Scottish GP Malcolm Kendrick has a wonderful way with words about diabetes – and lots else besides. Here’s an oldie but goldie from Kendrick. In it, he argues why so many endocrinologists have got it so wrong about effective treatment for type 2 diabetes. Why they, in effect, look at type 2 diabetes from the wrong way round.
Upside down, if you like.
Kendrick says that insulin is not really the key hormone. It is ‘merely’ the subservient hormone. The body produces it counter the effects of too much of another hormone, glucagon.
He’s not saying that insulin isn’t important, just that it is far from essential. He is also saying that drug treatment for diabetes misses the mark. And while useful, metformin is not a wonder drug. If you don’t follow Kendrick, do so. On his blog, he has written a fascinating 40-part series on heart disease. – Marika Sboros
By Malcolm Kendrick
I have written about diabetes quite a few times. Thus far, I must admit, I have kept the discussion relatively conventional. Anyone who has read my previous blogs may not think so. But compared to what I really believe, everything has taken place close to the middle ground.
Time, I believe, to start turning diabetes upside down, give it a good shake. And see what it looks like from a completely different angle.
Some of you may have watched Professor Roger Unger’s fascinating YouTube lecture on type II diabetes. If not, here it is. I recommend it. To keep things as simple as possible, his view is that the key hormone that drives diabetes is glucagon, not insulin.
Indeed, by focusing almost entirely on insulin and sugar/glucose, we cannot understand what is going on with type 2 diabetes. That’s because we are only looking at a small part of the picture. In addition, we are looking at it the wrong way round.
He is, of course, right. Now, stop, stand on your head…
Ready, here we go. The critical requirement of human metabolism is to ensure that there is a high enough level of glucose to power the brain. Without sufficient glucose, the brain shuts down and dies.
Not all the cell types in the brain need glucose and all brain cells can also metabolise ketone bodies, to an extent. (Ketone bodies are synthesised in the liver from fatty acids).
However, the bottom line is this. If your blood sugar level drops below about 2mmol/l, and stays there, you will enter a hypoglycaemic coma and die. Which means that it is absolutely critical that this does not ever occur.
To prevent this happening, we have a hormone that keeps blood sugar from dropping this low. It is called glucagon. the body produces it in alpha-cells in the pancreas (right next to where the body produces insulin).
How does it work? Here is a short, standard, explanation from diabetes.co.uk:
Glucagon plays an active role in allowing the body to regulate the utilisation of glucose and fats. The body releases glucagon in response to low blood glucose levels and to events whereby the body needs additional glucose, such as in response to vigorous exercise.
Glucagon can perform the following tasks:
- Stimulating the liver to break down glycogen to be released into the blood as glucose
- Activating gluconeogenesis, the conversion of amino acids into glucose
- Breaking down stored fat (triglycerides) into fatty acids for use as fuel by cell
Of course, this statement from diabetes.co.uk is true. However, I would ask you to review 10 of the words again and think about them for a moment or two. ‘Glucagon is released in response to low blood glucose levels.’
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Now, you almost certainly do not recognise it but here is the crux of the entire blood diabetes/insulin /glucose discussion. Upside down thinking has driven those 10 words, innocent though they may seem. Thus, they represent the exact point where things go wrong.
This is not deliberate. Indeed the concept is so familiar, so unquestioned, that you almost certainly have no idea what I am talking about.
At this point, you are probably wondering, ‘what the hell is Kendrick on about here?’
Indulge me for a moment whilst I re-frame that statement.
As it stands, we are given to believe that glucagon is the reactive hormone; that it is only produced when blood sugar levels drop. Insulin, on the other hand, is the key hormone, the controller of metabolism and blood sugar levels. Glucagon only activates to increase blood sugar after insulin (or exercise) has caused it to fall too far. Which is why we have these 10 words: ‘Glucagon is released in response to low blood glucose levels’
You think this is not important, just playing with words. Then try this alternative statement on, and see how it fits.
‘Glucagon keeps the blood sugar level high enough to ensure that the brain has sufficient glucose to function. If, however, the glucose levels rise too high, the body produces insulin to counteract the effects Glucagon. This brings blood sugar back down.’
In one way, I am saying exactly the same thing as diabetes.co.uk said. Looked at another way, however, and I have just changed everything. No longer is insulin the key hormone, it is now ‘merely’ the subservient hormone. It is produced to counter the effects of too much glucagon.
