By MYNDARO 04-22-2021

Diabetes, A Look into the Past

Although we’ve known about diabetes for a long time, the disease has never been as prevalent as it is today. Due to our modern-day indulgence in carbohydrate-rich foods, our world is witnessing an epidemic of diabetes and obesity. In 1500 BCE,1 2 Indian physicians noticed ants were drawn to certain urine. They described this urine as “Madhumedha” or “honey urine.” Again, in 1500 BCE, Egyptians described diabetes as “too great emptying of the urine,” making diabetes one of the first diseases ever described.3 While this description probably refers to Type 1 diabetes, it’s safe to say neither the ancient Egyptians or Indians ever imagined the global diabetes epidemic we face today.
Galen, a prominent Greek physician, named the disease “diarrhea of the urine,” or “diarrhea urinosa.”4 Apollonius of Memphis, a Greek from around 230 BCE, was the first to apply the label “diabetes”. The word “diabetes” means “a siphon” or “a pass through.” The word was used in a text by Aretaeus of Cappadocia, a Greek physician, about the first century BCE to describe the disease as an “excessive discharge of urine.”5 The first time the term was used in the English language was around 1425 CE in a medical text, where it was written as “diabete.”6
A few hundred years before Apollonius, in 400–500 BCE, two Indian physicians, Sushruta and Charaka, had already noted one key difference between type 1 and type 2 diabetes. Type 1 was typically prevalent in younger humans, while type 2 
typically plagued those who were overweight.7 It wasn’t until the late 1700s that John Rolle added the term “mellitus” or “from honey” to the term “diabetes”, giving it the name, as we know it today.
Type 1 diabetes used to be known as juvenile diabetes, childhood-onset diabetes, and insulin-dependent diabetes mellitus (IDDM). Type 2 diabetes has also been labelled as obesity-related diabetes, adult-onset diabetes, and noninsulin- dependent diabetes mellitus (NIDDM). Other than type 1 and type 2 diabetes, no other standardized classification is now used. 

History of Diabetes Treatment

In the seventeenth century, there were two prevalent theories on how to treat diabetes with diet. The first advocated a high- carbohydrate diet to replace sugar lost in urine. The other theory posited carbohydrates should be restricted to cut back on extra sugar. This second theory is likely the first recorded example of the identification of excessive carbohydrates as harmful to diabetics.
But nevertheless, the first theory appears to have been much more popular in the 1700s. The idea of restricting carbohydrates does not resurface for centuries. Proposed bizarre treatments for treating diabetes in the late 1800s included bleeding, doping and even blistering.
Our understanding of glucose metabolism and its regulation has advanced incredibly in the past 200 years, and this understanding has been built upon the visionary research of Claude Bernard. Bernard identified the importance of both the liver and the absorption of ingested carbohydrates in regulating blood glucose levels.12 He determined that the liver is an integral piece of glucose production from non-glucose precursors. From his foundational discoveries, other researchers built upon this knowledge by identifying enzymes responsible for carbohydrate absorption and decomposition, the function of anterior pituitary hormones at diabetes onset and glucose metabolism. Other important hormones like Glucagon and Epinephrine were also discovered to increase the concentration of blood glucose and play a critical role in diabetic hyperglycemia (elevated blood sugar levels).13 14 

