An Interview with Professor Manuel Varela: Who was Frederick Banting, and what does he have to do with Insulin and Diabetes?

Jun 24, 2019 by

Frederick Banting

Michael F. Shaughnessy –

1) Professor Varela- we have heard those terrifying words- often misunderstood by non-medical personnel- and those words are DIABETES.  First of all, I know there are different types – but could you elaborate on these different types (Type 1, Type 2)? DIABETES.  First of all, I know there are different types – but could you elaborate on these different types (Type 1, Type 2)? 1) Professor Varela- we have heard those terrifying words- often misunderstood by non-medical personnel- and those words are DIABETES.  First of all, I know there are different types – but could you elaborate on these different types (Type 1, Type 2)?

The medical disease called diabetes has been a scourge for centuries. In many developed countries it’s considered a major health problem, affecting approximately 5 percent of the world’s human population. Diabetes can be defined in patients as having an excess of the sugar called glucose, in the blood. The technical name for the illness is diabetes mellitus, in which the term diabetes itself refers to the excessive urination exhibited by patients whereas the term mellitus refers to the Latin phrase “sweetened with honey,” as diabetic patients can have detectable sugar in their urine.

Diabetes is a complicated clinical disease involving many aspects pertaining to the function and behavior of the human body. These aspects include diet, obesity, metabolism, biochemistry, autoimmunity, chronic inflammation, genetics, infection, and medicine.

As you mentioned in your question above, there are, in general, two types of diabetes, type 1 and type 2.  Type 1 diabetes is generally known as insulin-dependent diabetes mellitus (IDDM). Type 2 diabetes is known also as non-insulin-dependent diabetes mellitus (NIDDM) and insulin-resistant diabetes. Both clinical conditions of diabetes are characterized by abnormal glucose metabolism in which the blood levels of this sugar are elevated above normal concentrations.

Type 1 diabetes typically arises in patients early on in their lifetimes. It affects approximately 0.2 percent of children in the U.S., an incidence rate that has actually doubled in the 20 years between 1999 and 2019. Type 1 diabetes is an autoimmune based disease.  The body seeks out its own pancreas, and destroys the insulin-making islet cells. Thus, type 1 diabetics cannot produce insulin, and it is, thus, required as a daily treatment.

The type 2 diabetes often manifests itself in later stages of a patient’s life. The so-called adult onset of type 2 diabetes is stunning in its incidence and represents a serious public health concern. Approximately 90% of clinical diabetes is of the type 2 variety, and it affects 9% of the world’s population and 10% of the U.S. population. Furthermore, throughout the U.S. it is a major cause of kidney malfunction, blindness, and of amputation. Obesity and chronic inflammation are closely linked with type 2 diabetes. In recent years, however, infection involving Staphylococcus aureus bacteria has also been associated with the onset of type 2 diabetes.

Treatment for diabetes can be somewhat different depending upon whether the patient has type 1 or type 2 diabetes. For type 1 diabetes, treatment lasts a lifetime of the patient and includes activities like daily insulin injections, monitoring the sugar concentration in the blood, and eating a proper diet with regular exercise. The daily insulin dosage will invariably depend upon the individual situation for each patient.

For type 2 diabetic patients, treatment involves management of the illness. This includes maintaining low weight, eating a proper and healthy diet, exercising regularly, monitoring blood sugar concentrations, and perhaps medication such as insulin, and other medications. These other medications may be used for decreasing glucose synthesis in the liver and enhancing the body’s reaction to insulin so that the insulin is used efficiently. Some medications will stimulate more insulin production by the pancreas. A more recent medication is represented by a class of drugs called SGLT2 inhibitors, which are used to prevent the uptake of sugar into the blood. These medications inhibit the activity of a glucose transporter (called SGLT2) in humans.

2) First, let’s talk sugar—how is sugar related to diabetes first of all, and then how is sugar related to insulin?

In general, insulin is a protein hormone that regulates the appropriate levels of sugar in the blood. In diabetes, however, blood sugar levels are elevated, producing symptoms of the disease.

In type 1 diabetes, elements of a patient’s own immune system will attack their own body. This so-called autoimmunity is not a normal process. In this case, it’s the patient’s insulin-producing cells, called beta cells (β-cells) of the pancreas, which are targeted for attack and are destroyed. The pancreatic β-cells have also been referred to as the islets of Langerhans. The attacking autoimmune cells are the individual’s own cytotoxic T-lymphocytes (CTLs), which are a form of white blood cells that are normally used by the body’s immune system to target and destroy harmful antigens. In the case of diabetes, however, the autoantigens are the individual’s own useful, life-necessitating, pancreatic cells, and their destruction by the auto-CTLs is a serious pathological process. These autoimmune system cells, the auto-CTLs, invade the pancreas and turn on a patient’s own macrophages, a condition known as insulitis.

The macrophage activation, in turn, stimulates an immune system-based reaction, called a delayed-type hypersensitivity (DTH) process.  During the DTH response process, small messenger protein molecules, called cytokines, are released and result in the synthesis of so-called auto-antibodies. This is an abnormal process in which the type 1 diabetic patient’s own pancreatic cells are targeted for destruction, because the self-antibodies (auto-antibodies) that were produced are specific for the patient’s own pancreatic β-cells.

The auto-antibodies can turn on an immune system component called complement, which in turn breaks apart the β-cells into cellular debris. Another part of the destructive process involving the β-cells by the immune system is called antibody-dependent cell-mediated cytotoxicity (ADCC).  Whatever the case, complement or ADCC, the pancreatic β-cells are destroyed, and insulin levels in the blood drop down to abnormally low levels. Consequently, blood glucose levels are elevated, and type 1 diabetes ensues.

In the type 2 diabetic patients, their levels of blood insulin are normal or maybe even somewhat elevated. However, such type 2 diabetes patients are non-responsive to the blood insulin, a condition called insulin resistance. The end result is that blood glucose levels become abnormally elevated.

The type 2 diabetes ailment is also associated with a component of chronic inflammation, messenger molecules called the cytokines. These cytokines are small protein molecules, and there are many of these that are involved in the immune system. In our case, the two cytokines that are of prime importance are called tumor-necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The IL-6 and TNF-α cytokines trigger a process called a signal transduction pathway, sometimes called a signaling cascade.

Signaling cascades in general function to activate a physiological system by using an amplification process in which one molecule can activate ten other molecules, and each of these 10 molecules can in turn activate 10 more molecules, and so on.  The end consequence is a massive physiological function that may be turned on, or perhaps turned off, depending on the process in question. In our case involving type 2 diabetes, one cascade is turned on, and another is, thus, turned off. 

