Insulins
The time to complete this module is approximately 45 minutes.
How will this help my clinical practice?
Insulins types and characteristics are discussed.
The rationale for insulin management is explained.
Pens and pumps are covered.
The pharmacodynamics of insulin types will help with prescribing decisions.
Synthetic Insulin Characteristics and Practical Issues
There are three broad categories of synthetic insulin based on their length of action. They are rapid-acting , short/ intermediate-acting, and long-acting. All are available in pen forms. Pumps use only short-acting or rapid insulins. The various available brands can be found in multiple formularies, either local or national, such as the British National Formulary.
Insulin concentrations are standardised as U100, meaning 100 units per millilitre. There are now available U300 insulins which are primarily used in type 2 diabetes, where larger volumes are typically used. There are intended absorption advantages of highly concentrated insulin, but they will not be part of a ketogenic lifestyle, so they can be ignored here.
Modern synthetic insulin is produced by altering bacterial genes to make them produce insulin. Saccharomyces (baker’s yeast) or E. Coli. have been manipulated using recombinant DNA technology to make insulin. Enzymes can cut and paste gene sequences of interest so that insulin can be modified as required. In this way, an amino acid in an insulin protein chain can be changed to subtly alter the insulin molecule’s structures and pharmacodynamics. The modifications are primarily done in regions of the amino acid chain that affect the insulin absorption rate but do not affect its affinity for binding to insulin receptors.
Insulin Brands
Amino acids can be altered to create a patentable form of insulin. It allows manufacturers to make forms of insulin that can be branded and hence compete in the pharmaceutical market. This technology of insulin manipulation can be used to modify insulin around unimportant amino acids in the insulin peptide chains. It is said to extend the life of a patent on insulin. The practice, called evergreening, has been cited as a reason for the continual high price of insulin.
Insulin price has implications in private medical systems and leads to affordability issues and risk-taking behaviour with medication. In socialised healthcare systems such as the UK, insulin is free at the point of use. The cost of insulin varies widely from country to country, with a vial cost ranging from $25-$300. The reference below highlights the findings of a worldwide survey of how the price of insulin and consumables affects people’s behaviour in managing Type 1. https://www.sciencedirect.com/science/article/pii/S0168822721003557
In the UK, the relative cost of a year’s supply of insulin as pens or vials is around £372 per year (2012).
Absorption
Subcutaneous insulin injection is absorbed directly into the bloodstream. The lymphatic system has a minor role in transport. The absorption of insulin into the bloodstream after absorption is the rate-limiting step of insulin activity. Absorption is inconsistent, varying around 25% within an individual and up to 50% between patients.
https://www.ncbi.nlm.nih.gov/books/NBK278938/.
Most of this variability of insulin absorption is correlated to blood flow differences at the various sites of injection (abdomen, deltoid, gluteus, and thigh). For regular insulin, this impact is approximately two times faster rate of absorption from the abdomen than other subcutaneous sites. https://www.ncbi.nlm.nih.gov/books/NBK278938/
People should therefore be discouraged from randomly using different sites for their injections. The abdomen is the preferred injection site because it is the least susceptible to insulin absorption factors.
Some insulins have less day-to-day variation in absorption rates. Insulin Aspart, glulisine and Lispro, Glargine and Degludec have been quoted as having these characteristics. https://www.ncbi.nlm.nih.gov/books/NBK278938/.
In addition to the pharmacodynamic properties of insulin at injection sites, some other factors alter absorption.
Examples of factors that increase absorption are massage of the injection site, heat, and physical activity of a limb.
Examples of factors that decrease absorption are: cold, fat hypertrophy, injecting into a scar, and injecting large volumes of insulin.
Examples of factors that cause variable absorption are: the potency of insulin. Not all U100 is as potent mostly due to improper storage, https://pubmed.ncbi.nlm.nih.gov/19797814/ . Imprecise absorption into the tissue due to scarring etc. This can be as much as 20% and of course, be a daily variable. Pumps will be more reliable in this respect. https://www.researchgate.net/profile/Lutz-Heinemann/publication/11019768_Variability_of_Insulin_Absorption_and_Insulin_Action/links/5744fc1c08aea45ee8538385/Variability-of-Insulin-Absorption-and-Insulin-Action.pdf
Synthetic insulins are categorised as;
The principle of using insulin to control Type 1 is discussed in these practical modules.
Current practice is to use the basal-bolus regimen or a pump. Twice-daily mixed insulin is still used for around 8% of people with Type 1, but these insulin types are not recommended for a ketogenic lifestyle and conversion to basal-bolus or pump is recommended.
The principle of basal-bolus is that the basal long-acting insulin is used for ‘background’ glucose-raising processes such as gluconeogenesis and various stress responses operating through glucagon through hormones such as cortisol or adrenaline. Rapid insulin is then used to cover the carbohydrate and proteins in a meal.
