The innocent clinical diabetologist

I recently saw an interesting video somewhere on social media and shared it. Here is the link. See it to get amazed and amused. But beware. It’s not a comedy show. It has very deep real life relevance. It’s a demonstration of how you can make a cooked up theory explain everything! No counterargument stands.

What immediately came to my mind was that the state of the theory of type 2 diabetes is almost the same. I could imagine the cute little girl in the video to be an innocent clinical diabetologist (ICD) talking to an old tired and frustrated researcher (TiFR). The dialogue would go somewhat like this. (But see the video first in order to understand the dialogue.) https://www.facebook.com/milind.watve.5/videos/10217641702652704/?t=0

TiFR: And this is my lab

ICD: What do you do?

TiFR: I am a diabetes researcher. We address unanswered questions, we try to seek answers and ultimately help patients.

ICD: Unanswered questions? In diabetes? Like what? And what’s the use?

TiFR: For example, how can we prevent the diabetic complications.

ICD: Well we do that by reducing blood sugar. Simple enough!!

TiFR: But that doesn’t work, in clinical trials the result of meticulously regulated sugar is hardly better than the moderately regulated controls. Take the example of ADVANCE trial, in the control group, the rate of developing complications was 20%, in the treated it was 18.1 %, so only 1.9% difference made by the treatment?

ICD: Oh, you don’t know how to use statistics. It is 1.9% of 20 %. So it is about 10 % difference. And 10% lower rate in only 6 years so in the 60 years of lifespan there would be 100% difference.

TiFR: Oh I didn’t know you could calculate that way. But look at the bad effects of treatment. The treatment increased the chance of going in a hypoglycaemic shock by 170% by your calculation. See the UKPDS results.

ICD: You are completely dumb in statistics. Look at the actual frequencies. In the control group the chance is 0.7 %, and in insulin treated it is 1.8%. So it is only a 1.1% difference. 1.8 may be 270% of 0.7. But you don’t look at that. You look at only the absolute values.  

TiFR: This is strange. For the benefit of treatment you take relative difference, for its bad effects, you take absolute difference.

ICD: That’s how researchers should behave. Don’t use statistics indiscriminately. Use the right calculation at the right time. See how the UKPDS groups reports statistics differently to report different outcomes.

TiFR: Oh, so reducing sugar is the right treatment you mean.

ICD: It is obvious. Diabetes is defined by increased sugar, so when sugar is reduced back to normal, it is under control by definition. Why should other things matter?

TiFR: Then why is mortality in the meticulously sugar controlled group higher than the loosely controlled group? The ACCORD trial was stopped abruptly in three and half years because mortality in treated group increased alarmingly.

ICD: So what is a reliable trial? We believe in trials that were conducted over long time. They show 10-12 % benefit of treatment. Why should we believe in a trial that was aborted in a short time?

TiFR: But the 10-12 % difference could only be placebo. Just the feeling that I have my sugar levels normal can make some difference in health. Why can’t we have another placebo control in which patients are only told that their sugars are normal after treatment? Whatever they may actually be. If they also show 10-12% improvement, it could just be a placebo effect.  

ICD: No that will be unethical. Patients in clinical trials have the right to know.

TiFR: But if you don’t have this placebo, how would we know that the benefit observed is because of reduced sugar, not just a feel good effect?

ICD: May be very meticulous sugar control doesn’t make additional difference. But moderate sugar control would certainly be better than no treatment.

TiFR: But in any of these trials there is no control group with no treatment.

ICD: That’s because It would be unethical to leave a group without treatment.

TiFR: But when you don’t know whether the treatment works or not, how can you say not giving the treatment is not ethical?

ICD: But we know regulating sugar IS effective as a treatment.

 TiFR: Who told you that?

ICD: Our textbooks. We studied that 25 years ago. It’s old knowledge. Time tested !!

TiFR: So you haven’t updated your knowledge in 25 years.

ICD: How can you say that? Pharma companies keep on sending us latest literature. They hold meetings and conferences. So we are always up to date in our knowledge.

TiFR: Ok, so what is the latest view on why blood sugar goes up?

ICD: Well that hasn’t changed. It is insulin resistance and relative insulin deficiency. Obesity leads to insulin resistance. For some time insulin levels increase to compensate insulin resistance. But ultimately they fail and then blood sugar goes up.

TiFR: What is compensation you said?

