Treating type II diabetes - Pharmacology

- [Voiceover] Type II diabetes receives a lot of attention in the laypress as a public health threat, as it affects about 10% of the global population, and is currently the eighth most common cause of death worldwide. As such, understanding how to treat type II diabetes is very important because if it's treated properly, one can avoid nearly all of the complications of type II diabetes and live a happy and healthy life. Now before we dive into the specific treatments, let's first discuss the glucose regulation pathway as it will help us to better understand the pharmacokinetics or the mechanisms of action for the different treatments of type II diabetes. Now in the center here is the blood glucose level, and as blood glucose levels increase, say after eating a meal, this is sensed by the pancreas, and the beta cells within the pancreas secrete insulin which acts on cells throughout the body to lower the blood glucose level. Then as blood glucose levels decrease, this is also sensed by the pancreas, and then the alpha cells secrete glucagon which acts to raise the blood glucose levels. And one of the mechanisms by which it does so is by promoting the conversion of glycogen to glucose in the liver which is then released into the blood stream. Now diabetes mellitus is a group of disorders that's caused by dysfunction of the insulin pathway resulting in an inability to lower blood glucose levels. And as you can see by this diagram, there are two main steps that must occur for this pathway to work properly. First, insulin must be secreted by the beta cells of the pancreas. Then second, the cells throughout the body must respond to insulin for it to have an effect. And this glucose regulation pathway can be thought of as similar to that of the temperature regulation in a building. The thermostat is analogous to the pancreas in that it senses the changes in temperature and sends different signals accordingly. If the temperature increases, then it sends a signal to the air conditioner to turn on, which then lowers the temperature. Conversely, if the temperature decreases, this is also sensed by the thermostat and it sends a signal to the boiler and radiator to turn on, which then raises the temperature. Now once again, there are two important steps. The thermostat must sense the change in temperature and send a signal, which is similar to the first step in the insulin pathway, and second, the air conditioner must be able to act upon this signal in order to have an effect. So let's go back to our insulin pathway. When we think of the types of diabetes, in general we think of type I diabetes as dysfunction of the first step, and type II diabetes as occurring due to dysfunction of the second step. So it would make sense that the treatment of the different types of diabetes will be different as their underlying mechanisms are different. In the treatment of type II diabetes, some medications are given to increase insulin secretion, to help overcome the resistance, and others are given to directly decrease the insulin resistance in the second step. So let's now discuss the specific treatments for type II diabetes and the mechanisms by which they work. And we'll begin with lifestyle modifications. The first lifestyle intervention is that of proper nutrition and weight loss. Regardless of one's initial weight, proper nutrition and associated weight loss improves the body's ability to regulate blood glucose levels. And proper nutrition for type II diabetes includes a well-balanced low-calorie and low-carbohydrate diet. Admittedly, this can be a very difficult change for many people with type II diabetes. As it takes a great deal of dedication and self-control. However, it is extremely important because a proper diet and weight loss have been shown to both increase insulin secretion and decrease insulin resistance. The other lifestyle modification is physical activity. Independent of weight loss, increased physical activity has been shown to improve glycemic control through reducing insulin resistance. And the benefits of exercise begin almost immediately, however they can be short lived if physical activity is not maintained. Persisting only about three to six days after the cessation of routine exercise. So the recommendations for routine exercise include 30 minutes a day, five days a week, of moderate intensity aerobic activity such as walking, jogging, or biking. And the great thing about these lifestyle modifications is they don't just treat type II diabetes. A proper diet and routine physical activity will also improve one's cardiovascular function, lipid profile, as well as their general mental wellbeing. In addition to lifestyle modifications, there are many different medications available to treat type II diabetes, however it can be confusing to keep them all straight. Instead of discussing each of the medications individually, let's classify the different medications into groups based on their mechanism of action and how it relates to our diagram of glucose regulation. And we'll start with a group of medications known as the biguanides, and I know I just said we won't be discussing the individual medications, however there is one exception, and that is with metformin. And this is because metformin is by far the most common biguanide prescribed for type II diabetes. And it's also the first line medication for the disease. Now, metformin has three mechanisms of action that improve glucose regulation. Most importantly, metformin directly increases the peripheral insulin sensitivity. It also acts by decreasing the action of glucagon in the liver. So instead of just augmenting the insulin pathway, metformin also inhibits the opposing glucagon pathway. Then lastly, although not shown in this diagram, metformin reduces intestinal absorption of glucose which then decreases the amount of glucose available to enter the blood stream. And fortunately, metformin is also very effective. On average, metformin can reduce someone's hemoglobin A1c by about 1%, however it is important to note that individuals with liver failure can not take metformin and a small percentage of individuals who take the medication will need to stop taking it due to an adverse side effect known as lactic acidosis. The next group of medications have a somewhat difficult name. They are the thiazolididiones or TZDs for short. Similar to metformin, TZDs also work to increase type II diabetes by acting on the second step to increase insulin sensitivity, however the means by which they do so is different. TZDs activate a receptor known as the peroxisome proliferator-activated receptor gamma or PPAR gamma for short. And PPAR gamma is a transcription factor for multiple genes that increase insulin sensitivity in adipose, muscle, and liver cells. As such, by activating PPAR gamma, TZDs indirectly increase insulin sensitivity. Now the next group of medication is the sulfonylureas which are another common group of anti-diabetic medication. Sulfonylureas inhibit the potassium channels on the beta cells within the pancreas and by inhibiting these channels, potassium builds up within the cell and this depolarizes the cell membrane which opens voltage gated calcium channels. This causes an influx of calcium into the beta cells which triggers the release of insulin into the blood stream. So instead of decreasing insulin resistance, sulfonylureas treat type II diabetes by overcoming the insulin resistance through increased insulin secretion. The last two groups of type II diabetes medications act upon the incretin pathway, and are therefore known as incretins. And they are the glucagon-like peptide one or GLP-1 agonists and the dipeptidyl peptidase four or DPP-4 antagonists. Incretins such as GLP-1 are hormones that have two synergistic effects that result in the lowering of blood glucose levels. First, they directly stimulate the release of insulin from the beta cells in the pancreas. And second, they inhibit the release of glucagon. DPP-4, on the other hand, is an enzyme that inhibits the action of GLP-1. Therefore GLP-1 agonists can be given to directly stimulate this incretin pathway to augment the insulin pathway and treat type II diabetes. Similarly, DPP-4 inhibitors can be given to indirectly augment the insulin pathway by inhibiting the inhibition of the incretin pathway. So it's important to know that any of the treatments for type II diabetes that act upon this first step in the insulin pathway, and therefore increase insulin secretion, will therefore also carry a risk of inducing hypoglycemia or low blood sugar levels. And the treatments that act upon this step and carry this risk include lifestyle modifications, sulfonylureas, and the incretins. And one way to decrease this risk is to take the medications with a meal. Now this is just an overview of the pharmacokinetics of the different interventions used to treat type II diabetes and this is helpful for understanding how we can use medications to reverse and treat the underlying mechanisms that cause the disease, however just understanding the mechanisms does not convey a very practical approach to treating this disease. For most individuals, treating type II diabetes requires a combination of lifestyle modifications, potentially multiple medications, and routine care by a primary care provider to achieve a happy and healthy life free of the complications of type II diabetes.