Diabetes Research and Clinical Practice 78 (2007) 149–158

www.elsevier.com/locate/diabres

Review
Insulin’s 85th anniversary—An enduring medical miracle§
Simon Heller a,*, Plamen Kozlovski b, Peter Kurtzhals c
a
Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield, Royal Hallamshire Hospital,
Glossop Road, Sheffield, South Yorkshire S10 2JF, UK
b
Global Development, Novo Nordisk A/S, Copenhagen, Denmark
c
Diabetes Research, Novo Nordisk A/S, Copenhagen, Denmark
Received 24 November 2006; accepted 2 April 2007
Available online 4 May 2007

Abstract
In 1922, the discovery of insulin led to a revolution in diabetes management. Since then, many improvements have been made to
insulin preparations: early preparations of bovine and porcine insulins were purified and their duration of action prolonged, giving
rise to the introduction of Neutral Protamine Hagedorn (NPH) insulin and monocomponent insulins. Then, with the advances in
genetic engineering in the 1980s, it became possible to produce recombinant human insulin. Nowadays, modern molecular biology
techniques enable the production of insulin analogues, which have several advantages over human insulin preparations including a
reduced risk of hypoglycaemia. Insulin delivery is still predominantly via subcutaneous injections, but alternative routes of insulin
administration are being investigated. Pulmonary delivery has emerged as the most feasible option thus far but oral delivery is an
ultimate goal, although basic problems of insulin stability in the gut and absorption from the gastrointestinal tract still need to be
resolved. The availability of a true artificial pancreas by means of a closed-loop system, linking continuous glucose monitoring with
insulin-pump technology, would also constitute a significant advance, but major technological problems still need to be overcome.
# 2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Analogues; Delivery; Device; Insulin

Contents

1. The discovery of insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

2. Advances in the development of insulin preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
2.1. Prolongation of insulin action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
2.2. Purified and human insulins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2.3. Insulin analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2.3.1. Insulin analogue characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
2.3.2. Advantages of insulin analogues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
3. Insulin delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
3.1. Subcutaneous delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
3.1.1. Syringes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
3.1.2. Insulin pen devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

§
Preparation of this manuscript was supported by an unrestricted grant from Novo Nordisk A/S.
* Corresponding author. Tel.: +44 114 271 3479; fax: +44 114 271 1901.
E-mail address: s.heller@sheffield.ac.uk (S. Heller).

0168-8227/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.diabres.2007.04.001
150 S. Heller et al. / Diabetes Research and Clinical Practice 78 (2007) 149–158

3.1.3. Insulin-pump therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

3.1.4. Continuous glucose monitoring: the pathway to an artificial pancreas? . . . . . . . . . . . . . . . . . . . . 154
4. Non-invasive delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
4.1. Oral insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
4.2. Intranasal insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
4.3. Pulmonary insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Potential conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

