Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

General principles of insulin therapy in diabetes mellitus

AUTHOR: Ruth S Weinstock, MD, PhD
SECTION EDITOR: David M Nathan, MD
DEPUTY EDITOR: Katya Rubinow, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023.

This topic last updated: Nov 08, 2023.

INTRODUCTION

Insulin is used in the treatment of people with most types of diabetes. In general, the need for
insulin depends upon the degree of insulin deficiency. All people with type 1 diabetes need
insulin treatment; many individuals with type 2 diabetes will require insulin as their beta cell
function declines over time.

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 adults who become hyperglycemic are discussed separately.

● (See "Management of blood glucose in adults with type 1 diabetes mellitus".)

● (See "Insulin therapy in type 2 diabetes mellitus".)

● (See "Glycemic control in critically ill adult and pediatric patients".)

● (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control", section

on 'Insulin pharmacotherapy'.)

● (See "Gestational diabetes mellitus: Glucose management and maternal prognosis",

section on 'Insulin'.)

● (Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant

adults with type 2 DM.)
INSULIN PREPARATIONS

Most people with diabetes use either human insulin or an insulin analog injected
subcutaneously. 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 people 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 [1].

The time to peak and the duration of action of older human insulin preparations (regular insulin
and neutral protamine Hagedorn [NPH]) do not replicate endogenous postprandial insulin
secretion and basal insulin secretion, respectively, which is particularly important in treating
insulin-deficient type 1 diabetes. The rapid-acting (lispro, lispro-aabc, glulisine, aspart, and
faster aspart) and long-acting (glargine, detemir, and degludec) insulin analogs were developed
to provide a more physiologic insulin profile ( table 1 and figure 1) [2].

The usual concentration of insulin is 100 units per mL (U-100). More concentrated formulations
(U-200, U-300, U-500) of some types of insulin are available to treat hyperglycemia in severely
insulin-resistant individuals (eg, requiring more than 200 total units of insulin daily). (See
"Insulin therapy in type 2 diabetes mellitus", section on 'Insulin resistance'.)

U-300 insulin glargine is also used in people who are not insulin resistant because of its longer
half-life when compared with U-100 insulin glargine.

Human insulins

Regular insulin — Regular insulin (short-acting) is a soluble insulin complexed with zinc that
has the same amino acid sequence as endogenous human insulin. It can be used to control the
postprandial rise in glucose. After regular insulin is injected subcutaneously, the hexamers that
have formed dissociate into dimers and monomers that are absorbed. This causes a delay in
rise of insulin concentrations in the bloodstream, resulting in a need to inject at least 30
minutes before the meal to best cover post-meal glycemic excursions.

This timing of mealtime injections is difficult for many individuals with diabetes. In addition, the
duration of action of regular insulin exceeds the duration of the postprandial rise in glucose
observed after most meals, particularly meals that are not high in carbohydrate and fat. This
can cause hypoglycemia several hours after eating, which can be prevented by eating a snack.
Regular insulin is also used intravenously in inpatient settings (eg, to treat diabetic
ketoacidosis). (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults:
Treatment", section on 'Intravenous regular insulin' and "Glycemic control in critically ill adult
and pediatric patients".)

NPH insulin — NPH (intermediate-acting insulin) is a crystallized suspension of human insulin,

protamine, and zinc in a neutral buffer that delays the release of the insulin into the
bloodstream ( figure 1). To provide 24-hour basal coverage, NPH needs to be administered at
least twice daily. When given in the morning, there is an increased risk of hypoglycemia if food
is not consumed during the time of its peak action. When given in the evening or at bedtime, a
bedtime snack may be needed to avoid nocturnal hypoglycemia. Subsequently, fasting glucose
concentrations may be above target.

NPH, which is a suspension, should be administered at room temperature and mixed

immediately before injection. This is accomplished by rolling the insulin pen or vial in your
hands at least 10 times and then inverting the pen or vial at least 10 times [3].

Although NPH can be mixed with regular insulin or rapid-acting insulins in a single syringe for
injection, which may be convenient and advantageous, the two insulins should be mixed
immediately before injection. The regular ("clear") insulin should be drawn up before the NPH
("cloudy") insulin. It is important to avoid introducing protamine (NPH) into the regular insulin
vial since that would change the pharmacokinetics of the regular insulin. This mixture should
then be injected immediately after preparation. If NPH is mixed with a rapid-acting insulin
analog, it should be injected within minutes prior to a meal.