Discovery of Insulin and the Role of the Pancreas

In 1889, Joseph von Mering and Oskar Minkowski were the first to recognize the integral role of the pancreas in regulating glucose. The pair removed the pancreases from dogs and noted the fatal diabetes that resulted.15 Later, in 1910, Edward Albert Sharpey-Schafer defined the word “insulin” after hypothesizing that this chemical’s deficiency in the pancreas resulted in diabetes.16 Based on Langerhans, the islet of pancreatic cells, he derived the term “insulin” from the Latin word insula, which means “island.”
Prior to the 1920s, diabetes had no effective treatment. Type 1 diabetes diagnosis was fatal. Prior to insulin, the primary method of diabetes management was a “starvation diet.17
In the decade before the discovery of insulin, prominent American physicians Frederick Allen and Elliott Joslin advocated for severe fasting and undernutrition to prolong the lives of diabetic patients. Allen and Joslin promoted the therapy out of desperation, because no other treatment existed at the time.
Fasting does usually reduce glucose levels in diabetics, but prolonged calorie-restricted diets also introduces new hazards, most obviously death by starvation, which Allen and Joslin bluntly called "inanition." Today, physicians agree that 
calorie restriction is beneficial for overweight diabetics. But even those in Allen’s time understood that, for those of normal or lower weight, severe calorie restriction could lessen resistance to infection and even stunt growth in children. Fasting and undernourishment therapy was a balancing act, overseen by a specialist while the patient remained closely supervised in a hospital or clinic. A permanently calorie- restricted diet was unpleasant, difficult to maintain, and incapacitating. Many patients withdrew from the regimen. Joslin commented retrospectively, “We literally starved the child and adult with the faint hope that something new in treatment would appear...It was no fun to starve a child to let him live.”
Dr. Allen's most famous patient was Elizabeth Hughes, the daughter of Charles Evans Hughes, Governor of New York, Republican candidate for the presidency in 1916, and Chief Justice of the U.S. Supreme Court. Elizabeth developed diabetes in 1919, at age 11. At that time, her height was 4" 11 1/2" and she weighed just 75 pounds. She was treated initially by Dr. Allen, who put her on a week of fasting followed by a diet of 500 calories per day and one fast day per week. This brought her weight down to 55 pounds. Freed of glycosuria (sugar in the urine), her diet was raised to 1,250 calories, except on fast days, and her weight rose to over 60 pounds. At that time, most child diabetics died from coma within a few months or years of diagnosis.

Though an ideal patient, Elizabeth deteriorated seriously by the winter of 1921/22, and her weight dropped to just 45 pounds. Her mother pleaded with Canadian doctor Frederick Banting, a recent discoverer of insulin, to include Elizabeth as a trial patient. The trial proved a marvelous success. Elizabeth regained weight and eventually graduated from college. She married, had three children, and was active throughout her life in civic affairs, all the while on insulin, until she died of pneumonia in 1981 at the age of 73.
Frederick Banting changed the disease’s then-bleak treatment options dramatically. This book would be incomplete without special mention of Banting. His contribution changed the lives of many patients with diabetes. 

         Banting's Idea

 In October 1920, in Toronto, Canada, Dr. Frederick Banting, an unknown surgeon with a bachelor's degree in medicine, had the idea that the pancreatic digestive juices could be harmful to the secretion of the pancreas produced by the islets of Langerhans. This secretion was thought to be the substance which regulates blood glucose levels.

He therefore wanted to ligate the pancreatic ducts to stop the flow of nourishment to the pancreas. This would cause the pancreas to degenerate, making it shrink and lose its ability to secrete the digestive juices. The cells thought to produce an antidiabetic secretion could then be extracted from the pancreas without being harmed.
Early in 1921, Banting took his idea to Professor John Macleod at the University of Toronto, who was a leading figure in the study of diabetes in Canada. Macleod didn't think much of Banting's theories. Despite this, Banting managed to convince him that his idea was worth trying. Macleod gave Banting a laboratory with a minimum of equipment and ten dogs. Banting also got an assistant, a medical student by the name of Charles Best. The experiment was set to start in the summer of 1921.


Banting and Best began their experiments by removing the pancreas from a dog. This resulted in the following: 
  • It's blood sugar rose.
  • It became thirsty, drank lots of water, and urinated more often.
  • It became weaker and weaker.
The dog had developed diabetes. Experimenting on another dog, Banting and Best surgically ligated the pancreas, stopping the flow of nourishment, so that the pancreas degenerated.
After a while, they removed the pancreas, sliced it up, and froze the pieces in a mixture of water and salts. When the pieces were half frozen, they were ground up and filtered. The isolated substance was named "isletin."18 The extract was injected into the diabetic dog. Its blood glucose level dropped, and it seemed healthier and stronger. By giving the diabetic dog a few injections a day, Banting and Best could keep it healthy and free of symptoms.19
Banting and Best showed their result to Macleod, who was impressed, but he wanted more tests to prove that their pancreatic extract really worked. For the increased testing, Banting and Best realized that they required a larger supply of organs than their dogs could provide, and they started using pancreases from cattle. With this new source, they managed to produce enough extract to keep several diabetic dogs alive.
The new results convinced Macleod that they were onto something big. He gave them more funds and moved them to a better laboratory with proper working conditions. He also suggested they should call their extract "insulin." Now, the work proceeded rapidly.
In late 1921, a third person, biochemist Bertram Collip, joined the team. Collip was given the task of trying to purify the insulin so that it would be clean enough for testing on humans.
During the intensified testing, the team also realized that the process of shrinking the pancreases had been unnecessary. Using whole fresh pancreases from adult animals worked just as well.

