Welcome my friend to this article on Diabetes. In this article we’re going to look at the common methods of treating diabetes in the 20th and 21st Centuries. The treatment strategies of diabetes are ever-changing as more studies on diabetes patients are done, revealing details about diabetes that were previously unknown. Let’s look at some common treatment strategies for Diabetes Mellitus.
Insulin has evolved over the course of its first clinical use in 1922. The first preparations of insulin were grown in the pancreas of pigs (porcine) and cows (bovine) where it was extracted and purified in order to be injected subcutaneously (under the skin). It was available only in the original insulin form. This was done for the first 10 years after the successful clinical use of insulin. This regular form of insulin was short-acting and a person required multiple injections per day. Adherence to medication therapy is lower when someone requires multiple injections per day.
In 1936, a modified longer-acting version of insulin was introduced to the market by Hans Christian Hagedorn. It was the first delayed-action insulin preparation that required less frequent dosing per day. Next, insulin zinc protamine was invented in 1936, globin insulin in 1939, then Neutral Protamine Hagedorn insulin (NPH – Isophane) was invented in 1946. Then in 1952, an even longer-acting version of insulin called Insulin Lente was invented.
The purpose of long-acting insulin is to decrease the amount of insulin injections per day and avoid or minimize the insulin peaks that occur as a result of the injections. The long-acting insulin preparations do have their benefit of a longer action, however they can still put a patient at a higher risk of low blood glucose (hypoglycemia, blood glucose <70 mg/dL [<3.88 mmol/L]) but less than with shorter-acting insulins. In fact, the physicians that prescribed them in the 1930s-1950s were concerned about persons with diabetes injecting these long acting insulins and slipping unknowingly into severe hypoglycemia. Severe hypoglycemia can easily turn into a life-threatening medical emergency. Severe hypoglycemia is when the blood glucose is <54 mg/dL [<3 mmol/L]. It can quickly turn into a life-threatening hypoglycemia and it requires immediate medical attention.
From the 1930s until the 1970s, there were many different types of insulins that were prepared. The focus during this time period was to make versions that were highly purified from pork and cow pancreases. This trend continued until 1980 when recombinant DNA technology allowed for insulin to be grown in Escherichia Coli (E. Coli) bacteria in large volumes. From here on, the structure of insulin was able to be modified to create “designer” insulin preparations that would have different effects on how long they took to absorb, how long they took to start working, and how long their effects on blood glucose lasted. Some of these designer insulins would make the onset of insulin action much faster than regular insulin (called Rapid Acting Insulin at that time) or make it much slower than the regular insulin (called Long Acting Insulin at that time). The reason for creating “designer” insulins was to have better types of insulins, like instruments, that a medical provider can “fine tune” the insulin injections to get the blood glucose under more precise control.
Before the 1980s, insulin was injected under the skin (called subcutaneous injection) by drawing up the insulin from a vial into a syringe. However, this can easily become a burdensome process so in Scotland John Ireland invented a pen device to inject insulin in 1981 which took away the process of having to draw up insulin into a syringe for injection (even though it’s still commonly done today to inject insulins from vials).
The insulin pump was actually designed in London in the late 1970s by John Pickup. It was rather large and not as intuitive to use as the smaller and more sophisticated insulin pumps of today. However, the ingenuity was there as many clinicians and researchers looked into maintaining better blood glucose control and prevent hypoglycemia after the insulin was injected.
There was an inhaled insulin that was briefly on the market in 2006. However, the insulin was pulled off the market because of its low market demand. In addition, this inhaled insulin would cause respiratory problems in patients that used it. There is currently an inhaled insulin on the market now called Afreeza which shows promising results.
Anti-Diabetic Medications for Diabetes Treatment
The oral anti-diabetic medications have come a long way since they were first used. The first anti-diabetic medication was used in 1926 called Synthalin. However, it was withdrawn from the market because of toxicity problems. Medication Toxicity means that a medication causes problems beyond the normal tolerable side effects, oftentimes resulting in more severe side effects called toxicity.