1. The discovery of insulin On 3 May 1922, MacLeod presented a summary of

On 23 January 1922, the first injection of a pancreatic
extract into a human patient was carried out at Toronto
General Hospital, Canada. The 14-year-old patient,
Leonard Thompson, had been diagnosed with diabetes
two and a half years previously. He was emaciated,
pale and exhausted by the disease and a diet of just
450 calories per day. However, after treatment with the
purified pancreatic extract, Thompson achieved, after
only a few days, significant improvements in his general
health and well-being. Blood and urine glucose levels
were reduced, and ketone bodies disappeared from his
urine. This was the first clearly successful clinical test of
the pancreatic secretion in a human with diabetes, and
subsequently, similar results were obtained in a further
six patients. The results of this research were published
in the Canadian Medical Association Journal in March
1922, where it was recorded that ‘‘These results. . .leave
no doubt that in these extracts we have a therapeutic
measure of unquestionable value in the treatment of
certain phases of the disease in man’’ [1].
The men who saved Thompson’s life and set the
scene for saving hundreds of thousands of lives in the
decades to come were Frederick Banting and his
assistant Charles Best. In the summer of 1921, they had
begun work in the laboratory of Professor John
MacLeod, a leading authority on carbohydrate meta-
bolism, to isolate the pancreatic extract responsible for
glucose regulation [2,3]. They extracted a secretion
(then named ‘isletin’) from dog pancreases, which was
subsequently administered to other dogs with diabetes
due to removal of the pancreas [2,4]. Early results
suggested that intravenous administration of the extract
lowered blood and urinary sugar, but only for a short
duration, and most of the animals did not survive long
after the surgery due to toxic impurities in the extracts,
or infection [2,4]. In December 1921, James Collip, an
experienced Canadian biochemist, joined the team to
work on further purification of the pancreatic extract so
that it could be injected into humans [2].
the Toronto team’s work at the Association of American
Meetings in Washington. The ‘active agent’ had by now
been named ‘insulin’. Eighteen months later, Banting
and MacLeod were awarded the 1923 Nobel Prize in
Physiology or Medicine in recognition of their work,
which they shared with Best and Collip. A second Nobel
Prize related to insulin was awarded in 1958, this time to
Frederick Sanger for his work on the structure of
proteins, especially that of insulin [5–7]. Sanger’s work
on the primary structure of insulin was the basis for all
subsequent work on the protein, and in 1977, Rosalyn
Yalow received the Nobel Prize in Medicine for the
development of the radioimmunoassay for insulin [8].
In 1922, the Toronto team then moved towards
manufacturing insulin on a large scale [2]. The group
agreed to collaborate with Eli Lilly & Co, who
developed a method of precipitating a much purer
form of insulin, allowing production in greater
quantities than previously [2,3]. In 1923, insulin
production began in Copenhagen, Denmark, at the
non-profit Nordisk Insulin Laboratory [2,9], and by the
end of 1923, insulin was available for the majority of
patients with diabetes throughout the Western world [3].
2. Advances in the development of insulin
preparations
2.1. Prolongation of insulin action
In the early days of insulin therapy, many patients
found it inconvenient to receive several injections a day.
Therefore, researchers began to look for a way to
prolong the action of insulin. In the early 1930s,
investigators at Nordisk Insulin Laboratories began
working on ways to retard the absorption of insulin
following subcutaneous injection. They found that the
addition of protamine to insulin substantially reduced
its solubility at the normal pH of body fluids, thus
slowing its absorption and prolonging its action [10]. At
around the same time, Scott and Fisher of the University
 S. Heller et al. / Diabetes Research and Clinical Practice 78 (2007) 149–158
of Toronto’s Connaught Laboratories reported that the
addition of zinc to insulin also prolonged its effect [11].
At that time, the amorphous protamine insulin was
available in a two-ampoule system containing the acidic
protamine insulin and a buffer, which was inconvenient
for patients and did not allow mixing with fast-acting
insulin. Subsequently, in 1946, the first crystalline
(protamine/isophane) insulin was produced, known as
Neutral Protamine Hagedorn (NPH). With NPH, it
became possible to produce stable mixtures with fast-
acting insulin [12]. Insulin was also available as the
long-lasting protamine-zinc insulin (PZI) [3].
In the mid-1950s, the Lente insulin formulations,
with different ratios of amorphous and crystalline zinc
insulin, were introduced. By then, patients had a wide
choice of fast- and long-acting insulin preparations to
choose from. However, most patients developed
antibodies to the foreign bovine or porcine insulins,
and so the development of purified monocomponent
(MC) insulin, and subsequently of human insulin, was a
significant advance.
2.2. Purified and human insulins
