Insulin for diabetes: 100 years of therapy

On the 23 January 2022 we will celebrate the 100th anniversary of insulin successfully being used to treat diabetes in humans. This development marked a new era in the management of diabetes.

Before the discovery of insulin, the prognosis for people living with diabetes was very poor. People with diabetes followed various diets like the ‘meat diet’ that severely restricted carbohydrates or the ‘starvation diet’ that advocated total fasting. These diets had limited success in preventing deaths from ‘diabetic comas’, known today as diabetic ketoacidosis. Diabetic ketoacidosis is caused by extremely high glucose levels due to a lack of insulin (Schadewaldt, 1989).

In the last 100 years, insulin has become widely used to manage various forms of diabetes. Everyone with type 1 diabetes, except those who have received pancreas or islet-cell transplants, and more than half of people with type 2 diabetes use insulin to manage their diabetes (Gough and Narendran, 2017). For many people with access to insulin, being diagnosed with type 1 diabetes is no longer a death sentence. Instead, it is seen as a long-term condition that can be self-managed for people with access to insulin and glucose monitoring technology.

Who discovered insulin?

During the summer of 1921, an unlikely team consisting of Frederick Banting, a newly established physician specialising in orthopaedics and a professor of physiology, and Charles Best, one of his lab assistants who was an undergraduate student studying physiology and biochemistry, worked together in a lab near Tononto, Canada provided by John Macleod, a professor of physiology. Banting and Best developed a technique to extract pancreatic secretions from dogs' pancreases and then inject this solution they called ‘isletin’ into other dogs whose pancreases had been removed. The 14 November 1921 is the day that Banting and Best officially presented their initial findings that isletin reduced the blood glucose levels at a small scientific meeting. This day now marks the celebrations for World Diabetes Day. However, more work would be needed before isletin would be used in humans. The early formulations caused infections and death in many of the animals that received it (Bliss, 1993).

Historical insulin injections

On the 11 January 1922, Leonard Thompson, a 14-year-old boy with diabetes who was severely unwell with high glucose levels, was injected with Banting and Best's formulation of isletin at the Toronto General Hospital in Canada. This is a historical milestone in diabetes care and is widely regarded as the first time insulin was injected into a person as a treatment for diabetes (Schadewaldt, 1989). However, the reduction in blood glucose was minimal and no clinical benefits were observed. Leonard also developed a sterile abscess at an injection site from the impurities in the solution. Use of that formulation was put on hold (Li, 2021).

A significant step occurred when Dr James Collip, a physiologist working with the team, developed a technique to purify these ‘isletin’ extracts. This purified extract was injected into Leonard Thompson on 23 January 1922 and was successful in significantly reducing his glucose levels and improved his physical state and energy levels. This is regarded to be the first successful use of ‘isletin’ in humans. Further tests on six other patients lead to similar results (Rosenfeld, 2002; Li, 2021).

The team of Banting, Best, Macleod and Collip, also known as the ‘Toronto Team’, changed the name of their extract to ‘insulin’ to align it with a term that had previously been used by European researchers studying the pancreas. Best and Collip were granted a patent for insulin. This patent was transferred to the University of Toronto for $1 with the aim that insulin could be made available to everyone who needed it. Banting and Macleod were awarded a Nobel Prize in 1923, which they shared with Best and Collip (Bliss, 1993).

While these achievements by the ‘Toronto Team’ are hailed as the ‘discovery of insulin’, other researchers had made significant discoveries that receive less attention. For example, a researcher named Nicolae Paulescu, based in Europe, had developed a similar extract, ‘pancreine’ which he had tested in humans and published the results between July and August 1921 (Schadewaldt, 1989). While his contributions may have informed the work done by the Toronto Team, Paulescu's discovery is, controversially, not as widely recognised (Bliss, 1993; Karamitsos, 2011; Ionescu-Tirgoviste and Buda, 2017).

Since the Toronto Team's historical injections of insulin into Leonard Thompson, they and many other scientists have continued making significant scientific discoveries that have led to purer forms, such as the modern insulins that are produced on a global scale (Table 1).

While the first insulins derived from pig (porcine) and cow (bovine) pancreases kept people with diabetes alive, their actions were unpredictable. People routinely developed insulin allergies and infected injection sites due to impurities in these initial formulations (Tibaldi, 2012). The insulin only lasted 6 hours, so multiple injections were required.

Notable discoveries relating to the development of insulin that also led to Nobel Prizes were made by Frederick Sanger, a English biochemist who identified the amino acid sequence of insulin. He was awarded the Nobel Prize for Chemistry in 1958. Dorothy Crowfoot Hodgkin, an English chemist, who identified the three dimensional structure of insulin using X-ray crystallography won a Nobel Prize for Chemistry in 1964 (Tattersall, 2017).

To support people with diabetes who use insulin, it is important to understand the action profiles of different insulins:

• Onset: when does it start working?
• Peak: when is its peak of action?
• Duration: how long does it last?

This information can be used when trying to identify why glucose levels may be rising and falling and inform which insulin dose to change (see Figure 1). For example, knowing the onset of rapid acting insulin (i.e. it starts working approximately 15 minutes after it is injected) is why people with diabetes are advised to inject this insulin 15 minutes before they eat. Understanding the insulin action profiles can help health professionals and people with diabetes to better understand and predict changes in blood sugar levels.

