There are two main types of diabetes: type 1 and type 2. With type 1, your body stops making insulin due to an autoimmune reaction (the body attacks itself by accident) against beta cells in the pancreas. With type 2, it still makes insulin, but your body doesn't use it efficiently. So, with type 1, you need insulin injected into your body daily or you will die. You may not even know you have type 2 because of a range of severity; it begins slowly over time and affects mostly adults. Women may also contract diabetes when they are pregnant.
Pancreatic islet cells from human stem cells used to treat diabetes (sciencenews.com)
The number of people in the world with type 1 diabetes was 9 million in 2017 (WHO), with most living in high-income countries. There is no known cause. Overall, including type 2 diabetes, the number rose from 200 million in 1990 to 830 million in 2022. Over 2 million died in 2021, and other consequences of diabetes can be blindness, kidney failure, heart attacks, stroke and lower limb amputation. Clearly, controlling diabetes is very important across the globe.
The pancreas is the gland that makes insulin, which is a hormone. The pancreas is also an organ that is part of the digestive system because it makes various enzymes that break down food in the first section of the small intestine called the duodenum. Insulin is made by beta cells, which are part of a cluster of cells called the Islets of Langerhans.
Location and anatomy of the human pancreas (Wikipedia)
The body breaks down carbohydrates, fats, and proteins into smaller chemical compounds that become easier for cells to use. The small intestine absorbs most of the food breakdown products, and special cells help these nutrients cross the intestinal lining so they go into the bloodstream. From there, the blood carries them to places where they are used or stored. Carbohydrates are broken into sugars like glucose, proteins are broken into amino acids, and fats are broken into fatty acids and glycerol.
Inside the small intestine, the inner layer is made of tiny folded ridges called villi. Each of these villi has even more, smaller ridges called microvilli. From there, the epithelial cells take glucose from the intestine and pass it to capillaries or the lymph system.
Cross-section of the small intestine, closer look at the microvilli and glucose uptake
(Modified from Wikipedia)
Glucose is your body’s main source of energy. Insulin helps it to get inside cells so they can use it. Below are 2 diagrams to show this. The one on the left is a simplified one; the one on the right shows more details.
How insulin acts to bring glucose into cells (modified from news-medical.net)
- Left diagram: Insulin and glucose have separate receptors that attach to them on a cell surface. Insulin binds first and opens the glucose receptor to let it enter.
- Right diagram: (1) insulin binds to its receptor. (2) that causes the receptor to change on the inside portion. (3) The change sends biochemical signals to a glucose transporter called GLUT4 inside cells. It floats on standby until this happens and is attached to a membrane bubble called a vesicle. (4) When insulin receptors change inside the cell, a signal is sent to move the GLUT4 vesicle to the cell membrane where it fuses. Now, GLUT4 acts as a gateway to let only glucose inside the cell.
How did we learn about the pancreas and insulin?
An Egyptian document described a condition where patients produced excessive urine. Physicians of the 5th and 6th century BCE first noticed that some people had urine with a sweet taste and called the condition madhumeha ("honey urine"). Chinese doctors described a "wasting thirst" which included excessive thirst and urination. The Greeks named the condition diabetes from a word meaning "to pass or run through". Diabetes mellitus was given as the full name from the Latin word meaning "honeyed" or "sweet". But until the late 19th century, the pancreas was not thought to be involved.
In 1869, Paul Langerhans, a German medical student, discovered two different groups of cells in the pancreas: one produced fluids for digestion, and the others (named the islet cells after his name) which had an unknown function. But, in 1889, two German scientists Oskar Minkowski and Joseph von Mering removed the pancreas from a dog and observed that the dog then developed diabetic symptoms, suggesting it was an important organ for controlling blood sugar. Eugene L. Opie as a medical student at Johns Hopkins University noticed in 1900 that islet cells were damaged in people who had diabetes (probably type 1), so the islet cells were thought to produce insulin. From 1899 to 1906, many researchers investigated the different cell types in the pancreas by staining them with different chemicals. In 1906, pathologist and anatomist Lydia DeWitt tied off the pancreatic duct in cats and noticed that even though this caused damage to the pancreas and its digestive function, it didn't stop glucose metabolism (by insulin, which had not yet been isolated). Islet cells secrete it directly into the bloodstream from surrounding capillaries. These and other findings narrowed down the source for insulin.
