fasting glucose levels, and lower insulin requirements.
In one retrospective paired study, 279 patients who were switched from MDI to CSII had data
compared from one year prior to the switch to after the switch. After the switch, there was a
mean drop of 0.5% in HgA1c. More improvement in HgA1c was especially seen in those whose
initial HgA1c was higher. There was also less hypoglycemic events. (13)
Another important component of management of T1DM is glucose monitoring. The
most common method done by most patients currently is self monitoring of blood glucose
(SMBG) which includes a home glucose monitor that tests the blood from a finger prick. The

current recommendation is to check glucoses at least four times a day: before each meal and at
bedtime. Increased frequency of glucose testing is also recommended during exercise, during
illnesses, and during early diagnosed T1DM. For patients with newly diagnosed T1DM, more
frequent blood glucose testing allows for fine-tuning and adjustments of insulin therapy.
Studies have shown that more frequent testing is associated with better glycemic control
leading to less long term complications (4). Something that is newer in the area of glucose
monitoring is continuous glucose monitoring (CGM). There are several devices on the market
that provide noninvasive methods of glucose monitoring by checking interstitial glucose which
correlates well with plasma glucose. The CGM is achieved by a sensor that sits just under the
skin lasting for several days; however, it has not completely eliminated the finger prick because
the machine has to be calibrated several times a day. Studies with adult T1DM patients have
showed that those with the CGM compared to SGBG have lower HgA1c levels. However, theses
results have not been demonstrated yet in pediatric patients. In a randomized clinical trial of
146 T1DM patients aged four to less than 10 years, those in the CGM group compared to the
SMBG group met the primary outcome of having greater than or equal to 0.5% reduction in
HgA1c less frequently than those in the SMGB group (17% compared to 28% respectively, p =
0.17) (11). Of note, several studies showed that there was a correlation between better
glycemic control and the consistent use of the CGM. A new feature on the CGM devices
includes an alarm, which goes off when there is hyperglycemia or hypoglycemia detected.
Several issues with the alarm include false alerts, meaning the glucose levels were actually
normal but were detected as abnormal, and patients not waking up from the alarms during the
night when hypoglycemia is most dangerous. In addition, some CGM devices have the feature
of insulin infusion suspension when the sensor detects hypoglycemia. This has shown to
decrease nocturnal hypoglycemic events without increasing the HgA1c (4).
More innovations with CSII developed once studies showed promising results from
CGM. In efforts to create an artificial pancreas, there is now a closed-loop system which
requires 3 components: continuous glucose monitoring, continuous insulin infusions, and an
algorithm. Currently, insulin infusions work as an open loops system; infusion rates must be
manually entered and changed. Therefore, the rate is usually quite constant. Glucose levels
associated with this method are still quite variable meaning there are frequent episodes of
hypoglycemia and hyperglycemia. The goal of the artificial pancreas and the closed-looped
system is that there is more constant blood glucose levels achieved by varying insulin infusion

rates. The is theoretically done by the sensor sending the glucose level to the computer where
it will be entered into an algorithm which will then provide the insulin infusion rate. This is done
anywhere between every minute to every ten minutes resulting in insulin infusion rates that
vary instead of being constant. This mimics the physiological way insulin is made in the body. A
randomized control trial of eight adult patients with intraperitoneal insulin pumps compared the
closed loop system to the open loop system. Results showed that there was significantly more
time spent with glucose levels within the target range of 4.4-6.6mmol/dL in the closed loop
group compared to the open loop group (39% vs 27.7%, p=0.05). It also showed that the overall
dispersion of blood glucose levels was lower. In another randomized clinical trial of 16
adolescent participants, the closed loop system was compared to the open loop system during
nocturnal hours for 3 weeks each. Time spent with glucose within target range of 3.0 - 8.0
mmol/dL was higher in the closed loop system (p<0.001). The mean overnight glucose was
reduced by 14 (p<0.001). Therefore, the study suggests that the closed loop system is safe to
use overnight in adolescents patients. Finally, in a third randomized clinical trial of 12
adolescent patients comparing the closed loop system to the open loop system, more time was
spent with glucose levels within target range for the closed loop vs open loop (84% vs 49%
p=0.02) and the mean glucose levels were also lower (7). In this study, the patients were also
made to exercise without making changes to the closed loop system and algorithm. There were
frequent episodes of hypoglycemia, which raised concern. This along with how the closed loop
system would function during illnesses still require further studies.
Yet another innovation with CSII, taking the closed loop system one step even closer to
becoming an artificial pancreas is the insulin-glucagon closed loop system. Standard of care for
mild hypoglycemia is 15g of some form of oral glucose. It can also be treated with 0.1mg of
injected glucagon. Severe hypoglycemia is often treated with 1mg of the glucagon injection. The
pancreas itself also creates glucagon raising the blood glucose levels by stimulating the liver to
release glucose from stored glycogen. With this new system, glucagon would be pulsely released
whenever the CGM senses an impending episode of hypglycemia but before hypoglycemia
actually develops. In a randomized crossover study of 15 adults T1DM patients, the closed loop
dual hormone system was compared to the standard CSII therapy; those in the dual hormone
group spent a larger percentage of time with glucose levels within the target range (70% vs 57%,
p=0.003). There was also a significant decrease in the percentage of time spent with glucose
that was low (0% vs 10.2%, p = 0.01) (9). Another randomized cross over study, compared

