An Introduction To Prediabetes

Prediabetes

            Prediabetes is the condition that affects millions of people in the United States and worldwide. Pre-diabetes is not full-blown diabetes mellitus, rather, it’s the starting point towards developing diabetes. According to the Center for Disease Control (CDC), in 2015 it was estimated that about 84.1 million Americans have pre-diabetes. If pre-diabetes is not treated, it can lead to diabetes within 5 years. Prediabetes refers to the initial stages of Type 2 Diabetes. Type 1 Diabetes on the other hand doesn’t have a “Prediabetes Type 1” since Type 1 Diabetes is associated with having an insulin deficiency earlier on in life (usually). In Type 1 Diabetes, the lack of insulin release results in an absolute decline in insulin release, and thus, the symptoms of Type 1 Diabetes (increased thirst, high blood glucose, increased urination, increased hunger beyond normal). From here on now, when we refer to Prediabetes, we’ll be referring to the condition that leads up to having Type 2 Diabetes.

            Prediabetes is when there is a noticeable increase in insulin resistance in the body. The cells of the body are beginning to become less sensitive towards the action of insulin when they see high levels of blood glucose. With Type 2 diabetes, one of the main problems is increased insulin resistance where the cells of the body cannot effectively sense the insulin in the bloodstream and allow the blood glucose to enter into the cell. In the realm of prediabetes, this is the early stage of insulin resistance where the body is beginning to be unable to take in as much glucose as it normally would. Usually someone who has insulin resistance will have increased blood glucose levels, both fasting and/or mealtime, and increased blood triglycerides, elevated LDL cholesterol, and lowered HDL cholesterol, with one or all of these present in someone with pre-diabetes. A person with Prediabetes might also show signs of atherosclerosis, which is hardening and plaque formation inside of the blood vessels throughout the body.

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            A person with prediabetes is generally found to be overweight, having a body max index (BMI) of being outside of their normal range.  Due to all of the excess fat, usually stored around the organs and abdomen, this fat acts as the contributor to inflammation, impaired glucose tolerance, problems with the circadian rhythm of blood pressure, and dysfunction of the endothelial cells (cells that line the blood vessels). In addition, the increased body fat results in an even higher risk for developing atherosclerosis of the blood vessels. All of these problems are believed to be caused by or contributed to having excess fat in the body. It is believed that the visceral fat in the body acts like an endocrine organ, secreting substances that control blood glucose and blood pressure.

            Visceral fat is the fat that is found deeper in the abdomen surrounding the organs. This fat is more metabolically active when tapped into for triglycerides, releasing larger amounts of triglycerides into the bloodstream than peripheral fat. Visceral fat is found below the subcutaneous fat in the abdomen.  Visceral fat secretions are involved in maintaining a balance between the inflammation and anti-inflammatory responses in the body. TOO MUCH visceral fat on a person results in tipping the balance of inflammation vs anti-inflammatory secretions towards more inflammation. This increased inflammatory response results in further damage to the blood vessels, leading to many of the symptoms of prediabetes.

            In order to get a better understanding of the role of visceral fat in inflammation, lets take a look at Figure 1 below, which shows how the delicate balance of inflammation vs. anti-inflammation secretions of the visceral fat results in someone progressing towards diabetes.

Figure 1 – Effects of Visceral Fat Substance Secretion on Pre-Diabetes

            As we can see from Figure 1, as a person becomes more sedentary and then obese, their body begins to accumulate more and more fat. This fat is both the visceral fat (fat surrounding the abdominal organs) and the subcutaneous fat (fat just right underneath the skin, all over the body). As a persons BMI (Body Mass Index) increases, the visceral fat of the body begins to cause more and more inflammation to the blood vessels of the body. This inflammation leads to a steady progression towards having insulin resistance, high blood pressure, increased clots, and atherosclerosis formation inside of the blood vessels throughout the body. The insulin resistance causes the insulin of the body not to work as well to take in the blood glucose into the cells, leading to the next step (step 4), which is pre-diabetes. This pre-diabetes stage (step 4 in Figure 1) is when the body shows signs of a fasting blood glucose and/or impaired glucose tolerance. Impaired fasting blood glucose occurs when the effects of insulin are not sufficient enough to maintain a normal fasting blood glucose of <100 mg/dL. The mealtime levels of glucose are also affected in pre-diabetes, where someone will have blood glucose levels of 140-199 mg/dL. The normal mealtime blood glucose level should not go above 140 mg/dL 2 hours after a meal in someone without symptoms of Pre-diabetes or diabetes.

