817011
editorial2018
DSTXXX10.1177/1932296818817011Journal of Diabetes Science and TechnologyPettis et al
Editorial
Subcutaneous Insulin Administration:
Sufficient Progress or Ongoing Need?
Ronald J. Pettis, PhD1, Douglas Muchmore, MD2,
and Lutz Heinemann, PhD3
Keywords
insulin therapy, subcutaneous injection, needles, syringes, pens, insulin infusion
Millions of people with diabetes around the globe practice
subcutaneous (SC) insulin administration (SIA) every day.1
The significant progress made in insulin needle technology
over the last 10 to 20 years has considerably improved insulin
injection. With modern short, narrow-diameter, thin-walled
cannula, sharper needle tips, and silicone lubrication, insulin
administration from syringes or pens is far less painful in
comparison to the situation when insulin was discovered.2,3
Likewise, introduction of continuous subcutaneous insulin
infusion (CSII), has enabled better glycemic control, espe-
cially when paired with recent automated insulin delivery
(AID) systems.4 However, many SIA unmet needs remain,
including delivering insulin in the most minimally invasive
and physiologically relevant manner.5,6 Characteristics of
“ideal” SIA would include
-  completely free from side effects
-  pain free
-  highly reproducible and predictable
-  low cost
Research About SIA and Call for
Increased Action
Considering an almost 100-year history of insulin usage, the
ubiquity of the SC route for insulin administration, increas-
ing diabetes prevalence, and intense focus on tighter control
using advanced algorithms and decision support systems,
one might think that all aspects of SIA are a hot topic with
extensive ongoing research. Interestingly the opposite
appears to be the case, with few new contributions to SIA
appearing at scientific meetings or in the literature. This is
demonstrated by a brief survey analysis of SIA publications
and patents over time (Figure 1). It appears that publications
on this topic have begun to level off and even decrease in
recent years, despite a considerable increase in the number of
patents issued per year in the area. From our point of view,
this reflects that background technical knowledge around
insulin delivery and absorption from the SC depot into the
blood stream has remained static, despite the increased num-
ber of patents on the topic.
Journal of Diabetes Science and Technology
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Another interpretation of this literature analysis is that is
already sufficient understanding of SIA, with little to be gained
from further investigation of this topic. However, despite the
availability of rapid-acting insulin analogs (RIA) for a number
of years, many—if not the majority of—patients with diabetes
still fail to achieve optimal postprandial glucose (PPG) control.7
This elusive goal highlights the issues around SIA consistency
and predictability. Increased knowledge about SIA might also
assist development of novel ultrafast insulins (UFI) and predic-
tive control algorithms.8 Improved understanding of factors
influencing insulin absorption could achieve more physiologic
and predictable time-action profiles, leading to better PPG con-
trol. We believe there is a significant need to expand the body of
SIA knowledge and improve our intrinsic understanding of the
SIA process including the mechanics and systems for delivery,
tissue perfusion and uptake, and local and systemic factors that
impact PK and PD (pharmacokinetics and pharmacodynamics)
of insulin.
Factors Influencing SIA
SIA is known to have both substantial intra- and intersubject
variability in both insulin uptake and metabolic control.9 It is
generally accepted that the rate of insulin absorption, from
injection or infusion, depends on multiple factors, which can
be biological, mechanical, formulation-based, or intercon-
nected in nature. Intrinsic biological factors known to impact
absorption such as tissue type (intradermal, SC, or intramus-
cular), dispersion of insulin depots, and degree of local blood
flow can also in turn be affected by mechanical or formula-
tion influences. For example, increased local blood flow
affects SIA by increasing the diffusion gradient between the
insulin depot and the insulin concentration in the blood
1
Becton Dickinson, Research Triangle Park, NC, USA
2
La Jolla Endo, LLC, La Jolla, CA, USA
3
Science Consulting in Diabetes GmbH, Neuss, Germany
Corresponding Author:
Lutz Heinemann, PhD, Science-Consulting in Diabetes GmbH,
Geulenstr 50, 41462 Neuss, 0160 8877401, Germany.
Email: lutz.heinemann@profil.com
2 Journal of Diabetes Science and Technology 00(0)