U-500 regular insulin — U-500 regular insulin contains 500 units per mL of regular insulin. It
is used infrequently given the availability of potent GLP-1 receptor agonists as well as
concentrated forms of insulin analogs (see 'Analog insulins' below). U-500 insulin may be useful
for treating severely insulin-resistant individuals (eg, requiring more than 200 total units of
insulin daily). In one observational study of 11 individuals with obesity and severe insulin
resistance (requiring >200 units of insulin daily), substituting U-500 regular insulin for U-100
NPH insulin improved glycemic management (mean glycated hemoglobin [A1C] decrease from
9.9 to 7.1 percent) [4].

The duration of action of U-500 regular insulin is most similar to that of NPH, but with a faster
time of onset. Higher doses can result in significantly longer duration of insulin action
( figure 1) [5,6]. The pharmacokinetics can be highly variable and hypoglycemia remains a
potential risk [7,8]. Dosing is reviewed separately. (See "Insulin therapy in type 2 diabetes
mellitus", section on 'Insulin resistance'.)
Analog insulins — Insulin analogs, which are manufactured using recombinant DNA
technology, were designed to produce more physiologic insulin profiles and reduce the risk of
hypoglycemia. The rapid-acting insulin analogs (insulin lispro, lispro-aabc, aspart, faster aspart,
and glulisine) have both faster onset and shorter duration of action than regular insulin for pre-
meal coverage [9-13], while the long-acting analogs have a longer, flatter, and more predictable
day-to-day profile than NPH for basal coverage ( table 1 and figure 1). Insulin analogs with
even longer durations of action (dosed once weekly) are under development [14,15].

Rapidly acting insulin analogs — 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
( figure 1) [16,17].

● 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 [18]. 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 [19-21]. The total glucose-lowering effect
is similar for faster aspart and insulin aspart.

● Insulin lispro is identical to human regular insulin except for a lysine and proline at
positions B28 and B29, respectively. Another formulation of insulin lispro (lispro-aabc),
produced by adding treprostinil (a prostacyclin analogue) and citrate, results in slightly
faster initial absorption than lispro, and when administered at mealtime, slightly better
postprandial glucose control [22,23].

● Insulin glulisine has a lysine and glutamic acid at positions B3 and B29 respectively.

With respect to short-term outcomes, such as A1C and risk of hypoglycemia, rapid-acting
insulins may have a glycemic advantage over short-acting (regular) insulin in people with type 1
diabetes but not necessarily in people with type 2 diabetes. Although rapid-acting insulins are
more expensive than regular insulin, the convenience for timing of pre-meal administration and
reduction in hypoglycemia reported in some studies represent distinct advantages. For
individuals using hybrid artificial pancreas systems, rapid-acting insulin analogs should be used
since the algorithms driving the automatic insulin delivery are based on their pharmacokinetics.
The trials examining these issues are reviewed separately. (See "Management of blood glucose
in adults with type 1 diabetes mellitus", section on 'Prandial insulin options' and "Insulin therapy
in type 2 diabetes mellitus", section on 'Designing an insulin regimen' and "Continuous
subcutaneous insulin infusion (insulin pump)".)

Concentrated rapidly acting insulin analogs, U-200 lispro and U-200 lispro-aabc, contain 200
units/mL instead of 100 units/mL in the U-100 preparation. They are useful for individuals
requiring high doses of prandial insulin and are available in prefilled pens to minimize the risk
of dosing errors. The dose window shows the number of units of insulin to be delivered, and no
conversion is needed. U-200 compared with U-100 lispro was shown to improve glycemic
management in some people with type 2 diabetes [24].

Basal insulin analogs — Different alterations result in the slower absorption and longer
duration of action of basal insulin analogs ( table 1 and figure 1).

● Insulin glargine – 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 to the
amino terminus of the B-chain of the insulin molecule [25]. After subcutaneous
administration, glargine precipitates in the tissue, forming hexamers, which delays
absorption and prolongs duration of action.

Glargine, which is in an acidic solution, cannot be mixed with rapid-acting insulins, as the
kinetics of both the glargine and rapid-acting insulin will be altered. U-100 glargine has no
appreciable peak; however, it does have somewhat greater glucose-lowering effect in the
first 12-hours than the subsequent 12 hours. Glargine has less nocturnal hypoglycemia
than is observed with NPH insulin [26,27]. The duration of action of U-100 insulin glargine
is usually 24 hours enabling once-daily dosing, but because its half-life is 12 hours, some
individuals, especially with type 1 diabetes, have better basal coverage with twice-daily
dosing.

