The Ominous Octet of Diabetes Causes

Have you ever heard of the Ominous Octet?

Have you ever asked your doctor, “what causes my diabetes?” If you have Type 2 diabetes, then you may get the answer of “insulin resistance.” Maybe you get the answer that you are overweight, genetics, eating too much sugar, etc etc, but do you want to know more about the pathophysiology of it? The real answer is that there are many causes of high blood sugars in diabetes and they are outlined in this blog as the Ominous Octet.

In 1889, a novel discovery helped a scientists found the role of the pancreas in regulating blood sugar level when he removed the pancreas from dogs, which led them to develop diabetes and they died shortly afterward.

In 1921, insulin was discovered when an extract of pancreatic islet cells from healthy dogs into dogs with diabetes and cured their diabetes.

We are still thankful for the discovery of insulin. Without it, people with type 1 diabetes would die in weeks or months. People with type 1 diabetes and some people with type 2 diabetes need to use insulin every day. In 1936, there was published research that differentiated between type 1 and type 2 diabetes because it was theorized that that many people had insulin resistance rather than insulin deficiency.

The problem was that people with diabetes were still going blind and losing their limbs, so we needed to find more ways to treat people and treating diabetes was a problem because people hated to give themselves injections of insulin. Thus, sulfonylureas (Glimepiride, Glipzide, etc) were pills created as a solution to people with Type 2 diabetes who did not want to take insulin injections. They became available around 1955. They worked by making the pancreas to squeeze out every last drop of insulin that it can produce.  Eventually, that burns out the pancreas and people would end up on insulin injections.

Insulin resistance is one big factor that leads to type 2 diabetes and decreased function of the pancreas is usually more like an end result.

All the way until about 27 years ago, there was this ultimate focus on the pancreas function when treating diabetes. Around 1979, it was recognized that the liver played a part in the diabetes story and contributed to elevated glucose when people were not eating. Along came biguanides (AKA Metformin), which was released to the US market in 1995 and Metformin is still the master of all diabetes medications. In fact, more is to be learned about the liver yet. Excess glycogen accumulation in the liver is seen in 80% of diabetic patients. Soon next, when it was noted that the actual muscle cells played a role and were often resistant to the insulin, then thiazolidinediones or “glitazones,”Pioglitazone  came to the rescue in the late 90's.  At this point in history, there was the "triumvirate" of causes of diabetes included the pancreas (beta cells), liver and muscle.

Over the last 10-12 years a flurry of activity has occurred in diabetes research and the development of new drugs and therapies.  The GI tract was introduced as an endocrine organ secreting hormones in response to food.  Some claim to have known about this for years but without any real treatment options there was not much they could do. Then incretin therapy hit the scene.  Now we felt we could move forward in treating diabetes. More recently the brain, adipose tissue, alpha cells and kidney have all been identified as major players in diabetes management and control.

So let's quickly review the ominous octet – the beta cells of the pancreas, the liver, muscle cells, the gut, the brain, adipose cells, the kidney, and malfunctioning of the alpha cells causing hyperglucagonemia all contribute to the elevated glucoses of diabetes.

So what does all of this mean?

Let’s break down each one:

1. Decreased Insulin Secretion

Although insulin resistance typically causes increased amounts of insulin initially, these amounts are not enough to overcome the amount of glucose in the blood. The inability to correct blood sugars to normal levels is called impaired glucose tolerance (IGT). It has been found that once IGT is present, about 80% of pancreatic beta cell function has been lost. Further, over time, the remaining pancreas beta cells get “tired” and stop producing insulin altogether. This is why some type 2 diabetes patients are considered “insulin-dependent”.

2. Decreased Incretin Effect

Another set of important hormones for glucose regulation are referred to as incretins. These are hormones that come from the intestine, and they have direct beneficial effects on some of the other defects listed here (total of 6 out of 8).

3. Increased Lipolysis

This simply refers to increased fat breakdown. What is the problem with that, right? Well it’s not the same as breaking down fat with exercise. Fat cells release more free fatty acids, and the excess lipid accumulates in liver (fatty liver), muscle and pancreas. This worsens overall insulin resistance and decreases insulin secretion.

4. Increased Glucose Reabsorption

The kidney has a remarkable ability to hold on to the glucose it filters, which is critical to providing for the energy demands of the body’s tissues. However, in diabetes, it is problematic since it holds on to most of the glucose, even if the glucose levels are already high.

5. Decreased Glucose Uptake

Muscle cells have decreased ability to take up glucose and remove it from the blood stream. Tip: Exercise can improve this dysfunction.

6. Neurotransmitter Dysfunction

The brain plays an important role in glucose metabolism. Neurotransmitters are natural chemicals that stimulate the brain and nervous system. These signals are disrupted, and one of the major consequences is an increase in appetite. This is likely why obesity and type 2 diabetes are highly correlated.

7. Increased Hepatic Glucose Production (HGP)

In times of need, the liver produces blood sugar through processes called gluconeogenesis and glycogenolysis. This system goes unchecked in diabetes, where the liver continues to produce significant amounts of sugar, even when blood sugars are already high.

8. Increased Glucagon Secretion

The pancreas has beta cells that produce insulin and alpha cells that produce glucagon. Glucagon causes the liver to produce more glucose for energy demand. It is counteracted by insulin. So if insulin is impaired, this regulation is also unchecked and broken, leading to even higher glucose levels.

We have come a long way in learning the ins and outs, literally. Not too long ago in our medical history, it seemed so simple to explain Type 1 Diabetes as caused by lack of insulin and Type 2 diabetes as caused by insulin that just does not work well. However, now we know that it is not necessarily that simple. Well, actually if you have Type 1 diabetes then it is simple... Your body produces insulin like a cow produces rainbows.

But if you have Type 2 diabetes, then there is a possibility of 8 different defects in sugar metabolism that lead to high blood sugars. They are still discovering all the ways that Metformin works in the body. We know that it helps to decrease liver release of sugar, but research has also found that it alters the gut microbiota composition by enhancing the growth of some bacteria, such as Akkermansia muciniphila, Escherichia spp. or Lactobacillus and by decreasing the levels of some other ones like Intestinibacter.

You may be wondering, "which defect do I have and which medications work best for me?" That is a fair question because an individual's response of glucose lowering to a drug may vary greatly from one to the other. The research on medications looks at large groups of people in clinical trials. This means there is little information available on whether a specific person in the clinic is more or less likely than the average trial participant to respond well to a particular treatment or develop side effects. Identifying specific genetic, ethnic and metabolic make-ups is certainly a very interesting arena of research. Although, in clinical practice it is still mostly theoretical than practice. In fact, the theories are still expanding. This is a picture of 14 theorized defects of diabetes, where there is the addition of dopamine, Vitamin D, testosterone, iron overload, gut microbiome, and the renin-angiotensin system. But if it was as simple as giving someone Vitamin D and probiotics to reverse diabetes, then there would not be a billion dollar pharmaceutical company. Keep in mind that the pancreas still matters because the “beta cells” of the pancreas are functioning at a less than maximal capacity. When too many beta cells are lost, people have to start taking insulin. So the goal is to never get there. Recognizing your diabetes and keeping your blood sugars really well controlled preserves your pancreas, as well as the rest of your body and health. If your blood sugars have been out of control, there is still hope that those beta cells can recover with really good blood sugars. Come see me at  Evolve Diabetes with an appointment.