Minkowski (left) and von Mering (right) (from the FDA "100 Years of Insulin")
Canadian physician Frederick Banting and University of Toronto researcher John Macleod were the first to extract insulin successfully in 1921 from islet cells, not whole pancreases. They worked initially on live dogs as sources, then switched to fetal calves from a slaughterhouse. Banting and Macleod's team was using the name "isletin" for the chemical they had isolated because it came from islet cells in the pancreas. But the term "insulin" was being used in Europe more commonly since 1916 when Belgian researcher Jean de Meyer, had already proposed the term “insulin”, from insula (Latin for “island,”).
Notebook entry from Banting's lab with dog subject. Note the word "isletin" used. (Harvard Countway Library)
The work was done at Connaught Laboratories, part of the Department of Hygiene at the U of Toronto. After promising results of injecting the insulin into dogs and rabbits, the first human test subject was in 1922.
(left) Banting's laboratory; (right) Connaught Laboratories insulin extraction equipment (University of Toronto)
But their method (patented in 1923) to produce insulin couldn't provide a large quantity. American pharmaceutical giant Eli Lilly and Company took over, and with its access to slaughterhouses, they were able to source thousands of pounds of pig and cattle pancreases as sources of insulin. Their product Iletin was the first commercially available insulin. Even though it was a mixture of pig and cattle insulin, it was still effective in humans, and the mixture's content differed depending on which animal pancreas was more available at the time.
Package of Iletin from Eli Lilly (collection.sciencemuseumgroup.org.uk)
In the 1940s-1950s, pig-derived insulin was found to have fewer allergic reactions, and by the 1970s-1980s most or all of Lilly's insulin came from pig pancreases. The next phase in insulin production came in 1975 at the birth of the recombinant DNA revolution. The Swiss company Ciba-Geigy created the first synthetic insulin, and it was from human DNA. In 1978, Genentech demonstrated how this could be made by E. coli bacteria after the gene was inserted. The first human trials took place in 1980. The next 5-6 years saw several companies learning to produce it this way.
One-minute explanation of making recombinant human insulin. (YouTube)
Currently, cellular production is the commonest method to produce recombinant insulin. E. coli and two types of yeast contribute equally to the world's supply. Three pharmaceutical companies manufacture 90-96% of it, making marketing and sales concerns problematic.
There are 5 types of insulin used by patients depending on a variety of factors. They involve how fast they take effect and how long they stay active: rapid-acting, short-acting, intermediate-acting, long-acting, and ultra-long-acting. Type 1 diabetes patients usually need injections 1-2 times a day. Type 2 patients might need only the long-acting type. To get it into the body, there are 3 basic devices: syringe, pen, or subcutaneous pump. There is even an inhaler with powdered insulin.
Insulin delivery systems
A fifth method is experimental at this time. Instead of injecting or inhaling insulin itself, the new treatment involves transplanting insulin-making cells. Here are three examples.
- CellTrans, Inc. Lantidra is a recently FDA-approved (2023) cell therapy which takes pancreatic cells from deceased donors and infuses them into type 1 diabetics.
- ViaCyte. Another proposed cell therapy method is to put cells in a membrane capsule which is implanted in the body. These are stem cells from embryos that were stimulated to become pancreatic cells. The membrane is like Gore-Tex and allows blood vessels to grow across the walls and through the cell mass, but not to allow the body's immune system to contact the encapsulated cells.
Encapsulation system from ViaCyte (Cell Reports Medicine, 2021)
- Vertex Pharmaceuticals. A third cell therapy system involves taking healthy adult bone marrow donors' cells, isolating mesenchymal stem cells, and programming them like the embryo stem cells mentioned above, so that they transform into beta-like cells which respond to glucose in the blood. These cells naturally settle in the liver instead of the pancreas.
Schematic of removing bone marrow cells to produce cells transformed for transplantation
(BioMedical Research & Therapy, 2021)
Many factors are involved in deciding which treatment for diabetes is best.
- efficacy of the type of insulin
- ease of use (for example, a pen vs an insulin syringe)
- cost (varies by country, but when immunosuppressive drugs are needed for cell therapy, the price is very high)
- availability (sometimes where ethical or religious concerns about the source of insulin or stem cells blocks access)
- patient conditions (age, type, and extent of diabetes)
- doctors' advice