The more concentrated formulation of insulin glargine (U-300 glargine) contains 300
units/mL instead of 100 U/mL. It has an even flatter and more prolonged duration of
action than U-100 insulin glargine, lasting >24 hours ( figure 1) [28]. It is used in type 1,
as well as in type 2 diabetes, and in individuals with and without insulin resistance. Two
prefilled pens are available: 1.5 mL (contains 450 units) and 3.0 mL (contains 900 units).
These pens allow 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 U-100 glargine [29,30].

In trials comparing U-300 glargine with glargine 100 units/mL in people 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 [30-32]. In a network meta-analysis of trials
comparing U-300 glargine with other basal insulin preparations in individuals with type 2
diabetes, glycemic control was similar among the preparations. The risk of nocturnal
hypoglycemia was lower with U-300 glargine, compared with NPH and pre-mixed insulins,
but the total frequency of hypoglycemia was not significantly different. Moreover, the
frequency of severe hypoglycemia requiring assistance for treatment was very low and not
significantly different among insulin types [33].

● Insulin detemir – Detemir is an acylated insulin; the fatty acid side chain allows reversible
albumin binding as well as concentration-dependent self-association (ie, formation of
dihexamers) that results in prolongation of action ( figure 1). Higher doses are
associated with longer durations 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 people with type 1 diabetes have suggested that twice-per-day injections
may be necessary to achieve acceptable basal rate coverage and optimal glycemic control
[34]. In type 2 diabetes, where endogenous insulin secretion may mask any deficiencies in
basal insulin, the data are less clear [35]. However, in our clinical experience, detemir also
often requires twice-daily administration in people 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 – Degludec is almost identical to human insulin, except for deletion of
threonine at position B30 and the addition of a glutamyl link from LysB29 to a
hexadecanedioic fatty acid, facilitating self-association and albumin binding [36]. Soluble
multihexamers form 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 ( figure 1). Steady-state insulin
concentrations are attained in three to five days. 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.

The more concentrated formulation of insulin degludec (U-200 degludec) contains 200
units/mL instead of 100 units/mL in the U-100 preparation, and it is useful in adults with
high dose insulin requirements. It is available in a prefilled pen to minimize the risk of
dosing errors. The dose window shows the number of units of insulin to be delivered and
 no conversion is needed. The pharmacokinetics and pharmacodynamics of U-100 and U-
200 insulin degludec are similar.

● Insulin icodec – Insulin icodec is an investigational ultra-long-acting basal insulin (half-life

of one week) [37]. Additional studies are needed to determine which individuals may
benefit in clinical practice from use of ultra-long-acting insulin compared with daily basal
insulin.

• Type 2 diabetes – In a preliminary trial comparing once-weekly insulin icodec with

once-daily U-100 insulin glargine in 247 adults with type 2 diabetes inadequately
controlled on oral agents, the reduction in A1C was similar in the two groups (-1.33 and
-1.15 percentage points, respectively) [14]. Mild (≤70 mg/dL [≤3.9 mmol/L], 53.6 versus
37.7 percent) and clinically important (<54 mg/dL [<3 mmol/L], 16 versus 10 percent)
hypoglycemia were more common in the icodec group, but the latter difference did not
reach statistical significance.

• Type 1 diabetes – In a trial comparing once-weekly insulin icodec with once-daily

insulin degludec in 655 adults with type 1 diabetes, the mean reduction in A1C after 26
weeks was similar in both groups (-0.47 and -0.51 percentage points, respectively) [38].
However, icodec treatment led to a higher rate of clinically significant (<54 mg/dL [<3
mmol/L]) or severe hypoglycemia (85 versus 76 percent with degludec).

● Basal insulin-Fc (LY3209590) – LY3209590 is an investigational ultra-long-acting

immunoglobulin G (IgG) Fc-fusion insulin. In the first phase 2 trial of weekly administration
of LY3209590 compared with daily insulin degludec in 399 adults with type 2 diabetes,
LY3209590 was noninferior to degludec with respect to the primary endpoint (A1C) over 32
weeks [15]. Results from additional trials will help inform the safety and efficacy of this
insulin in the treatment of type 1 and type 2 diabetes.

