Open access peer-reviewed chapter

Optimal Insulin Delivery

Written By

Anders Frid, Laurence Hirsch and Kenneth Strauss

Submitted: January 13th, 2018 Reviewed: March 6th, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.76232

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Insulin therapy is only effective if it is delivered into the right tissue in the right way. Exogenous insulin is intended for the subcutaneous (SC) tissue, not the muscle or skin. If delivered into the latter, its absorption (pharmacokinetics (PK)) and action (pharmacodynamics (PD)) are unpredictable, which often leads to poor glucose control. Correct insulin therapy begins with matching the insulin to the site used. Typically, four sites are used for insulin injection or infusion: the abdomen lateral to the umbilicus all the way to the flanks, the anterior lateral upper half of the thigh, the deltoid region of the arm, and the upper outer quadrant of the buttocks. Regular insulin and neutral protamine Hagedorn (NPH) are both absorbed more rapidly from the arm and abdominal sites and more slowly from the thigh and buttocks. The newer insulin analogs, both rapid- and slow-acting, do not appear to be influenced by the site used for injection. In order to avoid intramuscular (IM) injections, patients should use the shortest needles currently available (the 4-mm pen needle and the 6-mm syringe needle). Very young children should raise a skin fold and inject into it even when using the 4-mm needle. Giving injections with the 6-mm needle at a 45° angle converts this needle into the equivalent of the 4 mm. Injection sites should be rigorously rotated, with the new injection being approximately 1 cm from previous injections. This measure helps prevent the most common complication of injection therapy, lipohypertrophy (LH). Injecting into LH leads to unstable PK and PD and deregulated glucose control, manifested as unexpected hypoglycemia, glycemic variability, and elevated HbA1c values. Comprehensive insulin deliver recommendations have recently been published.


  • insulin
  • injection needles
  • subcutaneous
  • lipodystrophy
  • lipohypertrophy

1. Introduction

Current insulin therapy requires delivery into the subcutaneous (SC) tissue either by injection or by infusion. Optimal insulin delivery requires that accidental intramuscular (IM) or intradermal (ID) delivery be avoided since the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin are significantly altered in these tissue spaces. Optimal delivery also requires that sites of injection or infusion be rotated systematically in order to avoid the most common complication of insulin therapy, lipohypertrophy (LH). Insulin delivered into LH also has significantly altered PK and PD, which can lead to unexpected hypoglycemic episodes and glycemic variability. The latter are associated with worsened overall glucose control, increased short- and long-term complications, and higher costs.

Recently, new recommendations have been published as a consensus document from international diabetes experts [1]. This publication was the collective output of 183 experts from 54 countries who wrote and vetted a practical, evidence-based roadmap for optimal insulin delivery at the FITTER (Forum for Injection Technique and Therapy: Expert Recommendations) workshop from October 23 to 24, 2015, in Rome. FITTER was the fourth in a sequence of workshops on optimal insulin delivery [2, 3, 4]. The FITTER recommendations were also based on the results of the fourth Injection Technique Questionnaire (ITQ) survey conducted from 2014 to 2015. In total, 13,289 insulin-injecting patients from 42 countries participated [5].

Each recommendation is followed by a grade (e.g., A2). The letter indicates the strength of each recommendation: A. Strongly recommended; B. Recommended; C. Unresolved issue. The number indicates the degree of scientific support for each recommendation: 1. At least one rigorously performed study which is peer-reviewed and published; 2. At least one observational, epidemiologic, or population-based study which is peer-reviewed and published; 3. Consensus expert opinion based on patient experience. Since FITTER, many diabetes groups from countries around the world have adapted and adopted these recommendations as local guidelines. We draw on certain of these recommendations in the review that follows as well as summarize studies that have been performed since FITTER and will follow a thematic format, beginning with the anatomy of injection sites.


2. Current insulin delivery practice

A large survey of current insulin delivery has shown that there are many aspects of injection practice which are suboptimal [5, 6]. For decades, professionals had been advising patients to use insulin needles which, we now know, were too long for them, with no scientific rationale. However, after the shortest pen needles (4 mm) became available and studies on injection site anatomy and needle performance began to be published, starting in 2010 [7, 8], showing the safety and efficacy of these needles, the recommendations of experts changed. It was recognized that 4-mm pen needles were the optimal choice for nearly all injecting patients, whether adults or children: thin, normal-weight or obese, male or female, and of all ethnicities. These needles were felt to be a key step toward reducing the risk of IM injections. As a result, the use of the 8-mm needle, the dominant size in 2010, has decreased dramatically since then, with a corresponding increase in the use of the 4-mm needle.

However, the latest survey revealed that the longer lengths (8 mm and higher) are still being used by approximately 30% of patients worldwide and that the 5- and 6-mm needles are still used by approximately 20% each. This means that only 30% of patients worldwide currently use the recommended 4-mm needles. Longer needles are being used in sites where IM injection risk is very high (thighs and arms) and by patients who are at an increased risk because they have thin SC layers (slim and normal-weight adults as well as all adolescents and children).

The same survey has shown that lipohypertrophy (LH) is very common at injection sites. LH was found in almost a third of patients worldwide, many of them having LH at multiple injection sites. Injecting into LH has serious consequences for glucose control as well as possibly adverse effects on long-term outcomes and costs. Patients with LH consume a mean of over 10 IU more insulin per day than those without LH, and their HbA1c is on average 0.55% higher. LH is associated with increased rates of unexplained hypoglycemia, glucose variability, and more frequent diabetic ketoacidosis (DKA).

