A Brief History of Diabetes Mellitus
A Brief History of Diabetes Mellitus
Welcome to Diabetes and Medical my friend. You’ve made an excellent choice by taking the initiative to learn about Diabetes. As the ancient philosophy goes: “Knowledge is Power.” Having a general overview of Diabetes is very important for learning how to control diabetes so it doesn’t control your life or the life of a loved one.
Origins of the words: "Diabetes Mellitus"
So, what is Diabetes Mellitus? The word “diabetes” refers to increased urination. The word “Diabetes” goes back thousands of years ago when it was first described in Egypt, and then by Arataeus of Cappadocia in the 2nd century AD. The Greek word “Diabetes” means a syphon, since it was believed that a person’s fluid would go right through them, as though through a syphon. Many other physicians throughout the centuries have described the symptoms of Diabetes Mellitus but had no specific cure or remedy for diabetes. The treatment plan for diabetes mellitus throughout history ranged from drinking more water to help supplement the fluid loss, to actual starvation of a person in the 19th century. It has been only in the last 100 years that great strides in the understanding of Diabetes Mellitus have been made. A lot of this advancement has been done with the discovery of insulin, which we’ll discuss in greater detail later on.
From here on out throughout this course, when we discuss Diabetes, we’ll be referring to Diabetes Mellitus and NOT Diabetes Insipidus. These are two different medical conditions. Diabetes Mellitus is a problem with the balancing of blood glucose while Diabetes Insipidus is problem with too little of Anti-Diuretic Hormone being produced by the body, resulting in too much fluid loss.
Cause of Increased Urination in Diabetes Mellitus
The increase in urination in Diabetes Mellitus is actually caused by a problem of too much glucose found inside of the blood, glucose levels that are NOT normal. Blood glucose levels will normally fluctuate on a consistent basis throughout the day, however, there is a balance of blood glucose in the blood that MUST be maintained in order for the body to function properly. High levels of blood glucose overwhelms the body’s ability to compensate for it, causing glucose to go right through the urine and not be reabsorbed as it normally should be. This leads to the second part of the medical term in Diabetes Mellitus, which is the mellitus portion. The “Mellitus” word means “sweet urine.” The sweet urine is caused by the kidney’s inability to effectively reabsorb all of the excess sugar going through the kidneys, leading to urine that is sweet to the taste. Back 100 years ago, one method of diagnosing Diabetes Mellitus was by tasting the urine of the patient and finding out if it’s sweet or not (in addition to the other symptoms of diabetes).
In the 17th and 18Th century in Europe, diabetes was being investigated by physicians as people began to get easier access to food and drinks (drinks such as wine). As Thomas Willis in the 1600’s described it, he indicated that diabetes was a disease that was rarely seen, but was now seen more often as a variety of foods began to be consumed more frequently (the types of foods and how often a person would eat those foods).
During the 1700s and going into the 1800s, a treatment for diabetes was essentially lacking. Physicians would describe the symptoms of sweet urine in patients with diabetes but wouldn't know the cause of diabetes. The physicians merely functioned as learning about diabetes and writing down the symptoms, but no actual life changing treatment was used at this time. Some physicians would even evaporate the urine in person with diabetes, leaving behind the glucose that was found in the urine, as done by Matthew Dobson in 1776. Mr. Dobson also first described hyperglycemia (high blood glucose) as well, which he published in 1776.
The term “Mellitus” in Diabetes Mellitus was first described by a surgeon named John Rollo. The adjective “Mellitus” was adapted from the latin word meaning “honey” since the urine of patients with diabetes was sweet. After that Diabetes Mellitus became the standard definition that has been used by medical professionals thereafter.
In the 19th Century, physicians and chemists were focusing their attention on identifying the sugary substance in the urine of patients with Diabetes. It was a French Alchemist by the name of Michel Chevreul who identified that the sugary substance in the urine of patients with diabetes was in fact glucose. The first methods at collecting blood glucose were very brute in the 1800s, requiring a lot of blood samples and highly skilled chemists to analyze the glucose. Significant progress in analyzing blood glucose occurred in 1913 when a physician by the name of Ivar Christian Bang created a method to measure glucose repeatedly and required only small volumes of blood was needed. In fact, the glucose tolerance test that is used to diagnose diabetes today was actually invented between 1913-15.
