Intrapulmonary insulin has onset and duration comparable to SC rapidacting insulins
Renal function Renal failure lowers insulin clearance; may prolong and intensify action of
exogenous and endogenous insulin
IgG antibodies bind insulin as it is absorbed and release it slowly, thereby
delaying or prolonging its effect
Thyroid function Hyperthyroidism increases clearance, but also increases insulin action,
making control difficult; patients stabilize as they become euthyroid
effect on intermediate- and long-acting insulins is minimal
Site of injection Rate of absorption is fastest from the abdomen, intermediate from the arm,
88 Less variation is observed in type 2 diabetes
patients; less variation is observed with current rapid-acting and longacting insulins
Site Half-life absorption (minutes)
Exercise of injected area Strenuous exercise of an injected area within 1 hour of injection can
increase absorption rate; rate of absorption of regular insulin is increased,
but little effect on intermediate-acting insulin
Ambient temperature Heat (e.g., hot weather, hot bath, sauna) increases absorption rate; cold
Local massage Massaging injected area for 30 minutes substantially increases absorption
rate of regular insulin as well as longer-acting insulins
Smoking Controversial; vasoconstriction may decrease absorption rate
Insulin absorption is more rapid, probably secondary to increases in surface
Lipohypertrophy Insulin absorption is delayed from lipohypertrophic sites
Insulin preparation More soluble forms of insulin are absorbed more rapidly and have shorter
durations of action (see Table 53-7 and text); human insulin may have
shorter action than animal insulin
Insulin mixtures The short-acting properties of rapid-acting insulins may be blunted if mixed
with NPH insulin (see Case 53-2, Question 15)
Insulin concentration More dilute solutions (e.g., U-40, U-10) are absorbed more rapidly than
more concentrated forms (U-100, U-500)
Insulin dose Lower doses are absorbed more rapidly and have a shorter duration of
Insulin aspart (NovoLog) is a rapid-acting insulin analog that differs from human
insulin by substitution of aspartic acid at B28. Insulin aspart is approved for use in
pediatric patients, age 2 and older.
It is pregnancy category B. Insulin aspart
controls postprandial glucose excursions similar to insulin lispro. Insulin aspart is
available in both vials and prefilled pen (FlexPen and FlexTouch) formulations.
Insulin glulisine (Apidra) is a rapid-acting insulin analog that differs from human
insulin by substitution of lysine for asparagine at position B3 and glutamic acid for
lysine at position B23. Insulin glulisine has been studied in pediatric patients with
Type 1 diabetes age 4 and older.
It is pregnancy category C. Insulin glulisine
lowers postprandial glucose excursions similar to insulin lispro and insulin aspart.
Insulin glulisine is available in both vials and prefilled pen (Solostar) formulations.
Insulin human powder for inhalation (Afrezza) is a rapid-acting insulin indicated for
postprandial coverage in patients with Type 1 or Type 2 diabetes.
and metabolism and elimination are similar to that of regular insulin following
pulmonary absorption. The pharmacodynamic profile of inhaled Afrezza is similar to
that of rapid-acting insulin. It is pregnancy category C and has not been studied for
use in patients less than 18 years old. Insulin human powder for inhalation is
available as prefilled inhalers containing 4, 8, or 12 units of rapid-acting insulin to
be used at the beginning of a meal. It is contraindicated for use in patients with
chronic lung disease such as asthma and chronic obstructive lung disease as well as
Regular insulin 100 units/mL(Humulin R and Novolin R) has an onset of action of 30
to 60 minutes, a peak effect at 2 to 4 hours, and a duration of action of 5 to 7 hours.
The broad range in peak effect and duration reflects the many variables that affect
insulin action (Table 53-7). The 30- to 60-minute onset of action requires proper
timing of premeal regular insulin, which is difficult for most patients. Use of regular
insulin in patients with both Type 1 and Type 2 diabetes is much less common with
the advent of the newer rapid-acting insulins.
Regular insulin U-500 (500 units/mL) is a concentrated insulin that is indicated for
SC only. Being 5 times more potent than the 100 units/mL formulation, it is useful in
patients who are severely insulin resistant requiring daily insulin doses of greater
than 200 units/day because a large insulin dose may be given in a much smaller
volume. Its onset of action is approximately 30 minutes and peaks similar to regular
insulin U-100. Regular insulin U-500 however has a longer duration of action (up to
24 hours) compared to the U-100 formulation and is therefore recommended to be
administered between 2 and 3 times daily.