The survey showed that LH is most frequently associated with an incorrect rotation of injection sites and reusing pen needles. Rotating injection sites carefully appears to be the best method of avoiding LH. HbA1c values are lower in patients who rotate their injections over larger injection areas and who get their sites inspected regularly. Checking of injection sites routinely by health-care givers is associated with less LH and lower HbA1c levels, yet nearly 40% of patients reported that they could not remember their injection sites ever being examined. Patients are also more likely to rotate correctly if they have obtained injection instruction from their carer in the last 6 months. However, less than two out of five claim to have obtained such instructions on injecting in that time period. Ten percent of total injectors claim that they have never obtained injection training at all. The survey also shows that incorrect disposal of sharps after use is rampant. The majority of used sharps end up in public trash and constitute a major risk factor for accidental needle sticks.


3. Skin thickness

The skin is the main obstacle the needle must overcome. Needles must be at least long enough to traverse the skin and reach the SC tissue. Adult skin, according to a number of studies using imaging techniques ranging from ultrasound (US) to computer tomography (CT), has yielded remarkably similar results across genders, ethnicities, age groups, and body mass index (BMI) categories. The skin averages approximately 2–2.5-mm thick and varies in its 95% confidence interval (CI) between 1.25 and 3.25 mm. These studies included patients with type 2 diabetes (T2DM) from the Philippines [9], Korea [10], China [11], and India [12]; both type 1 diabetes (T1DM) and T2DM adults from the USA (including four different ethnic groups) [7]; and children from South Africa [13] and Italy [14].

The skin in children is slightly thinner than in adults, but these differences are largely irrelevant for insulin infusions and injections. Skin thickness increases during adolescence and reaches adult size in the late teens.


4. SC thickness

The SC tissue is the target for insulin. Injections must reach the SC tissue, but not go deeper into the muscle fascia or the muscle itself. Therefore, the thickness of the SC is critical in determining the desired length of the needle as well as the injection technique (e.g., lifting a skin fold or not). SC tissue thickness varies widely depending on gender, site of injection, and BMI. Women, on average, have approximately 5-mm thicker SC fat than men, when one controls for BMI and body site. Truncal sites (abdomen and buttocks) have more SC fat than limbs (arm and thigh), in the same patient. The higher the BMI, the thicker the SC fat. Studies within the last decade have used precision US to determine the SC tissue thickness in a diverse group of adults [7, 9, 15, 16], adolescents, and children [13, 14].

Babies have more SC tissue than preschool children. Children from 2 to 6 years have very little SC tissue regardless of gender. Children from 7 to 13 years gain SC tissue slowly but SC tissue thickness is almost the same in both genders until puberty. At puberty, girls increase their SC tissue more rapidly than boys as a result of hormonal differences.

SC tissue thickness when combined with the currently available needle lengths yields a relatively clear indication of the risk of IM injection. Tables 1 and 2 show the risks for adult and pediatric persons with diabetes, respectively. It is clear from these data that the shorter the needle, the lower the risk of IM injection.

Needle lengthCombinedThighArmAbdomenButtock
4 mm0.4%1.6%1.0%0.3%0.1%
5 mm1.8%4.7%3.1%1.1%0.5%
6 mm5.7%10.0%7.0%2.8%1.3%
8 mm15.3%25.0%19.5%9.7%5.5%
12.7 mm45.0%63.0%55.0%38.0%26.9%

Table 1.

Estimated IM injection risk in adults, by body site*.

Assumes injection straight at 90° without pinch-up (the table adapted from Hirsch [16]).

With kind permission from Hirsch L et al. [16]. Intramuscular risk at insulin injection sites—measurement of the distance from the skin to the muscle and rationale for shorter-length needles for subcutaneous insulin therapy.

Marran, 2014 [13]Lo Presti, 2014 (pooled) [14]
4 mm27.5%12.5%12.5%0%20.2%4.6%2.4%
5 mm47.5%22.5%30.0%0%46.0%18.4%16.1%
6 mm62.5%30.0%37.5%5.0%66.5%38.0%34.5%
8 mm87.5%62.5%50.0%15.0%83.9%65.3%66.1%
12.7 mm100%90.0%85.0%35.0%97.2%93.9%96.4%

Table 2.

Calculated risk of IM injection in children and adolescents as a function of injection site, age, and needle length*.

Assumes that injections are into flat skin and not into lifted skin fold.


5. IM insulin

IM-injected insulins have a much greater variability in absorption and effect (PK and PD) compared to SC-injected. This variability is influenced by both exercise and the properties of the individual insulins. Human insulins and the new analogs also differ as to their PK when injected IM. In general, IM insulin is often associated with a more rapid absorption and unexplained hypoglycemia [17, 18, 19]. Because of the difficulty of predicting the impact of IM injections on PK and PD, various measures can be taken to avoid injecting IM: using of shorter needles, lifting of a skin fold into which one injects the insulin, or choosing injection sites with thicker layers of SC fat. A combination of the above techniques can also be used [20].


6. Needle length

In the last decade, insulin needle lengths have decreased dramatically. Previously, adults were given needles that were ≥ 8 mm long and children ≥6 mm. As shown in Tables 1 and 2, these lengths are now universally recognized as too long. They make IM injections more likely, and on the whole, the length of the needle has little or nothing to do with glucose control, according to a multitude of studies [8, 21, 22, 23, 24, 25, 26, 27, 28]. Longer needles also tend to have larger diameters (smaller G or gauge), which correlates with a greater injection pain.

Hirsch [8] compared the 4-mm pen needle to 5- and 8-mm needles and showed the former to be safe and efficacious in adults (i.e., comparable glucose control); leakage from the skin was equivalent and both pain scores and overall preference were better with the 4 mm. In Japan, Miwa [29] compared the 4-mm needle with 6 mm and showed equivalent results, as did Nagai [30] when comparing 4-to 5-mm pen needles. Hirose [31] found equivalent modeled PK/PD results for the 4 mm compared to the 6- and the 8-mm needles, in young non-diabetics. Birkebaek [32] found a reduced IM risk with 4 versus 6-mm PNs in children and lean adults. Lo Presti [14] measured the skin and SC in children and adolescents with diabetes (ages 2–17) and concluded that the safest needle length for all ages is the 4 mm.

