General Principles of Insulin Therapy in Diabetes Mellitus

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General principles of insulin therapy in diabetes mellitus

Author: David K McCulloch, MD
Section Editor: David M Nathan, MD
Deputy Editor: Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2019. | This topic last updated: May 31, 2018.
INTRODUCTION
Insulin is used in the treatment of patients with diabetes of all types. The need for insulin depends
upon the balance between insulin secretion and insulin resistance. All patients with type 1 diabetes
need insulin treatment permanently, unless they receive an islet or whole organ pancreas
transplant; many patients with type 2 diabetes will require insulin as their beta-cell function
declines over time.
Indications for insulin therapy, available formulations of insulin, insulin pharmacokinetics, and
determinants of efficacy will be reviewed here. The specifics of insulin therapy for type 1 and type
2 diabetes and intensive insulin therapy for critically ill patients who become hyperglycemic are
discussed separately. (See "Management of blood glucose in adults with type 1 diabetes mellitus"
and "Insulin therapy in type 2 diabetes mellitus" and "Glycemic control and intensive insulin
therapy in critical illness".)
WHICH PATIENTS NEED INSULIN
● Type 1 diabetes – Insulin must be given to all patients with type 1 diabetes, which is usually
due to autoimmune islet-cell injury that eventually leads to virtually complete insulin deficiency.
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Ideally, physiologic replacement of insulin, emulating the secretory pattern of the nondiabetic
pancreas, but keeping in mind the limitations associated with subcutaneous administration, is
desirable. (See "Pathogenesis of type 1 diabetes mellitus".)
● Type 2 diabetes – A more difficult question is when to use insulin in patients with type 2
diabetes. This disorder is characterized by both insulin resistance and relative insulin
deficiency. Therapy should begin with diet, weight reduction, and exercise, which can
frequently induce normoglycemia if compliance is optimal. Metformin, based on its safety
profile, neutral effect with regard to weight gain, and ability to lower glycemia, is recommended
early in the course of type 2 diabetes. Patients with persistent hyperglycemia are often started
on a second oral hypoglycemic drug or an injectable agent, potentially including "basal"
insulin, which is meant to supplement endogenous insulin. (See "Initial management of blood
glucose in adults with type 2 diabetes mellitus".)
Initiation of insulin therapy, however, is often unnecessarily delayed, owing to clinician or

patient reluctance and other factors, thus exposing patients to the pathologic consequences of
prolonged hyperglycemia. Patients' preconceptions about the use of insulin need to be
addressed (table 1) [1]. Patients should be made aware that initiating insulin does not
represent a personal "failure" and that many patients with type 2 diabetes will eventually
require exogenous insulin, due to decline in endogenous insulin production. (See "Insulin
therapy in type 2 diabetes mellitus".)
● Atypical presentations – It is occasionally difficult to distinguish between type 1 and atypical