            As a person approaches the level of pre-diabetes, the hallmark symptoms of pre-diabetes will be:

1. Fasting Blood Glucose of 100-125 mg/dL (normal 70-100 mg/dL)
2. 2-Hour Postprandial (after mealtime) blood glucose of 140-199 mg/dL (normal <140 mg/dL)
3. Hemoglobin A1C of 5.7-6.4% (normal 5-5.5%)

            When a person has impaired glucose tolerance (fasting blood glucose 100-125 mg/dL), they have and increased risk of cardiovascular disease. In fact, an impaired glucose tolerance of 110-126 mg/dL puts someone at an even higher risk of moving towards diabetes. In general, the higher the blood glucose levels are, the higher the risk for developing diabetes. It is estimated that someone with pre-diabetes has a 6-29% chance of moving into full blown diabetes within 4 years. As we can see, Pre-diabetes is a serious condition because it is a transition point towards moving into clinical diabetes.

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            The higher the fasting blood glucose, mealtime blood glucose, and the Hemoglobin A1C, the faster someone with pre-diabetes progresses towards diabetes. In fact, someone with impaired glucose tolerance (impaired fasting glucose) has a 6-10% chance of develop diabetes every year they have pre-diabetes. In addition, about 65% of those with BOTH impaired fasting glucose AND impaired glucose tolerance develop diabetes annually. If that wasn’t enough, the rate of impaired fasting glucose and impaired glucose tolerance will depend on how high the initial blood glucose was, the race and ethnicity of the person, and the specific environment that a person surrounds themselves with on a daily basis. Basically, the higher the blood glucose, the higher the risk of developing actual diabetes and diabetic complications.

Table 1 – Criteria for Diagnosis of Pre-Diabetes and Diabetes Criteria

It is estimated that 84.1million Americans age >/= 18 have Pre-Diabetes and the numbers climb higher and higher each year. Throughout the world, it’s estimated that by 2025, approximately 418 million people will have pre-diabetes. These people have either impaired fasting glucose, an impaired glucose tolerance, or maybe even have both. Generally, the blood glucose is elevated and will increase based on how much physical exercise a person gets, their current diet, their specific ethnicity, and other environmental conditions. Once a person is diagnosed with Pre-diabetes, a medical provider will focus on managing the blood glucose level in order to decrease the long-term effects of hyperglycemia, which are the small and large blood vessel complications (micro- and macrovascular complications, respectively). A medical provider will also focus on all of the other associated medical conditions that exacerbate the blood glucose such as obesity, high blood pressure, and elevated lipids (HDL, LDL, Triglycerides).

The Progression of Pre-diabetes to Diabetes

            The progression towards having Type 2 Diabetes does not occur overnight. Rather, the process occurs on a set pace that is determined by someone’s current state of health. The primary cause of pre-diabetes, and leading to type 2 diabetes, is the loss of beta-cell function in the pancreas. The environmental conditions that a person lives in will determine how fast someone progresses towards pre-diabetes and eventually diabetes. The rate of beta-cell loss over time will determine how soon someone gets pre-diabetes symptoms and then diabetes. This is unlike Type 1 diabetes where someone just suddenly shows symptoms after 80% of the beta cells in the pancreas are dead/dysfunctional and their body does not produce insulin.

            The environmental factors that determine if someone will get pre-diabetes and progress to diabetes are the following:

1. Genetics
2. Race/ethnicity
3. Age
4. Level of physical activity
5. Environmental toxins, such as smoking
6. Previous and current diet. The more unhealthy the diet, the faster someone will get diabetes.
7. Obesity, based on the body mass index (BMI).
8. Current medical conditions, such as high blood pressure, high lipids.
9. Certain medication classes, such as antipsychotics.

These factors all play a role in whether someone will get pre-diabetes or not. It is not one factor that plays a major role, rather it’s more of a combination multiple environment factors. The main factors that plays the most role are insulin resistance AND how good the beta cells in the pancreas function. In general, insulin resistance will be determined by someone’s level of physical activity, weight, and diet. The function of the beta cells will be determined by the majority of the factors we’ve just listed.

The Beta-Cells in the Pancreas

            The beta-cells are one of the major keys to getting pre-diabetes and progressing towards diabetes. As insulin resistance throughout the body increases, the pancreas must keep up the production of insulin to keep up with the increasing blood glucose levels. Eventually, the beta cells in the pancreas will begin to show signs of wear/dysfunction as the blood glucose levels rise over time. In fact, when someone approaches the fasting blood glucose state 100 mg/dL, they begin to slow down the first phase of insulin release, which intensifies the speed at which someone approaches having clinical fasting hyperglycemia (100-125 mg/dL). As someone approaches a fasting blood glucose of 115 mg/dL, they will lose the first phase insulin release, making the problem of hyperglycemia even worse.