In obese adults, Bergenstal [33] recently showed that the 4-mm pen needles deliver equivalent glycemic control (HbA1c) to both 8- and 12.7-mm pen needles. These obese patients were taking relatively high doses of glargine (>40 IU), with total daily dose (TDD) insulin up to 300 U daily. No differences between 4- and both 8- and 12.7-mm PNs in hypo- or hyperglycemic events or insulin leakage were found in obese subjects with BMI up to nearly 60 kg/m2. The 4-mm needle was found to be less painful, easier to use, easier to insert, and less anxiety-provoking than 8 or 12.7 mm (all at p < 0.05).

Based on these studies, FITTER recommended the following:

  • The 4-mm needle inserted perpendicularly is long enough to penetrate the skin and enter the subcutaneous tissue, with little risk of intramuscular (or intradermal) injection. Therefore, it should be considered the safest pen needles for adults and children regardless of age, gender, ethnicity, and BMI. A1

  • The 4-mm needle should be inserted perpendicular to the skin (at 90° to the skin surface), not at an angle, regardless of whether a skin fold is raised. A1.

  • Very young children (6 years old and under) and very thin adults should use the 4-mm needle by lifting a skin fold and inserting the needle perpendicularly into it. Others may inject using the 4-mm needle without lifting a skin fold. A1

  • Patients with tremors or other disorders, which make them unable to hold a 4-mm pen needle in place, may need longer needles. B3


7. Injection site care

Recommended injection sites include the abdomen, lateral thigh, arms, and buttocks [34, 35, 36, 37, 38]. In the abdomen, injections or infusions in adults may be given within the following boundaries: 1 cm above symphysis pubis, 1 cm below the lowest rib, 1 cm away from the umbilicus, and laterally at the flanks. In the lateral thighs, patients should use the upper third anteriorly. The posterior lateral aspect of the upper buttocks and flanks may be used. In the arm, one may use the mid-third posterior aspect. In children, the abdominal boundaries are similar to adults, but 2 cm is used instead of 1 cm for all distances. A degree of clinical judgment must be used in all cases, adult and pediatric.


8. Human insulin

Soluble human insulin (e.g., regular insulin) has a slower absorption profile than the rapid-acting analogs (lispro, aspart, and glulisine). The PK and PD of regular insulin, as well as those of neutral protamine Hagedorn (NPH), are highly dependent on the body site injected and the technique used. FITTER recommendations state that:

  • IM injections of NPH and long-acting insulin analogs must be strictly avoided due to the risk of hypoglycemia [17, 39, 40, 41]. A2

  • The abdomen is the preferred site for soluble human insulin (regular), since absorption of this insulin is fastest there [35, 42, 43, 44, 45, 46]. A1

  • The regular/NPH mix should be given in the abdomen to increase the speed of absorption of the short-acting insulin in order to cover postprandial glycemic excursions [18]. A1

  • If there is risk of nocturnal hypoglycemia, NPH- and NPH-containing mixes given in the evening should be injected into the thigh or the buttock as these sites have slower absorption of NPH [38, 47, 48]. A1


9. Insulin analogs

There are fewer studies of optimal delivery methods for the newer insulin analogs and GLP-1 s. However, insulin analogs are not as dependent on injection sites as are human insulins or NPH. From the existing studies, FITTER recommended the following:

  • Rapid-acting insulin analogs may be given at any of the injection sites, as absorption rates do not appear to be site-specific [49, 50, 51, 52, 53]. A2

  • Rapid-acting analogs should not be given IM although studies have shown that absorption rates are similar from fat tissue and resting muscle. Absorption from working muscle has not, however, been studied [50, 51, 54]. A2

  • Pending further studies, patients may inject long-acting insulin analogs in any of the usual injecting sites, with appropriate technique to prevent IM injection which can lead to profound hypoglycemia [55]. B2


10. GLP-1 agents

  • Pending further studies, patients using non-insulin injectable therapies should follow the recommendations already established for insulin injections with regards to needle length, site selection, and site rotation [56, 57, 58]. A2

11. Lipohypertrophy

LH is the most common complication of insulin injection [59, 60, 61, 62] or infusion [63, 64], with prevalence rates of 50% or higher. Risk factors for LH appear to be longer time on insulin, more daily injections, failure to carefully rotate injection sites, and extensive reuse of needles [59, 65, 66, 67, 68]. The latter two risk factors are modifiable. Insulin injected into LH has been reported to have delayed or erratic absorption which may worsen glucose control, although these trials are older with less rigor, less precise insulin assays, or very small sample sizes which in one case led to a conclusion that injecting into LH did not worsen inherent variability of insulin uptake [69, 70, 71, 72]. A crossover glucose clamp study [73] showed that both insulin absorption and action when injected into LH are blunted and are 3–5X more variable than when the same insulin dose is injected into non-LH areas. A controlled mixed-meal tolerance test in the same study also showed a reduced insulin absorption, and prolonged postprandial hyperglycemia when the insulin was injected into the LH area. When patients change from delivering insulin into LH and move to normal tissue, they are at risk of hypoglycemia and must lower their doses. Gentile [74, 75] has shown convincingly that HCPs trained to detect LH can do so with extremely high efficiency using the physical examination alone, achieving up to 97% consistency levels. FITTER issued the following recommendations:

  • Switching injections from lipohypertrophy to normal tissue often requires a decrease in the dose of insulin injected. The amount of change varies from one individual to another and should be guided by frequent blood glucose measurements. Reductions often exceed 20% of their original dose [66, 76]. A1

