I suppose I should start this particular blog by stating that my interest in diabetes (type II) first came about as an extension of my interest in heart disease. This means that I approached diabetes in a different direction from most people. I was not looking at type II diabetes as an isolated condition; I was searching for the underlying links between heart disease and diabetes. This is probably why I have never thought about diabetes from the obesity, insulin resistance, perspective.
Instead, I was studying the impact of stress hormones, specifically cortisol, on various physiological systems. I knew that stress and cortisol levels were closely linked to cardiovascular disease. I also knew that type II diabetes increased the risk of cardiovascular disease – or perhaps vice-versa. Could both conditions be linked by abnormal cortisol levels?
Obviously I was aware that stress – however you define it – is a far more complex thing than simply raised blood cortisol levels. The stress response, or ‘flight or fight’ response or whatever you feel most comfortable with calling it is far more complex than that. It also involves a myriad of different mechanisms triggered by the sympathetic nervous system. Many other hormones are also involved, from glucagon to growth hormone, adrenaline and nor-adrenaline – and others too numerous to mention.
However, I decided to keep things simple and keep my attention focused on cortisol. I did this for two reasons. First, because I find that if you try to look at too many things at the same time you get dragged down into endless complexity. Second, I felt that cortisol may be the key hormone to study, because it is the primary ‘catabolic’ hormone. By which I mean that it triggers a whole series of ‘energy burning’ processes.
For example, a high cortisol level will convert glycogen in the liver into glucose – which is then released into the bloodstream, raising blood sugar levels. This is known as ‘glycogenolysis’. Cortisol also drives ketone synthesis in the liver. Furthermore, it breaks down fat and protein stores, releasing them for energy use. It also stimulates glucagon production in the alpha cells in the pancreas.
Looking at things from this perspective you could say that cortisol does the exact opposite of insulin. Insulin is the energy storage hormone; cortisol is the energy burning hormone. Therefore it seemed likely that people with high cortisol levels would develop insulin resistance and, in many cases, type II diabetes. I knew that stress raises cortisol levels and so here, perhaps, was an obvious link between stress, heart disease and type II diabetes.
This thought immediately led me to look at of people with Cushing’s disease (sometimes called Cushing’s syndrome). People with Cushing’s disease have a tumour on their adrenal glands which pumps out excess cortisol, in an uncontrolled fashion. This creates a whole series of metabolic problems:
‘Chronic cortisol hypersecretion causes central obesity, hypertension, insulin resistance, dyslipidemia, protrombotic state, manifestations which form a metabolic syndrome in all patients with Cushing’s syndrome. These associated abnormalities determine an increased cardiovascular risk not only during the active phase of the disease but also long after the “biomedical remission”’ 1
It is not exactly a state secret to announce that people with Cushing’s disease suffer from a wide, wide, spectrum of abnormalities, from increased visceral obesity to type II diabetes, high triglyceride levels, low HDL, raised blood pressure and on and on. They also have a very, very, high rate of death from heart disease. In some studies a 600% relative increase in risk. [Stick that in your pipe and smoke it…cholesterol].
Some of you may have looked at that list of abnormalities and thought. Hey, isn’t that also called the ‘Metabolic Syndrome.’ Why, yes, indeed, it is. Just to make research extra confusing, it is also called, at least, four other things:
- Syndrome X
- Reaven’s syndrome
- Insulin resistance syndrome
Anyway, leaving behind the terminological inexactitude in this area, it is beyond the slightest shadow of doubt that a high cortisol level can causes enormous and widespread metabolic disruption. Possibly this is all modulated by severe insulin resistance. Here is Wikipedia on the effects of Cushing’s syndrome (sometime called Cushing’s disease, sometimes called Cushing’s syndrome) on insulin resistance:
…Other signs include polyuria (and accompanying polydipsia), persistent hypertension (due to cortisol’s enhancement of epinephrine’s vasoconstrictive effect) and insulin resistance (especially common in ectopic ACTH production), leading to high blood sugar and insulin resistance which can lead to diabetes mellitus.’2
But is it definitely the raised cortisol that causes these problems? Could other things be going on in Cushing’s disease? To be absolutely certain that it cortisol was the culprit, I felt the need to double check.