Figure 2 – The Pancreas, Beta-Cells, and Alpha-Cells

            The first sign of beta-cell loss is when a person shows fasting blood glucose. This is in the 100-125 mg/dL range. The blood glucose will slowly creep up throughout the years and someone will not even notice it. As they approach the fasting hyperglycemia for pre-diabetes, they may start to notice themselves suddenly putting on more weight than usual because of the higher amounts of insulin the pancreas is releasing to overcome the insulin resistance. They will show signs of insulin resistance, such as being more tired after eating carbohydrate rich meals, need to take a nap after a large meal, being more fatigued throughout the day. These are signs of high amounts of insulin in the body and insulin resistance.

            The next step is the loss of mealtime glucose control. This usually occurs when someone has a fasting blood glucose of 115 mg/dL where their mealtime blood glucose levels will be between 140-199 mg/dL, the normal being <140 mg/dL 2 hours after the start of a meal. This is the loss of first phase insulin release, indicating the progression towards diabetes. Someone will show impaired glucose tolerance with a 2-h oral glucose tolerance test that is done at a doctor’s office (for diagnosis of pre-diabetes). A person receives 75 grams of oral glucose (dissolved in water), and a plasma blood glucose measurement will be taken and sent off to a lab for results. The medical provider will get the results back and relay the results to the patient, telling them if they have pre-diabetes, which is a mealtime blood glucose level of 140-199 mg/dL, or diabetes, which is blood glucose >/= 200 mg/dL.

            Not everyone who is obese (BMI >/= 30 kg/m2) will progress into pre-diabetes and diabetes. The reason for this is that beta cell function and insulin resistance are also partially controlled by genetics. There is a very small population of people in the world who have “super beta-cells,” which are beta-cells that keep producing insulin despite having increasing fasting and mealtime blood glucose levels. It’s as though those beta-cells are just “tougher” and able to withstand the hardships that high blood glucose causes throughout the body. In addition, some people may be even obese, yet they still have low insulin resistance, normal blood pressure, and normal lipid levels. This is a very small percentage of the total population and they are the exception, not the rule. Rather, most people will not fit into this category and are at a higher risk of diabetes.

           
Screening for Prediabetes

            Pre-diabetes is associated with a higher risk than usual for damage to blood vessels in the body as the blood sugar, both fasting and mealtime, begins to increase beyond normal. These damaged blood vessels result in damage to the tissue, whether it be the heart, kidneys, brain, nerves, etc. As a result, the current recommendations are to screen the general population that are high risk for developing diabetes or watch those who are already have pre-diabetes.

            The current American Diabetes Association 2020 guidelines give some examples of the types of people medical providers should screen for pre-diabetes. These are generally people who are believed to get pre-diabetes or even progress into diabetes in the coming 5 years or so. The following is a list of groups of people who should be screened for prediabetes:

Table 2 – Populations to Screen for Pre-Diabetes, Currently Having No Symptoms of Diabetes

            In addition to the recommendations for pre-diabetes screening from the American Diabetes Association, there are other recommendations for screening. Some medications can cause an increased risk for pre-diabetes/diabetes, and these are for people with schizophrenia and bipolar disorder. These people are usually on medications that can cause increase blood glucose.

            The older we get, the more at risk we are for weight gain and pre-diabetes. The primary problem with getting older is that our metabolism tends to slow down, we tend to exercise less due to a busy schedule, and our diet suffers because of poor food choices. These factors all contribute to increased body fat and weight gain. As we can guess, an increase in body fat can lead to insulin resistance, pre-diabetes, and ultimately diabetes if the weight and diet are not addressed early on enough. In light of these risk factors, it’s recommended that someone be tested for pre-diabetes beginning at age 45 and tested every year. This is to catch someone early on and hopefully prevent them from acquiring diabetes.

There are essentially 3 ways to diagnose someone with Pre-Diabetes. These are:

1. Hemoglobin A1C
2. Impaired Fasting Glucose
3. Impaired Glucose Tolerance

            Let’s start with the Hemoglobin A1C (HbA1C). Hemoglobin is a protein found in red blood cells. The main role of hemoglobin is to carry oxygen in the blood cells to the remainder of the cells in the body. This is normal physiology. When red blood cells come across glucose in the blood, the glucose will non-enzymatically and irreversibly attach itself to the hemoglobin protein in the red blood cell (process is called glycation). This is a normal process. Red blood cells have a 90-120 day life span. Normally, approximately 5% of the total hemoglobin in the blood has glucose attached to it. When blood glucose concentrations begin to increase, more and more blood glucose attaches to hemoglobin, resulting in a higher concentration of hemoglobin that is glycated (glucose attached to it.). The glucose stays attached to the hemoglobin for the life of the red blood cell.

