Insulin is one of the most powerful drugs the medical community can use against diabetes. In this month’s article on landmark drugs, Jenny Bryan looks at the history of insulin

Now, 90 years after it was first used to treat diabetes, insulin keeps nearly a million people in the UK alive, and no product has ever been subject to such prolonged and intensive post-marketing development. Indeed, insulin pioneers, Banting and Best, would be hard-pressed to recognise the life-saving therapy with which they revived a wardful of dying children with diabetes in 1922.

Simon Heller, professor of clinical diabetes and director of R&D at Sheffield Teaching Hospitals Foundation Trust, explains that the past 30 years have seen the introduction of human insulin, pens, pumps and analogue insulins, all of which have had a huge impact on the lives of people with diabetes. But he regrets the shortfalls in education and training about insulin use, which continue to prevent many patients from getting the best from their treatment.

“Insulin is one of the most powerful drugs that people can use. It saves lives but it can also kill, and it has major limitations if it isn’t used properly. Patients get shown how to use it in outpatients, but it’s a complicated business to match your insulin dose to your carbohydrate intake and exercise, and to do that every day for the rest of your life. So high quality, peer reviewed, structured training shouldn’t be an optional extra, it should be a right for everyone who is prescribed insulin,” says Professor Heller.

Insulin, fame and fortune

Banting and Best will be forever linked to the introduction of insulin treatment, but other key players struggled for recognition in the decades following the breakthrough.1 Canadian surgeon Frederick Banting approached John Macleod, professor of physiology at Toronto University, in 1921 for laboratory space to experiment with new techniques to extract islet cells from the pancreas.2

The importance of the cells in diabetes had been known since the early 1900s, but previous efforts to use them for treatment had been thwarted by pancreatic enzymes that broke down the islet extracts when whole pancreatic samples were administered.2 Banting got his facilities, some dogs for his studies, and the services of medical student Charles Best. They ligatured the pancreatic ducts of one of their animals, thereby halting production of digestive enzymes, shrinking the pancreas, and making it easier to remove the islet cells.2 Purified islet extract was injected into other dogs following pancreas removal, restoring glucose control and relieving diabetic symptoms.

Biochemist Bertram Collip joined the team to purify more insulin and, in January 1922, this was injected into a 14-year-old boy who was dying from diabetes.2 The first dose had no clinical effect, but the boy responded well to subsequent, more concentrated doses and, within a short time, dozens of children were successfully treated. The 1923 Nobel Prize in Physiology or Medicine was awarded to Banting and Macleod. Banting shared his prize money with Best, and Macleod split his with Collip. The key players gave away their patent rights — and potential fortune — to the University of Toronto, but wrangled for decades over whose contribution had been greatest.1

Eli Lilly was contracted to develop a standardised product and, during the first five months of 1923, distributed over seven million units of insulin, some of which came to the UK.

Porcine or bovine insulin was used in the early trials, which confirmed the efficacy of short acting insulin and, by the mid 1930s, Hans Christian Hagedorn and other researchers at Nordisk (now NovoNordisk) in Denmark had found ways to mix insulin with protamine to prolong its activity3 and later produce it in a crystalline formulation, marketed in 1950 as neutral protamine Hagedorn (NPH) insulin, also called isophane insulin.

The arrival of human insulin

Lilly’s introduction of genetically engineered human insulin in 1982 heralded the start of the modern era of insulin therapy. It was naturally assumed that administering human insulin would yield better responses than bovine or porcine insulin but, as Professor Heller recalls, that was not the case.

“Unfortunately, patients were rather pushed on to human insulin and, following the switch, there was an increase in reports of hypoglycaemia. Some people asked to go back to pig insulin, but it’s only a small minority who aren’t on human insulin today. The great thing about human insulin wasn’t that it was better than animal insulin, but that we now had an infinite supply and were no longer reliant on pigs and cattle.”

During the late 1980s and early 1990s, evidence accumulated that some patients experienced a loss of “hypo” warning signs when switched to human insulin, and that warning symptoms were different from those with porcine insulin. Around the same time, research showed that intensive treatment for type 1 diabetes patients, and then those with type 2 diabetes, could reduce long-term complications,4,5 so patients were encouraged to achieve tighter glucose control, which also had the downside of more hypos. Although the Medicines Control Agency (now the Medicines and Healthcare products Regulatory Agency) carried out a review that concluded that the safety of human and animal insulin was comparable, the debate rumbled on.

Insulin analogues

The arrival of the next big thing in insulin therapy — insulin analogues — replaced the human insulin controversy with a new one that continues to this day over whether the advantages of the analogues justify their extra cost.

Insulin analogues were designed with one or more amino acid changes to the polypeptide chains of human insulin, aimed at improving absorption and duration of action.