ICD: The insulin producing beta cells make more insulin to compensate insulin resistance.

TiFR: Wonderful, but how do beta cells know that there is insulin resistance?

ICD: By glucose itself. When there is insulin resistance, glucose is not disposed rapidly. So glucose levels go up. And everybody knows that high glucose stimulates more insulin production. The excess insulin pushes back the glucose to normal so that you have a high-insulin-normal-glucose state prior to diabetes.

TiFR: Aha, I see. But after glucose is back to normal, why should insulin remain high?

ICD: Well, just like that. It might just linger on.

TiFR: But insulin has a short half-life, only 5-6 minutes.

ICD: Oh, all those details are not relevant. We know that there is a high-insulin-normal-sugar phase before diabetes sets in. When the beta cells get exhausted and are unable to produce compensatory insulin, sugar starts rising.

TiFR: Why should beta cells get exhausted?

ICD: because they have to keep on producing more insulin.

TiFR: But that’s not the case. In a high fasting-insulin condition, the number of beta cells increases. The rate of insulin production per cell doesn’t. They are not working more so why should they get exhausted?

ICD: See the cause is not important. Ultimately they make less insulin, that is for sure.

TiFR: Ok, going back to insulin resistance. How do you know that there is insulin resistance and how much?

ICD: When insulin is unable to control sugar, it is insulin resistance. We measure insulin resistance by the inability of insulin to regulate sugar.

TiFR: Amazing logic. Normal or higher amount of insulin fails to regulate glucose because of insulin resistance. And insulin resistance is measured as insulin’s failure to regulate glucose. Let me put the two statements together. It means that insulin is unable to regulate glucose because insulin is unable to regulate glucose. What an infallible logic!!

ICD: Yes. That is the strength of the theory. You will never be able to prove this theory wrong by any experiment. Whenever blood sugar is not controlled by insulin, it will be called insulin resistance. So there is no scope for any other cause for a change in sugar level. This theory just does not allow any other theory to stand. I wish all theories were like this. We won’t have to waste so much money on research then!!

TiFR: But people have done experiments. They knocked out insulin receptors on muscle cells and liver cells but in neither case fasting blood sugar was affected.

ICD: Simple my boy. It means that knocking out insulin receptor does not induce insulin resistance. Insulin may be still acting by some other means. We call it insulin resistance only when we observe insulin resistance.

TiFR: But experimentally increasing or decreasing steady state insulin also does not affect fasting glucose in experiments.

ICD: That is because some other compensation mechanism must be acting.

TiFR: Then why these compensation mechanisms fail in diabetes?

ICD: That is because the insulin resistance is stronger in diabetes than what you could induce experimentally.

TiFR: How do you know insulin resistance is stronger?

ICD: Because the effect is observed. So it must be strong enough to overcome any compensation mechanisms.

TiFR: Ok, but where does all of it begin?

ICD: In eating bad diet. Bad diet induced obesity that leads to insulin resistance.

TiFR: But what diet is a bad diet?

ICD: That depends upon which time you lived. Fat was bad for the past thirty years. For the next thirty years sugars will be bad.

TiFR: After that?

ICD: May be proteins, but can’t say now. You will have to wait till then. In any case avoid eating whatever is considered bad at that time.

TiFR: Ok. On a different line. Over the last decade, so many researchers are talking about the role of brain in regulating hunger, obesity, glucose regulation etc. So many experiments also show that.

ICD: We have a brain so it ought to have some role. But nothing useful comes out of that. The pharmacology of the brain is too tough. It is a nightmare to pursue drug discovery for a brain target. Liver, pancreas, stomach are easier targets. So we target all our treatments on these organs. Brain is useless.

TiFR: Yes, I can see that very clearly!!! Brain is useless!!!

TiFR: So let me have a quick recap. The insulin resistance theory of diabetes is perfect and can never be proved wrong. According to this theory, controlling sugar is the only treatment target and will remain so for ever. Whether it reduces complications and mortality rates or not is not relevant.

ICD: You got everything right.

TiFR: Thanks for explaining me everything.

ICD: you are welcome but you didn’t tell me what do you do exactly?

TiFR: Well, now I will answer more carefully. We do PhD, post doc, generate lots of data, do lots of analysis, publish lots of papers in high rank journals. That is all about research. I learnt something important today. One thing that we researchers should never do is to ask questions. That will spoil research. Thanks for enlightening me about the real world!!