In 1973, purified MC insulin from animal pancreas
was introduced, which, as far as possible, eliminated
proinsulin and other immunogenic peptides from the
preparation [13,14]. This insulin reduced the incidence
of local injection reactions and insulin antibody
formation. Following the elucidation of its amino acid
structure, MC human insulin was first synthesized from
porcine insulin by transpeptidation in the 1970s [15,16].
The advent of genetic engineering has allowed the
biosynthesis of recombinant human insulin. Pioneered
by Lilly and Genentech, this technique involves
inserting chemically synthesized genes into the bacteria
Fig. 1. Hypoglycaemia: the price of improved diabetes control [20].
151
E. coli, fermenting the bacteria, and then harvesting the
expressed polypeptides prior to cleavage [15–17]. An
alternative method is to insert the genes into the yeast S.
cerevisiae, which secretes the resulting polypeptide into
the culture medium, thus simplifying the purification
process [16]. The introduction of genetic engineering of
human insulin not only safeguarded future insulin
supply, but also made it possible to restructure the
insulin molecule to overcome some of the therapeutic
limitations of the conventional molecule.
2.3. Insulin analogues
2.3.1. Insulin analogue characteristics
Administration of soluble insulin with a bolus
subcutaneous injection results in a plasma insulin
profile that is very different from the normal prandial
response seen in individuals without diabetes; an initial
delay or lag phase is followed by an increase in plasma
insulin concentration that peaks after 1–2 h and returns
to basal concentrations within 6–8 h [18]. Similarly,
long-acting insulin preparations such as Lente and NPH
do not accurately mimic the physiological basal insulin
secretion in the individual without diabetes [19].
Hypoglycaemic episodes are, therefore, often a problem
with these insulin preparations. Human insulins, as
shown in the Diabetes Control and Complications Trial
(DCCT; 1983–1993), could effectively control glycae-
mia to near-normal values, but this was at the expense of
a significantly increased hypoglycaemia risk [20]
(Fig. 1).
Research to improve the characteristics of the
available insulin preparations has been ongoing since
the 1980s. In 1988, Danish scientists first published the
concept of insulin analogues. They developed insulin
analogues with amino acid substitutions on the insulin B
152 S. Heller et al. / Diabetes Research and Clinical Practice 78 (2007) 149–158
Table 1
Recombinant DNA insulin analogue preparations commercially available in Europe
Name Brand name
Insulin aspart NovoRapid
Insulin glulisine Apidra
Insulin lispro Humalog
Insulin detemir Levemir
Insulin glargine Lantus
Aspart/protaminated aspart NovoMix
Lispro/protaminated lispro Humalog Mix
chain that produced charge repulsions at the sites where
monomers would come together and form dimers, but
without altering the receptor binding properties [21].
Several insulin analogues are now available to facilitate
the use of a broad range of insulin replacement regimens
(Table 1).
Rapid-acting insulin analogues differ from human
insulin by a few amino acid substitutions, leading to
changes in their ability to self-associate [21]. These
include insulin aspart, insulin lispro and insulin
glulisine, which are characterized by a more rapid
onset and shorter duration of action than soluble human
insulin, allowing administration just before or after
mealtimes and a more physiological time–action profile
[22–24]. Structurally, insulin glulisine, for example,
differs from human insulin at position B3, where the
amino acid asparagine is replaced by lysine, and at
position B29, where lysine is replaced by glutamic acid
[25] (Fig. 2).
The increased risk of hypoglycaemia – especially
nocturnal hypoglycaemia – with basal human insulins
(i.e. NPH and insulin-zinc suspensions) is mainly due to
the variability in absorption of these preparations, and
also to the insulin peak they produce after injection
[26,27]. Hence, long-acting insulin analogues were
Fig. 2. Insulin glulisine structure [25].
Manufacturer Category
Novo Nordisk Rapid-acting
sanofi-aventis Rapid-acting
Eli Lilly Rapid-acting
Novo Nordisk Long-acting
sanofi-aventis Long-acting
Novo Nordisk Pre-mixed
Eli Lilly Pre-mixed
engineered to provide a more physiological basal
insulin profile. Insulin glargine contains three amino
acid substitutions, resulting in a molecule that is less
soluble at the injection site, but soluble and stable at
acidic pH. After injection, precipitation occurs, and a
depot is formed in the subcutaneous tissue from which
insulin glargine is slowly released [22,24]. Insulin
glargine is labelled for once-daily injection, but must
sometimes be administered twice daily, for example in
patients with little or no residual insulin secretion [28].
Insulin detemir is an acylated derivative of human
insulin, which binds reversibly to albumin through its
fatty acid chain (Fig. 3). The presence of this chain
facilitates the self-association of two insulin hexamers
which, combined with albumin binding, results in slow
absorption [29]. It also provides a prolonged duration of
action of up to 24 h [22,30,31]. It is indicated for use
once or twice daily, although most patients with type 2