  • Injections should be systematically rotated in such a way that they are spaced at least 1 cm (or approximate width of an adult finger) from each other in order to avoid repeat tissue trauma. A2

  • One scheme with proven effectiveness involves dividing the injection site into quadrants (or halves when using the thighs or the buttocks), using one quadrant per week and moving quadrant to quadrant in a consistent direction (e.g., clockwise) [77]. A3

A multicenter interventional study in the UK [78] showed that education focused on these recommendations resulted in significantly reduced clinically detectable LH after 6 months, with LH either disappearing completely or decreasing by approximately 50% from its original size. The mean HbA1c fell by more than 4 mmol/L, and there were significantly reduced levels of unexpected hypoglycemia and glycemic variability. The mean TDD of insulin in the study population fell by an average of 5.6 IU by study close.

In a controlled, prospective, multicenter study in French patients [79], all of whom had LH, the intervention consisted of instructions to move injections to non-LH areas, to correctly rotate within injection sites, to forego needle reuse, and to switch to 4-mm needles in order to facilitate correct rotation without increased IM injections. These patients were also given intensive education on the injection recommendations as summarized in this chapter. Control patients were informed of the presence of LH and were told that injections should not be given into LH. They received usual and standard education. In the intervention group, there was a significant decrease of TDD of insulin of approximately 5 IU versus baseline (P = 0.035). There were significant decreases in HbA1c (up to 0.5%) in both intervention and control groups, with no significant differences between groups. A significant number of intervention patients improved their IT habits. The authors concluded that the intervention was effective in both groups, but that intensive education in LH management yielded more rapid and superior outcomes.

An interventional study in Moscow [80] followed three groups of T1DM and T2DM patients for 6 months. Two groups received structured injection training (with one group receiving 4-mm needles for each injection while the other did not) and a control group which did not get training or needles. Both training groups had HbA1C reductions of approximately 1% but the non-training group saw no change. Needle reuse and LH declined in the training groups and injection technique improved but none of these changes were seen in the non-training group.

The available data from intervention trials in patients with insulin-related LH show consistently positive outcomes. However, there are limitations to each trial—some were not randomized; in another, the control group received meaningful parts of the educational intervention [79]. Results of one or more ongoing randomized clinical trials should provide more definitive answers to the impact of injection technique training in the near future.

12. Needle reuse

Reusing needles is a common practice of injecting patients, mainly for reasons of convenience and cost-saving. However, a number of studies have linked needle reuse to LH [59, 65, 66, 81, 82, 83], especially when the reuse is excessive (≥5 times/needle). Injection pain was associated with reuse in one study [84] although another one disputed these results [85]. Another study found bacterial growth on reused needles and inflammatory changes (skin redness) at injection sites of patients who reused needles [86, 87]. Although local infections or abscesses have not been reported with needle reuse, FITTER recommends against reusing needles, which are labeled by regulatory agencies for single use.

13. Safety

Patients should never share insulin pens, whether in the hospital or at home setting. Blood can be aspirated back into the pen cartridge even after one injection, and this could possibly transmit a blood-borne disease such as HIV or hepatitis to the next user. Sonoki [88] found hemoglobin in a number of cartridges which patients had used only once. Le Floch [89] also studied the contamination of cartridges after one use and found similar findings. A recent US study corroborated these findings [90]. The rule with insulin injections is clear: one patient/one insulin pen.

Insulin needles are the most commonly used sharp worldwide. If not disposed of properly, needle-stick injuries with used insulin needles could transmit hepatitis, HIV, or other blood-borne pathogens. This is a major public health issue. Technologies exist to minimize this risk. FITTER recommended the following to minimize the risk of needle-stick injuries, particularly in a hospital or other inpatient setting:

  • Safety-engineered devices play a critical role in protecting injectors, pump users, and downstream workers [91]. A1

  • Needle recapping should not be done. A2

  • Sharp containers must be easily accessible at the point of care beside the patient, prior to the injection or infusion. A2

  • Safe disposal should be taught to patients, caregivers, and all others who may come in contact with the sharp device from the beginning of injection or infusion therapy and reinforced throughout [92] A2

  • Under no circumstance should sharps material be disposed of into the public trash or rubbish system. A3

14. Insulin infusion

Continuous subcutaneous insulin infusion (CSII) has been used for 40 years [93, 94]. Insulin infusion sets (IISs) deliver insulin into the SC, and they have been associated with numerous adverse side effects [95]. It is generally agreed that if a patient has otherwise unexplained hyperglycemia, they should administer a correction bolus via their pump. If the blood glucose does not decline at least 50 mg/dL by 90 min, they should (1) remove the set, (2) give a correction with a pen or a syringe, and (3) insert a new set. FITTER recommended the following additional recommendations for CSII and IIS users:

  • CSII cannula should be changed every 48–72 h in order to minimize infusion site adverse events and potential metabolic deterioration. However, these times are very patient-dependent and should be adjusted accordingly. A1

  • All CSII patients should be taught to rotate infusion sites along the same principles that injecting patients are taught to rotate injection sites. A1

  • Any CSII patients with unexplained glucose variability including frequent hypoglycemia/hyperglycemia should have infusion sites checked for lipohypertrophy, nodules, scarring, inflammation, or other skin and SC conditions that could affect insulin flow or absorption. A1

15. Conclusion

Insulin has a very low therapeutic index. The margin between its greatest therapeutic benefit and its unacceptable side effects is low. Without careful attention to optimal insulin delivery, patients can find themselves on either side of a slippery slope: either suboptimal therapeutic benefit or high toxicity. Optimal insulin delivery is complex and involves choices that patients and professionals may not have previously considered: the choice of injection sites as a function of the insulin delivered, the choice of needle length as a function of SC thickness, the injection or infusion technique which ensure consistently effective SC delivery, the precise and systematic rotation of delivery sites, reduced or non-reuse of sharps, and safe disposal of used sharps which reduces needle-stick injury risk to family members or the community at large [96]. We have provided both evidence-based recommendations and proof that these work in practice and deliver insulin with an improved therapeutic index and better outcomes—both clinical- and patient-reported. The challenge now is to scale these recommendations so that all insulin-using patients and insulin-prescribing professional know and follow them.