The storage form of blood glucose was found by a Frenchman named Claude Bernard. Mr. Bernard was looking at finding how the sugar can be synthesized by plants and came across the discovery in 1846-48 that blood sugar remained in the blood between meals. He discovered large quantities of glucose in the liver and called it “glycogen.” From here on, that’s where the word glycogen comes from. He hypothesized that glucose gets absorbed into the bloodstream from the intestines where it is converted into the storage form of glucose in the liver called glycogen. This glycogen is then released steadily into the blood during periods of fasting (NOT eating).
During the late 1800s and early 1900s, there were a lot of investigations into the role and function of the pancreas in diabetes. Many clinicians and physiologists would look into removing the pancreas of animals and see how their body responded. This usually resulted in the animal becoming incontinent because of all the excess urine (the animals became diabetic).
In 1869, Paul Langerhans discovered the “islands” of cells in the pancreas that seemed to release substances into the blood but didn’t know the real function of these “islands of cells.” In honor of the discovery of these “islands of cells” in the pancreas, they were called the “Islets of Langerhans” by Gustave Laguesse in 1893. It was also in 1893 that Gustave Laguesse believed that these little “islands” inside the pancreas were responsible for secretions. The secreted substance from these Islets of Langerhans was later hypothesized to be glucose-lowering internal secretions, and in 1909 was named “insuline” by a Belgian named Jean de Meyer. Insuline in Latin means “Island,” named in honor of the Islets of Langerhans. Insulin is now known in fact to be that glucose-lowering substance that is secreted into the bloodstream by the pancreas.
Figure 1 – The Islets of Langerhans found in the Pancreas
Physicians in the 19th century were essentially powerless to treat or cure diabetes. The role of the pancreas and insulin in diabetes were still being learned about in the late 1800s and early 1900s. Physicians were left with merely writing down their observations about the causes of diabetes and hypothesizing which organs were responsible for the symptoms of diabetes. In the late 19th century, physicians would give their patients various extracts such as sheep thyroid extract or testicular extracts in order to find out what they did for diabetes symptoms. Clinicians hypothesized that the brain, liver, and pancreas were involved in diabetes. Based upon their experiments, other clinicians suspected that the thyroid, pancreas, and parathyroid glands were also involved in diabetes.
Complications of Diabetes
In the late 1800s, physicians wrote about the complications of diabetes beyond the increased urination and sweet urine. Eduard von Jaeger was the first to described diabetic retinopathy in 1869, which is damage to the blood vessels of the eye caused by diabetes. Other researchers such as Sir Edward Nettleship and Stephen Mackenzie in the late 1800s also described the microaneurysms in the retina of the eye, and later found them to be related to diabetes. The term “Diabetic Retinopathy” was described in 1890 by Julius Hirschberg and claimed that the retinopathy he observed was connected to diabetes.
The neuropathic (nerve) symptoms of diabetes were also described in the late 1800s. In 1885, Frederick Pavy described the neuoropathic symptoms of diabetes (neuropathic = disease of the nerves). This physician wrote about his patients with diabetes showing symptoms of “lightning pain” in their legs or the legs feeling heavy, numb, or darting feelings as well. In addition, he also described the increased pain sensations that occur during a simple touch of the skin (called hyperesthesia).
The kidneys of person’s were also investigated, and the findings were published in the medical literature as well. In 1859, Wilhem Griesinger looked at the kidneys of adults (from 64 autopsies) and found that the kidneys had damage to them caused by hypertension (high blood pressure) and atherosclerosis (hardening and narrowing of the arteries). However, the connection of this type of kidney damage with diabetes was not made until the 1930s.
The Treatment Methods of Diabetes
The physicians of the late 1800s noticed that there seemed to be different types of diabetes, even subtypes of diabetes. One such physician, Dr. Etienne Lancereaux in 1880 classified diabetes of persons of lean and obese body types.
The treatment strategy for diabetes in the early 1900s was rather brutish. At that time, the basic treatment strategy of physicians was a starvation method. A person with diabetes would have their calories per day severely restricted in order to decrease the symptoms of diabetes (ketoacidosis, increased urination – we’ll talk about these later on).