Compared with NPH, there can be a glycemic advantage to the long-acting insulin analogs
(glargine, detemir, and degludec) due to less symptomatic and nocturnal hypoglycemia,
particularly in individuals with type 1 diabetes. In type 2 diabetes, the frequency of severe
hypoglycemia (requiring assistance) is much lower than in type 1 diabetes, but risk of nocturnal
hypoglycemia is lower with the long-acting analogs than with NPH. (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 [17]. 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 participants randomly assigned to glargine
had an increase in three steps or more on the Early Treatment Diabetic Retinopathy Study
(ETDRS) scale [39]. However, the results from a randomized trial and retrospective cohort study
do not support this conclusion [40,41]. In the five-year trial in over 1000 participants 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
people randomly assigned to once-daily glargine versus twice-daily NPH [40].

Although there are conflicting data regarding use of insulin analogs and risk of cancer [42-52],
there is insufficient evidence to make a recommendation against glargine (or other insulin
analogs) based on risk of malignant neoplasms [53]. 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 — Basal insulin suppresses hepatic glucose production and when used in
appropriate doses should maintain near normoglycemia in the fasting state, while prandial
(pre-meal) bolus insulin covers the extra requirements after food is absorbed, thereby
decreasing postprandial glucose excursions. Physiologic replacement of insulin with "basal-
bolus" insulin therapy should be started as early as possible following the diagnosis of type 1
diabetes. People with type 2 diabetes requiring insulin often start with basal insulin first (in
addition to oral and non-insulin injectable agents), but bolus insulin may be necessary as insulin
secretion wanes. (See "Management of blood glucose in adults with type 1 diabetes mellitus",
section on 'Insulin regimens' and "Insulin therapy in type 2 diabetes mellitus", section on
'Insulin initiation'.)
(Related Pathway(s): Diabetes: Initiation and titration of insulin therapy in non-pregnant adults
with type 2 DM.)

● Basal – Intermediate- to long-acting preparations (NPH, 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 rapidly acting insulin given at mealtimes.
 Basal insulin levels can also be achieved by continuous infusion of a rapid-acting insulin via
an insulin pump, used mostly in type 1 diabetes. (See "Continuous subcutaneous insulin
infusion (insulin pump)".)

● Bolus – Short-acting (regular) or rapid-acting (lispro, lispro-aabc, 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. The approximate time of onset, peak activity,
and duration of action of the most commonly used insulins are shown in the table
( table 1).

Both glucose and insulin metabolism are altered in individuals with chronic kidney disease. The
changes in the insulin regimen that must be made in these individuals are discussed separately.
(See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic
kidney disease or end-stage kidney disease".)

Pre-mixed insulins — We almost never prescribe 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 people who will not or cannot comply with an
intensive regimen, pre-mixed lispro/NPH in type 1 diabetes may be appropriate [54].

Some people with type 2 diabetes can use pre-mixed preparations with reasonable effect, and
pre-mixed human insulins are generally less expensive than insulin analogs [55]. However, if the
aim is to truly vary the dose of fast-acting insulin before a meal, it would be optimal to adjust
the dosing of premeal insulin independently, rather than using a fixed ratio. Nevertheless, some
people with type 2 diabetes who require pre-meal insulin in addition to basal insulin prefer pre-
mixed insulins for convenience and lower cost. When using pre-mixed NPH and regular insulin,
the peak action varies directly with the proportion of regular insulin in the combination
( figure 2).

Inhaled insulin — In 2014, a second formulation of regular insulin in a dry powder received
approval by the US Food and Drug Administration (FDA) for oral inhalation. A previously
approved inhaled insulin introduced in 2006 was withdrawn from the market by the
manufacturer, largely owing to poor sales. Studies have shown that oral inhaled insulin causes a
more rapid rise in serum insulin concentration (and reduced hypoglycemia two to five hours
after eating) compared with rapid-acting insulin analogs [56]. However, due to its inefficient
absorption, higher doses of insulin must be administered to achieve a therapeutic response.
Inhaled insulin dosing can only be adjusted in 4-unit increments, and it is contraindicated in the
presence of chronic lung disease. Use requires initial pulmonary function testing, with repeat
testing after six months of use and yearly thereafter. (See "Inhaled insulin therapy in diabetes
mellitus".)

INSULIN DELIVERY

Subcutaneous insulin is delivered by injection or infusion using an insulin pump. Injectable

insulin is available in prefilled disposable insulin pens, reusable insulin pens with disposable
insulin cartridges, or in vials. Insulin pump therapy is reviewed separately. (See "Continuous
subcutaneous insulin infusion (insulin pump)".)