presentations of type 2 diabetes. Clinical features that, if present in a patient with diabetes at
any age, suggest the need for insulin therapy include marked and otherwise unexplained
recent weight loss (irrespective of the initial weight), a short history with severe symptoms,
and the presence of moderate to heavy ketonuria.
The peak incidence of type 1 diabetes is around the time of puberty, but approximately 25
percent of cases present after 35 years of age [2]. Diabetic ketoacidosis at first presentation
usually indicates that the patient has type 1 diabetes and will require lifelong insulin treatment.
However, some patients with type 2 diabetes, especially in the Afro-Caribbean populations
(so-called "Flatbush diabetes"), may present with ketoacidosis. (See "Classification of
diabetes mellitus and genetic diabetic syndromes" and "Syndromes of ketosis-prone diabetes
mellitus".)
● Pancreatic insufficiency – Insulin is also indicated for patients with secondary diabetes due
to pancreatic insufficiency, including from cystic fibrosis, chronic pancreatitis, or after
pancreatectomy. (See "Treatment of chronic pancreatitis", section on 'Glucose intolerance'
and "Cystic fibrosis-related diabetes mellitus", section on 'Insulin therapy'.)
INSULIN PREPARATIONS
Most patients use either human insulin (eg, neutral protamine hagedorn [NPH], regular) or an
insulin analog (eg, glargine, lispro). Animal-sourced insulins (derived from the pancreas of cows
and pigs) are no longer produced in the United States but are available on a limited basis in some
countries (eg, United Kingdom) for rare patients who cannot manage their diabetes with
biosynthetic insulin. Compared with human insulin, porcine insulin differs by one amino acid and
bovine by three amino acids, and the generation of antibodies to these animal insulins may change
their pharmacokinetics [3].
Human versus analogs — The time to peak and the duration of action of human insulin
preparations (NPH and regular insulin) do not replicate endogenous basal and postprandial insulin
secretion, which is particularly important in treating insulin-deficient, such as type 1, diabetes.
Thus, insulin analogs (lispro, aspart, glulisine, glargine, detemir, degludec) were developed. The
very rapid-acting insulin analogs have both faster onset and shorter duration of action than regular
insulin for pre-meal coverage, while the long-acting analogs have a longer and flatter profile than
NPH for basal coverage (figure 1).
To produce an insulin preparation with a faster onset and shorter duration of action than regular
insulin, modifications were made in the insulin molecule to prevent it from forming hexamers or
polymers that slow absorption and delay action [4,5]. As an example, insulin aspart is identical to
human regular insulin except for a substitution of aspartic acid for proline at position B28. This
substitution results in a reduction in hexamer formation and, consequently, more rapid absorption,
faster onset of action, and shorter duration of action [6]. Another formulation of insulin aspart,
produced by adding L-arginine and nicotinamide, results in slightly faster initial absorption than
aspart and a higher glycemic effect within the first 30 minutes [7-9]. The total glucose-lowering
effect is similar for faster aspart and insulin aspart. The rapid-acting insulin analogs (insulin lispro,
aspart, faster aspart, and glulisine) have an onset of action within 3 to 15 minutes, peak action at
45 to 75 minutes, and a duration of action of two to four hours (table 2) [10-14].
Different alterations result in the slower absorption and longer duration of action of other insulin
analogs:
● Neutral protamine lispro (NPL, also called insulin lispro protamine suspension) is a protamine-
based suspension (like NPH) of the short-acting analog insulin lispro. It has an activity profile
very similar to that of NPH [15]. Although it is only available in the United States in a pre-
mixed combination with insulin lispro, in other countries it is available as a separate insulin
analog for basal coverage.
● Insulin glargine is identical to human insulin except for a substitution of glycine for asparagine
in position A21 and by the addition of two arginine molecules in the B-chain of the insulin
molecule [16]. These modifications result in a change in the pH such that, after subcutaneous
administration, glargine precipitates in the tissue, forming hexamers, which delays absorption
and prolongs duration of action. Glargine has no appreciable peak and a duration of action
that usually lasts 24 hours. Glargine cannot be mixed with rapid-acting insulins, as the kinetics
of both the glargine and rapid-acting insulin will be altered.
● Insulin detemir is an acylated insulin; the fatty acid side chain allows albumin binding and
results in prolongation of action. It is considerably less potent than human insulin and,
therefore, it is formulated using a 4:1 molar ratio (ie, one detemir unit contains four times as
many insulin detemir molecules as one unit of any other insulin). Compared with glargine, it
does have a noticeable peak and rarely lasts 24 hours. Clinical trials in patients with type 1
diabetes have suggested that twice-per-day injections may be necessary to achieve
acceptable basal rate coverage and optimal glycemic control [17]. In type 2 diabetes, where
endogenous insulin secretion may mask any deficiencies in basal insulin, the data are less
clear [18]. However, in our clinical experience, detemir also often requires twice-daily
administration in patients with type 2 diabetes. Detemir cannot be mixed with rapid-acting
insulins, as the kinetics of both the detemir and rapid-acting insulin will be altered.
● Insulin degludec is almost identical to human insulin, except for deletion of the last amino acid
from the B-chain and the addition of a glutamyl link from LysB29 to a hexadecanedioic fatty
acid [19]. This feature allows it to form soluble multihexamers at the injection site, from which
monomers slowly separate and are absorbed. This property confers a long duration of action
(>40 hours) and reduces variability in plasma concentration with once-daily dosing. In contrast
to glargine and detemir insulins, degludec may be mixed with rapid-acting insulins without
appreciably altering the kinetics of the degludec or the rapid-acting insulin.
Efficacy
● Rapid-acting insulin – With respect to short-term outcomes, such as glycated hemoglobin

(A1C) and risk of hypoglycemia, the newer rapid-acting insulins may have a minor glycemic
advantage over short-acting (regular) insulin in patients with type 1 diabetes but not in patients
with type 2 diabetes.
● Long-acting insulin – The long-acting insulins (glargine, detemir, and degludec) may have
some modest clinical advantages over NPH (less symptomatic and nocturnal hypoglycemia) in
type 2 diabetes, with the important disadvantage of higher cost. Degludec may have less risk
of symptomatic and nocturnal hypoglycemia than glargine. In type 2 diabetes, the absolute
reduction of chemical hypoglycemia with longer-acting versus NPH insulin (measured, for
example, as the number of episodes with capillary glucose <70 mg/dL per patient year) is
usually small. The frequency of severe hypoglycemia (requiring assistance) is very low and
usually not different among long- and intermediate-acting insulins.
In type 1 diabetes, insulin glargine may have a slight glycemic advantage and detemir less risk
of severe hypoglycemia compared with NPH. Compared with glargine, degludec has similar
glycemic efficacy with less nocturnal hypoglycemia.
The trials examining these issues are reviewed separately. (See "Management of blood glucose in
adults with type 1 diabetes mellitus", section on 'Basal insulin options' and "Insulin therapy in type
2 diabetes mellitus", section on 'Insulin initiation'.)
Safety — There is theoretical concern that changes in the structure of the insulin molecule (as
occurs with the synthesis of insulin analogs) may inadvertently change other properties of insulin.
As an example, glargine and detemir have different affinities (glargine higher, detemir lower) than
human insulin for the insulin-like growth factor-1 (IGF-1) receptor, which theoretically could alter
mitogenic activity [5]. An increase in mitogenic activity could increase the risk of some known
diabetes complications, such as retinopathy, and could theoretically increase neoplastic
transformation.
There are few studies comparing insulin analogs and human insulin with respect to long-term
outcomes, such as diabetic complications or mortality. In a retrospective review of four
multinational trials of glargine versus NPH, more patients randomly assigned to glargine had an
increase in three steps or more on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale
[20]. However, the results from a randomized trial are more reassuring. In a five-year trial in over
1000 patients with type 2 diabetes previously treated with oral hypoglycemic agents, insulin, or
both, there was no evidence of a greater risk of retinopathy progression (defined as three ETDRS
steps or more) in patients randomly assigned to once-daily glargine versus twice-daily NPH [21].
Although there are conflicting data regarding use of insulin analogs and risk of cancer [22-30],
there is insufficient evidence to make a recommendation against glargine (or other insulin analogs)
based on risk of malignant neoplasms [31]. Insulin choices should continue to be individualized.
(See "Management of blood glucose in adults with type 1 diabetes mellitus" and "Insulin therapy in
type 2 diabetes mellitus".)
Basal versus bolus — The term "conventional insulin therapy" has been used to describe simpler
insulin regimens, such as single daily injections, or two injections per day of regular and NPH
insulin, mixed together in the same syringe and given in fixed amounts before breakfast and
dinner. The term "intensive insulin therapy," originally coined to describe insulin regimens designed
to achieve near-normal glycemia in type 1 diabetes, describes more complex regimens that
separate basal insulin delivery (given as one to two daily injections of intermediate- or long-acting
insulin) with superimposed doses of short- or rapid-acting insulins three or more times daily. While
intensive regimens were initially used for patients with type 1 diabetes, they are increasingly used
for patients with type 2 diabetes. Conventional insulin therapy is unlikely to achieve target A1C
levels in patients with type 1 diabetes and may provide suboptimal glycemic control for patients
with type 2 diabetes as beta-cell function declines.
Basal insulin suppresses hepatic glucose production and maintains near normoglycemia in the
fasting state, while prandial (pre-meal) bolus insulin covers the extra requirements after food is
absorbed.
● Basal – Intermediate- to long-acting preparations (NPH, NPL, detemir, glargine, or degludec)