The signaling cascade turned on by TNF-α and IL-6 cytokines is called JNK, for c-Jun N-terminal kinase. Activation of JNK cascade turns off the insulin receptor signaling (IRS) process.  The IRS is normally supposed to respond to the blood insulin but doesn’t in type 2 diabetes. Thus the body is unresponsive to insulin (insulin resistance), and blood glucose levels accumulate to abnormally high levels, producing type 2 diabetes.

3) I have heard the insulin is a type of key that unlocks the door so to speak. Is this metaphor or analogy correct?

You are spot on with respect to your key-door insulin assessment. Insulin acts in a manner that is akin to a key. The proverbial door in our case is a protein that resides embedded in the membranes of fat and muscle cells and is referred to as the glucose transporter, known as GLUT4. That is, the door is GLUT4. Without actually entering the cell, the insulin key works to increase the entry of the GLUT4 transporter door into the cell membrane, where the GLUT4 door can then facilitate the entry of glucose from the blood through the channel hole of the GLUT4 transporter and into the cell for metabolism of the intracellular glucose.

The lock in this particular scenario is another membrane-bound protein called the insulin receptor. Activation of this lock opens up several doors. When extracellular insulin binds to its dedicated receptor (the lock), several doors are opened. The first cellular door opening involves the insertion of the GLUT4 glucose transporter that I mentioned above. The insulin key binds to the insulin receptor lock mechanism and opens up the glucose transporter door. This process permits entry of glucose into the cells so that glucose can be broken down biochemically for the generation of energy. This is a normal life-maintaining process.

This insulin-glucose connection involves certain signal transduction processes. One process is called the phosphoinositide 3-kinase (PI3K) pathway, and its activation by insulin receptor binding by insulin results in the activation of protein kinase B (PKB) which, in turn, permits GLUT4 to move into the plasma membrane of the cell. This GLUT4 transporter (door) insertion into the membrane allows the cell to increase the uptake of glucose. Thus, it’s the body’s mechanism for lowering blood glucose.

Insulin opens up other doors. These doors serve other important cellular functions. Two of these important doors are discussed in further detail below.

A second consequence (another door) of insulin activation of the PI3K pathway is the triggering of the enzyme activity of glycogen synthase in liver and muscle. This enzyme activation by insulin involves, however, a different intermediate called glycogen synthase kinase (GSK3).  In this process, glycogen synthase is activated by the GSK3. Thus, excess glucose that enters the cell (e.g., via GLUT4) is stored in the form of glycogen.

Another door, a signal transduction process that’s activated by insulin and its receptor binding is called the receptor tyrosine kinase system. Here, the insulin receptor binding by insulin leads to a series of phosphorylation events at the actual insulin receptor itself, the receptor part that’s on the inside-facing side of the cell. This so-called auto-phosphorylation (putting phosphates upon itself) of the insulin receptor leads to the activation of a cascade called mitogen-activated protein kinases (MAPK), sometimes called the MAP kinase cascade, which in turn ultimately leads to the turning on of the gene expression systems of over 100 different genes! One grand end-result of this insulin-activated cascade system is growth of the cell.

Now, I’ve mentioned above several distinctive ways in which insulin regulates the cellular entry and metabolism of glucose, like in the liver, muscle and in fat cells.  Oddly enough, however, glucose can actually regulate the release of insulin from pancreatic cells. In this process, glucose first enters the pancreatic β-cell via a GLUT2 transporter. The glucose then gets metabolized by glycolysis, the Krebs cycle, and undergoes oxidative phosphorylation to generate ATP energy. The ATP then prevents the exit of potassium ions (K+) from the cell by closing K+ channels. This K+ transport inhibition depolarizes the membrane of the pancreas cell, which in turn activates calcium ion (Ca2+) entry into these cells via their dedicated Ca2+ channels, called voltage-gated calcium channels. The increased entry of calcium results in the release of insulin from the cell. The insulin had been stored inside vesicles within the pancreas cells. The calcium influx causes the intracellular insulin-containing vesicles to move to the membrane and fuse with it, thus, allowing secretion of insulin from the pancreatic cells. 

4) Now I have also heard about pre-diabetes and hypoglycemia and hyperglycemia.  How do physicians test for this?  

Hypoglycemia is characterized by a lower than normal level of glucose in the blood, and hyperglycemia represents a higher than normal blood glucose level. Both of these glucose levels are considered abnormal. Prior to the development of type 2 diabetes, a phenomenon called insulin resistance can first emerge. In this type of pre-diabetic situation, the patient will require more and more insulin to mediate its biological effects, such as those alluded to above, like the GLUT4 transporter membrane insertion, enhanced glucose uptake into cells, increased glycogen production, etc.

During the initial stages prior to the type 2 diabetes onset, the β-cells of the pancreas are actually able to accommodate the increased requirement for insulin in order to maintain normal levels of blood glucose. Eventually, however, the body will not be able to compensate for the insulin resistance, and the body now enters a so-called metabolic syndrome stage.  Others may refer to this stage as syndrome X. In any case, it represents an intermediate state of affairs that are prominent just prior to the onset of the type 2 diabetes.

Patients with metabolic syndrome will exhibit obesity, a higher than normal blood pressure, elevated lipid content in the blood, and elevated levels of blood glucose (hyperglycemia).  This latter situation can be tested for by physicians by performing a so-called glucose-tolerance test. During this test, individuals with metabolic syndrome will have a more difficult time trying to clear glucose from their blood. These patients also have differences in their blood proteins, such as elevated fibrinogen molecules, indicating an abnormal ability with their blood clotting activities. Another abnormal blood protein is C-reactive peptide, indicating that these metabolic syndrome patients exhibit a higher than normal inflammation.

5) What are the signs and symptoms of Type I and Type II diabetes? And how do they relate to hypoglycemia and hyperglycemia?

The symptomology of both types of diabetes, type 1 and type 2, is characterized by excessive thirst, frequent urination (the medical term for this condition is polyuria), and considerable water consumption by the patient (the medical term is polydipsia). These symptoms are the result of an overabundant secretion of the sugar glucose into the urine of a patient, a medical condition referred to as glucosuria or sometimes glycosuria.