Subcutaneous Insulin Administraon

Patents and Publicaons
700
Patents
600

500

400
Publicaons
300

200

100

0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Figure 1.  Publications and patents found in literature and US patent database search about SIA.
PubMed search query: (“injections, subcutaneous” [MeSH Terms]) AND “insulin” [MeSH Terms] OR (subcutaneous*[Title/Abstract] AND insulin[Title/
Abstract]) AND (injection[Title/Abstract] OR administration[Title/Abstract]).
Patent search query: CTB=(subcutaneous* AND insulin) AND CTB=(administration OR injection) AND DP>=(18360101).

traveling through the capillaries, that is, more insulin will
diffuse across the capillary walls into the blood stream.
Increased local blood flow can be achieved by warming the
skin, rubbing the injection site, or by injecting formulation
additives that increase insulin distribution.10 Similarly, for-
mulation excipients may impart a range of effects including
keeping insulin molecules as monomers, increasing local
blood flow, or increasing insulin distribution in tissue. It is of
interest to note that most attempts to develop UFI using these
excipient options in the last 10 years have been unsuccessful,
with only one marketed product, Fiasp, using excipients to
increase local blood flow, although other UFI formulation
strategies are undergoing clinical trials. Undoubtedly, an
increased understanding of these interacting factors to
improve consistency of effect could have significant impact
on diabetes therapy.
Needle-Based SIA
Insulin administration into the SC tissue is still predominantly
accomplished with pen needles; studies have shown decreases
in pain with new shorter, narrower, and sharper pen needle
technology.2,3 Advantages of shorter, smaller gauge needles
include less pain, due to either physical or psychological per-
ception, lowered risk of intramuscular injection, and a sim-
pler technique with no pinch-up requirement.2,11 To the
inexperienced eye it might appear simple to design a new
needle or CSII set (for insulin infusion by means of pumps);
however, these represent high technological hurdles, particu-
larly when considering manufacturing at the consistency, vol-
ume, and quality needed to serve an extensive patient
population. Similarly, an optimal SIA needle-based injection
system should ideally accommodate the vast differences in
user techniques (eg, pinch up or not, pen grip, applied device
force), ergonomics, and site selection commonly encountered
during real-world patient usage.
Form of the Insulin Depot
The shape of the insulin depot as deposited in the SC tissue
is not spherical as commonly presumed. Animal studies have
shown that insulin depot exhibits broad variance, depending
on the anatomical structures in the SC tissue, with insulin
predominantly distributing in channels between adipocytes.12
Such differences in shape and thereby surface area of the
depot—even between equivalent insulin doses applied at the
same injection site—might explain why insulin absorption is
so highly variable. Significant limitations of this study
include that insulin delivery was into deceased swine tissue
and was infused rather than injected, potentially biasing the
results considering the different rates of delivery.
It is clear that the distribution in the SC tissue has an
impact on insulin absorption. “Insulin spreading” results in
faster absorption, demonstrated by a recent study in humans
showing that nine injections of two units acted faster than a
single injection of 18 units.13 In another study, use of hyal-
uronidase as an additive to enhance bulk fluid flow (ie,
“spreading”) in the SC space, both faster insulin absorption
and reduced variability in insulin absorption and action
were demonstrated.14 The more rapid absorption and
reduced variability seen in these studies were likely a prod-
uct of larger surface area: volume ratio. While the insulin
depot is an important factor in insulin distribution and
absorption, the articles referenced here, although notable,
have only been cited <20 times since their publication in
the years 2011 and 2013.
In a recent unpublished clinical study by one author (RJP),
clinical MRI has been used to examine depot formation of
saline injected via pen needle in the abdominal SC tissue of
normal subjects.15 Results demonstrate the irregular disper-
sion of injection depots in living human tissue, and depot
sizes proportional to the injected volume (Figure 2).
Hopefully, advanced imaging methodology such as this can
Pettis et al 3
Figure 2.  Reconstructed SC depots of 60 (green), 30 (blue),
and 10U (pink) volume equivalent of saline superimposed
over underlying abdominal muscle tissue (magenta) from high
resolution MRI. Tissue depots exhibit irregular deposition
patterns, and volumes correlated to injectate volume. Source:
Pettis and Rini, unpublished data.
