The Beginning

Frederick Banting with Dog

Frederick Banting – Co-discoverer of insulin.

Insulin, a hormone naturally produced in the pancreas, has been available since the 1920’s.  Research into the development of insulin has driven scientists to take significant steps towards understanding human biology and a few Nobel Prizes have been awarded for research into this very important hormone.  Insulin has been a life extender and lifesaver from the early days when in 1921 Dr Frederick Banting and medical student Charles Best performed experiments on the pancreases of dogs in Toronto, Canada.

One of the precursor experiments was performed by Romanian professor Nicolae Paulescu, in 1916, who developed an extract from the pancreas of dogs and showed that it lowered the blood sugar in the diabetic dogs. World War I prevented the experiments from continuing and it is not until 1921 that Paulescu published evidence derived from the experiments. Banting and Best were provided with a laboratory by Professor John Macleod to carry out experiments that eventually showed that when the pancreases were removed from dogs, they showed symptoms of diabetes.  The removed pancreases were used to develop an injectable format and injected into the dogs several times a day, which helped the dogs regain their health.

Professor Macleod then continued the experiments with cows, developing the first beef insulin and now the extract is formally called “insulin.” Once the insulin was purified for human testing, Banting and Best were the first humans to test the insulin by injecting themselves with it which caused them to experience weakness and dizziness, or signs of hypoglycemia. After the pair had experimented enough to gain an understanding of the required doses and how best to treat hypoglycemia, their insulin was deemed ready to be tried on patients.

Animal Insulins’ First Use

Man making insulin from pig parts

Production of animal-based insulin in the 1920’s being made from pork parts.

The first patient to receive insulin was a young adolescent boy with Type 1 diabetes (a type of diabetes where the pancreas in unable to produce insulin), in 1922.  During this time the average client with diabetes would be placed on a starvation diet and often lived only several months.  He The first patient died 13 years after initiation of the insulin therapy, of pneumonia. In 1923 Eli Lilly and Company, began to mass produce insulin derived from the pancreases of pigs and cattle, naming their product isletin.

Because these early animal-based insulins and their actions were of short duration, patients typically took several shots, investigators worked to find ways to prolong the duration of the animal insulin.  In 1936 protamine insulin was developed by Danish physician Hans Christian Hagedorn who discovered the action of insulin can be prolonged with the addition of protamine.  Even longer duration of action could be achieved by adding zinc resulting in the animal insulins semilente, lente, and ultralente which lasted 24-36 hours, depending on the relative amount of zinc.  This led to longer lasting animal insulins.

These later 3 insulins were used for many years but were discontinued in the mid-2000s with the advent of better profile insulins.  NPH insulin was created in 1946.  NPH stands for “neutral protamine (a fish protein) Hagedorn (after it’s discoverer).  It is an intermediate-acting insulin because it begins its action after about 1 to 2 hours, peaks at 4 to 12 hours and lasts more than 14-24 hours.  In 1950 Novo Nordisk, the second insulin manufacturer began marketing its’ NPH.

Human Insulin is Developed

Humulin R Vial 100 Units / mLIn the 1980s, the first generation of synthetic man-made insulin, called “human insulin,” was created. This man-made insulin was genetically identical to the body’s naturally produced insulin.  This synthetic insulin was a better alternative to animal insulin as it had the advantage of being less likely to cause allergic reactions.   The body recognized animal insulins as foreign “protein” and formed antibodies against it.  Human insulin was also more easily absorbed.  Mixtures of bovine and pork insulin were often less expensive than human insulin in the 1990’s.

To make these human insulins, recombinant DNA techniques were utilized consisting of altering genetic material outside an organism to obtain more enhanced and desired characteristics in living organisms. It was genetically engineered using “E. coli bacteria.”  Humulin R and Humulin N were then created by Eli Lilly and Company in 1982, followed by Novolin R and Novolin N by Novo Nordisk.  But when it is injected under the skin it doesn’t work as well as natural insulin. This is because injected human insulin clumps together and takes a long time to get absorbed. The activity of this synthetic human insulin is not well synchronized with your body’s needs.

Creation of Premixed Insulins

Humulin 70 / 30Pre-mixed insulins were now possible and had the advantage of combining the longer-term effects of N and the shorter-term effects of R, providing a “basal” insulin dose to last all day and bolus insulin for coverage for meals.  Resulting insulins included:  Novolin 70/30 which was 70% N or intermediate acting and 30% short acting Regular, Humulin 70/30 and Humulin 50/50.

Pre-mixed insulins are usually prescribed for patients needing a simple insulin treatment plan, and sliding scale therapy. Sliding scale therapy means that a person with diabetes can increase the administration of the pre-meal insulin dose based on the blood glucose level prior to the meal. The benefit of pre-mixed insulin is that the fast- and long-acting insulin is combined. No mixing of the insulin is necessary, and there is only one injection.  This category of patients includes those patients who are older and have regular meal and activity patterns, have diminished vision, or trouble with manipulation and coordination skills, or are just starting insulin therapy.