Conflict of interest

Authors KS and LH are employees of BD, a manufacturer of injecting devices. All other authors declare that they have no conflict of interest.


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.


BMIbody mass index
CSIIcontinuous subcutaneous insulin infusion
DKAdiabetic ketoacidosis
FITForum for Injection Technique
FITTERForum for Injection Technique and Therapy: Expert Recommendations
Ggauge (of needle).
GCPgood clinical practice.
GLP-1glucagon-like peptide-1 receptor agonists
HbA1cglycated hemoglobin
HBVhepatitis B virus
HCPhealth care professional
HCVhepatitis C virus
ITQinjection technique questionnaire
IUinternational unit (of insulin)
LH−patient without lipohypertrophy
LH+patient with lipohypertrophy
NPHneutral protamine hagedorn (also known as insulin N)
NSIneedle-stick injury
T1DMtype 1 diabetes
T2DMtype 2 diabetes.
TDDtotal daily dose (of insulin)


  1. 1. Frid AH et al. New insulin delivery recommendations. Mayo Clinic Proceedings; 91(9):1231-1255. Open Access at:
  2. 2. Strauss K. Insulin injection techniques: Report from the 1st international insulin injection technique workshop, Strasbourg, France—June 1997. Practical Diabetes International. 1998;15(6):16-20
  3. 3. Strauss K, De Gols H, Letondeur C, Matyjaszczyk M, Frid A. The second injection technique event (SITE), May 2000, Barcelona. Practical Diabetes International. 2002;19(1):17-21
  4. 4. Frid A, Hirsch L, Gaspar R, Hicks D, et al. New injection recommendations for patients with diabetes. Diabetes & Metabolism. 2010;36(2):S3-S18
  5. 5. Frid AH et al. Worldwide injection technique questionnaire study: Population parameters and injection practices. Mayo Clinic Proceedings. 2016;91:1212-1223. Open Access at:
  6. 6. Frid AH et al. Worldwide injection technique questionnaire study: Injecting complications and role of the professional. Mayo Clinic Proceedings. 2016;91:1224-1230. Open Access at:
  7. 7. Gibney MA, Arce CH, Byron KJ, Hirsch LJ. Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: Implications for needle length recommendations. Current Medical Research and Opinion. 2010;26(6):1519-1530
  8. 8. Hirsch L, Klaff L, Bailey T, Gibney M, Albanese J, Qu S, Kassler-Taub K. Comparative glycemic control, safety and patient ratings for a new 4 mm\32G insulin pen needle in adults with diabetes. Current Medical Research and Opinion. 2010;26:1531-1541
  9. 9. Catambing I, Villa M. Ultrasonographic measurement of skin and subcutaneous thickness at insulin injection sites among adult Filipinos with diabetes. Journal of the ASEAN Federation of Endocrine Societies. 2014;29(1):24-32
  10. 10. Sim KH, Hwang MS, Kim SY, Lee HM, Chang JY, Lee MK. The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes. Diabetes and Metabolism Journal. 2014;38(2):120-133
  11. 11. Wang W, et al. Skin and subcutaneous layer thickness at insulin injection sites in Chinese diabetic patients. Diabetes Technology & Therapeutics. 2014 Dec;16(12):867-873. DOI: 10.1089/dia.2014.0111. Epub 2014 Oct 20
  12. 12. Jain SM, Pandey K, Lahoti A, Rao PK. Evaluation of skin and subcutaneous tissue thickness at insulin injection sites in Indian, insulin naïve, type-2 diabetic adult population. Indian Journal of Endocrinology and Metabolism. 2013;17(5):864-870
  13. 13. Marran K, Segal D. SKINNY – Skin thickness and needles in the young. South African Journal of Chemistry. 2014;8(3):92-95. DOI: 10.7196/SAJCH.687
  14. 14. Lo Presti D, Ingegnosi C, Strauss K. Skin and subcutaneous thickness at injecting sites in children with diabetes: Ultrasound findings and recommendations for giving injection. Pediatric Diabetes. 2012;13(7):525-533
  15. 15. Wang W et al. Skin and subcutaneous layer thickness at insulin injection sites in Chinese diabetic patients. Diabetes Technology & Therapeutics. 2015, submitted
  16. 16. Hirsch L, Byron K, Gibney M. Intramuscular risk at insulin injection sites-measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy. Diabetes Technology & Therapeutics. 2014;16(12):867-873
  17. 17. Karges B, Boehm BO, Karges W. Early hypoglycaemia after accidental intramuscular injection of insulin glargine. Diabetes Medicine. 2005;22(10):1444-1445
  18. 18. Frid A, Gunnarson R, Guntner P, Linde P. Effects of accidental intramuscular injection on insulin absorption in IDDM. Diabetes Care. 1988;11(1):41-45
  19. 19. Spraul M, Chantelau E, Koumoulidou J, Berger M. Subcutaneous or nonsubcutaneous injection of insulin. Diabetes Care. 1988;11(9):733-736
  20. 20. Gentile S, Agrusta M, Guarino G, Carbone L, Cavallaro V, et al. Metabolic consequence of incorrect insulin administration techniques in aging subjects with diabetes. Acta Diabetologica. 2011;48:121-125
  21. 21. Kreugel G, Keers JC, Jongbloed A, Verweij-Gjaltema AH, Wolffenbuttel BHR. The influence of needle length on glycemic control and patient preference in obese diabetic patients. Diabetes. 2009;58:A117