be used to better correlate clinical PK/PD outcomes to the
varied effects of insulin deposition in future prospective clin-
ical studies.
SIA Into Lipohypertrophic Tissue
One unwanted side effect of SIA is tissue reactions against
repeated injections or infusions of insulin into the same skin
area. The root causes for the development of lipohypertro-
phy (LHT) or lipoatrophy are not fully understood; possible
mechanisms include immune reaction to insulin or its for-
mulation excipients for lipoatrophy,16 and to repetitive
injection trauma and / or the anabolic effects of insulin itself
in the case of LHT. One main reason for these unwanted side
effects of insulin therapy is incorrect injection technique,
such as chronic use of the same injection site (incorrectly
rotating injection sites), and reuse of needles, especially
more than 4 or 5 times.17-20 Additional nonmodifiable risk
factors include duration of insulin usage and more frequent
daily injections. The type of insulin, volume or dose of insu-
lin injection, type of needle, BMI, and age are not consid-
ered risk factors for LHT. Nearly all studies show that
patients with LHT take higher TDD (total daily dose) of
insulin, usually associated with worse glycemic control
(higher HbA1c). However, this is a result of injecting into
LHT, and not a causal factor.19-21
This known complication of insulin therapy shows up in a
surprisingly high number of patients, with the reported preva-
lence varying from 16 to 60%.21 More recent studies generally
put the prevalence at least 50%. One reason for this broad range
of reported frequencies is that LHT diagnostic procedures are
not well standardized and the outcome depends on the skill of
the clinical examiner. There is a need for a quick and reproduc-
ible method for diagnosis of LHT. Visualization of LHT via
thermography was evaluated in one small pilot study, but
showed limited sensitivity and specificity, suggesting it is not
likely to become widely used in this regard.22 Ultrasound has
been proposed to diagnose LHT, but there is no agreed-upon
standard for the appearance of LHT lesions vs normal SC adi-
pose tissue, to date.
The clinical relevance of SIA into LHT has been con-
firmed with a recent rigorously conducted euglycemic clamp
study demonstrating ~20-40% reduced insulin absorption
after SIA into SC areas with LHT, as well as a 3-5× worsen-
ing of within-subject variability (CV%) of insulin uptake,
compared to injecting into normal adipose tissue.23
Additionally, a standardized meal study also showed that
LHT again reduced insulin uptake, and not surprisingly, led
to clinically meaningful deterioration of PPG control.24
Despite these clear findings, there is limited research to
reduce the prevalence of this common SIA side effect beyond
the current training recommendations for promoting effec-
tive delivery site rotation and avoiding needle reuse.25,26
Recent interventional trials have evaluated the efficacy of
proper injection technique training to improve glycemic con-
trol and reduce glycemic variability, in both subjects with
and without preexisting LHT.24,27,28 While these studies have
been generally positive, one was uncontrolled and of short
duration, and one was a pilot trial; the third showed positive
effects but there was considerable contamination or “wash-
in” of the control group of patients. Definitive proof of the
cause-and-effect relationship between poor injection prac-
tice, LHT, and glycemic control is still lacking.
Local Blood Flow in the SC Tissue
Local blood flow is affected by numerous physiological and
patient-specific factors, including age, BMI and skin area,
leading to region-specific differences in insulin uptake. In
addition, environmental factors like temperature or other
drugs might also impact local blood flow. A number of meth-
ods and devices are commercially available that allow mea-
surement of blood flow in the skin; however, these do not
allow measurement of blood flow in the SC tissue. The cor-
relation between blood flow in both compartments is not
well understood, this is also due to concerns about the valid-
ity of methods proposed for measurement of blood flow in
the SC tissue. In view of the importance of this factor on
insulin absorption, it is of surprise that no validated tech-
nique is available.
Two potential techniques might be useful: laser Doppler
ultrasound and optical coherence tomography. The latter is
depth limited to the skin itself and shallow SC tissue. Doppler
ultrasound likely requires a contrast media. Laser Doppler
measurements of local skin blood flow have been shown to
increase along with temperature.29 This increased blood flow
results in faster absorption of insulin, as has been shown in
studies with a medical product that warms up the skin in the
area of the SC insulin depot.30 It has to be evaluated if mag-