The signs and symptoms of hypoglycemia, low levels of blood glucose, can involve anxiety, tiredness, shakiness, paleness of the skin, sweating, hunger, a feeling of irritability, and an irregular heart beat (arrhythmia). Prolonged hypoglycemia can further lead to more serious symptoms, such as confusion, difficulty in seeing clearly, seizures, and unconsciousness. These sorts of symptoms of hypoglycemia can be related to diabetes during treatment when a patient is having trouble adjusting their insulin intake.

The signs and symptoms of hyperglycemia are similar to those of hypoglycemia in that they, too, involve hunger, thirstiness, blurred vision, as well as an additional tingling sensation in the patient’s feet. The patient may also exhibit headache, fatigue, and frequent urination. Both type 1 and type 2 diabetes patients can exhibit the signs and symptoms of hyperglycemia.

6) Let’s link diabetes and insulin to organs in the human body- what are the specific organs involved?

As I mentioned above, insulin is produced by pancreatic β-cells (called islets of Langerhans), and that glucose plays an important role in regulating this insulin production by the pancreas. Let’s take a look at this relationship in a normal scenario that occurs after the consumption of a meal. Nutrients such as amino acids and sugars in the gut enter the blood and then go to the liver. This presence of glucose is a situation stimulates the pancreas to produce insulin and to secrete it.

The secreted insulin in turn now regulates the intracellular concentration of glucose in fat cells (called adipose tissue), the liver, and in muscle, by reporting the status of glucose in the blood. If the glucose concentrations in the blood are higher than normal, insulin then reports this blood-sugar occurrence and controls the fat, liver, and muscle cells to increase the uptake of glucose, thus lowering the blood glucose to normal levels. Normal levels of glucose range between 70 and 100 mg/100mL of blood.

In muscle and fat cells, the uptake of glucose, as mediated by the effects of the insulin, results in increased glucose metabolism, and glucose-6-phosphate (G-6-P) is, thus, produced. From this key starting point metabolite, the G-6-P, it can take one of a variety of fateful biochemical routes. Any excess G-6-P that is not used in the muscle can be stored as fat in within the adipose tissue.

In liver cells, insulin also regulates the glucose uptake, but in these cells the G-6-P generated from the excess intracellular glucose that is not used degradatively by glycolysis can then be stored in the form of glycogen.

In brain cells, glucose supplies the energy for neuronal functions. Insulin works in the brain to supply a continual dose of glucose. This is a critical function, as a depletion of brain glucose can be quite detrimental to this important organ. Additionally, insulin works in the brain to thwart the hunger feeling by acting on the hypothalamus.

This process works in the following manner. In certain brain cells called orexigenic nerve cells of the arcuate nucleus, insulin binds to the insulin receptor, which prevents the production of a protein called neuropeptide Y. On the other hand, in so-called anorexigenic nerve cells of the brain, insulin binding to its own receptor turns on the production of α-melanocyte-stimulating hormone (α-MSH), also called melanocortin. Then, the hunger feeling is, thus, alleviated.

Let’s take a look now at the disease process. In the case of untreated diabetes, an abnormal process, insulin may be absent (type 1), or the body may be unable to respond to insulin even though it can be present in the blood, i.e., insulin-resistance occurs (type 2).  In this type 2 insulin-resistant case, the organs and tissues are affected in ways fundamentally different from that seen after a meal in a normal individual. In essence, the body behaves in a fashion similar to that of prolonged fasting in these uncontrolled type 2 diabetic patients.

The lack of insulin (type 1) or an unresponsiveness to the insulin (type 2) results in the cells being unable to mediate the uptake of glucose to use as a fuel for making ATP. This condition can result in a severely detrimental consequence. Cells need glucose in order to survive. Instead, the glucose is aberrantly shunted for excretion, rather than being taken up normally to (and by) the tissues. The resulting lack of cellular glucose requires that the energy for cellular life must now be obtained by other means. Other sources of cellular energy include glucose stored as glycogen in the liver, and a little bit left in the muscles. But the main source of energy stores includes a large amount present within fat cells of adipose tissue. It is this latter alternate source of energy, the fatty acids of the adipose, which now constitutes the grand bulk of the required cellular energy.

In untreated diabetics, the fatty acids are now metabolized for energy. The fatty acids are, therefore, broken down by a biochemical pathway called β-oxidation. This β-oxidation process results in the production of massive amounts of a central metabolite called acetyl-coenzyme A (acetyl-CoA), which is then converted into large quantities of ketone bodies, acetoacetate, and β-hydroxybutyrate.

Each of these new metabolites can have unfavorable outcomes in diabetic patients. Let’s examine a couple of these metabolic fates, and we’ll start with the ketone bodies.

In patients with untreated diabetes, the excess amount of ketone bodies produced is called ketosis. If the ketone bodies are in the blood, it’s called ketonemia, and if present in the urine, ketonuria. Ketosis causes the liberation of new protons and results in an excessive condition of acidity, overwhelming the buffering capacity of the blood’s bicarbonate system. The consequence of this acid production is a lowering effect on the pH number in the blood, a condition called acidosis. The combination of ketosis and acidosis is often referred to ketoacidosis.

Further, the acetoacetate can be readily converted to acetone, which is a very small lighter-than-air type of molecule. The acetone may, therefore, be exhaled by diabetic patients, and occasionally, such patients will smell of acetone in their breath; sometimes the acetone breath is mistaken for alcohol breath.  When combined with a very high blood glucose level, an acetone breath, and a consequent confused mental state, the untreated diabetic patient is prone to misdiagnosis of alcoholism, rather than of the more appropriate diagnosis of diabetes. 

7) Finally a bit about Banting- I know he was born in Canada and spent some time in World War II. Can you give us a brief summary of his life and work?

Frederick Grant Banting was born on the 14th day of November in the year 1891 to Methodist parents Margaret Grant and William Thompson Banting. The Banting family owned a farm near the town of Alliston, Ontario, Canada. Young Frederick was the youngest of five siblings. He completed both elementary and high school in Alliston. After high school, in 1911, he enrolled in Victoria College at the University of Toronto, where he majored at first in divinity. During the course of his undergraduate studies, in 1912, Banting switched his major concentration in order to focus on the study of medicine, and he consequently enrolled in the Faculty of Medicine, a medical school that was housed also at the University of Toronto.