are typically administered once or twice daily to provide basal insulin levels. Intermediate-
acting insulin (NPH) also provides some peak coverage for breakfast and lunch intake,
although not as physiologic as replacement with faster-acting insulin given at mealtimes.
Basal insulin levels can also be achieved by continuous infusion of a short- or rapid-acting
insulin via an insulin pump, used almost exclusively in type 1 diabetes. (See "Management of
blood glucose in adults with type 1 diabetes mellitus", section on 'Continuous subcutaneous
insulin infusion (insulin pump)'.)
● Bolus – Short-acting (regular) or rapid-acting (lispro, aspart, faster aspart, or glulisine) insulin
is typically provided as a pre-meal bolus to control the glucose excursions that otherwise
occur after food is absorbed. Bolus insulin is an absolute requirement to obtain physiologic
glucose control in type 1 diabetes and may be necessary as insulin secretion wanes in type 2
diabetes.
The approximate time of onset, peak activity, and duration of action of the most commonly used
insulins are shown in the table (table 2).
Both glucose and insulin metabolism are altered in patients who have chronic renal failure. The
changes in the insulin regimen that must be made in these patients are discussed separately. (See
"Management of hyperglycemia in patients with type 2 diabetes and pre-dialysis chronic kidney
disease or end-stage renal disease".)
U-500 regular insulin — U-500 is a concentrated form of regular insulin that can be used to
control hyperglycemia in severely insulin-resistant patients (eg, requiring more than 200 total units
of insulin daily). In several reports, U-500 insulin has been used successfully in patients with
obesity, immune-mediated insulin resistance, and genetic abnormalities of the insulin receptor [32].
Because the high concentration of insulin delays absorption, the pharmacologic profile of U-500
regular insulin is most similar to that of NPH [33].
In one observational study of 11 obese, severely insulin-resistant, uncontrolled diabetic patients

(requiring >200 units of insulin daily), substituting U-500 regular insulin for U-100 NPH insulin
improved diabetes control (mean A1C decrease from 9.9 to 7.1 percent) [34]. For patients who
require over 300 units of insulin daily, the typical starting dose of U-500 regular insulin is 100 units
twice daily. Dose adjustments are made using the same approach as for adjusting NPH insulin
doses, eg, approximately every two weeks, or more frequently if indicated, based on fasting and
pre-dinner blood sugar measurements. (See "Insulin therapy in type 2 diabetes mellitus", section
on 'Designing an insulin regimen'.)
Although in the past U-500 insulin was dispensed using Tuberculin or U-100 syringes (which
required dose conversions to deliver the correct dose), a dedicated U-500 insulin syringe is now
available (as of November 2016). U-500 insulin should be dispensed with the U-500 insulin syringe
as it should be less confusing for patients and ultimately safer to use [35]. The syringe contains
scale markings from 25 to 250 units in 5-unit increments (total volume 0.5 mL). Prescribers who
order U-500 insulin should also prescribe U-500 syringes to avoid potentially dangerous
medication errors. The insulin dose should be expressed in units, rather than in volumetric terms
as was the convention with the Tuberculin or U-100 syringes. Patients previously using a
Tuberculin or U-100 syringe should be instructed on how to correctly draw the prescribed dose of
U-500 insulin into the U-500 syringe. The U-500 syringe should only be used with U-500 insulin.
U-500 insulin is also available in a pen device, which is easy to use and provides accurate dosing
[36]. The pen dosing window shows the number of units of U-500 to be injected (with no need for
dose conversion), and the pen delivers the volume that corresponds to the selected dose. The pen
contains 1500 units (500 units/mL) of insulin.
If neither dedicated U-500 insulin syringes nor the U-500 insulin pen device is available, U-500
insulin can be dispensed using a Tuberculin syringe, rather than a U-100 insulin syringe, to
emphasize that it is different from U-100 regular insulin. With the Tuberculin syringe, every 0.1 mL
would equal 50 units of insulin. The obvious concern when using U-500 insulin with a Tuberculin
syringe is the potential for confusion of volume and units.
U-300 insulin glargine — U-300 insulin glargine is a concentrated form of glargine insulin
(contains 300 units/mL instead of the 100 U/mL in Lantus) that can be used to control
hyperglycemia in severely insulin-resistant patients (eg, requiring more than 200 total units of
insulin daily). The prefilled pen contains 450 units and allows for delivery of the same number of
insulin units as glargine but in a smaller volume. However, on a unit-to-unit basis, U-300 glargine
has a lower glucose-lowering effect than glargine [37].
In trials comparing U-300 glargine with glargine 100 units/mL in patients with type 2 diabetes
inadequately controlled with oral agents and/or insulin, A1C levels decreased similarly in both
glargine groups with no difference in severe hypoglycemia and little difference in nocturnal
hypoglycemia [38-40].
Glargine cannot be mixed with rapid-acting insulins, as the kinetics of both the glargine and rapid-
acting insulin will be altered.
Pre-mixed insulins — We almost never recommend commercially fixed-ratio pre-mixed insulins in