            The normal Hemoglobin A1C is about <5.5%. As the blood glucose concentration increases, the Hemoglobin A1C concentration approaches the pre-diabetes phase, which is between 5.7-6.5%. The higher the hemoglobin A1C, the higher the 90-120 day average of blood glucose levels, which is both the fasting and mealtime blood glucose. The mealtime blood glucose level actually causes more glucose attachment to hemoglobin than fasting blood glucose does. Therefore, the Hemoglobin A1C measurement is the average of blood glucose levels for the past 90-120 days that are expressed in a percentage form. The normal is <5.5%, and the higher the HbA1C, the higher the average fasting and mealtime glucose values over the last 90-120 days. The A1C is generally accurate to show the average blood glucose levels, except in a few specific circumstances

Figure 3 – The Hemoglobin A1C

            The higher the Hemoglobin A1C, the higher the risk for cardiovascular disease and complications. As we already know, blood glucose in high concentrations causes damage to blood vessels, which in turn damages the tissues that the blood vessels supply (kidneys, nerves, eyes, heart, etc.). These are the micro- and macrovascular complication, which we’ll discuss later on.

            The Hemoglobin A1C level is not always accurate. There are certain medical conditions that can affect the level of red blood cells and hemoglobin that are present in the blood. Some medical conditions increase the A1C and some decrease the A1C, giving a false reading. Some of these medical conditions are:

Things that Increase the Hemoglobin A1C

1. Alcoholism
2. Iron Deficiency Anemia
3. Splenectomy (removal of the spleen)
4. Hyperbilirubinemia (too much bilirubin in the blood)
5. Chronic use of opioids and salicylates
6. Various Medical conditions that affect the normal breakdown and removal of the red blood cells.

Things that Decrease the Hemoglobin A1C Levels:

1. Chronic Kidney disease, liver disease, hemolytic anemia, blood loss, hemoglobin disease are examples of things that can shorten the lifespan of a red blood cell.
2. Pregnancy
3. Enlargement of the spleen
4. Rheumatoid arthritis
5. Antiretroviral medications (for HIV), ribavirin, dapsone.
6. High triglycerides (very high levels)
7. Vitamin C and E (not as severe)

            The accuracy of the Hemoglobin A1C can be questionable in certain race/ethnicities due to one or more problems with the red blood cells/hemoglobin itself. These are the special populations where the accuracy of Hemoglobin A1C values is not accurate and using it for diagnosis of pre-diabetes and diabetes MAY be avoided to avoid misdiagnosing someone. An example of this would in the African American population. In the African American population, about 8% of these people have a sickle cell trait called HbAS where they may show abnormally high or low A1C levels. In addition, some African Americans have the hemoglobin C trait (about 2.3%) where they also may show an abnormally high or low Hemoglobin A1C. Therefore, if someone is suspected of having a genetic dysfunction of the Hemoglobin A1C gene or has a condition that can cause a false reading of the A1C, then a medical provider will use the more reliable Oral Glucose Tolerance Test or Fasting Blood glucose test to measure for diabetes. They will take 2 separate tests on separate occasions to diagnose someone with pre-diabetes or diabetes. This applies for everyone being tested for pre-diabetes and diabetes, regardless if they are a special population or not.

Insurance and Pre-Diabetes

            An interesting issue regarding diagnosis of pre-diabetes is that once a person has a pre-diabetes diagnosis (a pre-existing condition now), their medical insurance provider may change the coverage and the rates that they will pay for. Life insurance policies may also change because pre-diabetes is considered a pre-existing medical condition on someone’s medical record.  The reason for this is that pre-diabetes has the associated cardiovascular risks with a lower life expectancy and is treatable with lifestyle changes and medication therapy if necessary. Oftentimes medical insurers will not cover the lifestyle change programs that are available, but the trend has been moving in the favor of covering lifestyle modification programs such as the federal government run Diabetes Prevention Program. Some insurance providers may pay for the services rendered, some will not.

Risk of Going from Pre-Diabetes to Diabetes

            There is a correlation between the Hemoglobin A1C value and the risk of developing diabetes in 5 years. In the following table, Table 3, we can see the association between these value and diabetes.