74 There are no U-500 insulin syringes
available; therefore, to avoid confusion, it is recommended to dose U-500 insulin in
volume and administer using a tuberculin syringe vs. a typical U-100 insulin syringe.
Additionally, the manufacturer of U-500 regular insulin has incorporated multiple
differences in packaging between regular insulin U-100 and U-500 to potentially
decrease the risk of dispensing errors. Specifically, the regular insulin U-500 vial
contains 20 mL compared to the U-100 vial which contains only 10 mL. The U-500
also marked with a band of diagonal brown stripes to distinguish it from the U-100
vial which contains no stripes.
75 The U-500 insulin pen (Humulin R U-500 KwikPen)
approved by the FDA in 2016 should eliminate many of these issues.
INTERMEDIATE-ACTING INSULIN (NPH)
Neutral protamine Hagedorn (NPH) or isophane is an intermediate-acting insulin
commercially available as Humulin N or Novolin N. Its onset of action is
approximately 2 hours (range, 1–3 hours), peak effects occur at approximately 6 to
14 hours, and the duration of action of NPH is approximately 16 to 24 hours. Again,
it must be emphasized that this pattern of response is at best a generalization. Patients
may have a variable pattern of response to NPH insulin with time, and those on
higher doses are likely to have a later peak and a longer duration of action. Up to
80% of these day-to-day fluctuations in BG responses can be accounted for by
variation in the absorption of this intermediate-acting insulin.
available only in vials, whereas Humulin N is available both in vials and in prefilled
Insulin glargine U-100 (Lantus) is a long-acting insulin that serves to provide a basal
level of insulin. It is pregnancy category C.
It is approved for once-a-day SC
administration for the treatment of adult and pediatric patients (age ≥6 year) with
Type 1 diabetes or adult patients with Type 2 diabetes. It can be administered any
time during the day, but it is important to take it at the same time each day. It is
usually administered at bedtime or, less commonly, in the morning. Insulin glargine is
available in both a 10-mL vial and a prefilled pen (Solostar).
Insulin glargine is an insulin analog in which asparagine in position A21 is
substituted with glycine and two arginines are added to the C-terminus of the B chain.
This change in the amino acid sequence causes a shift in the isoelectric point from pH
5.4 to 6.7, making it more soluble at an acidic pH.
77 Once injected, insulin glargine
(which is a clear solution with a pH of 4.0) precipitates at physiologic pH, forming a
depot that releases insulin slowly for up to 24 hours. This results in delayed
absorption and a less pronounced peak compared with NPH insulin.
to further prolong the duration of insulin glargine. In clinical trials of patients with
Type 1 and Type 2 diabetes, once-daily injections of insulin glargine were as
effective as NPH in lowering A1C values, with less nocturnal hypoglycemia.
Insulin glargine is associated with more injection site pain compared with NPH
(6.1% vs. 0.3% in one study and 2.7% vs. 0.7% in another), which is likely related
Insulin glargine is also available in a concentrated form which is available as 300
units/mL (Toujeo). It is approved for once-daily SC injection in adults with Type 1
or Type 2 diabetes. Toujeo has not been studied for use in the pediatric population.
Insulin glargine 300 units/mL is only available in a prefilled pen (Solostar device)
which does not require dose calculations or conversions when switching from insulin
Insulin detemir (Levemir) is another basal insulin available in the United States and
is approved for once- or twice-daily SC administration for the treatment of adult and
pediatric patients (age ≥2 years) with Type 1 diabetes or adult patients with Type 2
diabetes. It is pregnancy category B.
82 Unlike other insulin analogs, in which the
amino acid sequence is modified, for insulin detemir, a fatty acid moiety is added to
the last amino acid on the end of the B chain. Insulin detemir is a neutral, soluble
insulin preparation in which the B30 threonine has been removed and the B29 lysine
residue has been covalently bound to a 14-carbon fatty acid. The result is an insulin
that is more slowly absorbed in the SC tissue because the fatty acid moiety binds to
albumin, creating a long-acting insulin.
Insulin detemir’s kinetics and dynamics are
84 When used in Type 1 diabetes, two injections daily are usually
required to provide adequate basal coverage due to a smaller insulin dose
requirement in this patient population. Insulin detemir demonstrates less intrasubject
variability than NPH or insulin glargine.
