2 - The Production of Insulin (w/ Aliza Herman!)
2. The Production of Insulin
Three years of Nobel Prizes were directly related to insulin. Today, we’ll discuss what insulin is and why it’s important. Why did the world need a steady supply of insulin? Why did insulin lead to a 1923 Nobel Prize in Medicine or Physiology? How does diabetes play into all of this? Let’s learn to be scientifically conversational.
General Learning Concepts
1) General background on insulin and why insulin is important
a. What is insulin? Insulin is a hormone (chemicals that one part of your body releases to message other parts of your body; adrenaline is an example) made by the pancreas that helps glucose in your blood enter cells in your muscle, fat, and liver, where it’s used for energy. It was discovered in 1922.
b. What is the pancreas? A gland (ductless organ) located deep in the belly. It’s a part of the digestive system and important for the endocrine system (produces an enzyme, protein, that breaks down food in the (small) intestine) and incredibly important for blood sugar levels (produces a hormone).
c. What is glucose? A form of sugar. It comes from the food you eat. Cells need energy to do work; a primary way to do it is with glucose. Blood sugar is the measurement of how much glucose is in your blood per unit volume.
d. What is diabetes? Diabetes is a disease that occurs when your blood glucose, also called blood sugar, is too high. The issue is that your body either doesn’t make enough insulin (or any at all) or doesn’t use insulin well. There is also gestational diabetes (when a woman is pregnant), but that won’t be extensively discussed today.
i. Type I: Your body does not make insulin, or insufficient amounts. The immune system attacks and destroys the cells in the pancreas that would make insulin. Usually diagnosed at a young age, but not always. These individuals require external insulin to survive.
ii. Type II: Your body does not use insulin efficiently. Can be developed at any age, but tends to be more of an issue with middle to older aged people.
iii. Dangers of Diabetes: Can lead to heart disease, stroke, kidney disease, eye problems, dental issues, nerve damage, and issues with ones’ feet.
2) Why did the world need a steady supply of insulin?
a. Historical understandings of diabetes. Understood as a health risk from as early as medical texts from Egypt in 500 BC, ancient India and China. Life expectancy for those with type I insulin was short and prognosis for adult onset diabetes was not good.
b. Long-term Trends in diabetes. New England Journal of Medicine publication in 2017, contact is first author Dr. Mayer-Davis at UNC Chapel Hill, states: In the United States, 29.1 million people are living with diagnosed or undiagnosed diabetes, and about 208,000 people younger than 20 years are living with diagnosed diabetes.
i. The SEARCH for Diabetes in Youth study, funded by the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH), found that from 2002 to 2012, incidence, or the rate of new diagnosed cases of type 1 diabetes in youth increased by about 1.8 percent each year. During the same period, the rate of new diagnosed cases of type 2 diabetes increased even more quickly, at 4.8 percent. The study included 11,244 youth ages 0-19 with type 1 diabetes and 2,846 youth ages 10-19 with type 2.
ii. Some of this may be from recognizing cases that may not have been detected before but because diabetes is so dangerous but sometimes autoimmune attacks don’t kill off the beta cells in equal numbers. “These findings lead to many more questions,” said Barbara Linder, M.D., Ph.D., senior advisor for childhood diabetes research at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. “The differences among racial and ethnic groups and between genders raise many questions. We need to understand why the increase in rates of diabetes development varies so greatly and is so concentrated in specific racial and ethnic groups.”
iii. These differences saw the smallest increase in whites and largest increases in native Americans (type 2), Hispanics (type 1), Asian Americans / Pacific Islanders (type 2). It even varied between genders, with more cases in males than females (2.2 / 1.4 percent, type I).
iv. A simple line plot shows incidence of diabetes in the US increasing from 1% of the population in 1958 to nearly 8% in 2015.
3) The Nobel Prize and the work behind it
a. What is the method to produce insulin? Techniques developed in the late 1970’s, here referred to as molecular cloning, allowed for the large-scale production of insulin.
i. Molecular cloning: DNA is a book of instructions that allows for tiny, biological machines called proteins to be made. When the human body uses DNA to make insulin, one of these so-called biological machines (proteins), it does it in a very regulated way. Don’t make too many! This is similar for other mammals like dogs, cows, rabbits. However, bacteria (another domain of life) can be made to produce huge scales of protein and because they divide so quickly you can get literally billions of bacteria overnight. The trick is to give E. coli the chapter of our instruction book (piece of DNA) that expresses human insulin, which bacteria of course do not produce. We can take that chapter of our book, put it into a bacterial book, and then sneak that book into the bacterial library (genome) and game the system so they’re always reading that book. They produce huge amounts of human protein; we can crack open the bacterial cells and take that protein, clean it up, and give it to diabetics.