Table 3 – Hemoglobin A1C Values and Risk for Developing Diabetes

As we can see from the table above, the higher the A1C value is, the exponentially higher the risk for developing diabetes. The goal for people who are higher risk for diabetes is to prevent the onset of diabetes. Makes sense.

Slowing Down the Progression from Pre-Diabetes to Diabetes

            A person with Pre-diabetes will not always progress towards developing diabetes. There are several factors in play that can prevent someone from becoming diabetic. However, the higher the Hemoglobin A1C value, the higher the risk for developing diabetes. If someone does have pre-diabetes, the goal will towards slowing down the progression and ultimately reverse the progression towards diabetes. This is done in several ways. Adopting a healthy lifestyle is shown to decrease all-cause mortality by 57%! That’s incredible. A few lifestyle changes and consistently doing them will go a long way to preventing someone from dying sooner than they should.

            The first thing that will slow down the progression towards diabetes is getting enough exercise. The majority of people in the world have a sedentary inactive lifestyle. They don’t move around physically and don’t perform weigh bearing exercises. Exercise is useful in that it improves insulin sensitivity, allowing the fasting blood glucose to decrease as it should. In fact, in addition to a decrease in fasting blood glucose, over time, exercise will help to improve the mealtime glucose spikes and lower them towards normal. The general recommendation for someone who has been sedentary for a long time is to exercise 150 minutes per week of moderate-intensity exercises to get them started. This is basically the starting point for someone. With exercise, there are other factors involved such as getting clearance for an exercise program from your physicians, as well as other medical conditions present that may slow down the exercise progress that must be addressed as well. We won’t discuss these in detail here as we’ll dive deeper in nutrition and exercise further along in a diabetes education program in the future.

            There are other factors that help slow the progression towards diabetes. One of the most obvious is eating a balanced diet that will help to lower the blood glucose and insulin levels. This includes eating more fruits and vegetables. A person should also decrease their intake of high salt foods, saturated fats, trans fats, cholesterol, and refined grains. All of these contribute to increasing blood glucose levels by contributing to insulin resistance and cardiovascular disease. They also contribute to high blood pressure, which by itself, is a risk factor for diabetes. That’s right, high blood pressure alone is a risk factor for Pre-diabetes and diabetes. Therefore, it’s essential to control the energy expenditure in the body and eat and exercise healthy. We’ll discuss this in great detail in the nutrition/exercise module of the diabetes education program.

Reversal of Beta-Cell Loss and Dysfunction

            The question that many diabetes researchers have asked is: “can we reverse the loss of beta cell function in pre-diabetes and diabetes (type 2)?” In order to answer the question, studies were performed and they found that the use of lifestyle modifications decreased the risk of developing diabetes. One of the most famous studies that looked at this was the Diabetes Prevention Program that looked at using Lifestyle modification vs metformin therapy to delay the onset towards diabetes. They found that lifestyle changes resulted in a 6% weight loss and 58% decrease in diabetes than placebo alone. In people who are >/= 60 years old, lifestyle intervention resulted in a 71% decrease towards progressing to diabetes. Metformin on the other hand, was not as effective as lifestyle changes towards decreasing the diabetes risk or those less obese in the >60 years of age category.

Treatment of Pre-Diabetes

            The question arises: “can we prevent or delay the onset of pre-diabetes or diabetes?” I’m glad you asked the question. The answer is: ABSOLUTELY WE CAN! Not only we can, but we definitely should. The goal of pre-diabetes or diabetes prevention is to restore the impaired Fasting glucose (IFG) and impaired Glucose Tolerance (IGT). Restoring these to normal levels requires removing the things that cause insulin resistance and decreasing the blood glucose levels. This is a worthwhile goal and millions of people in the US and worldwide don’t need to suffer from diabetes and its complications. Let’s take a look at how to prevent or delay the onset of Pre-diabetes or diabetes (Type 2).

            The first thing that someone should focus their attention towards is their weight. If someone is overweight, they will be at a higher risk for having insulin resistance and higher blood glucose values. The estimation of weight is based upon height and current weight, calculated into what’s called a Body Mass Index (BMI). This BMI gives an estimated guess as to how “fat” someone is based upon their body size (height). The following is the equation for calculating BMI:

BMI = Kilograms divided by height in meters squared.