85 The clinical significance and impact of
this observation are unclear. Insulin detemir is available in both vial and pen
Insulin degludec (Tresiba) is a long-acting basal human insulin analog approved in
the United States in 2015 for once-daily SC administration for the treatment of adults
with Type 1 or Type 2 diabetes. It is pregnancy category C and is not indicated for
use in the pediatric population. Insulin degludec differs from human insulin in that the
amino acid threonine in position B30 has been omitted and a side chain consisting of
glutamic acid and a C16 fatty acid has been attached.
longer duration of action (>42 hours) compared to other available basal insulins and
is available as a prefilled pen (FlexTouch device) in concentrations of both 100 and
200 units/mL. The FDA has also approved a combination insulin degludec/insulin
aspart 70/30 combination (Ryzodeg 70/30) which is intended to be used once to
twice daily prior to a main meal.
Products that contain premixed NPH and regular insulin in a fixed ratio of 70:30 are
available from Lilly as Humulin 70/30 and from Novo Nordisk as Novolin 70/30.
Additional premixed formulations are available in which both insulin lispro and
are products with lispro protamine and insulin lispro in a fixed ratio of 75:25 and
50:50, respectively. NovoLog Mix 70/30 (Novo Nordisk) is aspart protamine and
insulin aspart in a fixed ratio of 70:30. These premixed insulins are useful for
patients who have difficulty measuring and mixing insulins and are dosed twice
daily. These insulins are compatible when mixed together and retain their individual
pharmacodynamic profiles. Each of these mixed insulin combinations is available as
both vials and insulin pens with the exception of Novolin 70/30 which is available in
insulin vials only (see Table 53-19 later in this chapter and Case 53-2, Question 15).
TREATMENT OF TYPE 1 DIABETES: CLINICAL
Clinical Presentation of Type 1 Diabetes
times a night), fatigue, and a 12-lb weight loss during this period, which she attributed to the
anxiety associated with her move away from home and adjustment to her new environment. Her medical
6 months. Her family history is negative for diabetes, and she takes no medications.
consistent with this diagnosis in A.H.?
A.H. meets several of the diagnostic criteria for diabetes. She has classic
symptoms of Type 1 diabetes (polyuria, polydipsia, glucosuria, fatigue, recurrent
infections), a random plasma glucose greater than 200 mg/dL, and a FPG greater than
126 mg/dL on at least two occasions as well as an A1C greater than 6.5%7
53-1 and 53-3). Features of A.H.’s history that are consistent with Type 1 diabetes,
in particular, include the relatively acute onset of symptoms in association with a
major life event (moving away from home), recent weight loss, ketones in the urine,
negative family history, and a relatively young age at onset.
CASE 53-2, QUESTION 2: A.H. will be started on insulin therapy on this visit. What are the goals of
therapy? Will normoglycemia prevent the development or progression of long-term complications?
The goal of diabetes management is the prevention of acute and chronic
complications. The results of the DCCT and DCCT-EDIC studies convincingly
demonstrated that lowering BG concentrations through intensive insulin therapy in
persons with Type 1 diabetes slows or prevents the development of microvascular
29,30 The ADA recommends an A1C goal of less than 7% for most
patients, and an individual goal as close to normal as possible (<6.5%) if it can be
achieved without significant hypoglycemia. For children and adolescents, the ADA
recommends an A1C goal of less than 7.5%, and an individualized goal of less than
7% if achievable without significant hypoglycemia.
It is important to understand that physiologic or basal-bolus insulin therapy
involves a complete program of diabetes management that includes a balanced meal
plan, physical activity, frequent SMBG, and insulin adjustments based on these
In summary, A.H. is a patient newly diagnosed with Type 1 diabetes who has not
yet developed any signs or symptoms of long-term complications. Therefore, she is
an ideal candidate for basal-bolus insulin therapy, and if she is willing and
with insulin therapy, diet, education, and strong clinical support. A desirable goal is
an A1C value as close to the normal range as possible with minimal episodes of
Basal-Bolus (Physiological) Insulin Therapy
A physiologic insulin regimen is designed to mimic normal insulin secretion as
closely as possible. Problems with insulin delivery include factors that affect the SC
absorption of insulin (Table 53-8).