Banting’s decision to become a physician was based on two life-changing events that transpired around him. First, he witnessed a roof downfall in which two workers were injured, and Banting was said to have quickly sought help.  The responding physicians to the scene were reported to have a calming effect in a seemingly calamitous situation, a response which deeply impressed Banting. The second influential event in Banting’s decision to become a medical doctor was the death of one of his very close friends, named Jane, whom Banting watched slowly pass away from the effects of diabetes at the age of 14 years. Banting viewed Jane’s untimely death as needless and resolved to study the pathological nature of diabetes.

While in medical school, in 1915, Banting briefly served in an ambulance corps of the Canadian Army Medical Service as a private and later as a sergeant. Dr. Banting earned an M.B. degree (bachelors of medicine) in 1916 after the faculty at the University of Toronto established an accelerated program, allowing medical students, such as Banting, to graduate one year earlier than scheduled.

Dr. Banting held a post as a physician at Granville Hospital, England until World War I broke out, and he was ordered to serve as a battalion medical officer, in 1918. During Banting’s deployment, he was wounded in the battle at Chambrai, earning the Military Cross medal as a result of his valor during the incident. After the war, Banting moved to Toronto where he worked as a physician intern at the Christie Street Hospital for Veterans, in 1919. Then, in 1920, Banting moved to the Hospital for Sick Children, also in Toronto, Canada. During this time, Banting held a part-time teaching post as a professor at the University of Western Ontario. One of his noteworthy lectures was on the topic of the pancreas, in which his background preparation for the lecture made him a noted expert on the organ. In 1922, Dr. Banting took his M.D. degree from the University of Toronto.

Back in 1920, Banting had formulated a hypothesis that islet cells of the pancreas secrete a substance that could improve the outcome of diabetics. In 1921, Dr. Banting began experiments in the laboratory of Dr. John J. R. Macleod, a professor who was initially skeptical of Banting’s idea but nevertheless allowed him (Banting) use of his (Macleod’s) facilities, and use of the expertise held by a young laboratory assistant Charles Herbert Best. At the time, Mr. Best had been a recent college graduate who had majored in biochemistry and physiology and was a medical student who had later on taken his doctorate of science, (D.Sc.) degree, in 1928. It turned out to be a fortuitous collaboration in 1921 because Dr. Banting provided expert surgical skills, and Mr. Best had an expertise in measuring sugar levels in animal blood and urine samples. It has been reported that as they progressed through their collaborative work, each investigator eventually acquired an astute proficiency in each other’s mode of expertise (surgery versus physiology).

Meanwhile, in the laboratory, in 1921, Dr. Banting and Mr. Best first ligated the pancreatic ducts in anesthetized dogs, leaving the pancreas to atrophy. From these atrophied pancreases, Dr. Banting and Best made a pancreatic extract material and injected it into another dog who had had its own pancreas surgically removed weeks earlier. This pancreas-free dog had been clearly suffering the artificially induced effects of diabetes, as she (the dog was named Marjorie) had had no pancreas. But with the pancreatic extract injection Marjorie improved her behavioral condition within the hour, and her blood sugar levels had increased as a result of the extract injection.

The active ingredient in the pancreatic extract was called “isletin” by Dr. Banting because the material that was involved in effectively treating Marjorie had been derived from the islet cells of the pancreatic organ. We now know that the islet of Langerhans consist of β-cells, which produce insulin.

We also know that α-cells (i.e., alpha-cells) of the islet of Langerhans make glucagon, which is synthesized in response to low blood glucose and which in turn lowers insulin production. The δ-cells (delta-cells) of the pancreatic islet of Langerhans produce somatostatin, which inhibits production of insulin and glucagon and which regulates other molecules such as growth hormone and thyroid hormone.

Unfortunately, Dr. Banting’s isletin extract was only temporarily successful. The laboratory dogs who had undergone the pancreas removal by using surgery (i.e., pancreatectomy) and were later improved by the injected isletin extract needed more of the life-improving substance. In fact, it seemed also that the diabetic dogs needed the isletin on a continual basis. Dr. Banting had further learned that fetal and newborn animals harbored greater concentrations of pancreatic extracts, and that cattle slaughter houses routinely discarded the embryos of pregnant cows who were going to slaughter. Thus, Dr. Banting was able to obtain these cow embryos (instead of letting them be discarded) as a source of the pancreatic isletin-containing extracts.

Using bovine-derived isletin extracts in the laboratory, Dr. Banting and Mr. Best found that they could improve the behavioral and physiological effects of pancreatectomized dogs, just as well. They recorded in their laboratory notebooks that on July 30, 1921, diabetic dog number 410 who had been injected with the cow isletin showed a dramatic lowering of blood glucose! 

Dr. Banting and Mr. Best later repeated the experiment in dog number 92 and found similar outcomes. These findings were to change the course of history. Insulin had been discovered!

Thanks to the investigative work of Dr. Banting, human beings with diabetes could, for the first time in history, actually survive in the face of its terrible effects. Because of the insulin, diabetics could live! Moreover, because of Banting’s daily insulin, diabetics might possibly be able to lead normal lives. Countless millions of lives have been affected in a most positive way. Accordingly, I consider the discovery of insulin an historic medical achievement of epic proportions.

8) What have I neglected to ask about diabetes and its relationship to insulin and the discoveries of Banting (and his colleagues?)

An Interview with Professor Manuel Varela: Who was Frederick Banting, and what does he have to do with Insulin and Diabetes?

Michael F. Shaughnessy

1) Professor Varela- we have heard those terrifying words- often misunderstood by non-medical personnel- and those words are DIABETES.  First of all, I know there are different types- but could you elaborate on these different types (Type 1, Type 2)?

The medical disease called diabetes has been a scourge for centuries. In many developed countries it’s considered a major health problem, affecting approximately 5 percent of the world’s human population. Diabetes can be defined in patients as having an excess of the sugar called glucose, in the blood. The technical name for the illness is diabetes mellitus, in which the term diabetes itself refers to the excessive urination exhibited by patients whereas the term mellitus refers to the Latin phrase “sweetened with honey,” as diabetic patients can have detectable sugar in their urine. 

Diabetes is a complicated clinical disease involving many aspects pertaining to the function and behavior of the human body. These aspects include diet, obesity, metabolism, biochemistry, autoimmunity, chronic inflammation, genetics, infection, and medicine. 

As you mentioned in your question above, there are, in general, two types of diabetes, type 1 and type 2.  Type 1 diabetes is generally known as insulin-dependent diabetes mellitus (IDDM). Type 2 diabetes is known also as non-insulin-dependent diabetes mellitus (NIDDM) and insulin-resistant diabetes. Both clinical conditions of diabetes are characterized by abnormal glucose metabolism in which the blood levels of this sugar are elevated above normal concentrations. 