  22. 22. Schwartz S, Hassman D, Shelmet J, et al. A multicenter, open-label, randomized, two-period crossover trial comparing glycemic control, satisfaction, and preference achieved with a 31 gauge × 6 mm needle versus a 29 gauge × 12.7 mm needle in obese patients with diabetes mellitus. Clinical Therapeutics. 2004;26(10):1663-1678
  23. 23. Ross SA, Jamal R, Leiter LA, et al. Evaluation of 8 mm insulin pen needles in people with type 1 and type 2 diabetes. Practical Diabetes International. 1999;16(5):145-148
  24. 24. Tubiana-Rufi N, Belarbi N, Du Pasquier-Fediaevsky L, et al. Short needles (8 mm) reduce the risk of intramuscular injections in children with type 1 diabetes. Diabetes Care. 1999;22(10):1621-1625
  25. 25. Strauss K, Hannet I, McGonigle J, et al. Ultra-short (5mm) insulin needles: Trial results and clinical recommendations. Practical Diabetes International. 1999;16(7):218-221
  26. 26. Kreugel G, Keers JC, Kerstens MN, Wolffenbuttel BH. Randomized trial on the influence of the length of two insulin pen needles on glycemic control and patient preference in obese patients with diabetes. Diabetes Technology & Therapeutics. 2011;13(7):737-741
  27. 27. Iwanaga M, Kamoi K. Patient perceptions of injection pain and anxiety: A comparison of Novo Fine 32-gauge tip 6 mm and micro fine plus 31-gauge 5 mm needles. Diabetes Technology & Therapeutics. 2009;11(2):81-86
  28. 28. McKay M, Compion G, Lytzen L. A comparison of insulin injection needles on patients' perceptions of pain, handling, and acceptability: A randomized, open-label, crossover study in subjects with diabetes. Diabetes Technology & Therapeutics. 2009;11(3):195-201
  29. 29. Miwa T, Itoh R, Kobayashi T, Tanabe T, Shikuma J, Takahashi T, Odawara M. Comparison of the effects of a new 32-gauge × 4-mm pen needle and a 32-gauge × 6-mm pen needle on glycemic control, safety, and patient ratings in Japanese adults with diabetes. Diabetes Technology & Therapeutics. 2012 Dec;14(12):1084-1090
  30. 30. Nagai Y, Ohshige T, Arai K, Kobayashi H, Sada Y, Ohmori S. Comparison between shorter straight and thinner microtapered insulin injection needles. Diabetes Technology & Therapeutics. 2013;15(7):550-555
  31. 31. Hirose T, Ogihara T, Tozaka S, Kanderian S, Watada H. Identification and comparison of insulin pharmacokinetics injected with a new 4-mm needle vs 6- and 8-mm needles accounting for endogenous insulin and C-peptide secretion kinetics in non-diabetic adult males. Journal of Diabetes Investigation. 2013;4(3):287-296
  32. 32. Birkebaek NH, Solvig J, Hansen B, Jorgensen C, Smedegaard J, Christiansen JS. A 4-mm needle reduces the risk of intramuscular injections without increasing backflow to skin surface in lean diabetic children and adults. Diabetes Care. 2008;31(9):e65
  33. 33. Bergenstal RM et al. Safety and efficacy of insulin therapy delivered via a 4mm pen needle in obese patients with diabetes. Mayo Clinic Proceedings. 2015;90(3):329-338
  34. 34. Koivisto VA, Felig P. Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients. Annals of Internal Medicine. 1980;92(1):59-61
  35. 35. Annersten M, Willman A. Performing subcutaneous injections: A literature review. Worldviews on Evidence-Based Nursing. 2005;2(3):122-130
  36. 36. Vidal M, Colungo C, Jansà M. Actualización sobre técnicas y sistemas de administración de la insulina (I). Avances en Diabetologia. 2008;24(3):175-190
  37. 37. Fleming D, Jacober SJ, Vanderberg M, Fitzgerald JT, Grunberger G. The safety of injecting insulin through clothing. Diabetes Care. 1997;20(3):244-247
  38. 38. Bantle JP, Neal L, Frankamp LM. Effects of the anatomical region used for insulin injections on glycaemia in type 1 diabetes subjects. Diabetes Care. 1993;16(12):1592-1597
  39. 39. Personal Communication: Anders Frid. Data on file: Novo Nordisk
  40. 40. Frid A, Östman J, Linde B. Hypoglycemia risk during exercise after intramuscular injection of insulin in thigh in IDDM. Diabetes Care. 1990;13(5):473-477
  41. 41. Vaag A, Handberg A, Laritzen M, et al. Variation in absorption of NPH insulin due to intramuscular injection. Diabetes Care. 1990;13(1):74-76
  42. 42. Frid A, Linde B. Intraregional differences in the absorption of unmodified insulin from the abdominal wall. Diabetic Medicine. 1992;9(3):236-239
  43. 43. Frid A, Linde B. Clinically important differences in insulin absorption from the abdomen in IDDM. Diabetes Research and Clinical Practice. 1993;21(2):137-141
  44. 44. Zehrer C, Hansen R, Bantle J. Reducing blood glucose variability by use of abdominal insulin injection sites. The Diabetes Educator. 1985;16(6):474-477
  45. 45. Henriksen JE, Djurhuus MS, Vaag A, et al. Impact of injection sites for soluble insulin on glycaemic control in type 1 (insulin-dependent) diabetic patients treated with a multiple insulin injection regimen. Diabetologia. 1993;36(8):752-758
  46. 46. Sindelka G, Heinemann L, Berger M, Frenck W, Chantelau E. Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects. Diabetologia. 1994;37(4):377-340
