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The Ominous Octet – How Type 2 Diabetes Develops

Back when I was in medical school, some 7+ years ago, diabetes mellitus didn’t seem so complex.  There were less big words – no canagliflozins, exenatides, sitagliptins, and the newest kid on the medication block were the TZDs.  And we were taught that there were 2 main mechanisms for the development of diabetes:

  1. Insulin-resistance – your muscles and liver don’t respond well to insulin
  2. Lack of insulin secretion – your beta-cells have lost their function

 

Today, we know that there are at least 8 different mechanisms that play an important role in Type 2 diabetes – the ‘ominous octet‘.  This was coined by Dr Ralph A. DeFronzo who delivered his Banting lecture on this topic (Dr Banting, by the way, was the good fella who first used insulin in humans) .  When I first came across the article, I was fascinated.

ominious octet

Who are the members of this ‘ominous octet‘?  I’ll explain it in lay terms that you can understand, even if you only know the basics of diabetes.

Let’s start with the old fogeys.

1. Pancreatic Beta cells. (codename: THE FACTORY)

These are the good folks that produce all the insulin our bodies need to survive. When they start failing (perhaps from overwork), overall less insulin is available for our cells to use.

grunts

2. Muscle cells (THE GRUNTS)

Our muscles are one of the largest utilisers of blood glucose in the body. Individuals who develop Type 2 diabetes inherit genes that make these tissues resistant to insulin.

When glucose is unable to enter the muscle cells, a lot of the glucose remains in the blood stream, especially after meals.

 

3. Liver (THE ALL-NIGHTER)

Our liver is the main player in glucose regulation when our bodies are in a fasting condition, such as during the night.

It produces glucose through a process called ‘gluconeogenesis’ – this maintains your blood glucose levels at a constant, even if it’s been a long time since your last meal.  This process is regulated by insulin.

When the liver becomes resistant to insulin however, the liver keeps producing more glucose even when the blood glucose levels are already high.

 

4. Fat cells (THE BOUNCER)

Fat cells which are not functioning well will cause an elevation in free fatty acid levels. These result in ‘lipotoxicity’, which overflows into muscle, liver and beta-cells causing insulin-resistance and reduced insulin secretion.

 

5. The gut (Gastrointestinal tract)

Although not typically acknowledged, our intestines are actually a major endocrine order. They secrete incretins (GLP-1 in particular), which are hormones that stimuate insulin and reduce glucagon secretion.  People with Type 2 diabetes often have an attenuated incretin response after meals.

 

6. Pancreatic Alpha cells (THE REBEL)

Pancreatic alpha cells are the siblings of the the beta cells, and they produce glucagon, which is a hormone that is counter-regulatory to insulin. It’s been shown that increased levels of glucagon cause the liver to produce more glucose (through gluconeogenesis), resulting in higher fasting glucose levels.

 

7. Kidneys (THE SCAVENGER)

Our kidneys filter a good amount of glucose each day.  In a normal individual, nearly 100% of the glucose is reabsorbed in the tubules, such that no glucose appears in the urine.

In type 2 diabetes however, instead of dumping glucose into the urine, the kidney maladapts by reabsorbing more glucose instead.

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8. The brain (THE MASTERMIND)

Insulin has a very powerful appetite-suppressant effect, which is mediated by our brains. Unfortunately, this effect is lost as our brain tissues become resistant to insulin and can lead to obesity.

 

Now that we know there are multiple pathways that can cause high blood glucose levels in type 2 diabetes – effective treatment is no longer a single drug that targets one or two pathways. Effective treatment will target all of these pathways early in the disease, so as to prevent beta-cell failure.

Interestingly, sulphonylureas (a common class of diabetic medications) have been shown to reduce A1c and glucose levels – BUT have no protective effect on disease progression in the long run, unlike TZDs or GLP-1 agonists.  Definitely something to think about.

(The full copy of referenced article can be found here – From the triumvirate to the ominous octet : A new paradigm for the treatment of type 2 diabetes mellitus)

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