First to market in 1995 was the short-acting analogue insulin lispro, marketed by Lilly, soon followed by Novo Nordisk’s insulin aspart and then by the long-acting analogues, insulin glargine and insulin detemir. In 2006, a Cochrane analysis concluded that short acting analogues conferred only minor benefits in terms of HbA1c control and hypoglycaemia over regular human insulin in type 1 and type 2 diabetes patients.6 A subsequent comparison of long-acting insulin analogues and NPH in type 2 diabetes showed significantly lower rates of overall, symptomatic and nocturnal hypos in patients using analogue insulin but, again, the benefits were considered only minor.7

“Insulin analogues haven’t revolutionised treatment, but they’ve certainly made a difference for patients, who get fewer hypos with them. The fast-acting analogues work more quickly than short-acting human insulin and wear off more quickly, so there’s less accumulation. There’s also a modest advantage for some patients who take long-acting analogues overnight and fast-acting analogues at mealtimes, but it’s essential that people understand how to use them correctly,” explains Professor Heller.

Long-term impact of DAFNE

Dose Adjustment For Normal Eating (DAFNE) structured education for insulin users started in the UK in 2000, and is based on a successful five-day training programme used in Germany since the 1980s that produced sustained improvements in glycaemic control without increasing severe hypos.8

DAFNE educates patients to adjust their insulin to fit their lifestyle and diet rather than the reverse. Patients are trained to match their insulin to their desired carbohydrate intake on a meal-by-meal basis, and an early study showed that patients who received DAFNE training experienced improved dietary freedom and quality of life, and glycaemic control, without any worsening of severe hypos or cardiovascular risk.9

Subsequent research has shown that clinically relevant improvement in glycaemic control can be achieved up to seven years after patients attend DAFNE courses,10 although follow-up support is recommended.11

“Over 20,000 adults have now received DAFNE training and, although 10 to 20 per cent lap it up, about 80 per cent struggle and need further help. It takes doctors and nurses who specialise in diabetes years to understand insulin fully, so I don’t know why patients are expected to get it right straight away,” points out Professor Heller.

Insulin pumps the answer?

Like structured training programmes, insulin pumps have been used to improve insulin use and glycaemic control since the early 1980s, but uptake remains disappointing.

Professor Heller considers insulin pumps the best way to deliver insulin because they enable patients to adjust their dose minute by minute, but only about 3 per cent of type 1 diabetes patients in the UK are using them, compared with 20 per cent in the US. Increasingly sophisticated, a new generation of closed loop devices automatically adjusts insulin dose in response to glucose levels. But, as Professor Heller points out, they are not for everyone, even if cost was not an issue.

“People who do well on pumps tend to be the same people who do well with conventional injections and, unfortunately, those who find injections difficult don’t tend to do any better with pumps. Some people find pumps too invasive and others are nervous that a pump could ‘run away with itself’ and deliver too much insulin,” he says.

For Professor Heller, the holy grail of insulin therapy remains delivery of insulin in the place where it is needed — the liver — at the time it is needed — the moment food arrives. “We’ve come a very long way since those first injections in 1922. We’ve virtually removed the risk of late stillbirth in pregnant women with diabetes, and we’ve halved the rate of kidney damage, but about 20 per cent of diabetes patients end up blind, with amputations or die early because they never get their glucose right. Insulin therapy is a very crude approximation of beta cell activity, and we’re still not putting insulin where it’s most needed, even with pumps. In the 1980s, I predicted we’d have the cure for diabetes in 20 years, but here we are in 2012, and I find myself saying the same thing: ‘It’ll be another 20 years’.”

References

1 Bliss M. Rewriting medical history: Charles Best and the Banting and Best myth. Journal of the History of Medicine and Allied Sciences 1993;48:253–74.

2 Banting FG, Best CH, Collip JB et al. Pancreatic extracts in the treatment of diabetes mellitus. Canadian Medical Association Journal 1922;12:141–6.

3 Lawrence RD, Archer N. Zinc protamine insulin. BMJ 1937;1:487–91.

4 Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine 1993;329:977–86.

5 Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. The Lancet. 1998;352:837–53.

6 Siebenhofer A, Plank J, Berghold A et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database of Systematic Reviews 2006;(2):CD003287.

7 Horvath K, Jeitler K, Berghold A et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2007;(2):CD005613.

8 Mühlhauser I, Jorgens V, Berger M et al. Bicentric evaluation of a teaching and treatment programme for type 1 (insulin-dependent) diabetic patients: improvement of metabolic control and other measures of diabetes care for up to 22 months. Diabetologia 1983;25:476.

9 DAFNE Study Group. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. BMJ 2002;325:746.

10 Gunn D, Mansell P. Years after dose adjustment for normal eating — glycaemic control and weight 7 years after dose adjustment for normal eating (DAFNE) structured education in type 1 diabetes. Diabetic Medicine 2011 Dec 1. doi: 10.1111/j.1464-5491.2011.03525.x. (Epub ahead of print).

11 Rankin D, Cooke DD, Clark M et al. UK NIHR DAFNE Study Group. How and why do patients with type 1 diabetes sustain their use of flexible intensive insulin therapy? A qualitative longitudinal investigation of patients’ self-management practices following attendance at a dose adjustment for normal eating (DAFNE) course. Diabetic Medicine 2011;28:532–8.