netic resonance could provide a better insight into blood flow
in the SC tissue; however, this technique requires specific
expertise and expensive hardware.
4 Journal of Diabetes Science and Technology 00(0)
Absorption of Insulin via the Lymphatic
System and Effects of Tissue
Microenvironment
Until recently, insulin was believed to be almost exclusively
absorbed via the blood stream, that is, to be more precise,
that insulin dimers and monomers dissociate from hexamer
form, and the monomers diffuse from the insulin depot
through the SC interstitial matrix to be absorbed through the
capillary vascular endothelium into the blood stream. This
belief is based on a number of historical studies with radio-
labeled insulin that were performed some 30 to 40 years ago
(many in Denmark).31-33 However, recent studies performed
with swine and humans in which dyes34 or insulin35-37 were
applied intradermally (ID) have shown much more rapid
transfer of insulin via the lymphatic system than was previ-
ously reported. Additionally, multicompartment input mod-
els have been shown to have better fit to actual clinical PK
data, implying parallel uptake pathways.38,39 This implies
that insulin absorption via the lymph may be an underappre-
ciated aspect of insulin uptake. In addition, vascular and
lymphatic capillary densities within the tissue, molecular dif-
fusion rates through the extracellular matrix, dissociation
rates of various insulins and their specific formulation depen-
dence, and local cellular utilization or degradation may also
all contribute to the total uptake during SIA.40 Clearly, a
more comprehensive approach and increased research focus
on local tissue microenvironment would lead to better under-
standing and control of the SIA process.
Summary and Outlook
The aim of this editorial is to generate more interest in SIA
and serve as a call to action. Improvement of our knowledge
and more interest about the details of SIA and insulin trans-
port from the SC into the blood stream will help further
improve insulin therapy in patients with diabetes. A system-
atic and comprehensive evaluation of factors influencing
SIA and basic research to achieve a better understanding of
the details of SIA is needed, ideally from a company inde-
pendent perspective. Various approaches may be used to
speed up SIA to have even better UFI in the future.
Clearly, research has a lot to do with funding, that is, if
academic sites / research facilities would like to be more
active in this area, respective funding organizations (like
NIH) should value such patient oriented research more highly.
Industrial players in diabetes tend to invest into research in
proportion to the market size for a given business segment
and return on their research investment, therefore funding for
core mechanistic understanding of SIA might be below that of
developing new products. While understandable from a busi-
ness perspective, this limitation may be shortsighted from the
broader viewpoint of the comprehensive diabetes community.
Ways to facilitate such vital research needs via a consortia-
based approach are warranted.
In view of the digital revolution that our world is undergo-
ing, the impact of “smart” products for insulin applications (eg,
for insulin pens, dosing algorithms, carbohydrate calculators)
is also just beginning to be felt. To have precise and accurate
information about the timing and dose of insulin delivery, along
with better assessment of carbohydrate intake, will also be a big
step forward toward AID systems without insulin pumps.
Abbreviations
AID, automated insulin delivery; ARIA, alternative routes of insu-
lin administration; CSII, continuous subcutaneous insulin infusion;
ID, intradermal; LHT, lipohypertrophy; MDI, multiple daily injec-
tions; PD, pharmacodynamics; PK, pharmacokinetics; PPG, post-
prandial glucose; SC, subcutaneous; SIA, subcutaneous insulin
administration; TDD, total daily dose; T1D, type 1 diabetes; T2D,
type 2 diabetes; UFI, ultrafast insulins; RAI, rapid-acting insulins?
Acknowledgments
We’d like to thank Susan Craft of the NC Biotechnology Center for
her extensive information resourcing and editorial assistance on this
communication, and our numerous technical and clinical colleagues
for their helpful comments and discussion.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: RJP: BD employee and shareholder; JDRF Triangle/Eastern
NC Region Board of Directors. DM: Capillary Biomedical consul-
tant; Halozyme Therapeutics shareholder. LH is a consultant for a
number of companies that are developing novel diagnostic and
therapeutic options for diabetes treatment. He is a shareholder of
Profil Institut für Stoffwechselforschung GmbH, Neuss, Germany
and ProSciento, San Diego, CA.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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