The starvation method for treating diabetes was first started in 1875 by Apollinair Bourchardat, and later implemented in the clinical treatment of diabetes by Frederick Madison Allen and Elliott Joslin in the early 1900s. Dr. Joslin was one of the most important researchers and clinicians in diabetes care research at that time. He analyzed many people with diabetes in the early 1900s and wrote extensively about his findings. His treatment of choice for diabetes was intensive exercise and caloric restriction. Unfortunately, many of his patients with Type 1 diabetes were extremely underweight, looked pale and fragile, had a low quality of life, and many of them diet of malnutrition complications. The reason for the starvation method of treating type 1 diabetes (unknown as Type 1 Diabetes to the researchers at that time) was because the insulin extraction method from the pancreas was very inefficient and very difficult to extract.
Since the late 1800s, between 1889-1921, the attempts to reliably isolate insulin (to lower blood glucose) from the pancreas of animals was unsuccessful. The insulin extracts were either inactive or had unacceptable side effects. For this reason, the diagnosis of diabetes was considered a “death sentence” because no effective treatment or cure was available at that time. Persons with Type 1 Diabetes were sent to hospital wards to live out the rest of their days, oftentimes starving to death or succumbing to complications from diabetic ketoacidosis (we’ll discuss this in more detail later on).
The First Successful Use of Insulin in a Person
Up until 1922, the methods for the extraction of insulin in order to lower blood glucose was highly unsuccessful. Insulin extraction from animal pancreases was inefficient. However, the treatment for diabetes took a dramatic turn for the better when two Canadian researchers, a surgeon Frederick Banting and Charles Best in January 1922 were able to isolate insulin from dog and beef pancreases. The researchers used the pancreas from a pancreatized dog and beef pancreas to isolate the extract. They eventually refined the process and were able to isolate a purer form of insulin from the pancreas. The first clinical trial of this was performed on a 14-year old boy in January 1922 with successful results. This boy was undergoing the current diabetes starvation treatment method. Over a 10-day course of insulin treatment, the boy was given a series of injections of insulin and the results were amazing. The researchers found a clinical improvement in symptoms. The increased glucose in the urine was gone as well as the ketone bodies in the blood as well. The results were a success. After publication of this clinical trial in the Canadian Journal of Medical Association in March 1922, the research into insulin isolation took off due to the excellent clinical results of insulin on patients with diabetes.
Insulin production took off very quickly in the United States and in Europe. By October 1923, insulin was widely available throughout North American and in Europe. A medical breakthrough in diabetes care took place and millions of lives have been vastly improved as a result! The two researchers, Banting and Best shared a Noble Price for Physiology or Medicine in 1923 as two other researchers involved, Banting and McLeod.
The effects on insulin for treating diabetes was revolutionary. Clinicians found that it was necessary to inject insulin in varied amounts and on a consistent basis throughout the day. The effects of low blood sugar (hypoglycemia) were also an important concern. The regular use of insulin injections in the short-term resulted in a dramatically improved clinical situation for those with diabetes. Person’s with diabetes were being treated with insulin now, which resulted in an improved quality of life and living longer. However, living longer with diabetes means that the complications of uncontrolled diabetes will start to show themselves as well. This is essentially what occurred after the first widespread use of insulin in 1923. Persons with diabetes were living longer and were showing the long-term effects of diabetes, which were the complications such as kidney disease, eye disease, neuropathy (disease of the nerves).
Researchers and clinicians realized that the treatment for diabetes shifted from a death sentence to one of persons living with the chronic complications of diabetes. As a result, the strategy of diabetes care expanded and took on a different direction. The treatment focus shifted towards treating the long-term complications of diabetes.
After the successful first use of insulin in treating diabetes in the early 1920s, research into diabetes really took off. It was found that diabetes is in fact not a single type of disease, rather diabetes is a medical condition of different “types” of diabetes. In the 1930s, Wilhem Falta and Harold Himsworth proposed the idea that there are generally two types of persons with Diabetes: Type 1 and Type 2 Diabetes.
Type 1 Diabetes - those where are sensitive to the glucose lowering effects of insulin and require injecting insulin to maintain appropriate blood glucose levels. Persons with Type 1 Diabetes were found to have a leaner body type and needed insulin to prevent ketosis (ketone bodies in the body) from occurring.