Sulfonylureas Medication Class
A major prescription medication class for diabetes treatment was the sulfonylurea class. These medications were first used in France in the 1940s as glucose-lowering medications. These sulfonylureas work by telling the pancreas to release insulin in order to lower blood glucose. They are only used for Type 2 diabetes, not Type 1 Diabetes. In 1955, Carbutamide, a sulfonylurea medication, was the first sulfonylurea used in a clinical setting (doctors office) for diabetes treatment (Type 2 diabetes). Tolbutamide followed in 1957 for diabetes use as well.
Biguanides Medication Class
The next prescription medication class that was used was called the biguanides. This medication class is used for Type 2 diabetes (and currently for pre-diabetes also) to treat Diabetes. The first medication was called Phenformin, which was used in 1959 first for research. Then in the 1960s, another biguanide called metformin was used in Europe for type 2 diabetes. Metformin finally came to the United States where it has been used since 1994 in treating blood glucose in diabetes.
Glitazones Medication Class
The “glitazones” are another prescription medication class that are used for Type 2 Diabetes treatment to lower blood glucose levels. The first medication, called troglitazone, was used in 1994 but was then pulled off the market due to liver damage. After that, two more medications were created called pioglitazone (Actos) and rosiglitazone (Avandia). Currently, pioglitazone is used for type 2 diabetes and rosiglitazone is essentially pulled off the US market, except in very specific situations where someone absolutely needs rosiglitazone because it works. Rosiglitazone was found to cause heart problems in patients.
The Incretins Medication Class
The research into diabetes medications is currently progressive and consistent as millions and millions of people every year are diagnosed with diabetes throughout the world. In 2005, the Incretin medications were introduced to the market. Some examples of this type of this prescription medication class would be Byetta or Victoza. These are injectable medications that work to help with mealtime blood glucose spikes throughout the day.
Dipeptidyl-Peptidase-4 Inhibitors Medication Class
Another medication class that works on the same system as the Incretins was also created around that time. These prescriptions medications are known as the oral Dipeptidyl Peptidase-4 Inhibitor class such as Onglyza, Januvia, etc. These medications are used for lowering blood glucose in Type 2 Diabetes.
Sodium-Glucose Cotransporter-2 Inhibitors Medication Class
In 2010, another drug class of Type 2 Diabetes prescription medication was invented called the Sodium-Glucose Cotransporter-2 inhibitors (the gliflozins). Examples of some of these medications are Invokana, Farxiga. These medications work by removing excess glucose (from hyperglycemia) during the kidney filtration process, allowing it to pass through the kidneys into the urine and not reabsorb back into the blood. The effect is to lower the blood glucose.
Controlling Blood Glucose through Blood Glucose Monitoring
Throughout the 1900s, medical providers and researchers were learning more and more about diabetes. The more they learned about how diabetes works, the more prescription medications to lower blood glucose came onto the market. However, the questions always came up amongst the medical community: What are the appropriate blood glucose values to target?” This was a very good question that researchers looked into.
In the 1920s, the thinking for blood glucose values was that young people needed to give the pancreas a “rest” and let it recuperate from diabetes. The strategy at that time was to eat anything that a person wanted and merely test the urine for glucose and try to keep the urine free from glucose. This brutish attempt at blood glucose control caused problems with low blood sugar and didn’t do much to prevent complications from diabetes. Persons’ would simply inject a morning dose of insulin, go about their day eating anything they wanted, and simply test their urine for glucose. They would cut back on the foods they ate if the urine glucose was “too high.” This rather crude way of monitoring glucose levels persisted for the next 40 years or so.
During the years from the 1920s to the late 1960s, persons would monitor their blood glucose by measuring the urine glucose to make sure it wasn’t “too high.” During this time, medical providers struggled with the questions of finding appropriate blood glucose levels. They also questioned if lowering the blood glucose levels to “normal” would actually do something to prevent diabetes complications (diabetic neuropathy, diabetic retinopathy, diabetic foot, diabetic nephropathy). These questions led to the invention of measuring blood glucose levels through finger-sticks in the 1970s. Someone would prick their finger with a lancet device in order to take a blood sample and measure it on a glucose meter to find out their blood glucose value. As this blood glucose measurement strategy took on more momentum, traction into research for the appropriate target blood glucose levels and questions about proper blood glucose control went forward in order to minimize diabetes complications.