  47. 47. Henriksen JE, Vaag A, Hansen IR, Lauritzen M, Djurhuus MS, Beck-Nielsen H. Absorption of NPH (isophane) insulin in resting diabetic patients; evidence for subcutaneous injection in the thigh as preferred site. Diabetic Medicine. 1991;8(5):453-457
  48. 48. Kølendorf K, Bojsen J, Deckert T. Clinical factors influencing the absorption of 125 I-NPH insulin in diabetic patients. Hormone and Metabolic Research. 1983;15:274-278
  49. 49. Mudaliar SR, Lindberg FA, Joyce M, et al. Insulin aspart (B28 asp-insulin): A fast-acting analog of human insulin: Absorption kinetics and action profile compared with regular human insulin in healthy nondiabetic subjects. Diabetes Care. 1999;22(9):1501-1506
  50. 50. Rave K, Heise T, Weyer C, et al. Intramuscular versus subcutaneous injection of soluble and lispro insulin: Comparison of metabolic effects in healthy subjects. Diabetic Medicine. 1998;15(9):747-751
  51. 51. Frid A. Fat thickness and insulin administration, what do we know? Infusystems Internationl. 2006;5(3):17-19
  52. 52. Guerci B, Sauvanet JP. Subcutaneous insulin: Pharmacokinetic variability and glycemic variability. Diabetes & Metabolism. 2005;31(4):4S7-4S24
  53. 53. Ter Braak EW, Woodworth JR, Bianchi R, et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin. Diabetes Care. 1996;19(12):1437-1440
  54. 54. Lippert WC, Wall EJ. Optimal intramuscular needle-penetration depth. Pediatrics. 2008;122(3):e556-e563
  55. 55. Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R. Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: Comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care. 2000;23(6):813-819
  56. 56. Byetta Pen User Manual. Eli Lilly and Company; 2007
  57. 57. Calara F, Taylor K, Han J, et al. A randomized, open-label, crossover study examining the effect of injection site on bioavailability of exenatide (synthetic exendin-4). Clinical Therapeutics. 2005;27(2):210-215
  58. 58. Gentile S, Strollo F. Subcutaneous nodules during treatment with an exenatide long-actin once-weekly formulation: An ultrasound evaluation. Diversity and Equality in Health and Care. 2016;13(4):313-318
  59. 59. Blanco M, Hernández MT, Strauss KW, Amaya M. Prevalence and risk factors of lipohypertrophy in insulin-injecting patients with diabetes. Diabetes & Metabolism. 2013 Oct;39(5):445-453
  60. 60. Grassi G, Scuntero P, Trepiccioni R, et al. Optimizing insulin injection technique and its effect on blood glucose control. Journal of Clinical & Translational Endocrinology. 2014;1(4):145-150. This is an open access article under the CC BY-NC-ND license (
  61. 61. Ji L, Li Q, Wei G. Lipohypertrophy - prevalence, risk factors and clinical characteristics of insulin-requiring patients in China. Abstract, EASD Vienna. 2014. Tracking Number: A-14-747
  62. 62. Gentile S, Ceriello A, Strollo F. Insulin Shot Dependent Lipodystrophy: Evidence, Uncertainties and Current Terminology Overlaps. Journal of Diabetes, Metabolic Disorders & Control. 2016;3(3):00067. DOI: 10.15406/jdmdc.2016.03.00067
  63. 63. Conwell LS, Pope E, Artiles AM, Mohanta A, Daneman A, Daneman D. Dermatological complications of continuous subcutaneous insulin infusion in children and adolescents. The Journal of Pediatrics. 2008;152:622-628
  64. 64. Pickup J, Yemane N, Brackenridge A, Pender S. Nonmetabolic complications of continuous subcutaneous insulin infusion: A patient survey. Diabetes Technology & Therapeutics. 2014;16:145-149
  65. 65. Vardar B, Kizilci S. Incidence of lipohypertrophy in diabetic patients and a study of influencing factors. Diabetes Research and Clinical Practice. 2007;77:231-236
  66. 66. Saez-de Ibarra L, Gallego F. Factors related to lipohypertrophy in insulin-treated diabetic patients; role of educational intervention. Practical Diabetes International. 1998;15:9-11
  67. 67. Raile K, Noelle V, Landgraf R, Schwarz HP. Insulin antibodies are associated with lipoatrophy but also with lipohypertrophy in children and adolescents with type 1 diabetes. Experimental and Clinical Endocrinology & Diabetes. 2001;109(8):393-396
  68. 68. Sandro Gentile S, Strollo F, Ceriello A. Lipodistrophy and associated risk factors in insulin-treated people with diabetes. International Journal of Endocrinology Metabolism. 2016;14(2):e33997. DOI: 10.5812/ijem.33997 Published online 2016 Apr 26
  69. 69. Young RJ, Hannan WJ, Frier BM, Steel JM, Duncan LJ. Diabetic lipohypertrophy delays insulin absorption. Diabetes Care. 1984;7:479-480
  70. 70. Chowdhury TA, Escudier V. Poor glycaemic control caused by insulin induced lipohypertrophy. British Medical Journal. 2003;327:383-384
  71. 71. Johansson UB. Impaired absorption of insulin aspart from lipohypertrophic injection sites. Diabetes Care. 2005;28:2025-2027
  72. 72. Frid A, Linden B. Computed Tomography of Injection Sites in Patients with Diabetes Mellitus. Injection and Absorption of Insulin. Stockholm: Thesis. 1992