closed looped insulin and glucagon system with a closed loop insulin andn placebo system. It
also showed a reduction in the time spent with hypoglycemic blood glucose levels (15 min vs 40
min, p= 0.04) (3).
Several oral medications have been studied as supplemental management for T1DM.
Some studies have showed that Metformin can lead to a decrease in insulin requirements.
However, the studies were small; there are ongoing studies currently examining its use in T1DM.
Another oral medication is pramlintide. It is an analogue of amylin which is normally secreted by
the pancreas along with insulin. Amylin delays gastric emptying, blunts pancreatic secretion of
glucagon, and enhances satiety (4). It is approved for adult T1DM patients having shown a
reduction in HgA1C, induction of weight loss, and a decrease in insulin requirements. However,
there is no clear evidence for its use in the pediatric population. Other medications such as
monoclonal antibodies and disease modifying anti-rheumatic drugs could target the antibodies
in hopes to preserve islet cell function. However, no clear evidence has been shown yet of its
efficacy and further studies are needed.
Lastly is the pancreatic transplant, the last resort treatment for management of T1DM.
A pancreatic transplant alone would require immunosupression, which is quite risky; therefore,
it is not recommended. However, pancreatic and kidney transplants, either simultaneously or
pancreatic after kidney, are done in patients with end stage renal disease and poor glycemic
control since immunosupression would already be required for the kidney transplant. The
pancreas lasts about 6-9 years and often leads to better glucose control and quality of life.
However, these transplants are rarely done in pediatric patients. Another option is islet cell
transplant. This transplant is non-invasive and is usually for patients who cannot undergo
pancreatic transplants. The results are transient usually lasting about only 3 years. In 2013, a
pediatric patient with T1DM and bilateral renal hypoplasia received kidney and islet cell
transplants. Within 1 month post transplant, the patients insulin requirements decreased
compared to pre-transplant. By 6 months post transplant, the patient was not requiring any
insulin therapy at all. However, by 15 months his insulin requirements had increased to slightly
less than pre-transplant. (1)
Type 1 Diabetes Mellitus is a prominent chronic disease in the pediatric population.
With several advances in insulin therapy heading toward, management of T1DM has improved
survival allowing patients to live longer into adulthood with the disease. These advances in

glucose monitoring, closed looped systems, and glucagon incorporation into CSII are promising
and exciting advances that are going to change T1DM therapy.

References
1. Benedict, K.A., Moassesfar, S., Adi, S., Gitelman, S.E., Brennan, J.L., McEnhil, M., Stock,
P.G., Portale, A.A. and Posselt, A.M. (2013), Combined Pancreatic Islet and Kidney
Transplantation in a Child with Unstable Type I Diabetes and End-Stage Renal Disease.
American Journal of Transplantation. 13: 2207-2210.
2. Buckinghma B. Block J. Burdick J. Kalajian A. Kollman C. Choy M. Wilson DM. Chase P.
Response to nocturnal alarms using a real time glucose sensor. Diabetes Technol Ther.
2005; 7:440-447.
3. Castle, J.R., Engle, J.M., Youssef, J.E., et al. Novel Use of Glucagon in a Closed-loop
System for Prevention of Hypoglycemia in Type I Diabetes. Diabetes Care 2010: 33:
1282- 1287
4. Chiang, J.L., Kirkman, M.S., Laffel, L.M.B., et al. Type 1 Diabetes Through the Life Span: A
Position Statement of the American Diabetes Association. Diabetes Care 2014; 37: 2034
2054.
5. Cooke, D.W., Plotnick, L. Type 1 Diabetes Mellitus in Pediatrics. Pediatrics in Review
2008;29;374.
6. Diabetes Res in Children Network (Di-recNet) Study Group. The accuracy of the
GlucoWatch G2 biographer in children with type 1 diabetes: results of the diabetes
research in children network (DirecNet) accuracy study. Diabetes Technol Ther 5:791
800, 2003
7. Elleri, D., Allen, J., Kumareswaran, K., et al. Closed-Loop Basal Insulin Delivery Over 36
hours in Adolescents with Type I Diabetes. Diabetes Care 2013: 36: 838 844.
8. Gregory, J.M., Moore, D.J., Simmons, J.H. Type I Diabetes Mellitus. Pediatrics in Review.
2013; 34;203.
9. Hadair, A., Laurent L., et al. Glucose-responsive insulin and glucagon delivery (dualhormone artificial pancreas) in adults with type 1 diabetes: a randomized crossover
controlled trial. CMAJ 2013: 185: 297 305.

10. Hovorka, R., Elleri, D., Thabit, H., et al. Overnight Closed- Loop Insulin Delivery in Young
People with Type I Diabetes: A Free-living, Randomized Clinical Trial. Diabetes Care
2014: 37: 1204 1211
11. Mauras, N., Beck, R.,Xing, D. et al. A Randomized Clinical Trial to Assess the Efficacy and
Safety of Real-Time Continuous Glucose Monitoring in the Management of Type 1
Diabetes in Children Aged 4 to <10years. Diabetes Care 2012: 35: 204 -210
12. Renard, E., Place, J., Cantwell, M., Chevassus, H., Palerm, C.C. Closed-Loop Insulin
Delivery Using a Subcutaneous Glucose Sensor and Intraperitoneal Insulin Delivery.
Diabetes Care 2010; 33: 121-127.
13. Revital Nimri, Naomi Weintrob, Hadassa Benzaquen, Regina Ofan, Gila Fayman and
Moshe Phillip. Insulin Pump Therapy in Youth With Type 1 Diabetes: A Retrospective
Paired Study. Pediatrics 2006;117;2126