Type 2 Diabetes - those with insulin resistance. This form of diabetes is called insulin-insensitive diabetes and persons who have type 2 diabetes initially do not require the use of injected insulin. Those with Type 2 diabetes who did not require insulin were usually found to be of older age, were obese, and were not as big of a risk for ketosis compared with those who did require insulin.
In Type 2 diabetes research in the 1970s by Ralph DeFronzo, this researcher was able to measure the effects on insulin action on blood sugar and this showed some interesting results. From there on during the 1970s, many studies were done to find the relationship between insulin resistance and vascular disease with Type 2 Diabetes. It was found that the insulin-producing cells in the pancreas, (called the Beta-Cells) were not working correctly and were contributing to the insulin resistance in the body. Insulin resistance is when the body is unable to effectively use insulin to put glucose into the cells in order to lower the blood glucose to normal levels (during fasting and mealtimes). In addition, a specific subtype of Type 2 Diabetes was discovered in 1974 called Mature Onset Diabetes of the Young (MODY), which is a less common form of Type 2 diabetes.
Type 1 Diabetes and Insulin Production in the Pancreas
Ever since the successful widespread use of insulin to treat Type 1 Diabetes in the 1920s, researchers didn’t really know what actually caused Type 1 Diabetes. They knew that the body needed insulin in order to survive but didn’t know why the pancreas was not producing enough insulin. Since the early 1900s it was believed that the pancreas was having a “insulitis” where the immune cells of the body were causing inflammation of the pancreas. However, it wasn’t until 1979 when Deborah Doniach and GianFranco Bottazzo came up with the theory that the beta cells in Type 1 Diabetes were being destroyed by the person’s own immune system (an autoimmune reaction).
Researchers also found that persons with a new diagnosis of Type 1 diabetes would go through a “Honeymoon phase” of diabetes, where the antibodies that were destroying the beta cells in the pancreas would disappear. This ‘Honeymoon” phase in new onset Type 1 Diabetes could even last for years. In light of this discovery, researchers tried various medications to extend this honeymoon phase, using such drugs such as cyclosporine. Cyclosporine, a potent immunosuppressive prescription medication, would prolong the honeymoon phase but the effect would stop working once the medication was discontinued. Other drugs such as nicotinamide and small doses of insulin during the new onset diagnosis of Type 1 Diabetes were also tried in the honeymoon phase but were not successful in humans.
Islet Cell Transplantation
Research into islet cell transplantation has been looked at for decades. Starting with Paul Lacy in 1967, “cures” for type 1 diabetes were done in inbred rats. However, in humans, islet cell transplantation has NOT been able to show positive results in curing Type 1 Diabetes. Another attempt at islet cells transplantation was done in 2000 in Canada, however after 5 years, 80% of those people were actually able to produce their own insulin, but only 10% were able to produce enough of their own insulin to function without having to inject insulin. There is a lot research that is still needed in order to cure Type 1 Diabetes with islet cell transplantation.
The Discovery of Alpha and Beta Cells in the Pancreas
Researchers knew that insulin was secreted from the Islet Cells of Langerhans in the Pancreas, however they didn’t know from which area. It wasn’t until 1938 that Frank Young and his colleagues found that the Beta cells in the pancreas were responsible for insulin secretion (the beta cells in dogs they researched on that had been damaged due to the injection of anterior pituitary extract, causing permanent diabetes in the dogs). This Beta cell theory was confirmed in 1959 by Paul Lacy. In addition, the counter-regulatory hormone Glucagon was also identified and found to be secreted from the Alpha Cells in the pancreas as well (from the Islet Cells of Langerhans)
In the late 1960s, researchers looked more into the structure of insulin and were able to recreate of what the insulin structure looks like. The complete insulin molecule was made from amino acids by Wan Ying-Lai in 1965 (in Shanghai, China).
The amino acid sequence of human insulin was described in 1980. In 1985 the insulin receptor was cloned, and the amino acid sequence of the receptor was also done. These discoveries with insulin and its structure allowed for the creating of medications to treat diabetes (type 2) in the future.
Conclusion
Sergio, Pharmacist
Reference:
Tattersall, RB., (2017). The History of Diabetes Mellitus. In R.I. Holt, & C.S. Cockram, & A. Flyvbjerg, & B.J. Goldstein (Eds.), Textbook of Diabetes (pp. 3-22). Wiley-Blackwell.