Type 1 diabetes typically arises in patients early on in their lifetimes. It affects approximately 0.2 percent of children in the U.S., an incidence rate that has actually doubled in the 20 years between 1999 and 2019. Type 1 diabetes is an autoimmune based disease.  The body seeks out its own pancreas, and destroys the insulin-making islet cells. Thus, type 1 diabetics cannot produce insulin, and it is, thus, required as a daily treatment. 

The type 2 diabetes often manifests itself in later stages of a patient’s life. The so-called adult onset of type 2 diabetes is stunning in its incidence and represents a serious public health concern. Approximately 90% of clinical diabetes is of the type 2 variety, and it affects 9% of the world’s population and 10% of the U.S. population. Furthermore, throughout the U.S. it is a major cause of kidney malfunction, blindness, and of amputation. Obesity and chronic inflammation are closely linked with type 2 diabetes. In recent years, however, infection involving Staphylococcus aureus bacteria has also been associated with the onset of type 2 diabetes. 

Treatment for diabetes can be somewhat different depending upon whether the patient has type 1 or type 2 diabetes. For type 1 diabetes, treatment lasts a lifetime of the patient and includes activities like daily insulin injections, monitoring the sugar concentration in the blood, and eating a proper diet with regular exercise. The daily insulin dosage will invariably depend upon the individual situation for each patient. 

For type 2 diabetic patients, treatment involves management of the illness. This includes maintaining low weight, eating a proper and healthy diet, exercising regularly, monitoring blood sugar concentrations, and perhaps medication such as insulin, and other medications. These other medications may be used for decreasing glucose synthesis in the liver and enhancing the body’s reaction to insulin so that the insulin is used efficiently. Some medications will stimulate more insulin production by the pancreas. A more recent medication is represented by a class of drugs called SGLT2 inhibitors, which are used to prevent the uptake of sugar into the blood. These medications inhibit the activity of a glucose transporter (called SGLT2) in humans. 

2) First, let’s talk sugar—how is sugar related to diabetes first of all, and then how is sugar related to insulin?

In general, insulin is a protein hormone that regulates the appropriate levels of sugar in the blood. In diabetes, however, blood sugar levels are elevated, producing symptoms of the disease. 

In type 1 diabetes, elements of a patient’s own immune system will attack their own body. This so-called autoimmunity is not a normal process. In this case, it’s the patient’s insulin-producing cells, called beta cells (β-cells) of the pancreas, which are targeted for attack and are destroyed. The pancreatic β-cells have also been referred to as the islets of Langerhans. The attacking autoimmune cells are the individual’s own cytotoxic T-lymphocytes (CTLs), which are a form of white blood cells that are normally used by the body’s immune system to target and destroy harmful antigens. In the case of diabetes, however, the autoantigens are the individual’s own useful, life-necessitating, pancreatic cells, and their destruction by the auto-CTLs is a serious pathological process. These autoimmune system cells, the auto-CTLs, invade the pancreas and turn on a patient’s own macrophages, a condition known as insulitis. 

The macrophage activation, in turn, stimulates an immune system-based reaction, called a delayed-type hypersensitivity (DTH) process.  During the DTH response process, small messenger protein molecules, called cytokines, are released and result in the synthesis of so-called auto-antibodies. This is an abnormal process in which the type 1 diabetic patient’s own pancreatic cells are targeted for destruction, because the self-antibodies (auto-antibodies) that were produced are specific for the patient’s own pancreatic β-cells. 

The auto-antibodies can turn on an immune system component called complement, which in turn breaks apart the β-cells into cellular debris. Another part of the destructive process involving the β-cells by the immune system is called antibody-dependent cell-mediated cytotoxicity (ADCC).  Whatever the case, complement or ADCC, the pancreatic β-cells are destroyed, and insulin levels in the blood drop down to abnormally low levels. Consequently, blood glucose levels are elevated, and type 1 diabetes ensues. 

In the type 2 diabetic patients, their levels of blood insulin are normal or maybe even somewhat elevated. However, such type 2 diabetes patients are non-responsive to the blood insulin, a condition called insulin resistance. The end result is that blood glucose levels become abnormally elevated. 

The type 2 diabetes ailment is also associated with a component of chronic inflammation, messenger molecules called the cytokines. These cytokines are small protein molecules, and there are many of these that are involved in the immune system. In our case, the two cytokines that are of prime importance are called tumor-necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). The IL-6 and TNF-α cytokines trigger a process called a signal transduction pathway, sometimes called a signaling cascade. 

Signaling cascades in general function to activate a physiological system by using an amplification process in which one molecule can activate ten other molecules, and each of these 10 molecules can in turn activate 10 more molecules, and so on.  The end consequence is a massive physiological function that may be turned on, or perhaps turned off, depending on the process in question. In our case involving type 2 diabetes, one cascade is turned on, and another is, thus, turned off.  

The signaling cascade turned on by TNF-α and IL-6 cytokines is called JNK, for c-Jun N-terminal kinase. Activation of JNK cascade turns off the insulin receptor signaling (IRS) process.  The IRS is normally supposed to respond to the blood insulin but doesn’t in type 2 diabetes. Thus the body is unresponsive to insulin (insulin resistance), and blood glucose levels accumulate to abnormally high levels, producing type 2 diabetes. 

3) I have heard the insulin is a type of key that unlocks the door so to speak. Is this metaphor or analogy correct?

You are spot on with respect to your key-door insulin assessment. Insulin acts in a manner that is akin to a key. The proverbial door in our case is a protein that resides embedded in the membranes of fat and muscle cells and is referred to as the glucose transporter, known as GLUT4. That is, the door is GLUT4. Without actually entering the cell, the insulin key works to increase the entry of the GLUT4 transporter door into the cell membrane, where the GLUT4 door can then facilitate the entry of glucose from the blood through the channel hole of the GLUT4 transporter and into the cell for metabolism of the intracellular glucose. 

The lock in this particular scenario is another membrane-bound protein called the insulin receptor. Activation of this lock opens up several doors. When extracellular insulin binds to its dedicated receptor (the lock), several doors are opened. The first cellular door opening involves the insertion of the GLUT4 glucose transporter that I mentioned above. The insulin key binds to the insulin receptor lock mechanism and opens up the glucose transporter door. This process permits entry of glucose into the cells so that glucose can be broken down biochemically for the generation of energy. This is a normal life-maintaining process. 