The disadvantage with the Human insulin NPH was that it had a relatively unpredictable action and at the time was the only intermediate-acting insulin that was available.  The protamine is a suspension of several different sized crystals that result in a cloudy insulin that must be resuspended prior to use by gentle rolling or turning. These variable crystal sizes result in an unpredictable absorption rate and action.  When the dose in a mixture is increased or decreased, the amount of both short acting insulin and long-acting insulin changes, and this results in an increased risk of both high and low blood sugars.   Because of the above factors, the use of NPH has declined as newer more predictable insulins have been developed.

Fast-Acting Analog Insulins Come Along

Human insulin was then genetically modified to improve how the insulin was absorbed, distributed, metabolized, and excreted.  The result was called “analog insulin” and Eli Lilly marketed it in 1996 by the name of Humalog, the first rapid-acting insulin.  Humalog insulin was followed by the invention of another fast-acting analog, Novolog by Novo Nordisk about the year 2000.  Apidra was subsequently developed by Sanofi-Aventis in 2004.   These synthetic-made insulins are called “analogs” of human insulin, but they have small structural or amino acid changes that give them special desirable features when injected under the skin. Once absorbed, they act on cells like human insulin, but are absorbed from fatty tissue more predictably.  Insulin injections are given subcutaneously into the fatty layer beneath the skin.

AdmelogHumalog (Insulin Lispro) Insulin Vials, another rapid-acting insulin was marketed in 2017 as a biosimilar drug to Humalog but made by Sanofi Aventis.   It is not quite identical due to the complex manufacturing process. A 5thh fast-acting insulin by the name of Lyumjev was introduced in 2020 by Eli Lilly.  It contained the same active ingredient as Humalog, but it had an additional ingredient that helped it absorb into the body more quickly. It also reduced blood sugar spikes 1 to 2 hours after meals better than Humalog.

Analog insulin is a sub-group of human insulin. Analog insulin is laboratory grown but genetically altered to create either a more rapid acting or more uniformly acting form of the insulin. Advantages of this include more predictable blood sugar levels, flexibility of timing of basal analogs, less fear of dose adjustments, mealtime administration of prandial (pre-meal) analogs, as well as user-friendly.  Insulin analogs are now replacing human insulin just like human insulin replaced beef and pork.

Insulin analogs have been developed because human insulins have limitations when injected under the skin. Because human insulin (as well as animal insulin) is in high concentrations when in a vial or pen cartridge, it tends to clump together. This clumping causes slow and unpredictable absorption from the subcutaneous tissue.  The greater the dose the longer the duration of action. In contrast, insulin analogs have a more predictable length of action. The fast-acting insulin analogs work more quickly, and the long-acting insulin analogs last longer and have a more level, and even a “peakless” effect.

Long-Acting Analogs Follow

Lantus Vial and Lantus SoloStar Insulin Injectable Pen (insulin glargine)The 6 available long-acting insulin analogues include: Lantus by Sanofi-Aventis and Levemir by Novo Nordisk each developed respectively in 2000 and 2005. Toujeo became available in 2015 as a successor to Lantus.   Lantus and Levemir insulin forms clusters when it is injected under the skin. As the individual insulin units detach from the cluster, the insulin analog can be absorbed into the blood stream. The slow break-up of the insulin cluster gives insulin glargine its long action.  Tresiba by Novo Nordisk was launched in 2013.  It is the first basal insulin that allows the patient to dose any time of the day.  In 2017 Eli Lilly began selling its biosimilar Basaglar long-acting insulin, a follow-up to Sanofi-Aventis Lantus insulin. Basaglar comes at a lower cost than Lantus.

Newer pre-mixed analog insulins combine an intermediate-acting insulin, NPH to form Novolog 70/30 (70% NPH; 30% Novolog), Humalog 50/50 and Humalog 75/25 with rapid=acting.   However, the long-acting insulins such as Lantus and Levemir cannot be mixed in the same syringe with any other insulin.  NPH is the only insulin that can be mixed with short or rapid-acting insulin, but this can result in an unpredictable response.  Newer premixed insulin can lower A1c and blood sugar after meals more than long-acting insulin. But long-acting insulin is better at lowering blood sugar before eating.  Newer premixed insulins (such as those mentioned above) are more likely to cause very low blood sugar and can also cause more weight gain than long-acting insulin.

But when comparing newer premixed insulin such as Novolog 70/30 (as an example) and premixed NPH/regular insulin, the different types of premixed insulin work about the same with respect to lowering A1C, lowering pre-meal blood sugar, episodes of hypoglycemia and weight gain.  But long-acting insulin is better at lowering blood sugar after eating.

The benefit of most insulin is that most of these are now available in pen format and rapid-acting insulins like Humalog, Novolog, and Apidra can be used in insulin pumps.  Because the pump delivers small amounts of insulin every few minutes the longer acting insulin is not needed.