Insulin pens are more convenient to use than insulin vials with syringes. 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 [57]. "Smart" or
"connected" pens are available, which communicate to smartphones to record insulin doses and
have additional helpful features, such as insulin calculators, temperature sensors, reminders,
and "share" features, but they are more expensive.

Use of insulin vials with syringes is less expensive than use of insulin pens. There are 0.3, 0.5
("low-dose") and 1 mL insulin syringes available. The 0.3 mL syringe is useful if the insulin dose
does not exceed 30 units; the 1 mL syringe is used for insulin doses up to 100 units. Magnifiers
for syringes are available for individuals with vision problems to assist with accurate dosing.

When using insulin pens or vials with syringes, the shortest available needle is recommended
(eg, 4 or 5 mm for pen needles) to avoid intramuscular injection and to minimize discomfort
and tissue damage.

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 [58,59]. 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.

DETERMINANTS OF INSULIN EFFICACY

Effective use of insulin requires an understanding of the major variables that affect the degree
of glycemic control. In addition to the type of insulin preparation discussed above, these include
the site of injection, injection technique, the size of the subcutaneous depot, and subcutaneous
blood flow.

Injection sites — Insulin can be injected into the abdominal wall, leg, arm, or buttock
( figure 3). Human insulins are absorbed fastest from the abdominal wall, slowest from the
leg and buttock, and at an intermediate rate from the arm. These differences can be useful
clinically:

● Pre-meal regular insulin should be rapidly absorbed, and injection into the abdominal wall
may therefore be preferable.

● Rapid-acting insulin absorption is increased when the insulin is injected into an exercising
limb due to increased blood flow.

● Pre-evening meal dosing of intermediate-acting insulin should be slowly absorbed to

ensure a duration of action that lasts through the night, and injection in the leg or buttock
may be preferable.

The absorption of the long-acting basal insulin analogs, glargine and degludec, do not appear
to be significantly influenced by injection site [60,61].

Injection technique — Adults initiating insulin therapy should be referred to a certified

diabetes care and education specialist (CDCES) to be taught proper insulin injection.

A clean site, without evidence of infection, inflammation, skin breakdown, fibrosis, or

lipohypertrophy, should be used. The depth of penetration affects 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 [62]. For very thin adults, young
children, or anyone in whom the length of the needle is thought to be greater than or equal to
the distance to muscle, the needle should be inserted perpendicularly into a lifted skinfold. For
many individuals who use a short (4 mm) needle, the risk of an intramuscular injection is low
and the needle can be inserted perpendicularly without "pinching" the subcutaneous fat
between two fingers [62]. If a 6 mm needle is used, the individual can inject at a 45-degree
angle instead of lifting a skinfold. Whether using insulin pens or syringes, the injection site
should be rotated to avoid lipohypertrophy.

Insulin pens need to be primed per manufacturer's instructions and insulin delivered (plunger
depressed) only after the needle is fully inserted. After insulin delivery, the needle should be
held in place for 10 seconds before being withdrawn to assure full delivery and prevent leakage.
For syringe users, first air should be drawn up in the syringe. The amount of air should be the
same or slightly more than the intended dose. The air should then be injected into the vial of
insulin before the insulin is withdrawn. Care should be made to remove any air bubbles from
the syringe before injecting.

The practice of cleaning the skin with an alcohol swab before injection is usually not necessary.
If used, the area should be completely dry before injecting. In a crossover study of 50
participants who received over 13,000 injections, there was no difference when the usual
manner of injection was compared with injections through clothing [63]. The only problem with
the latter was an occasional blood stain on the clothing. However, this is generally not
recommended, because the individual cannot inspect the site prior to injection or lift a skinfold
if needed [62].

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 [64]. This can become a limiting factor in people
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 usually only 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)
[65]. 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. (See "Continuous subcutaneous insulin infusion (insulin
pump)", section on 'General principles'.)

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 [66] and increased by any increases in skin temperature [67] induced by exercise,
saunas or hot baths, and local massage [68-71]. These variations are more marked with regular
and rapid-acting insulins than with longer-acting insulins [70].