Figure 1. Insulin action profiles

Insulin delivery devices

The way that insulin is delivered has also evolved since its discovery. Glass syringes with large and long reusable needles that required sharpening were the only tools available to people with diabetes. These were replaced by single-use, plastic insulin syringes to draw up insulin from 10 ml vials. The lengths of the needles have reduced from the standard 12 mm lengths to more comfortable 4 mm, 6 mm and 8 mm options. Reusable and disposable insulin pens with pen needles were introduced in 1981 (Tattersall, 2017). These have enabled people with diabetes to dial-up their insulin doses and are widely used for insulin delivery in higher income countries. Figure 2 shows the evolution of insulin delivery devices.

Figure 2. The way that insulin is delivered has also evolved since its discovery. a) Insulin being drawn up from a vial, b) A selection of insulin pens, c) An insulin pump.

The landmark Diabetes Control and Complications Trial (DCCT) and the follow up Epidemiology of Diabetes Interventions and Complications Study (EDIC) convincingly showed that intensively managing glucose levels in people with type 1 diabetes and reducing HbA1c levels decreased the risks of developing microvascular complications like retinopathy, neuropathy and nephropathy, and also stopped their progression in people who already had these complications (Nathan, 2013).

This evidence has shifted insulin regimens from the ‘conventional therapy’ of twice daily injections containing a mix of short- and long-acting insulins to ‘intensive management’ that involves one or two injections of long-acting (background or basal insulin) and injections of short-acting insulin with meals and snacks (Gough and Narendran, 2017). The trade-off of taking more injections can provide people with diabetes with more flexibility to increase or reduce their insulin based on the amount of carbohydrate they eat. Structured education programmes like Dose Adjustment For Normal Eating (DAFNE) teach people about self-managing their diabetes and train them to alter their insulin doses based on their meals, activity levels, and illness for example (DAFNE Study Group, 2002).

Intensively managing diabetes can involve taking 4 or more injections per day. Insulin pumps provide an alternative approach by constantly delivering a rapid-acting insulin into the subcutaneous tissue. Insulin can also be manually delivered with meals. Insulin pumps remove the need to inject insulin and led to sustained benefits in glucose control (Anyanwagu et al, 2017). Eligibility for insulin pumps in England and Wales depends on criteria set by the National Institute for Health and Care Excellence (2008).

Monitoring blood glucose

Technologies to monitor glucose have also advanced over the past 100 years. In 1921, the Toronto Team could measure blood glucose using a 0.2 ml sample, whereas Paulescu needed a 20 ml blood sample (Karamitsos, 2011). Self-monitoring of blood glucose (SMBG) has enabled people with diabetes to independently measure their blood glucose levels and adjust their insulin according to these measurements (Ajjan et al, 2019). In 2021, people with type 1 diabetes can use glucose sensors to continuously or intermittently measure their interstitial glucose levels. Commercial and Do-It-Yourself hybrid-closed loop systems are now used in a small percentage people with type 1 diabetes to automatically adjust insulin delivery based on sensor glucose readings (Jennings and Hussain, 2020).

Insulin accessibility and affordability

Unfortunately, many people living with diabetes are still unable to access affordable insulin, technologies and the support needed to self-manage their diabetes (Beran et al, 2016). People living in Lower and Middle Income Countries (LMIC) face a range of barriers that prevent them from accessing insulin as detailed by this woman who describes her experience of living with diabetes in Ghana:

‘Insulin is not available to every diabetic in Ghana. For those in the rural areas, access to constant supply of insulin is almost impossible. People living with type 1 diabetes have to travel from far places in order to obtain their insulin. Available ones are too expensive for universal affordability. Though the National Health Insurance Scheme (NHIS) provides patients their insulin, it is only a part payment of the total cost. Insulin pens and pumps are very expensive. These items are almost surreal to us and most diabetics have never seen them before. In a country such as Ghana with its erratic power supply, keeping insulin cool is another issue a diabetic has to contend with. Patients who are able to afford insulin have trouble preserving it because there is inconsistent supply of electricity.’

Bimpeh Amoah, 2016

In the US, the cost of acquiring insulin for those with and without health insurance has increased substantially in recent years (Luo et al, 2017). In total, 25% of people surveyed in studies based in the US (Herkert et al, 2019) and globally (Pfiester et al, 2021) reportedly under-used insulin due to its cost. Under-use of insulin was associated with poorer glycaemic control (Herkert et al, 2019). While calls to address these problems have been made, little progress appears to have been made (Rajkumar, 2020).

Conclusion

Nevertheless, advocacy groups like T1 international (https://www.t1international.com) continue to campaign for affordable insulin and access to healthcare and technologies for people with diabetes around the world. Associations for people with diabetes started approximately 5 years after insulin began being used to manage diabetes. The first diabetes association was formed in Lisbon, Portugal in 1926. By 1934, the Diabetic Association (now called Diabetes UK) was established in the UK. These groups and associations continue to provide important outreach, support, education and advocacy (Tattersall, 2017). They will play an important role in the struggle to ensure that people across the world can access affordable insulin. This would truly honour what Banting, Best, Macleod and Collip achieved 100 years ago.

KEY POINTS:

• Before the discovery of insulin, the prognosis for people living with diabetes was very poor
• Everyone with type 1 diabetes, except those who have received pancreas or islet-cell transplants, and more than half of people with type 2 diabetes use insulin to manage their diabetes
• The way that insulin is delivered has also evolved since its discovery, and technologies to monitor glucose have also advanced over the past 100 years
• On a global level, many people living with diabetes are still unable to access affordable insulin, technologies and the support needed to self-manage their diabetes

CPD reflective practice:

• How has the discovery of insulin impacted the lives of people living with diabetes?
• Do you understand the action profiles of different insulins?
• How has monitoring of blood glucose changed over the years?