Improvements in diabetes control occurred with the use of measuring the Hemoglobin A1C to get an average glucose level over a 90 – 120 day period. The Hemoglobin A1C test and fingerstick blood glucose measurements were used to then answer the question: “Does measuring blood glucose and treating to certain blood glucose target levels improve upon the complications of diabetes (microvascular complications – the small blood vessels)?” This was proven be the true in 1993 with the Diabetes Control and Complications Trial (DCCT) in persons with Type 1 Diabetes.
Figure 1 – The Hemoglobin A1C
Treating blood glucose levels to target goals significantly reduced developing microvascular complications. In addition to the DCCT study, another study was done to help answer this question for person’s with Type 2 Diabetes. This was the United Kingdom Prospective Diabetes Study (UKPDS) in 1998, which found that improving blood glucose control to target levels helps with the microvascular complications in Type 2 Diabetes as well. This study also found the beneficial effects on heart disease by lowering blood pressure to target levels.
As more and more studies were done in the diabetes populations in the 1900s, it was found that improvements blood glucose levels, blood pressure control, and blood cholesterol would each separately and significantly lower the quantity of heart attacks and deaths. These important landmark studies set the tone for future clinical studies into diabetes.
Chronic Diabetes Complications
In the early 1900s, physicians would describe the complications of diabetes on the kidneys, eyes, and later on the blood vessels. It was believed early on that atherosclerosis (hardening of the blood vessels, plaque formation in arteries) was the primary cause of kidney damage and damage to blood vessels in the retina of the eye. As time went on, research into the specific mechanisms of how blood vessels are damaged in the kidneys and eyes that lead to the kidney and eye damage were controversial. Even today, there is still some controversy about what really causes the blood vessel damage from chronically high blood glucose levels (called glucose toxicity). The undisputed fact however remains that chronic hyperglycemia does cause complications such as diabetic nephropathy, retinopathy, neuropathy, and diabetic foot.
During the 1970s, laser photocoagulation therapy was used to help prevent vision loss from the damage diabetes would do to the retina of the eye (maculopathy and proliferative retinopathy). In regards to blood pressure and the kidneys, during the 1980s, researchers found a correlation between achieving good blood pressure control to prevent damage to the kidneys (nephropathy). One of the main ways to see the degree of kidney damage is through measuring albumin in the urine. Albumin is a protein normally found in the blood. With damaged kidneys (from chronic hyperglycemia or uncontrolled blood pressure), the albumin would make its way into the urine. A physician would measure for microalbuminuria in the urine to gauge the level of kidney damage. Measuring albumin in the urine was actually developed in 1969 by Harry Keen and Costas Chlouverakis in London.
Diabetic Ketoacidosis (DKA) is a serious medical condition where the body does not have enough insulin to put blood glucose into the cells for use as energy. Diabetic Ketoacidosis is normally found in persons with Type 1 Diabetes where there is a lack of insulin production and this person is required to be on lifelong insulin. DKA can also be seen in persons with advanced Type 2 Diabetes who are insulin dependent and require insulin injections for blood glucose control but an insulin dose (s) are missed or under-dosed for days at a time.
Diabetic Ketoacidosis causes fat cells (and certain other cells too) to mobilize their fat stores of triacylglycerides and fatty acids and break down the fat inside of them since they are not receiving any glucose as fuel. The fatty acids in the form of Triglycerides are released into the bloostream during this process. The excess fats in the blood (called Triglycerides) go the liver where they are converted into ketone bodies called Beta-hydroxybutyrate and Acetoacetate to be used by the cells as a secondary emergency fuel source. These are called “ketone bodies.” A third ketone body called acetone is also produced but is exhaled out through the lungs because it is more volatile than the other ketone bodies. The acetone causes the classic “sweet fruity breath” smell in person with Diabetic Ketoacidosis. Diabetic Ketoacidosis is a very serious medical condition that requires immediate medical care.