the treatment of type 1 diabetes. Intensive regimens require frequent adjustments of the pre-meal
bolus of short- or rapid-acting insulin. For patients who will not comply with an intensive regimen,
pre-mixed lispro/NPH in type 1 diabetes may be of some benefit [41].
Many patients with type 2 diabetes can use pre-mixed preparations with reasonable effect.
However, if the aim is to truly vary the dose of fast-acting insulin before a meal, patients would do
best to give the fast-acting and intermediate-acting insulins as separate injections. If near
normoglycemia is the goal, it is preferable to keep basal and pre-meal insulin injections separate
and to adjust them independently. Nevertheless, some patients with type 2 diabetes who require
pre-meal insulin in addition to basal insulin prefer pre-mixed insulins for convenience.
Some pre-mixed (biphasic) insulin preparations are commercially available, but patients may also
draw up their pre-meal and basal insulins in the same syringe prior to injection. However, there are
potential problems with mixing different insulin preparations:
● When drawing up both insulin preparations in the same syringe, serum insulin concentrations
tend to approach a single peak. This is less of a problem when a rapid-acting insulin rather
than regular insulin is mixed with NPH and injected immediately after mixing [42]. It is also
less of a problem with pre-mixed insulins, such as Lispro Mix25 (25 percent insulin lispro and
75 percent of an intermediate-acting insulin) [43].
● The peak action also varies directly with the proportion of regular insulin in the combination.
One study, as an example, compared the time course of serum insulin concentrations with two
mixtures of different NPH-to-regular insulin ratios: 50/50 (equivalent to 10.5 units of each
preparation in a 70 kg patient) and 70/30 (equivalent to 14.7 units of NPH and 6.3 units of
regular insulin) [44]. The former, which contained more regular insulin, resulted in higher
serum insulin concentrations in the first six hours (figure 2).
● Changes in the proportion of NPH-to-regular insulin in these pre-mixed combinations are often
not sufficient to improve postprandial glycemic control [45]. In addition, because of the
variability in peak effect, it may be more difficult to achieve excellent glycemic control with pre-
mixed insulins even though they are easier to use [46].
When commercially or self-mixed insulins are used for patients with type 2 diabetes, the following
guidelines adapted from the American Diabetes Association (ADA) should be followed [47].
● Patients who are well controlled on a self-mixed regimen should continue the same procedure
for preparing their dose.
● Insulin glargine and insulin detemir should not be mixed with other insulins due to the low pH
of the diluents.
● After mixing NPH with regular insulin, the formulation should be used immediately.
● Rapid-acting insulin can be mixed with NPH. When this is done, the mixture should be mixed
and injected within 15 minutes prior to a meal.
Inhaled insulin — An inhaled form of rapid-acting insulin was available for a short time before it
was discontinued by the manufacturer in 2007, as the new technology failed to gain acceptance by
patients or clinicians. In 2014, another formulation of inhaled insulin (Afrezza) received approval by
the US Food and Drug Administration (FDA). Studies have shown that inhaled insulin causes a
very rapid rise in serum insulin concentration (similar to that after subcutaneous insulin lispro and
aspart and faster than that after subcutaneous regular insulin). However, due to its inefficient
absorption, higher doses of insulin must be administered to achieve a therapeutic response. (See
"Inhaled insulin therapy in diabetes mellitus".)
DETERMINANTS OF INSULIN EFFICACY
Effective use of insulin requires an understanding of the major variables that affect the degree of
glycemic control. These include the insulin preparation, the size of the subcutaneous depot,
injection technique, the site of injection, and subcutaneous blood flow.
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Type of insulin — The time of onset, peak activity, and duration of action of subcutaneous insulin
preparations can only be approximated since the usually quoted data are based upon the
administration of small amounts of insulin to a few normal subjects (table 2). Furthermore, the
degree of absorption of any dose, both among patients and in the same patient, can vary from day
to day by as much as 25 to 50 percent, leading to unexplained fluctuations in glycemic control
[48,49]. This effect is greatest with longer-acting insulins and least with regular, lispro, aspart, and
glulisine insulin. Thus, a dose of NPH insulin given before the evening meal may be sufficient to
last through the night in one patient but may dissipate in another, resulting in fasting
hyperglycemia. Part of the day-to-day variability in the absorption of NPH insulin may be due to
incomplete mixing of the suspensions of insulin and protamine or zinc.
The absorption of long-acting insulin analogs such as insulin glargine also seems to vary [50]. In
addition, there is some suggestion that the duration of action of detemir increases with higher
doses [51,52].
Size of subcutaneous depot — When insulin is injected subcutaneously, it forms a subcutaneous