  73. 73. Famulla S, Hövelmann U, Fische A, et al. Insulin injection into lipohypertrophic tissue: Blunted and more variable insulin absorption and action and impaired postprandial glucose control. Diabetes Care. 2016;39:1486-1492. DOI: 10.2337/dc16-0610
  74. 74. Gentile S, Guarino G, Giancaterini A, Guida P, Strollo F, AMD-OSDI Italian Injection Technique Study Group. A suitable palpation technique allows to identify skin lipohypertrophic lesions in insulin-treated people with diabetes. Springerplus. 2016;5:563. DOI: 10.1186/s40064-016-1978-y eCollection 2016
  75. 75. Gentile S, Strollo F, Guarino G, Giancaterini A, Ames PRJ, Speese K, Guida P, Strauss K, On behalf of the AMDOSDI Italian Injection Technique Study Group. Factors hindering correct identification of unapparent lipohypertrophy. Journal of Diabetes and Metabolic Disorders Control. 2016;3:00065. DOI: 10.15406/jdmdc.2016.03.00065
  76. 76. Jansà M, Colungo C, Vidal M. Actualización sobre técnicas y sistemas de administración de la insulina (II). Avances en Diabetologia. 2008;24(4):255-269
  77. 77. Diagrams courtesy of Lourdes Saez-de Ibarra and Ruth Gaspar, Diabetes Nurses and Specialist Educators from La Paz Hospital, Madrid, Spain
  78. 78. Smith M, Clapham L, Strauss K. UK LIpohypertrophy intervention study. Diabetes Research and Clinical Practice. 2017;126:248-253
  79. 79. Campinos C et al. An effective intervention for diabetic lipohypertrophy: Results of a randomised, controlled, prospective, multicentre study in France. Diabetes Technology & Therapeutics. 2017;19:623-632. DOI: 10.1089/dia.2017.0165 Epub 2017 Oct 23
  80. 80. Misnikova I, Gubkina V, Lakeeva T, Dreval A. A randomized controlled trial to assess the impact of proper insulin injection technique training on glycemic control. Diabetes Therapy. 2017;8(6):1309-1318. DOI: 10.1007/s13300-017-0315-y Epub 2017 Oct 13
  81. 81. De Coninck C, Frid A, Gaspar R, et al. Results and analysis of the 2008-2009 insulin injection technique questionnaire survey. Journal of Diabetes. 2010;2(3):168-179
  82. 82. Strauss K, De Gols H, Hannet I, Partanen TM, Frid A. A pan-European epidemiologic study of insulin injection technique in patients with diabetes. Practical Diabetes International. 2002;19:71-76
  83. 83. Hirsch L, Ji L, Sun Z, Li Q, et al. Lipohypertrophy – Prevalence, risk factors and clinical characteristics of insulin-requiring patients in China. DTT. 2015;17(Suppl 1):A57-A58
  84. 84. Misnikova I, Dreval A, Gubkina V, Rusanova E. The risk of repeated use of insulin pen needles in patients with diabetes mellitus. Journal of Diabetology. 2011;1:1-5
  85. 85. Puder J, Atar M, Muller B, Pavan M, Keller U. Using insulin pen needles up to five times does not affect needle tip shape nor increase pain intensity. Diabetes Research and Clinical Practice. 2005;67:119-123
  86. 86. Schuler G, Pelz K, Kerp L. Is the reuse of needles for insulin injection systems associated with a higher risk of cutaneous complications? Diabetes Research and Clinical Practice. 1992;16:209-212
  87. 87. Thomas DR, Fischer RG, Nicholas WC, Beghe C, Hatten KW, Thomas JN. Disposable insulin syringe reuse and aseptic practices in diabetic patients. Journal of General Internal Medicine. 1989;4:97-100
  88. 88. Sonoki K, Yoshinari M, Iwase M, Tashiro K, Iino K, Wakisaka M, Fujishima M. Regurgitation of blood into insulin cartridges in the pen-like injectors. Diabetes Care. 2001;24(3):603-604
  89. 89. Floch JPL, Lange F, Herbreteau C, Perlemuter L. Biologic material in needles and cartridges after insulin injection with a pen in diabetic patients. Diabetes Care. 1998;21:1502-1504
  90. 90. Herdman M, Larck C, Hoppe Schliesser S, Jelic T. Biological contamination of insulin pens in a hospital setting. American Journal of Health-System Pharmacy. 2013;70:1244-1248
  91. 91. Jagger J et al. The impact of U.S. policies to protect healthcare workers from bloodborne pathogens: The critical role of safety-engineered devices. Journal of Infection and Public Health. 2008;1(2):62-71
  92. 92. Bain A, Graham A. How do patients dispose of syringes? Practical Diabetes International. 1998;15(1):19-21
  93. 93. Pickup JC et al. Continuous subcutaneous insulin infusion: An approach to achieving normoglycaemia. British Medical Journal. 1978;1(6107):204-207
  94. 94. Dean Kamen, son of Mad Magazine cartoonist Jack Kamen, patented the Auto Syringe AS6C in 1977 (personal communication, Anders Frid, Dec. 12, 2017)
  95. 95. Heinemann L, Krinelke L. Insulin infusion set: The Achilles heel of continuous subcutaneous insulin infusion. Journal of Diabetes Science and Technology. 2012;6(4):954-964
  96. 96. Spollett G, Edelman SV, Mehner P, Walter C, Penfornis A. Improvement of insulin injection technique: Examination of current issues and recommendations. The Diabetes Educator. 2016;42(4):379-394. DOI: 10.1177/0145721716648017 Epub 2016 May 23

Written By

Anders Frid, Laurence Hirsch and Kenneth Strauss

Submitted: January 13th, 2018 Reviewed: March 6th, 2018 Published: November 5th, 2018