87,88 Before the development of the rapid-acting
insulin analogs and basal insulins, previous insulins lacked pharmacodynamic
profiles that allowed one to closely simulate normal pancreatic release of the
hormone. In the nondiabetic individual, the pancreas secretes boluses of insulin in
response to food. Between meals and throughout the night, the pancreas secretes
small amounts of insulin that are sufficient to suppress lipolysis and hepatic glucose
output (basal insulin). Clinicians now have more tools to mimic this basal-bolus
model. Two methods have been used to achieve this pattern of insulin release: (a)
insulin pump therapy (previously referred to as continuous subcutaneous infusion of
insulin) and (b) basal-bolus insulin regimens consisting of once- or twice-daily
doses of basal insulin coupled with premeal/snackdoses of rapid-acting insulin (see
The use of an insulin pump is currently the most precise way to mimic normal insulin
secretion. This consists of a battery-operated pump and a computer that can program
the pump to deliver predetermined amounts of insulin (i.e., regular, lispro, aspart, or
glulisine) from a reservoir to a SC inserted catheter or needle.
portable and designed to deliver various basal amounts of insulin over the course of
24 hours as well as meal-related boluses. Most patients using an insulin pump use a
rapid-acting insulin, rather than regular insulin. For meal coverage, the rapid-acting
insulin can be given 0 to 15 minutes before eating. The delivery of the bolus can be
adjusted depending on the type of food eaten (e.g., piece of cake versus slice of
pizza). Caveat: If SC delivery is interrupted, check for rise in glucose and urine
ketones after 2 or 3 hours. Because there is no SC pool, effects dissipate quickly.
The preferred meal-planning approach for patients using an insulin pump is
carbohydrate counting. The insulin-to-carbohydrate ratio, or how much carbohydrate
is covered by 1 unit of insulin, must be determined. One method is to use the “500
Rule.” The number 500 (or 450 for regular insulin) is divided by the total daily dose
(TDD) of insulin the patient is using to determine the insulin-to-carbohydrate ratio
(see Case 53-2, Question 11). Insulin pumps are capable of delivering many basal
insulin rates. The basal insulin infusion rate may be adjusted depending on the
situation. Many patients find it advantageous to decrease the basal rate during the
middle of the night when nocturnal hypoglycemia is most likely to occur. The basal
rate also may be increased before awakening to avoid hyperglycemia secondary to
the “dawn phenomenon” or adjusted when physically active—adjustments that are
not possible using SC basal insulin injections.
Features of the current pump models include the “bolus wizard,” which calculates
bolus doses based on preset carbohydrate-to-insulin ratios and correction factors,
carbohydrate counts for selected foods, and an “insulin-on-board” feature, which
helps avoid excessive dosing of insulin by indicating how much insulin from a
previously administered dose should still be acting. Most insurance plans provide
coverage for insulin pumps for patients with Type 1 diabetes and for some patients
with Type 2 diabetes. Factors to consider when choosing a pump include safety
features, durability, ability of the manufacturer to provide service, availability of
training, clinically desirable features, CGM compatibility, and cosmetic
90,91 The ADA website (www.diabetes.org) contains
helpful information about insulin pumps for patients under the Living with Diabetes
meals for short-acting insulin).
Endocrinologists have developed a variety of insulin regimens that are intended to
mimic the natural release of insulin from the pancreas.
displayed and illustrated in Figure 53-4. A TDD of insulin is estimated empirically
(e.g., 0.3–0.5 units/kg/day for patients with Type 1 diabetes) or according to
guidelines listed in Table 53-9. The TDD of insulin then is split into several doses.
In general, the basal dose comprises approximately 40% to 50% of the TDD, and the
other bolus doses comprise the remaining 50%. If a patient eats three meals/day, the
bolus dose would then be divided by three to calculate the number of units of bolus
insulin required to cover each meal.
Estimating Total Daily Insulin Requirements
weight gain or loss, changes in physical activity, stress or illness)
Honeymoon phase 0.2–0.5 units/kg
With insulin resistance 0.7–1.5 units/kg
Estimating Basal Insulin Requirements
TDD. A conservative approach is to reduce the calculated 50% basal dose by 20% to avoid hypoglycemia
Estimating Premeal Insulin Requirements
insulin. The rule is modified to the “450 rule” if using regular insulin
500/TDD of insulin = number of grams covered
underestimate their insulin requirements
Determining the “Correction Factor”
rule.” For regular insulin, the rule is modified to the “1,500 rule.” The equation is as follows:
1,700/TDD = point drop in blood glucose per unit of insulin
= 60 mg/dL. Therefore, the patient can expect a 60-mg/dL drop for every unit of rapid-acting insulin
SMBG, self-monitored blood glucose; TDD, total daily dose.
JAMA. 2003;289:2254; Walsh J, Roberts R. Pumping Insulin: Everything You Need For Success On A Smart
Need for Success With Insulin. San Diego, CA: Torrey Pine Press; 2003.