depot. The variability in absorption is increased and net absorption is reduced with increasing size
of the subcutaneous depot [48]. This can become a limiting factor in patients who are insulin
resistant and require large doses given several times per day.
One of the reasons why continuous subcutaneous insulin infusions may serve to smooth blood
glucose control is that only regular insulin, or, preferably, rapid-acting insulin, is used and the size
of the subcutaneous depot is very small (since the reservoir is held in a syringe or other chamber,
outside the body) [53]. Moreover, the consistent delivery site for each catheter placement reduces
the variability inherent in syringe injections, where each injection is in a different site, with varying
angles, depths, and underlying blood flow.
High-pressure jet injectors use a compressed spring or a compressed gas cartridge to supply
pressure to inject the insulin through the skin without using a needle. Although they reduce the size
of the subcutaneous depot and lead to a more rapid fall in blood glucose concentrations and a
shorter duration of insulin action, there is no evidence that the variability in insulin absorption is
improved [54,55]. Jet injectors may also cause less pain than traditional needles and syringes.
However, they are expensive, difficult to maintain, and are not recommended for routine use.
Injection technique — Patients should be referred to a certified diabetes educator to be taught

proper insulin injection technique. The recommended technique is to use an area of the body in
which approximately 2.5 cm (1 inch) of subcutaneous fat can be pinched between two fingers.
Injection technique is the same with insulin syringes and with pen injectors. Both the angle of
needle entry and the depth of penetration affect the rate of insulin absorption. Very shallow
insertion can cause a painful intradermal injection that is not well absorbed. In comparison, a
perpendicular injection in a lean area may result in an intramuscular injection, from which
absorption is more rapid [56,57].
The syringe, with a 1/2 or 5/16 (28- to 31-gauge) needle, is inserted perpendicular to the pinched
skin up to the hilt, and the insulin is then injected. The syringe barrel should not be pulled back
before injection or the needle removed if blood is obtained. The needle should be held in place for
several seconds before being withdrawn [47]. This is especially important when using pen
injectors, to avoid insulin leakage after withdrawal of the needle.
A variety of pen injectors, used with prefilled cartridges, are available and are more convenient
than conventional syringes and bottles but are more expensive. Replaceable needles, available in
various lengths and gauges, are placed on the insulin pen. When small doses of regular insulin
(less than 5 units) are being given, the error in measuring the dose is almost 50 percent less when
using pen injectors than with conventional insulin syringes [58].
The common practice of cleaning the skin with an alcohol swab before injection may not be
necessary. In a crossover study of 50 patients who received over 13,000 injections, there was no
difference when the usual manner of injection was compared with injections through clothing [59].
The only problem with the latter was an occasional blood stain on the clothing. Additional
information on injection technique, mixing insulin, and syringe disposal is found elsewhere [47].
Site of injection — Potential sites for insulin injection are the upper arms, abdominal wall, upper
legs, and buttocks (figure 3). A common cause of day-to-day variability in insulin action is the
random rotation of injection sites from one region of the body to another. Insulin is absorbed fastest
from the abdominal wall, slowest from the leg and buttock, and at an intermediate rate from the
arm; at any of these sites, the rapidity of insulin absorption varies inversely with subcutaneous fat
thickness [49,60]. In a study using radiolabeled, regular insulin, the percent of the dose that
disappeared at two hours was approximately 49 percent in the abdomen, 37 percent in the arm,
and 26 percent in the leg [60]. The postprandial rise in plasma glucose concentration varied
inversely with the rate of insulin absorption, being 30 to 50 mg/dL (1.7 to 2.8 mmol/L) less after
abdominal than after leg injection; the values after arm injection were intermediate between these
responses.
These differences can be useful clinically. Pre-meal regular or rapid-acting insulin should be rapidly
absorbed, and injection into the abdominal wall may therefore be preferable. On the other hand,
slower absorption from the leg or buttock may be desirable with the pre-evening meal dose of
intermediate-acting insulin to ensure a duration of action that lasts through the night.
Alterations in subcutaneous blood flow — The degree of insulin absorption is also determined
by the rate of subcutaneous blood flow. Thus, insulin absorption is reduced by smoking [61] and
increased by any increases in skin temperature [62] induced by exercise, saunas or hot baths, and
local massage [63-66]. These variations are more marked with regular and rapid-acting insulins
than with longer-acting insulins [65].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and
"Society guideline links: Diabetes mellitus in children".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Type 1 diabetes (The Basics)" and "Patient education:
Type 2 diabetes (The Basics)" and "Patient education: Using insulin (The Basics)" and
"Patient education: Should I switch to an insulin pump? (The Basics)")
● Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the
Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient
education: Type 1 diabetes: Insulin treatment (Beyond the Basics)" and "Patient education:
Type 2 diabetes: Insulin treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Insulin therapy is essential in all patients with type 1 diabetes and is often used in patients with
type 2 diabetes. Although initial treatment for type 2 diabetes should be diet modification and
exercise, usually followed or accompanied by metformin, additional oral agents, or injectable