diabetes can benefit from once-daily dosing [32].
2.3.2. Advantages of insulin analogues
The physiological pharmacokinetic and pharmaco-
dynamic profiles of the rapid-acting insulin analogues
translate into greater reductions in postprandial plasma
glucose than those seen with soluble insulin, occurring
twice as rapidly and for a shorter duration [33–35]. This
allows for immediate pre-meal dosing and therefore
Fig. 3. Insulin detemir structure.
 S. Heller et al. / Diabetes Research and Clinical Practice 78 (2007) 149–158
greater flexibility with mealtimes [36]. In addition, the
shorter duration of action of the rapid-acting analogues
reduces the risk of nocturnal hypoglycaemia [37–39].
The long-acting insulin analogues have a flatter and
more predictable time–action profile than NPH insulin
[40,41], which is associated with a reduced incidence of
hypoglycaemia – especially nocturnal – compared with
NPH [42–44]. In type 2 diabetes patients inadequately
controlled with oral anti-diabetes drugs, insulin initia-
tion with a basal insulin analogue results in more
patients achieving the target without experiencing
hypoglycaemia [26,43,45]. Interestingly, insulin dete-
mir has led to less weight gain in clinical trials
compared with regimens containing NPH [42,43] or
insulin glargine [46]. These properties represent
potentially useful advances in insulin therapy.
The use of a pre-mixed insulin preparation is a
convenient, simple, and effective way of administering
both prandial and basal insulin in one injection, for
those individuals who may not be able to manage the
administration of a basal-bolus regimen. Pre-mixed
biphasic insulin aspart (BIAsp) and biphasic insulin
lispro (Lispro Mix) contain both rapid- (aspart or lispro,
respectively) and longer-acting insulin components
(protaminated aspart or protaminated lispro, respec-
tively). Both BIAsp and Lispro Mix have been shown to
achieve superior postprandial glycaemic control to
either biphasic human insulin, or a basal insulin
analogue alone [47,48]. The addition of a pre-mixed
insulin analogue to existing oral medications can help to
attain target levels of glycaemic control in many
patients with type 2 diabetes [49–51].
3. Insulin delivery
3.1. Subcutaneous delivery
3.1.1. Syringes
Since insulin’s discovery in 1922, not only have
preparations for diabetes advanced significantly, but
also the technology for insulin delivery. Originally,
insulin was administered intramuscularly, but it soon
become apparent that subcutaneous injections were
equally effective, but less painful [52]. The syringe was
the sole method of insulin delivery for decades.
Originally, glass syringes were used, but today they
are plastic, disposable devices [53].
3.1.2. Insulin pen devices
Despite improvements in insulin syringes over the
decades, the syringe injection process remains incon-
venient, time-consuming and painful. The practice is
153
also associated with a high risk of dosage errors [54]. In
1985, insulin pens were introduced, which overcame
some of these barriers; they allowed more flexibility,
convenience and accurate dosing control. Such devices
combine the insulin container and syringe in a single
unit, and have smaller-gauge needles that are more
comfortable to use [53,55]. Such features may increase
patient collaboration [53]. Today, insulin pens have
many technological innovations, such as audible clicks
when the full dose has been delivered, digital displays,
and memory functions showing the time and amount of
the last administered dose.
Several studies have evaluated patient preference for
insulin pens; in the first of these, 80% of patients
reported that the pen’s advantages outweighed the
inconvenience of multiple injections [56]. Likewise, in
a 1993 study, 98% of respondents found the pen
convenient and easy to use [57]. A more recent Italian
survey found that 92–98% of adults found the device
easy to use, depending on pen type. In addition, 100%
compliance with the dosing schedule was 85% in insulin
pen users compared with 72% in syringe users, while
73% of pen users achieved more accurate dosing than
with insulin syringes [58].
3.1.3. Insulin-pump therapy
The DCCT established that the goals of intensive
insulin therapy are to achieve near-normal blood
glucose control and avoid short-term crises such as
hypoglycaemia [20]. In this way, the long-term
complications of diabetes are minimized, and patients’
quality of life is improved. The goals of intensive
therapy can be attained through the administration of
multiple daily injections (MDI) of insulin or through
insulin-pump therapy, also known as continuous
subcutaneous insulin infusion (CSII). CSII technology
delivers fast- or rapid-acting insulin into the subcuta-
neous tissue using a portable electromechanical pump.
The pump delivers insulin at pre-selected rates,
effectively mimicking non-diabetes insulin delivery
over 24 h, with patient-activated boluses at mealtimes
[59,60].
CSII is used in selected patients with type 1 diabetes
(Table 2), and was first introduced in the late 1970s. Its
efficacy in achieving strict glucose control in a subset of
patients with diabetes was evident even then [59,61],
and worldwide use of the insulin-pump has been