A regimen much less commonly used in patients with Type 1 diabetes involves
injecting a mixture of intermediate-acting and regular or rapid-acting insulin twice
daily, before breakfast and before dinner (Fig. 53-4A). The morning dose of regular
or rapid-acting insulin is intended to take care of the breakfast meal; the morning
dose of NPH takes care of the noon meal and provides basal insulin throughout the
day; the evening dose of regular or rapid-acting insulin takes care of the evening
meal; and the evening dose of NPH provides basal insulin levels during the night and
Also, when NPH is injected in the morning, the patient must eat lunch on time
because of this peak effect; otherwise, he/she will experience hypoglycemia. Also,
when NPH is taken with mealtime insulin before dinner, the patient is at risk for
nocturnal hypoglycemia from the peak effect of the evening dose of NPH. The
advantage of using a rapid-acting insulin (e.g., insulin lispro, insulin aspart, or
insulin glulisine) instead of regular insulin in this regimen is to facilitate the patient
being able to take insulin doses immediately before a meal. However, the peak effect
of the NPH component in this combined dose still presents the same problems. This
type of insulin regimen does not mimic physiologic insulin release.
Figure 53-4B depicts a variation of this method. It is the same except that the
evening dose of NPH is given as a third injection at bedtime. This shifts the time of
peak effect from approximately 2 to 3 AM to approximately 7 AM. By administering
NPH at bedtime, nocturnal hypoglycemia is reduced, and peak insulin activity occurs
when the patient is more likely to be awake and ingesting food. This method may be
useful for patients in whom nocturnal hypoglycemia and fasting hyperglycemia are
particularly troublesome; however, this regimen also does not mimic physiologic
The regimen that most closely mimics physiologic insulin release besides the use
of an insulin pump is the use of a once-daily basal insulin such as insulin glargine,
detemir, or degludec to provide basal insulin levels throughout the day, along with
doses of a rapid-acting insulin (preferred) or regular insulin before meals (Fig. 53-
4C depicts the long-acting insulin given at bedtime, but it can be given alternatively
in the morning). When smaller doses are used, twice-daily insulin detemir and
possibly U-100 insulin glargine will be required for 24-hour coverage.
U-100 and U-200 degludec and U-300 glargine will last 24 hours with once-daily
dosing. This method theoretically provides insulin similar to the insulin pump:
constant basal levels plus small boluses for meals and snacks. In doing so, it offers
some of the same advantages of the pump in that it permits some degree of flexibility
in the patient’s lifestyle. For example, if a patient with diabetes chooses to skip a
meal, he/she omits a premeal bolus; if the patient chooses to eat a larger meal than
usual, he/she increases the premeal bolus. Similar dose adjustments can be made to
accommodate snacks, exercise patterns, and acute illnesses. Alternatives to this
regimen are depicted in Table 53-4 where the long-acting insulin is replaced with
intermediate-acting insulin for basal coverage and or the rapid-acting insulin is
replaced with short-acting insulin for bolus coverage. These options however are not
preferred because they do not as closely mimic normal physiologic insulin release.
CASE 53-2, QUESTION 5: Should A.H. use an insulin pump or multiple daily insulin injections?
Indications for basal-bolus insulin therapy are listed in Table 53-10. Patients with
Type 1 diabetes should be placed on a basal-bolus insulin regimen. A.H. is an ideal
candidate to strive for an A1C goal of less than 6.5%. She is newly diagnosed, has
not yet developed the long-term complications of diabetes, and should derive the
benefits of normoglycemia. Assuming A.H. will be able to manage a basal-bolus
insulin regimen, individualized target BG levels that strive for the best level of
glucose control possible without placing her at undue risk for hypoglycemia should
be prescribed. She must be willing to test her BG concentrations 4 or more times
daily and inject herself 4 times daily or learn about the use and care of an insulin
pump. She also must be willing to keep detailed BG and food records and participate
in an extensive education program that enables her to adjust her insulin doses based
on BG concentrations, physical activity, and the carbohydrate content of her snacks
Transition to an insulin pump is facilitated by patients being able to attain these
skills using multiple daily SC insulin injections before insulin pump initiation. The
ADA recommends that the use of insulin pumps be limited to highly motivated
individuals under the guidance of a healthcare team trained and knowledgeable in
their use. Pumps offer the patient the ability to use multiple basal rates during the 24-
hour period and assist with the calculation of bolus and correction insulin doses.
Most studies have shown that pump therapy provides equivalent and sometimes
better glycemic control than does intensive management with multiple injections.
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