For example, someone is 6 feet tall and weight 200 lbs. 1 kg = 2.2 lbs, 1 inch = 0.0254 meters

BMI = 90.9 kg / (1.9m x 1.9m) = 90.9 kg/3.61m2 = 25.18 kg/m2

This person would be considered slightly overweight. A normal BMI is 18-24 kg/m2. Overweight BMI is 25 – 29 m2, Obese BMI = >/= 30 kg/m2

            A person who is overweight or obese is at a higher risk for pre-diabetes and diabetes. The obvious thing to do would be to lose the excess body weight safely with a good weight loss program that incorporates proper nutrition in order to be successful. This requires dedication, focus, and commitment. Exercising for weight loss works to lower the impaired fasting glucose and impaired glucose tolerance. However, the benefits of exercise on blood sugar will be reversed within 1-2 weeks if someone is not consistent with their exercise (and nutrition).

            Not every person is the same physically, therefore before any new exercise program or nutrition program is started, someone should DEFINETLY consult their medical provider and get their OK to begin a new program. The reason for this is because some people with pre-diabetes or diabetes already have complications that would cause more problems if they pushed themselves too hard while exercising. Some examples would be a person on dialysis who has a specific renal diet they must follow. They wouldn’t be able to handle a high protein diet because that would cause tremendous stress on severely damaged kidneys, causing more kidney problems. Another example would be someone with peripheral neuropathy where they can’t feel the bottom of their feet. This person should consult their medical provider and make sure they are cleared for a certain type of exercise first.

            Another example would be someone who already has 4 coronary artery stents placed in due to previous heart attacks. Their heart may not be able to take the excess strain caused by exercise and even a moderate exercise program would be a bad idea and dangerous for them. All of these factors play a role. We will not address the specifics of the nutrition and exercise program at this point, we’ll discuss that in the Exercise and Nutrition Modules in the Diabetes Education Course in the coming near future.

            The next thing someone would need to do would be modify their diet to decrease the intake of non-nutritious food and foods high in rapidly absorbing carbohydrates. We all know what these types of foods are. They are the glazed donuts, the fountain drinks, the enriched and milled breads and pastas that are bad for you and have lower nutritious content in them. This would be the next step.

            Unfortunately, not everyone who begins an exercise program and new diet program will be successful at first. It may take some time to adjust to the mindset and lifestyle to fit the new exercise routine and new types of foods to consume. The main goal is, once some is cleared for exercise and a nutrition change from their medical provider, to engage in exercise and clean up the diet. The diet needs to focus on eating more fruits and vegetables. There’s no way around eating a healthy diet (and exercise) if you want to be successful in warding off pre-diabetes.

Pre-Diabetes, Diabetes, and Exercise

            There are many exercise and nutrition programs currently available, each one with their specific benefits and downfalls. With so many to choose from, how does someone know to begin a certain type? Well, a few programs out there are better than others and a few diet programs out there are better than other when it comes to diabetes and reversing the damage from high blood glucose.

            In order to better understand exercise and nutrition, we’ll briefly discuss what the current recommendations are from the most reputable professional diabetes associations are, The American Diabetes Association and the American College of Clinical Endocrinologists. These various professional organizations provide some goals to strive for to reverse or at least delaying the progression to diabetes.

Let’s start with the American Diabetes Association. Their recommendations are the following:

1. Exercise 150 minutes per week of moderate physical activity dispersed over approximately 3 times per week with at least 10 minutes per session. This would be something like walking. Someone can do 75 minutes of strength training per week that can be applied towards the 150 minutes/week.
2. Changing the types of food to eat. ADA provides their food recommendations in Medical Nutrition Therapy and as part of a USDA Healthy Eating Pattern.
3. Weight loss by losing 7% of total body weight within 6 months. The goal is to lose 1-2 pounds per week over the course of 6 months. Cutting out 500-1000 calories per day from the diet can result in 1-2 pounds/week of weight loss, respectively.
4. Consider addition of metformin medication if someone has prediabetes and their lifestyle changes are still not adequate enough. Can consider metformin in those <60 years old. Metformin should be considered especially for someone with a BMI >/= 35 kg/m2 and women with previous gestational diabetes. Metformin is a prescription medication in the US that requires a visit with a primary care provider.
5. Monitor someone at least once a year to make sure they aren’t progressing into diabetes
6. Stop Smoking. Smoking can significantly increase the risk for Type 2 diabetes.

