Drug Tolerance – Hormonal Obesity IX

We are discussing insulin resistance and how it develops.  Clues from other biological systems suggests that looking at the agent itself may be important in resistance.Drug Tolerance

What about for drugs, particularly addictive drugs such as cocaine?  Resistance also develops, but the name is different.

When a drug (say, cocaine) is taken initially there is usually an intense reaction.  The ‘high’.  With each subsequent time cocaine is taken, there is a slightly lower ‘high’.  This is known as drug tolerance.  But this is really just another name for resistance.

In effect, the body becomes resistant to the effects of the cocaine with prolonged usage of the agent itself.  In other words, drugs cause drug resistance.

This effect is seen in many drugs, not just cocaine.  Narcotics, marijuana, nicotine, caffeine, alcohol, benzodiazepines, and nitroglycerin all have the same effect of drug tolerance.  People may start using higher and higher doses of the drug to achieve the same effect as the initial time it was used.  This is addictive behaviour.Vicious Cycle

This, too, is a natural response.  The automatic response to antibiotic resistance is to use more antibiotic.  The automatic response to drug resistance is to use more drug.  The automatic response of insulin resistance is increased insulin levels.  This has the effect of ‘overcoming’ the resistance.

However, it becomes clear that this is a self-defeating proposition.  If you use higher and higher levels of cocaine, then the body develops more and more resistance.  This continues until you can’t go any higher.

If you use higher and higher levels of antibiotics, then more and more resistance develops until you can’t go any higher.  This becomes a self reinforcing cycle – or a vicious cycle.

Exposure leads to resistance.  Resistance leads to higher exposure.  And the cycle keeps going around.

In the end, using higher doses has a paradoxical effect.  That is, the effect of using more antibiotics is to make antibiotics less effective.  The effect of using more cocaine is to make cocaine less effective.

For hormonal systems, this phenomenon is well described and is related to receptor downregulation.  Consider our lock and key example.  In a normal situation suppose we have 100 keys (insulin)  and 100 locks (insulin receptor).  Each key opens a lock and we have 100 open doors at the end.  This is what we want.

Under conditions of resistance, the locks no longer work as well.  It now takes 2 keys to open 1 lock.  With 100 keys we open 50 doors only.  Since we want 100 doors open, we now produce 200 keys to open 100 doors.  So now, we have the 100 door we want, but the price we pay is to produce 200 keys.ADHD

Insulin resistance works the same way.  As we develop resistance, our bodies increase the insulin levels to get the same end result – glucose in the cell.  However, the price we pay is increased insulin levels.

This is a well known effect of hormones and one that we take advantage of in the treatment of certain diseases.  One such example is ADHD (Attention Deficit Hypractivity Disorder).

In this disease, children are hyperactive.  The treatment involves the use of Methyphenidate (Ritalin).  But Ritalin is not a sedative (drug that calms).  Instead, Ritalin is a stimulant.

If you didn’t know better, you would say WTF?  Why would you treat a hyperactive kid with stimulants?  Wouldn’t that make things worse?

The answer is no.  And the clinical experience backs us up.  The drug (a stimulant) actually calms these kids down.  High persistent levels of a stimulant will eventually lead to resistance to the stimulant.  Stimulants cause stimulant reistance.  This stimulant resistance now leads to calming behavior.

So let’s recap:

Antibiotics cause antibiotic resistance.  High doses makes things worse.

Viruses cause viral resistance.  High doses make things worse.

Drugs (cocaine) cause drug resistance (tolerance).  High doses make things worse.

Stimulants cause stimulant resistance.  High doses make things worse.

So now lets go back and ask the question – what causes insulin resistance?

Well, the first place I would look is to high, persistent levels of insulin itself.  The implications of this are enormous.  If this is true, then the hormonal obesity theory looks like this:Hormonal Obesity theory step 2

Does insulin itself cause insulin resistance?  We will look into the evidence over the next few posts.  But consider the consequences here.  Insulin leads to insulin resistance.  Insulin resistance leads to higher insulin levels.  Higher insulin leads to even more resistance which leads to even higher levels.

Now, all of a sudden, instead of the diet being the major driver of insulin levels, it is insulin resistance that is the major driver of insulin.  This high insulin levels now drives further weight gain.  These are issues that will get worse over time, because it is a vicious cycle.

The fat get fatter.  But the reason is not that they are eating more or exercising less than the skinny people.  The point is that their insulin is driven largely by resistance and not their diet.  They are not lazy.  They are not gluttons.  They have a hormonal imbalance that needs to be addressed.

The implication is that people who have been obese for long periods of time will find it harder to lose weight.  Those who have recently gained weight will find it much, much easier to lose weight because they have not had a chance to develop significant resistance.

Those who have childhood obesity will find it hardest of all to lose weight since they have had it their entire lives.  Those born to obese mothers will have been marinating in insulin their entire lives and more.  They will have even more problems.  You already know this to be true even if there were no studies.

Maternal obesity leads to childhood obesity.  Childhood obesity leads to adult obesity.  Long term obesity makes it harder to diet and lose weight.  These are all consequences of the time-dependent effects.Predicting Obesity

But the studies are quite consistent.  This paper “Predicting Obesity in Young Adulthood from Childhood and Parental Obesity” published in NEJM 1997; 337:869-873 confirms our common sense observations.

One of the biggest risk factors for obesity in young adulthood is childhood obesity.  Those who have childhood obesity are have more than 17 times the risk of obesity going into adulthood!

The longer you have obesity, the harder it is to overcome.

Some of this results from the genetics of obesity, which we will discuss at a later date.  Needless to say, both the calories in, calories out as well as the carbohydrate-insulin hypothesis cannot account for the known genetic predisposition to obesity.

Having one parent more than doubles the risk of obesity.  But having two obese parents increases the risk of obesity more than 5 fold. And they completely ignore the time dependent effects.

Click here to continue to Hormonal Obesity X

Begin here with Calories I

See the entire lecture – The Aetiology of Obesity 2/6 – The New Science of Diabesity

5 Responses

  1. Well I think the carbohydrate insulin hypothesis can account for the known genetic predisposition to obesity. Maybe not directly, but if both parents were obese, at some point down the family tree, somebody was insulin resistant. So because somebody had increased levels of insulin, the obese child suffered. Like I said, not directly affected by the CIH, but indirectly affected. Correct me if I’m wrong? Great series btw I’m learning a lot.

  2. […] Some would argue that the beneficial effect of fasting is due to the caloric reduction. But why is there such a striking difference between reducing calories and fasting? Caloric Reduction as Primary (CRaP) has been tried innumerable times, and failed virtually every single time. Yet fasting is often effective where simple caloric reduction is not. The short answer is that the beneficial hormonal changes that happen during fasting are entirely prevented by the constant intake of food. It is the intermittency of the fasting that makes it so much more effective. This prevents the development of resistance as detailed in the previous post. […]


    I am Hindu. Our culture has fasting and it is attached to prayers. Our Vedas, dictate our livelyhood. From our sciptures,we know that poeple lived for more than 150 years! Your research seems to prove this. Hindus are and were vegetarians. This seems to say eating vegetable and fruits and nuts prolong your life.I have Type2 diabetes. My kidney function is at 31%. I am going to start the regimen of fasting and good vegetarian diet as of now. Thank you Dr Fung.

  4. […] פוסט זה מוגש כשירות לציבור. הזכויות על התוכן שייכות לכותב של הפוסט המקורי. את הפוסט המקורי ניתן למצוא בכתובת הזאת. […]

  5. u are right I have child hood obesity and now I get p diabetes

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