increasing ever since. Over the years, pumps have
become smaller, more durable, safer and easier to use.
The innovations in external-pump technology have
made CSII a safe and feasible alternative to MDI,
although part of its success may relate to the intensive
154 S. Heller et al. / Diabetes Research and Clinical Practice 78 (2007) 149–158
Table 2
Indications for insulin-pump therapy [65]
Insufficient glycaemic control (HbA1c above target; morning glucose
>140–160 mg/dL/7.8–9.0 mmol/L; distinct daily irregularity in
glucose levels)
History of impaired awareness of hypoglycaemia
History of severe hypoglycaemia
Low insulin requirements (<20 U/day)
Pregnancy; planned or confirmed
Unpredictable lifestyle (e.g. shift worker; business traveller)
skills training in insulin replacement and carbohydrate
counting that those starting CSII must undertake.
Advantages of CSII compared with MDI have been
demonstrated, including decreased risk of hypoglycae-
mia [62,63], improved control of morning glucose
levels (the ‘dawn phenomenon’) [64] and a lower risk of
activity-induced hypoglycaemia [65].
3.1.4. Continuous glucose monitoring: the pathway
to an artificial pancreas?
Until recently, self monitoring of blood glucose
(SMBG) was the only blood glucose level monitoring
tool available. However, this method has its limitations
because the readings are discrete, not continuous.
Technological progress in the past couple of decades
has led to the commercial availability of continuous
glucose monitoring systems (CGMS). These are
portable devices that provide numerous recordings
over a period of typically 72 h [66]. Blood glucose
readings may be viewed in real time or retrospectively.
Many CGMS feature an alarm that sounds if blood
glucose levels fall outside of a preset ‘normal’ range
[66]. In clinical practice, CGMS are especially useful
when adjusting therapy, assessing the impact of lifestyle
modifications on glycaemic control, in exceptional
situations such as intensive care patients, and during the
nocturnal period [66]. The system can help identify and
prevent periods of hypo- and hyperglycaemia, thereby
facilitating the decision-making process for optimal
treatment of the patient with diabetes. To date, there is
insufficient evidence from randomized controlled trials
to suggest that CGMS have a significant effect on
metabolic control in type 1 diabetes patients compared
with alternative monitoring methods [67–70].
The advances in CGMS have fuelled the develop-
ment of closed-loop system prototypes, which would
constitute a true artificial pancreas. Closed-loop
systems consist of a CGMS, a control algorithm, and
an insulin-pump, thereby linking glucose monitoring
with automated insulin infusion, so that no input from
the user is required. There are two main approaches: the
extracorporeal method, which employs subcutaneous
glucose monitoring and subcutaneous insulin delivery,
and the implantable approach, where glucose sampling
is intravenous and insulin delivery is intraperitoneal
[71]. Small-scale studies have revealed that the system
is limited mainly by the suboptimal accuracy and
reliability of the glucose monitor. More reliable pumps
and insulin delivery algorithms are also required before
closed-loop systems can become commercially viable
[72].
4. Non-invasive delivery
Currently, parenteral administration of insulin is the
predominant route of delivery available in clinical
practice. However, subcutaneous injection has many
limitations, including local degradation of insulin in the
subcutaneous depot, slow absorption from the sub-
cutaneous tissue, and high variability in absorption
rates. Since the discovery of insulin, researchers have
investigated various alternative routes of insulin
administration, such as oral, intranasal, pulmonary,
rectal, uterine, intrascrotal, intraperitoneal and intra-
tracheal [52,73]. To date, only pulmonary administra-
tion has proved clinically realistic. Research is
continuing into novel routes of delivery that could
improve the convenience of insulin therapy for many
patients.
4.1. Oral insulin
A major advantage of oral administration is that
insulin absorbed through the gut can be delivered
directly to the liver, where it is needed. However, insulin
undergoes extensive degradation by proteases in the
digestive tract [74] and faces a complete lack of
selective transport mechanisms across the intestinal
wall. This is because the gut epithelium is not designed
to transport macromolecules or hydrophilic molecules
such as insulin [75]. It is estimated that just 0.5% of
ingested insulin may reach the systemic circulation
[76], hence, very large doses would be required to
achieve a useful level of absorption [77]. In addition, the
transit time of insulin through the gut is unpredictable.
These problems make oral administration very difficult
[78]. As an alternative, a buccal insulin delivery
preparation that is sprayed into the mouth via a metered
dose inhaler is being developed, whereby a number of
enhancers have been added to the formulation to
facilitate absorption. The insulin is rapidly absorbed
into the mucosal lining, and a metabolic effect is
observed when applied preprandially [79,80]. More
clinical efficacy and safety data are required on oral