The American Association of Clinical Endocrinologists recommend the following for diabetes prevention:

1. Weight reduction of 5-10% over a period of time (usually 6 months).
2. Moderate intensity exercise regiment of 30-60 minutes/day, 5 days per week.
3. Lowering sodium intake, avoiding too much alcohol, decreasing the intake of calories, increasing fiber intake. Maybe even decreasing carbohydrate intake in certain conditions.
4. Use of Incretin medications to preserve the Beta-cells in the pancreas. Incretins are injectable medications for Type 2 Diabetes, usually used to help lower the mealtime blood glucose values, and ultimately, the Hemoglobin A1C. The Incretins can also help with weight loss (not FDA approved for this though, considered for off-label use in diabetes by some doctors).
5. Use of Metformin or Acarbose prescription medications for people with low risk of prediabetes. Use of pioglitazone prescription in high risk people or those who have failed metformin or acarbose.
6. Not targeting a Hemoglobin A1C for treatment.
7. Using statin medications to decrease the LDL to <100 mg/dL, Non-HDL-C to <130 mg/dL for most people.  Also, get the lipoprotein B level to </= 90 mg/dL. (Blood lipid goals may be lower for persons with a high cardiovascular disease risk, usually based upon the Framingham Risk Assessment for Cardiovascular Disease.
8. Decrease blood pressure to <130/80 mmHg.
9. Use of low-dose aspirin to prevent cardiovascular events. (Use of aspirin, even low-dose aspirin, is NOT to be used in someone with high risk for Gastrointestinal, intracranial, or other bleeding conditions. Using certain medications would also prevent someone from being on low-dose aspirin therapy)

Use of Prescription Medications in Pre-Diabetes

            The specific recommendations that a medical provider will follow will depend on how comfortable the medical provider is with diabetes management and how healthy a person is. Some providers will consider metformin (if appropriate), and some won’t. Some providers will consider adding low dose aspirin (if appropriate) in pre-diabetes and some wont. It all depends on a person’s current medical conditions and the medical providers decision (in harmony with the patient of course).

            Oftentimes the lifestyle changes recommended for exercise and nutrition by the ADA and the AACE guidelines will not be enough. Sometime a person will require the addition of a prescription medication to prevent or slow down the progression of pre-diabetes into diabetes. Let’s take a look at the recommendations for medications.

            The most commonly used medications for pre-diabetes is metformin. The reason for this is that it’s a cheap medication (reasonably) and it has been studied in a major diabetes study for its effectiveness again lifestyle changes. This study was in the Diabetes Prevention Program study. They compared metformin vs lifestyle changes, and they found that lifestyle changes produce the best results, decreasing a person’s weight more than on metformin alone. However, if the lifestyle changes don’t seem to be working, oftentimes a medical provider will add on metformin (if appropriate for the patient) in order to help with the fasting blood glucose. Metformin is used to lower the fasting blood glucose without increasing the risk for hypoglycemia. Metformin is known as an insulin sensitizer.

            Metformin is not appropriate for everyone with pre-diabetes. Usually, it’s reserved for someone who has a higher Hemoglobin A1C, say 6.2% and lifestyle changes are not enough to prevent the progression into diabetes. In order to be placed onto metformin with prediabetes, a person must usually be obese, having a BMI >/= 35 kg/m2 before a provider will consider adding metformin. The reason that it’s used sparingly in prediabetes is that, while being a weigh neutral medication, it has side effects and certain prescribing requirements. A person must not have severe kidney disease (GFR < 45 ml/min/1.73m2), have certain serum creatinine thresholds, and must not be high risk for lactic acidosis. All of these things will be considered by the medical provide before prescribing metformin for prediabetes treatment (and Type 2 Diabetes treatment as well).

            The long-term use of metformin can cause a deficiency in Vitamin B12, especially in someone with neuropathy. This vitamin is important for nerve and red blood cell function. Vitamin B12 has many uses in the body. Therefore, someone usually requires some form of Vitamin B12 supplementation if determined to be necessary by the medical provider. Medical providers will monitor Vitamin b12 levels once in a while to make sure someone is not deficient in it. Vitamin B12 can be given orally (sublingually and over the counter), or in an injected form (prescription version, given subcutaneously or intramuscularly). The injected forms of Vitamin B12 seems to produce more consistent Vitamin B12 delivery. The oral sublingual form of Vitamin B12 is not as potent but still can be considered by a doctor if the Vitamin B12 level is within range.

            There are other medications that can be considered for pre-diabetes because of their usefulness in lowering blood glucose and them being weight neutral, and some of them helping to preserve the beta-cell mass/function in the pancreas. Some of these prescription medications are acarbose, pioglitazone, sulfonylureas, DPP-4 inhibitors, GLP-1 analogs. Most commonly, prescribers will consider metformin, alpha-glucosidase inhibitors (ex. acarbose), and pioglitazone for diabetes prevention. These medications are usually given in addition to lifestyle changes. Each medication has its pros and cons, and the medical provider will consider which medications are most appropriate to prescribe (if at all) based on a person’s current medical situation. Medications for pre-diabetes generally will be considered for someone with a Hemoglobin A1C of >6% since they are considered to be a high-risk person for developing diabetes and diabetes complications.