medications including insulin should be used if individualized glycemic goals are not achieved.
When insulin therapy is indicated, its use should not be delayed when it becomes necessary.
(See 'Which patients need insulin' above.)
● While intensive insulin therapy, utilizing a basal insulin with multiple pre-meal injections of a
very rapidly acting insulin, has become standard therapy in type 1 diabetes, simpler regimens
are often used in type 2 diabetes. The approximate time of onset, peak activity, and duration
of action of the most commonly used insulins are shown in the table (table 2). (See 'Insulin
preparations' above.)
● We suggest not prescribing pre-mixed insulin for type 1 diabetes (Grade 2C). Pre-mixed
insulin may be considered in some patients with type 2 diabetes for convenience. Specific
guidelines should be followed for pre-mixing to avoid changes in speed of absorption and
peak action. Commercially available, pre-mixed insulins are a reasonable choice if the insulin
ratio is appropriate to the patient's insulin requirement. (See 'Pre-mixed insulins' above.)
● Effective use of insulin requires an understanding of the major variables that affect the degree
of glycemic control: the insulin preparation; the size of the subcutaneous depot; injection
technique; the site, depth, and angle of injection; and subcutaneous blood flow. (See
'Determinants of insulin efficacy' above.)
● Insulin absorption is variable between patients and in the same patient, especially for longer-
acting preparations. Variability is greater with larger injection doses. (See 'Size of
subcutaneous depot' above.)
● Injections should be given into an area of pinched skin, with needle inserted perpendicular and
up to the hilt; the barrel should not be pulled back. Pre-cleaning skin with alcohol is
unnecessary and may increase the pain of an injection. (See 'Injection technique' above.)
● Absorption is fastest from injections into the abdominal wall, which may be a preferable site for
pre-meal insulin. Slower absorption from the leg or buttock may be appropriate for evening
doses of intermediate-acting insulin. (See 'Site of injection' above.)
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Clin Pharmacokinet 2008; 47:7.
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analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo.
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17. Sanches AC, Correr CJ, Venson R, Pontarolo R. Revisiting the efficacy of long-acting insulin
analogues on adults with type 1 diabetes using mixed-treatment comparisons. Diabetes Res
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18. Swinnen SG, Simon AC, Holleman F, et al. Insulin detemir versus insulin glargine for type 2
diabetes mellitus. Cochrane Database Syst Rev 2011; :CD006383.
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insulin degludec, an ultra-long-acting basal insulin. Pharm Res 2012; 29:2104.
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insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2
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malignancies-a population-based follow-up study in Sweden. Diabetologia 2009; 52:1745.
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type 2 diabetes. Diabetologia 2009; 52:1766.
26. Rosenstock J, Fonseca V, McGill JB, et al. Similar risk of malignancy with insulin glargine
and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from
a 5 year randomised, open-label study. Diabetologia 2009; 52:1971.
27. Chang CH, Toh S, Lin JW, et al. Cancer risk associated with insulin glargine among adult
type 2 diabetes patients--a nationwide cohort study. PLoS One 2011; 6:e21368.
28. Morden NE, Liu SK, Smith J, et al. Further exploration of the relationship between insulin
glargine and incident cancer: a retrospective cohort study of older Medicare patients.
29. Suissa S, Azoulay L, Dell'Aniello S, et al. Long-term effects of insulin glargine on the risk of
breast cancer. Diabetologia 2011; 54:2254.
30. Wu JW, Azoulay L, Majdan A, et al. Long-Term Use of Long-Acting Insulin Analogs and
Breast Cancer Incidence in Women With Type 2 Diabetes. J Clin Oncol 2017; 35:3647.
31. US Food and Drug Administration. FDA Drug Safety Communication: Update to ongoing safe
ty review of Lantus (insulin glargine) and possible risk of cancer. http://www.fda.gov/Drugs/Dr
ugSafety/ucm239376.htm (Accessed on January 17, 2011).
32. Cochran E, Musso C, Gorden P. The use of U-500 in patients with extreme insulin resistance.
33. Ballani P, Tran MT, Navar MD, Davidson MB. Clinical experience with U-500 regular insulin in
obese, markedly insulin-resistant type 2 diabetic patients. Diabetes Care 2006; 29:2504.
34. Davidson MB, Navar MD, Echeverry D, Duran P. U-500 regular insulin: clinical experience
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h 13, 2015).
38. Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 300 U/ml compared with
glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering
drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab 2015; 17:386.
39. Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/mL versus glargine 100
units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and
hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care 2014;
37:2755.
40. Yki-Järvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 units/mL versus
glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin:
glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2).
41. Roach P, Bai S, Charbonnel B, et al. Effects of multiple daily injection therapy with Humalog
mixtures versus separately injected insulin lispro and NPH insulin in adults with type I
diabetes mellitus. Clin Ther 2004; 26:502.
42. Joseph SE, Korzon-Burakowska A, Woodworth JR, et al. The action profile of lispro is not
blunted by mixing in the syringe with NPH insulin. Diabetes Care 1998; 21:2098.
43. Koivisto VA, Tuominen JA, Ebeling P. Lispro Mix25 insulin as premeal therapy in type 2
diabetic patients. Diabetes Care 1999; 22:459.
44. Woodworth JR, Howey DC, Bowsher RR, et al. Comparative pharmacokinetics and
glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures. Diabetes
Care 1994; 17:366.
45. Brodows R, Chessor R. A comparison of premixed insulin preparations in elderly patients.