This insulin-glucose connection involves certain signal transduction processes. One process is called the phosphoinositide 3-kinase (PI3K) pathway, and its activation by insulin receptor binding by insulin results in the activation of protein kinase B (PKB) which, in turn, permits GLUT4 to move into the plasma membrane of the cell. This GLUT4 transporter (door) insertion into the membrane allows the cell to increase the uptake of glucose. Thus, it’s the body’s mechanism for lowering blood glucose. 

Insulin opens up other doors. These doors serve other important cellular functions. Two of these important doors are discussed in further detail below. 

A second consequence (another door) of insulin activation of the PI3K pathway is the triggering of the enzyme activity of glycogen synthase in liver and muscle. This enzyme activation by insulin involves, however, a different intermediate called glycogen synthase kinase (GSK3).  In this process, glycogen synthase is activated by the GSK3. Thus, excess glucose that enters the cell (e.g., via GLUT4) is stored in the form of glycogen. 

Another door, a signal transduction process that’s activated by insulin and its receptor binding is called the receptor tyrosine kinase system. Here, the insulin receptor binding by insulin leads to a series of phosphorylation events at the actual insulin receptor itself, the receptor part that’s on the inside-facing side of the cell. This so-called auto-phosphorylation (putting phosphates upon itself) of the insulin receptor leads to the activation of a cascade called mitogen-activated protein kinases (MAPK), sometimes called the MAP kinase cascade, which in turn ultimately leads to the turning on of the gene expression systems of over 100 different genes! One grand end-result of this insulin-activated cascade system is growth of the cell. 

Now, I’ve mentioned above several distinctive ways in which insulin regulates the cellular entry and metabolism of glucose, like in the liver, muscle and in fat cells.  Oddly enough, however, glucose can actually regulate the release of insulin from pancreatic cells. In this process, glucose first enters the pancreatic β-cell via a GLUT2 transporter. The glucose then gets metabolized by glycolysis, the Krebs cycle, and undergoes oxidative phosphorylation to generate ATP energy. The ATP then prevents the exit of potassium ions (K+) from the cell by closing K+ channels. This K+ transport inhibition depolarizes the membrane of the pancreas cell, which in turn activates calcium ion (Ca2+) entry into these cells via their dedicated Ca2+ channels, called voltage-gated calcium channels. The increased entry of calcium results in the release of insulin from the cell. The insulin had been stored inside vesicles within the pancreas cells. The calcium influx causes the intracellular insulin-containing vesicles to move to the membrane and fuse with it, thus, allowing secretion of insulin from the pancreatic cells.  

4) Now I have also heard about pre-diabetes and hypoglycemia and hyperglycemia.  How do physicians test for this?  

Hypoglycemia is characterized by a lower than normal level of glucose in the blood, and hyperglycemia represents a higher than normal blood glucose level. Both of these glucose levels are considered abnormal. Prior to the development of type 2 diabetes, a phenomenon called insulin resistance can first emerge. In this type of pre-diabetic situation, the patient will require more and more insulin to mediate its biological effects, such as those alluded to above, like the GLUT4 transporter membrane insertion, enhanced glucose uptake into cells, increased glycogen production, etc. 

During the initial stages prior to the type 2 diabetes onset, the β-cells of the pancreas are actually able to accommodate the increased requirement for insulin in order to maintain normal levels of blood glucose. Eventually, however, the body will not be able to compensate for the insulin resistance, and the body now enters a so-called metabolic syndrome stage.  Others may refer to this stage as syndrome X. In any case, it represents an intermediate state of affairs that are prominent just prior to the onset of the type 2 diabetes. 

Patients with metabolic syndrome will exhibit obesity, a higher than normal blood pressure, elevated lipid content in the blood, and elevated levels of blood glucose (hyperglycemia).  This latter situation can be tested for by physicians by performing a so-called glucose-tolerance test. During this test, individuals with metabolic syndrome will have a more difficult time trying to clear glucose from their blood. These patients also have differences in their blood proteins, such as elevated fibrinogen molecules, indicating an abnormal ability with their blood clotting activities. Another abnormal blood protein is C-reactive peptide, indicating that these metabolic syndrome patients exhibit a higher than normal inflammation. 

5) What are the signs and symptoms of Type I and Type II diabetes? And how do they relate to hypoglycemia and hyperglycemia?

The symptomology of both types of diabetes, type 1 and type 2, is characterized by excessive thirst, frequent urination (the medical term for this condition is polyuria), and considerable water consumption by the patient (the medical term is polydipsia). These symptoms are the result of an overabundant secretion of the sugar glucose into the urine of a patient, a medical condition referred to as glucosuria or sometimes glycosuria. 

The signs and symptoms of hypoglycemia, low levels of blood glucose, can involve anxiety, tiredness, shakiness, paleness of the skin, sweating, hunger, a feeling of irritability, and an irregular heart beat (arrhythmia). Prolonged hypoglycemia can further lead to more serious symptoms, such as confusion, difficulty in seeing clearly, seizures, and unconsciousness. These sorts of symptoms of hypoglycemia can be related to diabetes during treatment when a patient is having trouble adjusting their insulin intake. 

The signs and symptoms of hyperglycemia are similar to those of hypoglycemia in that they, too, involve hunger, thirstiness, blurred vision, as well as an additional tingling sensation in the patient’s feet. The patient may also exhibit headache, fatigue, and frequent urination. Both type 1 and type 2 diabetes patients can exhibit the signs and symptoms of hyperglycemia. 

6) Let’s link diabetes and insulin to organs in the human body- what are the specific organs involved?

As I mentioned above, insulin is produced by pancreatic β-cells (called islets of Langerhans), and that glucose plays an important role in regulating this insulin production by the pancreas. Let’s take a look at this relationship in a normal scenario that occurs after the consumption of a meal. Nutrients such as amino acids and sugars in the gut enter the blood and then go to the liver. This presence of glucose is a situation stimulates the pancreas to produce insulin and to secrete it. 

The secreted insulin in turn now regulates the intracellular concentration of glucose in fat cells (called adipose tissue), the liver, and in muscle, by reporting the status of glucose in the blood. If the glucose concentrations in the blood are higher than normal, insulin then reports this blood-sugar occurrence and controls the fat, liver, and muscle cells to increase the uptake of glucose, thus lowering the blood glucose to normal levels. Normal levels of glucose range between 70 and 100 mg/100mL of blood. 