Insulin pump infusion sites — The continuous flow of insulin from insulin pumps can be
partially or totally interrupted, by blockages at the aperture under the skin, kinking of the
infusion set tubing as well as dislodgment of the inserted cannula. This topic is reviewed
separately. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Pump
failure'.)
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

● Commonly used insulin preparations – Human insulin or an insulin analog can be used
to treat diabetes. The approximate time of onset, peak activity, and duration of action of
the most commonly used insulins are shown in the table ( table 1). The insulin analogs
(lispro, aspart, glulisine, glargine, detemir, degludec) were developed to provide more
physiologic insulin profiles. The rapid-acting insulin analogs (insulin lispro, lispro-aabc,
 aspart, faster aspart, and glulisine) 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). (See 'Insulin preparations'
above.)

● Concentrated forms of insulin – Concentrated forms of insulin can be used to control

hyperglycemia in severely insulin-resistant individuals (eg, requiring more than 200 total
units of insulin daily). (See 'U-500 regular insulin' above and 'Basal insulin analogs' above
and 'Rapidly acting insulin analogs' above.)

● Premixed insulin – We typically do not prescribe commercially fixed-ratio pre-mixed

insulins in the treatment of type 1 diabetes. Intensive regimens in people with type 1
diabetes require frequent adjustments of the pre-meal bolus of short- or rapid-acting
insulin. Pre-mixed insulin may be used in some people with type 2 diabetes for
convenience, if the insulin ratio is appropriate to the person's insulin requirement. Specific
guidelines should be followed for pre-mixing to avoid changes in speed of absorption and
peak action. (See 'Pre-mixed insulins' above.)

● Determinants of insulin efficacy – Effective use of insulin requires an understanding of

the major variables that affect the degree of glycemic control: the insulin preparation,
injection site, injection technique, the size of the subcutaneous depot, and subcutaneous
blood flow. (See 'Determinants of insulin efficacy' above.)

• Insulin injection sites – Absorption is fastest from injections into the abdominal wall,
especially with human insulins, and therefore, abdominal wall 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. The absorption of the long-acting basal
insulin analogs, glargine and degludec, do not appear to be significantly influenced by
injection site. (See 'Injection sites' above.)

• Insulin injection technique – All people using insulin should be instructed in proper
insulin injection technique. (See 'Injection technique' above.)

• Size of subcutaneous depot – Insulin absorption is variable between people and in the
same person, especially for longer-acting preparations. Variability is greater with larger
injection doses. (See 'Size of subcutaneous depot' above.)

ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

Topic 1752 Version 46.0

GRAPHICS

Pharmacokinetics of commonly used insulin preparations

(A) Prandial insulin

Insulin type Approximate onset of Effective peak Approximate
action duration of action*

Lispro, lispro- 15 to 30 minutes 1 to 3 hours 4 to 6 hours

aabc, aspart,
faster aspart,
glulisine ¶

Regular 30 minutes 1.5 to 3.5 hours 8 hours

(B) Basal insulin

Insulin type Half-life Δ Effective peak Approximate
duration of action*

NPH 4.4 hours 4 to 6 hours 12 hours

Insulin glargine

U-100 12 hours No pronounced peak 20 to >24 hours

U-300 19 hours No pronounced peak 20 to >24 hours

Insulin detemir 5 to 7 hours 3 to 9 hours 6 to 24 hours ◊

Insulin degludec 25 hours No pronounced peak >24 hours

(U-100, U-200)

* Glucose-lowering action may vary considerably in different individuals or within the same
individual; the duration of action is dose dependent.

¶ Lispro-aabc and faster aspart have quicker pharmacokinetic profiles than standard lispro and
aspart.

Δ In general, it takes 4 half-lives to reach steady state. Dose adjustments should not be made until
after steady state is achieved.

◊ At higher doses (≥0.8 units/kg), mean duration of action is longer and less variable (22 to 23 hours).

Graphic 130874 Version 1.0

Pharmacokinetic profile of currently available single insulin products

NPH: neutral protamine hagedorn.

Reprinted with permission from: Neumiller JJ. Insulin Update: New and Emerging Insulins. Available at:
https://professional.diabetes.org/sites/professional.diabetes.org/files/media/1-neumiller-insulin_update_-
_ada_clinical_conference_2018.pdf (Accessed on April 27, 2020). Copyright © 2018 American Diabetes Association.

Graphic 67242 Version 7.0

Variable serum insulin concentrations with pre-
mixed insulins

24-hour serum insulin profiles after the injection of two pre-mixed

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 microU/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.

Graphic 57000 Version 4.0

Insulin 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 with the arms or legs.

Graphic 78710 Version 4.0