For pumps, the basal insulin is dispensed with, and rapid-acting insulin is used in the pump chamber, where the infusion rate can be programmed as required. Both basal and bolus programmes can be set, with the additional flexibility of bolus boosting for hyperglycaemia and temporary disablement for physical activity.
A modern, rapid-acting insulin is designed for a high carbohydrate meal and has pharmacodynamic characteristics that work with carbohydrates. This would typically be rapid absorption to ‘catch’ the peak caused by carbohydrates and relatively fast decay. On a ketogenic diet which is low in carbohydrates, this profile is less than ideal, although injection timing can accommodate the use of these types of insulin. Rapid insulins may be adequate in people with Type 1 diabetes for many years and with more insulin resistance. However, less aggressive insulin, called regular or soluble insulin, which is short/intermediate insulin, can be helpful in more insulin-sensitive individuals. This was the original ‘rapid’ insulin, branded as Actrapid and Humulin S, and it has a profile more suited to protein. This is further discussed in the practical section.
There are many marketing claims made for various brands of rapid insulin. The advantages might have application in some circumstances. However, in the author’s opinion, these gains are irrelevant for those on a keto diet, and for most people, any choice of rapid insulin will suffice.
Look at this recent advertisement for a brand of insulin where claims of a super-rapid onset of action were made. Note the concentration of insulin at the peak that is to achieve this effect. It is 600 picomol/l. It is beyond a physiological prandial insulin concentration. which is typically half that value. At a dose of 0.2 units per kg to achieve the desired effect, this is equivalent to 14 units for a 70kg person, representing an ICR of 1 unit of insulin to 5g of carbohydrate. In real-world diabetes, only a minority of people will fit this profile.
As explained above, having such a rapid profile is not a requirement for prandial insulin on a ketogenic diet, where low carbohydrates require low insulin volumes. However, there are scenarios where a rapid insulin profile might be beneficial. The first is the gluconeogenic effect of glucagon and the subsequent glucose rise caused by the dawn effect. The second is a glucose rise caused by insulin miscalculation. In both scenarios, rapid insulin will give a fast correction back to normoglycaemia.
So there might be some patients who will suit a triple insulin regimen for some situations. It is unlikely to be more than a few as most people will be fine with whatever basal-bolus branded insulins they have chosen. But it should not be ruled out because of the current convention. Remember that any subcutaneous insulin is artificial, and this form of hormone replacement is a compromise. However, people heading to complicated pen regimens might be better considering a pump.
The current pump recommendations are not based on a ketogenic lifestyle, so negotiating this might not be easy at the time of writing. But as a keto lifestyle enters the mainstream, this situation will become more normal.
Basal insulins seem anecdotally to vary in their suitability for individuals. If someone is having trouble stabilising basal glucose, a change to a longer-acting formula such as Degludec (Tresiba) might help.
It has been known for people to use pumps for the purpose of achieving good basal control. The author has met one person who only stabilised their basal with a pump and six basal programmes for different times of the day.
Pens or Pumps?
Insulin Pens
Pens can be either disposable or reusable. The insulin is included in the pen in a glass vial or supplied as separate vials to be inserted into the pen. Pens are available in either rapid-acting( bolus), intermediate-acting ( bolus), long-acting ( basal), or a mixture. Mixtures are not suitable for a ketogenic lifestyle. If a patient uses mixed insulin, it is necessary to prescribe the individual insulin types included in the mixed insulin formula and inject the exact relative quantities.
Insulin Pumps. CSII ( Continuous Subcutaneous Insulin Infusion).
Pumps cost over three times that amount in addition to the pump cost itself. https://www.diabetes.co.uk/insulin-pumps/buying-an-insulin-pump.html.
Pumps are more accurate than pens and administering pump therapy costs between £2000-£3000 per year. The average pump lasts around four years and is primed with rapid-acting insulin. The rate of delivery of insulin can be programmed to suit individual needs. Bolus doses can be programmed or augmented as needed.
A pump is not necessarily better than a pen, and the REPOSE Trial found little difference in their effectiveness in controlling Hb A1c. https://bmjopen.bmj.com/content/4/9/e006204
According to the NICE Guideline Technical Assessment TA151 https://www.nice.org.uk/guidance/ta151/resources/insulin-pump-therapy-for-diabetes-pdf-374892589#:~:text=Insulin%20pump%20therapy%20should%20only%20be%20continued%20in%20adults%20and,person%20having%20fewer%20hypoglycaemic%20episodes.
The relevant extract is copied here.
‘Continuous subcutaneous insulin infusion or ‘insulin pump’ therapy is recommended as a possible treatment for adults and children 12 years and over with type 1 diabetes mellitus if
: • attempts to reach target haemoglobin A1c (HbA1c) levels with multiple daily injections result in the person having ‘disabling hypoglycaemia’, or
• HbA1c levels have remained high (8.5% or above) with multiple daily injections (including long-acting insulin analogues if appropriate) despite the person and/or their carer carefully trying to manage their diabetes.