In muscle and fat cells, the uptake of glucose, as mediated by the effects of the insulin, results in increased glucose metabolism, and glucose-6-phosphate (G-6-P) is, thus, produced. From this key starting point metabolite, the G-6-P, it can take one of a variety of fateful biochemical routes. Any excess G-6-P that is not used in the muscle can be stored as fat in within the adipose tissue. 

In liver cells, insulin also regulates the glucose uptake, but in these cells the G-6-P generated from the excess intracellular glucose that is not used degradatively by glycolysis can then be stored in the form of glycogen. 

In brain cells, glucose supplies the energy for neuronal functions. Insulin works in the brain to supply a continual dose of glucose. This is a critical function, as a depletion of brain glucose can be quite detrimental to this important organ. Additionally, insulin works in the brain to thwart the hunger feeling by acting on the hypothalamus. 

This process works in the following manner. In certain brain cells called orexigenic nerve cells of the arcuate nucleus, insulin binds to the insulin receptor, which prevents the production of a protein called neuropeptide Y. On the other hand, in so-called anorexigenic nerve cells of the brain, insulin binding to its own receptor turns on the production of α-melanocyte-stimulating hormone (α-MSH), also called melanocortin. Then, the hunger feeling is, thus, alleviated. 

Let’s take a look now at the disease process. In the case of untreated diabetes, an abnormal process, insulin may be absent (type 1), or the body may be unable to respond to insulin even though it can be present in the blood, i.e., insulin-resistance occurs (type 2).  In this type 2 insulin-resistant case, the organs and tissues are affected in ways fundamentally different from that seen after a meal in a normal individual. In essence, the body behaves in a fashion similar to that of prolonged fasting in these uncontrolled type 2 diabetic patients. 

The lack of insulin (type 1) or an unresponsiveness to the insulin (type 2) results in the cells being unable to mediate the uptake of glucose to use as a fuel for making ATP. This condition can result in a severely detrimental consequence. Cells need glucose in order to survive. Instead, the glucose is aberrantly shunted for excretion, rather than being taken up normally to (and by) the tissues. The resulting lack of cellular glucose requires that the energy for cellular life must now be obtained by other means. Other sources of cellular energy include glucose stored as glycogen in the liver, and a little bit left in the muscles. But the main source of energy stores includes a large amount present within fat cells of adipose tissue. It is this latter alternate source of energy, the fatty acids of the adipose, which now constitutes the grand bulk of the required cellular energy. 

In untreated diabetics, the fatty acids are now metabolized for energy. The fatty acids are, therefore, broken down by a biochemical pathway called β-oxidation. This β-oxidation process results in the production of massive amounts of a central metabolite called acetyl-coenzyme A (acetyl-CoA), which is then converted into large quantities of ketone bodies, acetoacetate, and β-hydroxybutyrate. 

Each of these new metabolites can have unfavorable outcomes in diabetic patients. Let’s examine a couple of these metabolic fates, and we’ll start with the ketone bodies.

In patients with untreated diabetes, the excess amount of ketone bodies produced is called ketosis. If the ketone bodies are in the blood, it’s called ketonemia, and if present in the urine, ketonuria. Ketosis causes the liberation of new protons and results in an excessive condition of acidity, overwhelming the buffering capacity of the blood’s bicarbonate system. The consequence of this acid production is a lowering effect on the pH number in the blood, a condition called acidosis. The combination of ketosis and acidosis is often referred to ketoacidosis. 

Further, the acetoacetate can be readily converted to acetone, which is a very small lighter-than-air type of molecule. The acetone may, therefore, be exhaled by diabetic patients, and occasionally, such patients will smell of acetone in their breath; sometimes the acetone breath is mistaken for alcohol breath.  When combined with a very high blood glucose level, an acetone breath, and a consequent confused mental state, the untreated diabetic patient is prone to misdiagnosis of alcoholism, rather than of the more appropriate diagnosis of diabetes.  

7) Finally a bit about Banting- I know he was born in Canada and spent some time in World War II. Can you give us a brief summary of his life and work?

Frederick Grant Banting was born on the 14th day of November in the year 1891 to Methodist parents Margaret Grant and William Thompson Banting. The Banting family owned a farm near the town of Alliston, Ontario, Canada. Young Frederick was the youngest of five siblings. He completed both elementary and high school in Alliston. After high school, in 1911, he enrolled in Victoria College at the University of Toronto, where he majored at first in divinity. During the course of his undergraduate studies, in 1912, Banting switched his major concentration in order to focus on the study of medicine, and he consequently enrolled in the Faculty of Medicine, a medical school that was housed also at the University of Toronto. 

Banting’s decision to become a physician was based on two life-changing events that transpired around him. First, he witnessed a roof downfall in which two workers were injured, and Banting was said to have quickly sought help.  The responding physicians to the scene were reported to have a calming effect in a seemingly calamitous situation, a response which deeply impressed Banting. The second influential event in Banting’s decision to become a medical doctor was the death of one of his very close friends, named Jane, whom Banting watched slowly pass away from the effects of diabetes at the age of 14 years. Banting viewed Jane’s untimely death as needless and resolved to study the pathological nature of diabetes. 

While in medical school, in 1915, Banting briefly served in an ambulance corps of the Canadian Army Medical Service as a private and later as a sergeant. Dr. Banting earned an M.B. degree (bachelors of medicine) in 1916 after the faculty at the University of Toronto established an accelerated program, allowing medical students, such as Banting, to graduate one year earlier than scheduled. 

Dr. Banting held a post as a physician at Granville Hospital, England until World War I broke out, and he was ordered to serve as a battalion medical officer, in 1918. During Banting’s deployment, he was wounded in the battle at Chambrai, earning the Military Cross medal as a result of his valor during the incident. After the war, Banting moved to Toronto where he worked as a physician intern at the Christie Street Hospital for Veterans, in 1919. Then, in 1920, Banting moved to the Hospital for Sick Children, also in Toronto, Canada. During this time, Banting held a part-time teaching post as a professor at the University of Western Ontario. One of his noteworthy lectures was on the topic of the pancreas, in which his background preparation for the lecture made him a noted expert on the organ. In 1922, Dr. Banting took his M.D. degree from the University of Toronto. 