Efficacy of 70/30 and 50/50 human insulin mixtures. Diabetes Care 1995; 18:855.
46. Dunbar JM, Madden PM, Gleeson DT, et al. Premixed insulin preparations in pen syringes
maintain glycemic control and are preferred by patients. Diabetes Care 1994; 17:874.
47. American Diabetes Association. Insulin administration. Diabetes Care 2004; 27 Suppl
1:S106.
48. Binder C, Lauritzen T, Faber O, Pramming S. Insulin pharmacokinetics. Diabetes Care 1984;
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49. Sindelka G, Heinemann L, Berger M, et al. Effect of insulin concentration, subcutaneous fat
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50. Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycemia with insulin glargine in intensive
insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes.
51. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study

investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin
analog detemir. Diabetes Care 2005; 28:1107.
52. Owens DR, Bolli GB. Beyond the era of NPH insulin--long-acting insulin analogs: chemistry,
comparative pharmacology, and clinical application. Diabetes Technol Ther 2008; 10:333.
53. Lauritzen T, Pramming S, Deckert T, Binder C. Pharmacokinetics of continuous

subcutaneous insulin infusion. Diabetologia 1983; 24:326.
54. Engwerda EEC, Tack CJ, de Galan BE. Pharmacokinetic and Pharmacodynamic Variability
of Insulin When Administered by Jet Injection. J Diabetes Sci Technol 2017; 11:947.
55. Engwerda EEC, Tack CJ, de Galan BE. A comparison of the pharmacodynamic profiles of
jet-injected regular human insulin versus conventionally administered insulin aspart in healthy
volunteers. Diabetes Res Clin Pract 2016; 121:86.
56. Galloway JA, Spradlin CT, Nelson RL, et al. Factors influencing the absorption, serum insulin
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57. Micossi P, Cristallo M, Librenti MC, et al. Free-insulin profiles after intraperitoneal,
intramuscular, and subcutaneous insulin administration. Diabetes Care 1986; 9:575.
58. Lteif AN, Schwenk WF. Accuracy of pen injectors versus insulin syringes in children with type
1 diabetes. Diabetes Care 1999; 22:137.
59. Fleming DR, Jacober SJ, Vandenberg MA, et al. The safety of injecting insulin through
clothing. Diabetes Care 1997; 20:244.
60. Koivisto VA, Felig P. Alterations in insulin absorption and in blood glucose control associated
with varying insulin injection sites in diabetic patients. Ann Intern Med 1980; 92:59.
61. Klemp P, Staberg B, Madsbad S, Kølendorf K. Smoking reduces insulin absorption from
subcutaneous tissue. Br Med J (Clin Res Ed) 1982; 284:237.
62. Riccio A, Avogaro A, Valerio A, et al. Improvement of basal hepatic glucose production and
fasting hyperglycemia of type I diabetic patients treated with human recombinant ultralente
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63. Koivisto VA, Felig P. Effects of leg exercise on insulin absorption in diabetic patients. N Engl J
Med 1978; 298:79.
64. Koivisto VA. Sauna-induced acceleration in insulin absorption from subcutaneous injection
site. Br Med J 1980; 280:1411.
65. Linde B. Dissociation of insulin absorption and blood flow during massage of a subcutaneous
injection site. Diabetes Care 1986; 9:570.
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subcutaneously injected insulin preparations. Diabetes Care 1982; 5:77.
Topic 1752 Version 27.0
GRAPHICS
Addressing patient resistance to insulin therapy for patients with type 2 diabetes
Patient concerned with pain from injection

Minimal with thinner, smaller needles
Use of insulin pens
Patient worried that starting insulin signifies worsening diabetes

Diabetes is a progressive disease
Taking insulin will control blood glucose and help prevent complications
Taking insulin may slow down the rate of beta cell failure
Patient believes that need for insulin signifies patient failure to follow treatment
regimen
Diabetes is a progressive disease; beta cell activity declines over time
Not related to patient compliance
Patient fears low blood sugar reactions

Explain that severe hypoglycemia is rare in type 2 diabetes
Self-monitoring glucose levels
Explain how to avoid and how to treat hypoglycemia
Patient concerned that taking insulin will upset daily routine

Address specific concerns
Taking insulin may be less intrusive than complicated drug regimens
Patient believes that insulin will decrease his/her quality of life

Benefits from glucose control: more energy, better sleep, overall well-being
Patient thinks insulin will lead to diabetic complications

Discuss role of insulin in reducing risk of diabetic complications
Patient concerned that he/she will be treated differently by friends and family
Educate friends and family: offer reading materials on diabetes, support groups for family
Patient has heard insulin causes weight gain

Role of diet and exercise
Patient wants a more natural alternative therapy

Insulin is the most natural therapy for diabetes. It is replacing the hormone that the patient does not make
enough of.
Data from: Brunton S, Carmichael B, Funnell M, et al. Type 2 diabetes: the role of insulin. J Fam Pract 2005; 54:445.
Graphic 52039 Version 2.0
Time-action profiles for NPH and insulin glargine
Serum insulin concentrations after subcutaneous injection of 0.4 U/kg body

weight of insulin glargine (solid line) or NPH human insulin (dashed line) on
two different study days in 15 normal subjects. In contrast to NPH insulin,
the time-action profile for insulin glargine has virtually no peak, which may
make it an ideal basal insulin for intensive insulin therapy in patients with
type 1 diabetes. To convert serum insulin values to µU/mL, divide by 6.
NPH: neutral protamine hagedorn.
Data from: Heinemann L, Linkeschova R, Rave K, et al. Time-action profile of the

long-acting insulin analog insulin glargine (HOE901) in comparison with those of
NPH insulin and placebo. Diabetes Care 2000; 23:644.
Pharmacokinetics of the most commonly used insulin preparations
Approximate onset Approximate

Insulin type Peak effect
of action duration of action*
Lispro, aspart, faster 3 to 15 minutes 45 to 75 minutes 2 to 4 hours

aspart, glulisine
Regular 30 minutes 2 to 4 hours 5 to 8 hours
NPH 2 hours 4 to 12 hours 8 to 18 hours, with usual

duration of action around
12 hours
Insulin glargine 2 hours No peak 20 to >24 hours
Insulin detemir 2 hours 3 to 9 hours 6 to 24 hours ¶
NPL 2 hours 6 hours 15 hours
Insulin degludec 2 hours No peak >40 hours
NPH: neutral protamine hagedorn; NPL: neutral protamine lispro.