The goals of prescribing medications for diabetes prevention are to:

1. Help preserve the beta-cell mass and function in the pancreas
2. Promote weight loss in obese persons
3. Maintain correct weight in non-obese persons

            Certain diabetes medications can cause low blood glucose called hypoglycemia. Hypoglycemia is when the blood glucose is <70 mg/dL (3.88 mmol/L). When using diabetes medications, it’s important to prevent hypoglycemia while on these medications and treat hypoglycemia appropriately if it does occur. If possible and appropriate to use them, these diabetes prevention medications should lower the risk of cardiovascular events such as heart attack and stroke by having some effects on blood pressure and blood lipids as well (using blood pressure and anti-lipid medications for these effects). These are the factors that a medical provider will consider before prescribing them in someone with pre-diabetes.

            Medications for diabetes prevention are NOT FDA approved for use in diabetes prevention. Rather, they are used “off-label” by prescribers because of studies showing their benefits on blood glucose. Medications can be legally used off-label by a qualified medical provider, given that they are prescribed appropriately for the patient.

            A person with pre-diabetes or diabetes may have other medical conditions such as high blood pressure, high lipids, and obesity. In addition to treating the pre-diabetes, the medical provider may treat the hypertension (high blood pressure) and cardiovascular risk as well, which is highly recommended. Certain medications can be prescribed for obese persons if they are appropriate for them. Metabolic surgery is also an option for someone with a BMI of >40 kg/m2, who are considered to be severely obese. Metabolic surgery is weight loss surgery with the goal of decreasing the intake of food. Currently, weight loss surgery is not recommended by experts to reduce the risk of going from pre-diabetes to diabetes.

Conclusion – Pre-Diabetes

            Pre-diabetes is the middle area between normal blood glucose and someone having diabetes. This is where someone is usually heavier than they should be and they may not be as active as they once were in life. As a person gets older, they become at higher risk for pre-diabetes because of age and lack of physical activity. In addition, a poor diet will definitely contribute to obesity, which is one of the fundamental problems of pre-diabetes.

            The obesity epidemic in the United States, and throughout various parts of the world, is a growing problem. More and more people are becoming less and less active, packing on the pounds on the body in excess fat. This results in increased risk of cardiovascular diseases such as high blood pressure, high lipids, and of course a higher risk for diabetes. As the weight stays on and doesn’t come off, a person will start to have symptoms of increasing blood glucose (fatigue, sleepiness, needing to rest after a heavy meal), which may indicate higher levels on insulin (called Hyperinsulinemia). Hyperinsulinemia is when the body produces more insulin than it normally would, resulting in effects of too high insulin. In addition, the body will show an increase in fasting blood glucose first, then eventually mealtime blood glucose. As the blood glucose increases over time, a person will become less healthy overall, which can spill over into developing diabetes.

            Not everyone will develop diabetes even if they have high blood pressure, high cholesterol levels, and increasing fasting and mealtime blood glucose. However, the higher the Hemoglobin A1C level is, the higher the risk for developing diabetes. The goal becomes to prevent the onset of diabetes through management of the things that cause insulin resistance and slow down/stop the decline in beta-cell function in the pancreas. This is done through appropriate weight management, appropriate nutrition, and if necessary, adding an appropriate medication to combat the progression into full blown diabetes. The goal is to prevent diabetes and hopefully reverse the damage done to the body by the high blood glucose levels. This is a major goal that everyone who is at risk for diabetes should be taking a serious look at. We cannot afford to not do something about pre-diabetes and diabetes because the consequences of this condition are very serious. These are heart attacks, strokes, peripheral arterial disease, a lower quality of life, and a shorter lifespan.

            I hope you enjoyed reading about Pre-Diabetes today. While this an overview of pre-diabetes, I wanted to include the main points that are relevant. If you enjoyed learning about diabetes and pre-diabetes, stay tuned in and subscribe to the Diabetes and Medical newsletter.

Sergio, Pharmacist

References:

American Diabetes Association. 2. Classification and diagnosis of diabetes. Standards of Medical Care in Diabetes - 2020. Diabetes Care;43(Suppl. 1):S14-31

Unger, Jeffrey. “Prediabetes.”  Diabetes Management in Primary Care, edited by Zachary Schwartz, 2nd Edition, Wolters Kluwer, Lippincott Williams & Wilkins, 2013, pp. 38-61.