Back in 1920, Banting had formulated a hypothesis that islet cells of the pancreas secrete a substance that could improve the outcome of diabetics. In 1921, Dr. Banting began experiments in the laboratory of Dr. John J. R. Macleod, a professor who was initially skeptical of Banting’s idea but nevertheless allowed him (Banting) use of his (Macleod’s) facilities, and use of the expertise held by a young laboratory assistant Charles Herbert Best. At the time, Mr. Best had been a recent college graduate who had majored in biochemistry and physiology and was a medical student who had later on taken his doctorate of science, (D.Sc.) degree, in 1928. It turned out to be a fortuitous collaboration in 1921 because Dr. Banting provided expert surgical skills, and Mr. Best had an expertise in measuring sugar levels in animal blood and urine samples. It has been reported that as they progressed through their collaborative work, each investigator eventually acquired an astute proficiency in each other’s mode of expertise (surgery versus physiology). 

Meanwhile, in the laboratory, in 1921, Dr. Banting and Mr. Best first ligated the pancreatic ducts in anesthetized dogs, leaving the pancreas to atrophy. From these atrophied pancreases, Dr. Banting and Best made a pancreatic extract material and injected it into another dog who had had its own pancreas surgically removed weeks earlier. This pancreas-free dog had been clearly suffering the artificially induced effects of diabetes, as she (the dog was named Marjorie) had had no pancreas. But with the pancreatic extract injection Marjorie improved her behavioral condition within the hour, and her blood sugar levels had increased as a result of the extract injection. 

The active ingredient in the pancreatic extract was called “isletin” by Dr. Banting because the material that was involved in effectively treating Marjorie had been derived from the islet cells of the pancreatic organ. We now know that the islet of Langerhans consist of β-cells, which produce insulin. 

We also know that α-cells (i.e., alpha-cells) of the islet of Langerhans make glucagon, which is synthesized in response to low blood glucose and which in turn lowers insulin production. The δ-cells (delta-cells) of the pancreatic islet of Langerhans produce somatostatin, which inhibits production of insulin and glucagon and which regulates other molecules such as growth hormone and thyroid hormone. 

Unfortunately, Dr. Banting’s isletin extract was only temporarily successful. The laboratory dogs who had undergone the pancreas removal by using surgery (i.e., pancreatectomy) and were later improved by the injected isletin extract needed more of the life-improving substance. In fact, it seemed also that the diabetic dogs needed the isletin on a continual basis. Dr. Banting had further learned that fetal and newborn animals harbored greater concentrations of pancreatic extracts, and that cattle slaughter houses routinely discarded the embryos of pregnant cows who were going to slaughter. Thus, Dr. Banting was able to obtain these cow embryos (instead of letting them be discarded) as a source of the pancreatic isletin-containing extracts. 

Using bovine-derived isletin extracts in the laboratory, Dr. Banting and Mr. Best found that they could improve the behavioral and physiological effects of pancreatectomized dogs, just as well. They recorded in their laboratory notebooks that on July 30, 1921, diabetic dog number 410 who had been injected with the cow isletin showed a dramatic lowering of blood glucose!  

Dr. Banting and Mr. Best later repeated the experiment in dog number 92 and found similar outcomes. These findings were to change the course of history. Insulin had been discovered! 

Thanks to the investigative work of Dr. Banting, human beings with diabetes could, for the first time in history, actually survive in the face of its terrible effects. Because of the insulin, diabetics could live! Moreover, because of Banting’s daily insulin, diabetics might possibly be able to lead normal lives. Countless millions of lives have been affected in a most positive way. Accordingly, I consider the discovery of insulin an historic medical achievement of epic proportions. 

8) What have I neglected to ask about diabetes and its relationship to insulin and the discoveries of Banting (and his colleagues?)

In their notebooks, Dr. Banting and his medical student assistant Charles Best recorded the magnitude of the difficulties encountered in conducting their famous insulin-discovering experiments. For example, the surgical removal of the dog pancreas required a laborious two-step process and which often resulted in many of their laboratory dogs dying from post-surgical infections. The physiological blood-sugar data required careful calculations. 

Dr. Macleod had been absent from his laboratory during the summer of 1921 when Dr. Banting and Mr. Best were conducting their famous insulin-discovering experiments. Banting and Best had accumulated a wealth of data. Upon returning to his laboratory, however, Dr. Macleod had challenged their behavioral and physiological data, and he also necessitated further experimentation, in order to confirm their findings. Apparently, Dr. Banting took this response by Dr. Macleod as a personal insult, and the rift it produced would last a lifetime for both biomedical scientists. 

Dr. Macleod soon focused his efforts in developing isletin for human use. Furthermore, he changed the name of the life-giving isletin to insulin, a term which had been derived from Latin meaning island. Dr. Macleod collaborated with Dr. James Collip to purify insulin for treatment of human diabetics. 

Another controversy had arisen between Drs. Banting and Macleod. The issue this time had been whether Macleod deserved equal credit for the insulin discovery. Dr. Banting claimed that Dr. Macleod had not participated in their day-to-day experiments during the summer of 1921, while Dr. Macleod countered that he had provided continual guidance during the entire summer that the experiments had been performed. 

When, in 1923, the Nobel Prize in Medicine or Physiology had been awarded to both Drs. Banting and Macleod, Banting was chagrined about the Nobel nod to Macleod. Dr. Banting felt that Dr. Macleod did not deserve credit for the insulin discovery. Dr. Banting was further annoyed that Charles Best had been completely ignored by the Nobel commission, and he shared his half of the prize money with Best. Countering Dr. Banting’s annoyance about the Nobel, Dr. Macleod publically announced that Dr. Collip deserved credit just as well, and he then shared his (Macleod’s) half of the Nobel Prize money with Collip. 

Dr. Banting had been the first Canadian and youngest individual at the time, at the age of 32, to receive the Nobel in his category, physiology or medicine. His discovery has saved the lives of countless millions over the many years since the breakthrough had occurred. However, Dr. Banting had certain aspects of his personal life which were to be publically scrutinized, such as a courtship with, the marriage to, and the divorce from, in 1932, Marion Roberson, after 8 years of marriage. The couple had had one child, William, born in 1929.  

In 1934, King George V knighted Dr. Banting. Sir Banting later married Lady Henrietta Elizabeth Ball, in 1939. That same year, Sir Dr. Banting volunteered for active duty in the Royal Canadian Army Medical Corps, during World War II.  While traveling to England on the 20th night of February, in 1941, the bomber that Banting was flying in, a Lockheed Hudson, went down shortly after takeoff near the eastern coast of Newfoundland. Badly injured, Sir Dr. Banting died of his injuries the next day, on the 21st day of February, in 1941, at the age of 49 years. 

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