Prevention of Resistance – Hormonal Obesity XII

By Jason Fung, MD

One of the keys to high insulin levels lies in insulin resistance.  To start the Hormonal Obesity series – click here.
Insulin resistance leads to high insulin levels.  It also appears that high levels of insulin also leads to insulin resistance in a vicious cycle.  How does the body normally defends against insulin resistance?

High levels of hormone by themselves cannot cause resistance.  After all, think about the previous post’s experiment with constant infusions of physiologic levels of insulin.  You might ask yourself this question.  If normal levels of insulin can cause insulin resistance, why don’t we all eventually develop insulin resistance?

The answer lies in how hormones are secreted in the body.  Hormones are always always always secreted in a pulsatile fashion.  Always.  Whether we are talking about cortisol, insulin, growth hormone, parathyroid hormone or any other hormone in the human body, they are released in pulses.

There is a well defined circadian rhythm.  Sometimes, certain hormone levels can be expected to be very high, and at other times of the day, they are virtually undetectable.  It is this very pulsatile nature that prevents the development of tolerance (resistance).  Whenever the body is exposed to a constant stimulus, it will become acclimated to it.

Think about a time that you were in a dark room.  Suddenly, you go outside into the bright sunny day.  Your eyes are suddenly blinded and you feel disoriented.  However, over the next few minutes, you become accustomed to the bright light.  Now things feels normal and you can see normally again.

You suddenly step back into that room – dark as the inside of a magician’s hat.  For a few minutes, you cannot see anything at all.  Even though you had previously been in this room and were able to see fine, you no longer are able to do so.  Over the next few minutes, you become accustomed to the dark and can start to see again.

The body has the ability to adapt to a constant stimulus.  In going from dark to light, the body develops resistance to the light.  In going from light to dark, the body develops resistance to dark.

This example shows how varying the levels of light can prevent the development of resistance.  If we are in the sun, and we are exposed to a sudden brief darkness, we do not lose the adaptation to the sun.

Hormones work in exactly the same way.  Most of the time, hormone levels are low.  Every so often, a brief pulse of hormone (thyroid, parathyroid, growth, insulin – whatever) comes along.  After it passes, levels are very low again.

By cycling low and high levels, the body never gets a chance to adapt.  There is never a chance to develop the resistance because the pulse of hormone is gone before this develops.

What our body does, in effect is to continually keep us in a dark room.  Every once in a while, we are exposed to bright light briefly, then returned to the dark room.  Each time this happens we experience the full effect of the light.  We are never given a chance to get ‘used to’ the higher levels of hormone.  So we are able to maintain the same sensitivity to light.

How does this apply to obesity?

The circadian pulses of insulin prevents the development of insulin resistance.  However, the situation changes when we are constantly exposed to insulin.  In response to insulin infusions at levels normally seen in the human body, healthy young men developed insulin resistance – the first step to diabetes type 2.

What was the difference between the experimental condition and normal behaviour?  The pulsatile release.  In the normal state insulin is released only occasionally, and this prevents the development of resistance.

In the experimental condition, insulin was constantly infused over 96 hours.  The constant bombardment of insulin led the body to develop insulin resistance.  There will be a down-regulation of receptors and the body will develop insulin resistance.

Over time, the insulin resistance leads to higher insulin levels to ‘overcome’ this resistance.  High levels alone do not lead to resistance.  There are 2 requirements for resistance – high hormonal levels and constant stimulus.

This is an effect that we use to our advantage in the drug therapy of angina (chest pain).  Patients that are prescribed a nitroglycerin patch for angina are often given the instructions to put the patch on in the morning and take it off in the evening.

By alternating periods of high drug effect and low drug effect, there is no chance for the body to develop resistance to the nitroglycerin.  If the nitro-patch is worn 24 hour/day every day, it quickly becomes useless.  The constant stimulus and high nitroglycerin levels produced resistance.

Going back to the case of obesity, you can now appreciate that changing the composition of food alone (leading to higher insulin levels) will not be enough to produce resistance.

If we eat 3 meals a day, there are higher levels of insulin but we do not have the persistent, constant stimulus of insulin required to produce insulin resistance.
In other words, if we turn back the clock to the 1950s, we can still eat white bread and Oreo cookies and still have very low levels of obesity.  That is because we are still balanced between feeding periods and fasting periods.  We eat (as an example) 3 meals a day 8 am (breakfast) to 6 pm (dinner).  In between, there are no snacks.

From 6pm to 8am, we do not eat (fasting).  That means we have 10 hours of feeding and 14 hours of fasting every single day.  Insulin resistance (a major driver of high insulin levels) does not develop.

Instead of eating 3 times/day, what would happen if we ate 6 times/day?  Then your insulin profile would look like this.

Now we have the two pre-requisites of insulin resistance.  We have high levels AND we have persistent levels.  Under these conditions, we would expect the development of insulin resistance.

In order to eat 6 times/day instead of 3 time, we would have to snack all the time.  Your grandmother could have told you that eating snacks all the time would make you fat.  What  appalling, hideously bad dietary advice to give.  Muy estupido.  That’s exactly the advice we have been giving for the last 40 years!  And we wonder why we have an epidemic of obesity.

A question often comes up here.  If all cells are resistant to the effect of the insulin, then the higher level of insulin should have no effect overall.  The answer is that insulin has different effects on different parts of the body – the main parts being the muscle, the liver and the brain.  Each part has a certain sensitivity or resistance to insulin, and this does not affect the other.

Exercise, for instance will increase the sensitivity of muscles to insulin but has no effect on insulin sensitivity in the liver or brain.  Hepatic (liver) insulin resistance which develops from fatty liver does not affect insulin resistance in the brain or muscle.  When we ingest excess carbohydrates, we develop hepatic insulin resistance.  This increases the overall insulin levels.  However, the brain has normal insulin sensitivity.

In the brain, we have increased insulin levels acting on normally sensitive receptors resulting in an increased insulin effect.  The effect is to increase the body set weight which will cause you to gain fat.  Ultimately, it the brain which ties together all the effects of hunger and energy expenditure.  That is how we gain. weight.

Continue to Hormonal Obesity XIII here
Begin here with Calories I
See the entire lecture The Aetiology of Obesity 2/6 – The New Science of Diabesity

Jason Fung, MD

By Jason Fung, MD

Jason Fung, M.D., is a Toronto-based nephrologist (kidney specialist) and a world leading expert in intermittent fasting and low-carb diets.

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