Testing on Humans
In January 1922 in Toronto, Canada, a 14-year-old boy, Leonard Thompson, was chosen as the first person with diabetes to receive insulin. The test was a success. Leonard, who before the insulin shots was near death, rapidly regained his strength and appetite. The team now expanded their testing to other volunteer diabetics, who reacted just as positively as Leonard to the insulin extract. 20
The Nobel Prize
The news of the successful treatment of diabetes with insulin rapidly spread outside of Toronto, and in 1923 the
Nobel Committee decided to award Banting and Macleod the Nobel Prize in Physiology or Medicine.
The decision of the Nobel Committee made Banting furious. He felt that the prize should have been shared between him and Best, and not between him and Macleod. To give credit to Best, Banting decided to share his cash award with him. Macleod, in turn, shared his cash award with Collip.21 

The Promise of Insulin 

Banting, Macleod, and the rest of the team patented their insulin extract but gave away all their rights to the University of Toronto.

Very soon after the discovery of insulin, the medical firm Eli Lilly started large-scale production of the extract. As soon as 1923, the firm was producing enough insulin to supply the entire North American continent. 
A bolstered interest in insulin’s chemistry and biology arose from its rapid discovery and successful effect on human health. In 1926, insulin was crystallized for the first time.22 This made the substance purer and allowed researchers to develop time-action profiles. Before extended-action insulin, diabetics required daily injections and even often had to wake up in the middle of the night for treatment. When children weren’t woken up for injections, they might suffer from diabetic dwarfism (Mauriac syndrome), or severely stunted growth. The first commercial extended-action insulin, Protamine zinc
insulin (PZI) hit the market in 1936. Oddly enough, this medication is still used today to treat diabetic cats.
In 1958, Frederick Sanger used insulin to demonstrate how amino acids in proteins are sequenced. He was later awarded a Nobel Prize in Chemistry for this work.23 Rosalyn Yalow and Solomon Berson developed radioimmunoassay in 1959, which allowed the quantitative measurement of the function of animal and human pancreatic beta cells. This tool measured metabolites, proteins, and many more chemicals even in low amounts. This breakthrough regarding the measurement of serum insulin levels has been a primary driver of our current understanding of diabetes.24 25
In 1983, recombinant human-sourced insulin was approved for commercial use.26 Recombinant DNA technology allows scientists to clone and produce insulin for therapeutic purposes and provides us with a virtually endless supply of insulin. Insulin was the first hormone to be produced using this method, and the biotechnology industry expanded rapidly because of this breakthrough. Before the invention of this process, all insulin had been primarily derived from cattle and pigs. But thanks to this advancement, the race to develop a long acting basal insulin and fast-acting mealtime insulin, which were similar to physiological insulin secretory patterns by the pancreas, accelerated quickly.
Lispro, the first fast-acting hormone that artificially mirrored human insulin, was approved in 1996. Aspart and glulisine (two other rapid-acting insulins) and glargine, detemir, and degludec (long-acting basal analogs) have followed Lispro’s discovery in the last 20 years.
Exciting advancements in the delivery and administration of insulin have also been invented. These include syringes, pumps, a closed-loop delivery system, and inhaled insulin. Today, insulin is one of the most predictable and effective
treatment methods for type 1 and type 2 diabetic patients. Insulin treatment is the most reliable of all contemporary antihyperglycemic agents in most but not all cases. 

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