* Glucose-lowering action may vary considerably in different individuals or within the same individual.
¶ Duration of action is dose dependent. At higher doses (≥0.8 units/kg), mean duration of action is longer and less
variable (22 to 23 hours).
Variable serum insulin concentrations with premixed

insulins
24-hour serum insulin profiles after the injection of two premixed insulin
preparations: one containing a total of 0.3 units/kg of NPH and regular
insulin in a 50:50 ratio (dashed line), and one containing the same total
amount of NPH and regular insulin in a 70:30 ratio (solid line). Serum insulin
concentrations were significantly higher during the first six hours with the
50:50 regimen, which contained more regular insulin. To convert serum
insulin values to µU/mL, divide by 6.
Data from: Woodworth JR, Howey DC, Bowsher RR, et al. Comparative
pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and
50/50 insulin mixtures. Diabetes Care 1994; 17:366.
Diabetic injection sites
The shaded areas may be used for insulin injections. Injection sites should be
rotated. Insulin is absorbed more rapidly when injected into the abdomen, as
compared to the arms or legs.
Contributor Disclosures
David K McCulloch, MD Nothing to disclose David M Nathan, MD Research Support: Abbott [Diabetes
(Point-of-care A1C assay)]. Jean E Mulder, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

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WHICH PATIENTS NEED INSULIN

Initiation of insulin therapy, however, is often unnecessarily delayed, owing to clinician or

● Atypical presentations – It is occasionally difficult to distinguish between type 1 and atypical

● Rapid-acting insulin – With respect to short-term outcomes, such as glycated hemoglobin

● Basal – Intermediate- to long-acting preparations (NPH, NPL, detemir, glargine, or degludec)

In one observational study of 11 obese, severely insulin-resistant, uncontrolled diabetic patients

Pre-mixed insulins — We almost never recommend commercially fixed-ratio pre-mixed insulins in

serum insulin concentrations in the first six hours (figure 2).

DETERMINANTS OF INSULIN EFFICACY

Size of subcutaneous depot — When insulin is injected subcutaneously, it forms a subcutaneous

Injection technique — Patients should be referred to a certified diabetes educator to be taught

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

Use of UpToDate is subject to the Subscription and License Agreement.

7. Biester T, Kordonouri O, Danne T. Pharmacological Properties of Faster-Acting Insulin

8. Heise T, Stender-Petersen K, Hövelmann U, et al. Pharmacokinetic and Pharmacodynamic

12. Hirsch IB. Insulin analogues. N Engl J Med 2005; 352:174.

35. http://www.fda.gov/Drugs/DrugSafety/ucm510318.htm (Accessed on October 20, 2016).

36. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/018780s135s152lbl.pdf (Accesse

37. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206538lbl.pdf (Accessed on Marc

45. Brodows R, Chessor R. A comparison of premixed insulin preparations in elderly patients.

51. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study

53. Lauritzen T, Pramming S, Deckert T, Binder C. Pharmacokinetics of continuous

clothing. Diabetes Care 1997; 20:244.

Topic 1752 Version 27.0

Patient concerned with pain from injection

Use of insulin pens

Patient worried that starting insulin signifies worsening diabetes

Not related to patient compliance

Patient fears low blood sugar reactions

Self-monitoring glucose levels

Explain how to avoid and how to treat hypoglycemia

Patient concerned that taking insulin will upset daily routine

Taking insulin may be less intrusive than complicated drug regimens

Patient believes that insulin will decrease his/her quality of life

Patient thinks insulin will lead to diabetic complications

Patient has heard insulin causes weight gain

Patient wants a more natural alternative therapy

Graphic 52039 Version 2.0

Time-action profiles for NPH and insulin glargine

Serum insulin concentrations after subcutaneous injection of 0.4 U/kg body

NPH: neutral protamine hagedorn.

Data from: Heinemann L, Linkeschova R, Rave K, et al. Time-action profile of the

Graphic 67242 Version 5.0

Pharmacokinetics of the most commonly used insulin preparations

Approximate onset Approximate

Lispro, aspart, faster 3 to 15 minutes 45 to 75 minutes 2 to 4 hours

Regular 30 minutes 2 to 4 hours 5 to 8 hours

NPH 2 hours 4 to 12 hours 8 to 18 hours, with usual

Insulin glargine 2 hours No peak 20 to >24 hours

Insulin detemir 2 hours 3 to 9 hours 6 to 24 hours ¶

NPL 2 hours 6 hours 15 hours

Insulin degludec 2 hours No peak >40 hours

NPH: neutral protamine hagedorn; NPL: neutral protamine lispro.

Graphic 73676 Version 11.0

Variable serum insulin concentrations with premixed

Graphic 57000 Version 3.0

Diabetic injection sites

Graphic 78710 Version 2.0