ii. The process to make large quantities of insulin from the original work from Banting and Macleod’s Nobel Prize was difficult, as molecular cloning as we understand it did not yet exist. According to the magazine Diabetes Forecast, it took nearly two tons of pig parts to produce 8 ounces of purified insulin.
b. Who is responsible for insulin production as we know it? Frederick Grant Banting, born in Ontario, and John James Rickard Macleod, a department head at the University of Toronto, received the Nobel Prize for their work on Diabetes and Insulin in 1923. However, this process was fueled from many understandings before Banting and Macleod’s time, and aided from two major other contributors: a student assistant named Charles Best and a biochemist named James Collip. The discovery and work that was required to produce pure enough insulin to treat a 14-year-old boy in 1922 produced tension and animosity between the scientists: enough to bring in a mediator to hear the story of the production of insulin from Banting, Best, and Macleod.
c. Did prescribed insulin work from the purifications before 1959? Sometimes! You can probably guess why; type II diabetes doesn’t necessarily respond to an increase of insulin. Mitchell Lazar, an endocrinologist at the University of Pennsylvania, says that the current treatment for type 2 diabetes—insulin injections when blood-sugar readings deviate from safe levels—works about as well as yelling into a malfunctioning telephone receiver. Beyond this, people were still at risk from allergic reactions to animal insulin. (1959 is an important year because Solomon Berson and Rosalyn Yalow [Bronx Veterans Administration Hospital], demonstrate the existence of two main types of diabetes. Yalow won the Nobel prize in 1977 in Physiology or Medicine, winning without Berson who died in 1972, for the development of a technique that allowed for measurements of tiny amounts of biological substances in fluids like blood – including insulin and other hormones)
4) Fun Tidbits
a. Why are dogs always mentioned during insulin production? The connection between pancreatic secretions and diabetes was first shown in 1889 by two German physiologists at the University of Strasbourg, Oskar Minkowski and Joseph von Mering. While investigating the effect of pancreatic secretions on the metabolism of fat, they performed a complete pancreatectomy on a laboratory dog, only to discover that the animal developed a disease indistinguishable from diabetes. They were further used by Banting and Best for tests.
b. Eli Lilly and Company is still around! They were involved in the production of insulin, manufacturing some of the doses of the Salk vaccine for polio, and numerous antibiotics. They are also credited in being instrumental for producing the first human insulin, approved by the FDA in 1972. Eli Lilly received FDA approval for CGRP type migraine prevention drug known as Emgality in 2018.
5) Solicited Naïve Questions
a. Why does my diabetic friend need to prick their finger? To measure one’s own blood glucose. One is capable of pricking other locations, like the abdomen, arm, or thigh.
b. What happens while a diabetic is sleeping? Type 1 diabetics at both a young and older age report worse sleep than those without diabetes (control subjects). There are reported hormonal differences (not just including insulin, which we previously discussed was a hormone). Being hypoglycemic, or not having enough glucose in the blood, can be a cause for waking up seen by crying out during sleep, excessive sweating, having nightmares, or excessive tiredness and can result from not eating enough carbohydrates, skipping meals, large amounts of physical activity, being sick, or excessive alcohol. There are non-diabetic versions of hypoglycemia but they are rare.   
c. Can diabetes be treated by diet? Can type II diabetes be “beaten”? An uncontrolled, non-randomized trial of only 30 people published in Diabetes Care with researchers from Newcastle University, the University of Glasgow, and Lagos University showed some successful work of 40% of the patients when using a very low-calorie diet. This is a highly idealized situation was only measured for 6 months post the very low-calorie diet step. This low-calorie diet was to 700 calories a day (eight weeks), which is a traditional way of treating those who are morbidly obese, followed by 6 months of diet control.
i. Before insulin treatment, low-calorie diets were the only way to treat type I diabetes and lessened symptoms at the cost of health and energy from the patient. It also didn’t necessarily always work.
ii. Type II diabetes can be treated with insulin but is not always effective. Exercise and diet are important for slowing the progression and severity of diabetes. UCSF says Type 2 diabetes is a genetic condition or pre-disposition that doesn’t change with treatment. But diabetes is defined as an elevated blood sugar. When your blood sugar is normal with no treatment, then the diabetes is considered to have gone away. However, even when the blood sugars are controlled, because type 2 diabetes is a genetic condition, the predisposition for diabetes always exists. High blood sugars can come back. It’s challenging to split the environmental factors that cause diabetes from the genetic factors.
Dr. Adam Lauring shared a nice video on why it’s important to fund basic science research that works very well at this topic. You can find the video at this link.