Sigh. I would normally comment on a person's blog if I read something like this: Insulin, the Un-dead and coffin nails, but since Peter doesn't want to distract his readership with potentially productive discussions amongst them, I refrain from posting there. In the article he makes two statements I find rather outrageous:
Hyperglycaemia causes insulin resistance. This is not controversial, as far as I am aware.
It's not controversial in those circles who repeat it uncritically. It's not really controversial that this statement is wrong. Let's take this together with another statement:
Let's summarise. This is very, very important:
Excess insulin causes insulin resistance
This is just day to day internal medicine. You have to pay the mortgage somehow.Only this too is at the very least controversial, and almost certainly not true in most cases.
Peter loves the FIRKO mouse. Knock out the fat insulin receptors, and mice are obesity resistant. This is all he needs to know about fat tissue regulation and insulin's role. Now LIRKO, not so much. I discussed that in LIRKO Wars. That is a rather long post, and I can't help the snark, Peter really brings it out in me with his presentation of "facts". So the Cliff Notes version is that the LIRKO mouse, one without liver insulin receptors, becomes profoundly hyperinsulinemic and hyperglycemic, though the latter outcome fades as the mice age. But remarkably, LIRKO are not obese!! Houston, there's a problem aboard the SS TWICHOO! Now Peter has given convoluted explanations for why this is the case and TWICHOO still rules, but none passes either the smell test or a modicum of scrutiny paid to the full texts of the studies he cites.
You see, the LIRKO mouse remains essentially insulin sensitive in both muscle and adipose tissue despite being described as IR. It stated so in one of the papers Peter likes to cite:
... we analyzed glucose transport in vitro in isolated soleus muscles from control and LIRKO mice. Basal glucose transport was not different between control and LIRKO mice ... stimulation of glucose transport by incubating the muscles in the presence of 33 nM insulin resulted in a 3.4-fold increase in glucose transport in muscles from both the controls and the LIRKO mice.
In other words, measured directly, glucose transport and insulin action are not impaired by either elevated insulin or the hyperglycemia. Therefore, in LIRKO:
hyperinsulinemia does not cause IR, and hyperglycemia does not cause IR, and
hyperinsulinemia + hyperglycemia still does not cause IR
If it did, one would also expect this to progress with age as the cumulative effects of excess insulin and glucose did more and more damage. Not the case. Before they kick the bucket, these mice actually become more normoglycemic as their livers start to give out while their beta cells hum happily (well maybe not happily) along. These mice, while mutant, establish physiologically relevant elevated levels of glucose and insulin, endogenously produced by "natural" means. They do so far in excess of the contribution of dietary carbohydrate in a normal mouse. If anyone can explain how this is consistent with hyperinsulinemia/hyperglycemia causing IR I'm all ears.
If we put too many more nails in the coffin it might lose structural integrity.