 S. Heller et al. / Diabetes Research and Clinical Practice 78 (2007) 149–158
buccal delivery before conclusions can be drawn on its
feasibility.
An alternative approach would be to engineer small
molecule insulin mimetics. This has, however, also
proven a significant challenge, because the binding of
insulin to its receptor is not confined to a few ‘hot spot’
interactions, but appears to implicate a number of
residues in the hormone. Recently, peptide agonists to the
insulin receptor were identified by phage display
technology which, both in vitro and in vivo, had a
biological potency close to that of insulin itself [81].
These findings demonstrate that, although too large for
oral delivery, functional insulin mimetics can be designed
and optimized. Very recent breakthroughs in determining
the insulin receptor ectodomain crystal structure could
provide a tool for rational design of insulin mimetics [82].
4.2. Intranasal insulin
Assessments of the efficacy of intranasally adminis-
tered insulin have shown that insulin is quickly
absorbed through the nasal mucosa and reaches the
systemic circulation. The pharmacokinetic profile
displays a rapid increase and decrease in serum insulin
concentration, which is similar to the physiological
state [83–85]. Pharmacodynamic data in healthy
patients show that the onset of action occurs within
10 min, and the peak of the glucose-lowering effect is
attained after 20–45 min. The duration of action
continues for up to 2 h [83,85–87]. In spite of this,
the results from trials of intranasally administered
insulin in patients with diabetes have been disappoint-
ing. In type 1 patients, no overall improvement in
metabolic control was achieved [87,88], while accep-
table postprandial glucose control in type 2 patients
could not be achieved without the administration of
multiple high doses [89].
Unfortunately, the bioavailability of intranasal
insulin is generally low; <10% [83,86,88]. Permeability
enhancers are often added to increase the bioavail-
ability, although many cause nasal irritation [87,90,91].
There is also an unpredictable variability in bioavail-
ability with the formulation [85,86], probably due to
differing rates and types of mucus production in the
nasal mucosa [18]. For these reasons, intranasal insulin
is considered unlikely to surpass subcutaneous delivery
in terms of clinically viable routes of administration.
4.3. Pulmonary insulin
Due to their large surface area, the lungs are an
obvious target for drug delivery and inhaled, or
155
pulmonary insulin, appears to be one of the most
promising alternatives to injection. This method
delivers insulin directly to the millions of alveoli in
the lungs, where it is readily absorbed into the blood
supply and has a rapid onset of action [92]. The first
reports of the feasibility of pulmonary delivery were
more than 80 years ago [93], and almost 50 years later,
the first proof-of-concept study on the topic was
published [94]. Subsequent studies have shown that the
bioavailability of pulmonary insulin ranges from 7 to
46%, depending on the study and the methods used
[83,86,88,89,95,96]. The predictability of the blood
glucose response with pulmonary delivery is equivalent
or equal to that of subcutaneous injections [97].
There are now several pulmonary insulin delivery
systems approaching the market. Systems by Lilly/
Alkermes, MannKind Corporation and Novo Nordisk
are currently in phase III development, and the
Exubera1 system (Nektar Therapeutics, San Carlos,
CA and Pfizer, Groton, CT) is now approved in the USA
and Europe. In clinical studies, the efficacy of these
systems has proven comparable with soluble human
insulin in the treatment of patients with type 1 and type
2 diabetes [98–101], and adverse events are similar in
nature and frequency, except for cough (although its
incidence decreases with continued use) [100]. Pul-
monary insulin has been associated with increased
serum insulin antibody levels and a small but significant
decrease in both forced expiratory volume at 1 s (FEV1)
and carbon monoxide diffusing capacity compared with
subcutaneous insulin [102]. Long-term studies are
ongoing to determine the clinical relevance of these
findings and these results will be critical if pulmonary
insulin is to achieve widespread use.
5. Conclusion
Since the discovery of insulin, a number of advances
have been made to allow patients to mimic the normal
pattern of insulin release more accurately and con-
veniently. However, insulin therapy needs to improve
still further to allow near normalization of blood
glucose with a low risk of hypoglycaemia and weight
gain. An active ongoing research programme should
yield a new generation of insulin preparations to
optimize treatment of diabetes still further.
Potential conflicts of interest
Simon Heller has received investigator fees and given
lectures at symposia for which he received payment from
Eli Lilly, Novo Nordisk and Sanofi-Aventis. Plamen
156 S. Heller et al. / Diabetes Research and Clinical Practice 78 (2007) 149–158
Kozlovski is employed by Novo Nordisk A/S as
International Medical Officer, Global Development.
Peter Kurtzhals is employed by Novo Nordisk A/S as
Senior Vice President, Diabetes Research.
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