Insulin pump therapy is recommended as a possible treatment for children under 12 years with type 1 diabetes mellitus if treatment with multiple daily injections is not practical or is not considered appropriate. Children who use insulin pump therapy should have a trial of multiple daily injections when they are between the ages of 12 and 18.
‘Disabling hypoglycaemia’ is when hypoglycaemic episodes occur frequently or without warning so that the person is constantly anxious about another episode occurring, which has a negative impact on their quality of life.
Insulin pump therapy should only be started by a trained specialist team. This team should include a doctor specialising in insulin pump therapy, a diabetes nurse and a dietitian (someone who can give specialist advice on diet).
Insulin pump therapy should only be continued in adults and children 12 years and over if there has been a sustained improvement in controlling their blood glucose levels. This should be shown by a decrease in the person’s HbA1c levels or by the person having fewer hypoglycaemic episodes. Such goals should be set by the doctor through discussion with the person or their carer.’
An audit survey by Diabetesuk in 2016-7 found that 15.6% of T1 in England were using a pump. In 43% of cases, a pump was started for hypo management .70-90% met their hypos reduction targets. The percentage of people with pumps achieving an HbA1c of 7.5% ( 58mmol.mol) increased from 29% on pens to 34% on pumps. The mean HbA1c on pumps was 65 mmol./mol and on pens 70mmol/mol.
There was little overall difference in the percentage of people receiving the monitoring processes that make up the annual check. This audit does not comment on dietary choices, but it has been mentioned elsewhere that vastly improved HbA1c levels can be achieved with a ketogenic lifestyle.
https://www.diabetes.org.uk/resources-s3/2018-12/Insulin_%20Summary_v4.pdf
So, it is still the case that the overwhelming majority of people with Type 1 will use a pen. Anecdotally, some people stop using a pump when they get improved control of a ketogenic lifestyle, though many prefer the accuracy and flexibility of a pump. One of the downsides of some pumps is that tubing can kink and obstruct the insulin supply. This leads to hyperglycaemia and, in some cases, an increased risk of DKA. The trend in newer pump designs is to have the insulin reservoir and pumping mechanism on a patch which circumvents this potential tube kinking problem.
Insulin pumps are increasingly being linked to continuous glucose meters. Algorithms are being developed to allow some automation of a pump. This once arcane practice was called looping and practised by self-experimenters, but systems are now being introduced into mainstream practice. It is beyond the scope of this module and course to discuss technical issues of insulin management. It is highly individual, but the basic principles apply to all delivery systems and lifestyle choices.
Nevertheless, even though the choice of the delivery system is important, overall, the mean HbA1c of people on a pump is still 65 mmol/mol. This remains disappointingly above the 58mmol/mol at which it has been estimated that people lose 100 days of life expectancy.for every year they are above this level.
Other issues that are relevant to synthetic insulins.
Mitogenic effects of synthetic insulins
https://www.ncbi.nlm.nih.gov/books/NBK278938/
In vitro studies have demonstrated the mitogenic effects of insulin at high concentrations of insulin binding to the insulin-like growth factor-1 (IGF-1) receptor, suggesting that hyperinsulinemia may promote tumorigenesis. Because insulin analogues are modified human insulin, these insulins’ safety and efficacy profiles have been compared to human insulin. Those wishing for more detail can access this reference https://pubmed.ncbi.nlm.nih.gov/24215311/.
Insulin Lispro and insulin Aspart have similar IGF-1 binding compared to human insulin, and Glargine was 6-8 fold more potency in binding to the IGF-1 receptor. However, glargine is rapidly degraded to active metabolites less potent than human insulin. Detemir and Degludec are less potent regarding affinity for IGF-1 than human insulin. The long-term clinical significance of differences in IGF-1 binding among available insulins is unknown.
Hypersensitivity
Hypersensitivity reactions to insulin can be immediate-type, local or systemic IgE-mediated reactions. Patients who experience a genuine allergic reaction to insulin have typically received insulin at some point in the past and experience the reaction after insulin is restarted. This is a mercifully rare occurrence.
Lipodystrophy,
Lipodystrophy results from insulin injections. The term encompasses Lipoatrophy and Lipohypertrophy
.Lipoatrophy is an immune-mediated condition resulting in fat loss at insulin injection sites. It is rare with modern insulins.
https://www.ncbi.nlm.nih.gov/books/NBK278938/
Lipohypertrophy
Lipohypertrophy is common. It is a non-immunological effect of fat deposition resulting from insulin’s effect on lipogenesis. It is exacerbated through repeated insulin injections into the same subcutaneous site. Lipohypertrophy can delay the absorption of insulin. Rotation of injections around the injection site is encouraged for this reason.