So, I looked for people who are given high doses of cortisol. You may think that this would be a very strange thing to do. However, as some of you may be aware, cortisol is also known as a ‘corticosteroid’. Corticosteroids are group of hormones synthesized in the adrenal glands (all made from cholesterol, by the way). Just in case you are wondering, anabolic steroids are an artificial form of testosterone (another corticosteroid hormone), but one that builds up muscle, rather than breaking it down.
Synthetic corticosteroids based on cortisol are usually referred to as just, plain old steroids. Steroids are used in a very wide variety of diseases from asthma, to rheumatoid arthritis, Crohn’s disease, Systemic Lupus and Sarcoidosis. Essentially, they are used in any disease which has a significant ‘inflammatory’ component.
They are prescribed in these conditions because they are the most powerful anti-inflammatory agents known to man. There is no doubt that they are brilliant, and fantastic… however if used for too long… they can be deadly. I think of steroids as the bazooka of medical intervention. They blow up things ahead, but they also blow things up behind. So you need to be very careful what you point them at. And for how long… which is where my bazooka analogy rather fails.
Anyway, as you might expect, long-term use of steroids leads to exactly, and precisely, the same metabolic abnormalities that are seen with Cushing’s disease. Here is a short section of a paper looking at the impact of steroids on human metabolism:
‘Clinical-overt and experimental cortisol excess is associated with profound metabolic disturbances of intermediate metabolism resulting in abdominal obesity, insulin resistance, and low HDL-cholesterol levels, which can lead to diabetes.’3
None of this should be in the lease bit surprising, and I found that I was just confirming facts which, it seemed, had to be true. I knew that cortisol was a ‘stress’ hormone, and the key catabolic hormone (food burning/energy usage). I knew that Insulin was the key hormone directing energy storage. Frankly, I would have been amazed if raised cortisol did not cause insulin resistance and type II diabetes, and a whole serious of other problems from raised blood pressure to visceral obesity, low HDL levels, increased blood clotting etc. etc. All of the things associated with a high risk of heart disease.
In fact, when you look at heart disease and diabetes as two sides of the same coin, with stress/cortisol linking them together, things that may seem difficult, or impossible to connect, snap into place. Just to give one example here. Depression is known to be linked to a higher rate of death from heart disease. Here is a meta-analysis of nearly nine hundred thousand people
‘The results of our meta-analysis suggest that depression is independently associated with a significantly increased risk of CHD and MI, which may have implications for CHD etiological research and psychological medicine.’4
Depression can also increase the risk of insulin resistance and type II diabetes:
‘A positive association was found between depressive disorder and insulin resistance in this population-based sample of young adult men and women. The association seemed to be mediated partially by waist circumference.’ 5
What is the underlying factor linking depression and insulin resistance?
‘PMD (PMD is shorthand for depression – my words in bold) is associated with increased cortisol levels during the quiescent hours. Enhanced cortisol activity, particularly a higher nadir, was related to depression severity and the interaction of depressive and psychotic symptoms. This increase suggests a defect in the action of the circadian timing system and HPA axis, creating a hormonal milieu similarly seen in early Cushing’s syndrome and potentially an (im)balance of mineralocorticoid and glucocorticoid receptor activity.’6
Sorry about the jargon, but I wanted to make clear that severe depression mimics early Cushing’s syndrome… Interesting? At this point I could go deeper and start discussing the Hypothalamic Pituitary Adrenal axis (HPA-axis) and how you can link post-traumatic stress disorder, depression, fibromyalgia, childhood abuse, smoking and a lack of exercise to HPA-axis dysfunction, abnormal cortisol levels, central obesity the metabolic syndrome diabetes and heart disease together. But maybe that is for another day.
What I wanted to make clear here is that, when you look at things from a different perspective, type II diabetes becomes a much more interesting condition. It is not, and never was, a simple case of: you eat too much > you get fat > you become insulin resistance > you get type II diabetes.
But it seems that we are stuck with this ‘energy-centric’ model forever. All facts must orbit round excess energy consumption, and the role of other hormones in the body shalt be ignored. Glucagon…what’s that got to do with diabetes. Cortisol – do not look through that telescope young man. Depression causing visceral obesity heart disease and diabetes… nonsense. Oh well, dogma, dogma, dogma. It seems indestructible.
More on this topic soon(ish).