The very high level of ketone bodies in the blood causes the blood pH to become lower and too acidic. A low blood pH will cause problems with breathing, low organ functioning, can cause low potassium as well, potentially causing death if someone doesn’t seek medical help immediately. DKA is treated in a hospital setting with a continuous infusion of regular human insulin, fluid replacement, bicarbonate drips if necessary. In addition, treatment of electrolyte imbalances such as low potassium, and overall close monitoring of blood chemistry are sometimes also necessary.
During the early 1900s, medical knowledge about the effects of Diabetic Ketoacidosis (DKA) were still in the learning phase. The early techniques to treat the DKA in the 1930s consisted of using high doses of insulin, which resulted in potentially reversing the DKA too quickly and causing hypoglycemia. The mortality rate of DKA ranged from 5% (in Boston) to an average of 30-75% in North America and Europe. As medical providers learned more about DKA, they focused on appropriately lowering the insulin dosing and correcting low potassium safely. Very low levels of potassium (or high potassium also) are also very serious conditions that need to be addressed immediately, usually in a hospital setting for very low or very high blood potassium levels. Very low or very high blood potassium levels can cause heart arrhythmias and eventually cardiac arrest (death).
Having low blood potassium (called Hypokalemia) is a medical emergency and requires potassium supplementation to prevent heart arrhythmias. The dangers of low potassium in DKA were first recognized in 1946 by Jacob Holler. Sometimes albuterol inhalation through a nebulizer is used to help reverse low potassium in the hospital setting as well.
Diabetes and Pregnancy
Pregnancy and diabetes were generally not a good mix in the early 1900s and through even the 1950s. The death rate of children born to women with diabetes was very high, sometimes 40-65% death rates. In fact, it was found that the perinatal death rate of babies born to women with diabetes was 10 times higher than in the general population. These mortality figures were astounding. These figures were like this in the United States and Europe. It was found that good blood glucose control in women with diabetes significantly improved the survival rates of babies born to women with diabetes. There were a few clinics that did have better survival rates of babies born to women with diabetes. One such clinic was the Joslin Clinic in Boston and Jorgen Pederson in Copehagen. Dr. Pederson found that the combination of excellent blood glucose control and a qualified team of medical providers significantly improved the death rates of babies. They aimed for a 6% mortality rate. Over the decades, medical providers had a difficult time achieving a low mortality rate of babies born to women with diabetes. In fact, it wasn’t until the 1980s where the standard of medical care in diabetes was able to achieve a 6% mortality rate in the United States or Europe.
Diabetes Care and Education
Many people with diabetes have been found to be lacking in diabetes education. If one were to ask a person with diabetes about some of the basics of diabetes, many would have a difficult time answering basic questions about diabetes. This doesn’t mean that there is something wrong with that person. It actually means that medical providers oftentimes are lacking in providing sufficient diabetes education to their patients. For example, in 1952 Samuel Beaser questioned 128 persons with diabetes and found that every one of them was severely lacking in diabetes knowledge. Basic diabetes knowledge is important for someone with diabetes or for someone who takes care of a person with diabetes because they are able to better manage the diet, exercise, and glucose control to improve the outcome of their diabetes. The goal is to learn at least the basic principles of diabetes and be better armed for managing diabetes and complications when they come up.
Medical provides themselves also have a problem with diabetes education. In the 1960s, studies done by Donnell Etziler found that many doctors and nurses didn’t know enough about diabetes in order to manage diabetes effectively. In light of this problem with diabetes education, many professional organizations have sprung up to fill in this knowledge gap. As a result, in the 1980s, diabetes specialists and nurse educators have played a very important role of filling in the knowledge gaps in patient education on diabetes topics. The original idea for this actually came from Mr. Elliott Joslin in 1916 to provide more diabetes education for medical providers as well as diabetes patients and caregivers themselves.
Professional Diabetes organizations have been around since the 1920s to help with patient education for diabetes topics and principles. Some of the civilized countries around the world have their own diabetes associations that focus on providing education to both medical providers and patients on diabetes topics. These professional diabetes organizations also focused on research into diabetes as well in order to further education into diabetes and potentially find a cure one day for Type 1 Diabetes. In the meantime, diabetes research will open up new treatment strategies as we learn more and more about diabetes.
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Sergey Simonovich, Pharm D.
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.