Once you have changed your thinking around this way, it should come as absolutely no surprise to find the following. If you have a mouse, and you destroy its beta-cells (insulin-producing dells in the pancreas) it will become diabetic and die.
However, if you get rid of the glucagon-producing cells as well, the animal will not have a high sugar level and will not be diabetic. That is despite having no insulin at all. It will also appear to be completely healthy.
In addition, if you give such a mouse, which cannot produce either glucagon or insulin, a glucose ‘meal’, the blood sugar level will rise and then fall. That is in pretty much the same pattern as a ‘normal’ mouse. Ergo, the body does not need insulin to keep blood sugar levels down.
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There are other mechanisms that the body can use. I am sure that having insulin helps to optimise blood sugar control but it is far from essential.
Of course, this type of experiment has never been done in a human – for obvious reasons. However, I do not think there is any reason to doubt that the results would be pretty much the same. Which means that, crikey, insulin is not required for blood sugar control…
If I tell my medical colleagues this they absolutely and completely refused to believe it. However, it is true. They choose not to believe it, because it undermines what they think is true.
In fact, they think what almost everyone else things. That the insulin/glucose: glucose/insulin model of diabetes is correct. It certainly appeared to explain what we saw in type I diabetes. You gave insulin to those with high sugar levels [those who could not produce insulin, the underlying cause of type I diabetes] and they were ‘cured’. While discovery of insulin and treatment of type I diabetes was a medical triumph, it is also where the thinking went wrong.
It blinded everyone to fact that insulin is not the key hormone in glucose metabolism. It is simply there to act as a negative feedback mechanism to control glucagon. Unfortunately, since Banting Best and MacLeod, we have become stuck with the insulin/glucose paradigm.
If the blood sugar rises, whatever the underlying cause, we call it diabetes and drive it down…sigh. The more it rises the harder you drive it down….sigh. The lower you get the blood sugar down the better…sigh.
How do you do this? Mainly by giving drugs that force beta-cells to produce more insulin. Or by adding in drugs that work with insulin to lower blood sugar levels. Or by injecting additional insulin.
How well does this work? Some of you will have heard of the ACCORD study, others will not. In this study researchers, tried to force blood sugar levels down as far as possible using intensive treatment. They found the following:
‘Until last week, researchers, doctors and every medical professional have believed for decades that if people with diabetes lowered their blood sugars to normal levels, they could not only prevent the complications from diabetes but also reduce the risk of dying from heart disease. But the Accord Study, (for Action to Control Cardiovascular Risk in Diabetes), a major NIH study of more than 10,000 older and middle-aged people with type 2 diabetes has found that lowering blood sugar actually increased their risk of death.’
There is one other way of lowering blood glucose: by using insulin ‘sensitising’ drugs. In diabetes, most doctors look at metformin as the wonder drug. This drug improves ‘insulin sensitivity’, ie, it helps to reduce insulin resistance. It is the absolute mainstay of type 2 diabetes treatment. Once again, however, the drug targets purely the insulin/glucose model:
‘Metformin has been the mainstay of treatment for type 2 diabetes since 1998 when the UK Prospective Diabetes Study showed reduced mortality with metformin use compared with diet alone. Recently a French meta-analysis of 13 random controlled trials questioned the central role of metformin in the care of patients with diabetes. In this meta-analysis, in which 9560 patients were given metformin and 3550 were given conventional treatment or placebo, metformin did not significantly affect the primary outcomes of all-cause mortality or cardiovascular mortality. The secondary outcomes—myocardial infarction, stroke, heart failure, peripheral vascular disease, leg amputation, and microvascular complications—were also unaffected by treatment with metformin.’3
Today we have a virtually unquestioned model of diabetes that is very simple, and easy to understand. It should be simple to understand as it works like this. If the blood sugar goes up, the body produces insulin to lower it. If the blood sugar goes down, the body produces less insulin and the sugar level goes up.
This has meant that, if you find someone had high blood sugar levels, you basically hit them with insulin. I call insulin the ‘glucose hammer’. And as a wise man once said. ‘If the only tool you have is a hammer, pretty soon everything starts to look like a nail’.
Reducing glucagon…. anybody?