Remember LIRKO? Grey & Kipnis?
So a recent research paper has been making the rounds. It has a "red meat" title for the die hard TWICHOOB: Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production. This paper was brought up in my comments section as well. Every time this happens I really do feel like I'm in some sort of nutritional remake Groundhog Day. I'm a bit backlogged at the moment, but luckily Stephan Guyenet has weighed in with his analysis and included some additional studies in support of his position.
Whenever I think hyperinsulinemia causes obesity, I'm reminded of the LIRKO mouse. LIRKO is normal except its liver lacks insulin receptors. The result is a mouse with raging hyperglycemia and hyperinsulinemia throughout much of its young life until its liver poops out. I blogged on this mouse here: Bloggo Science ~ LIRKO Wars Edition. (Incidentally that post links to an older post by Stephan on the role of hyperinsulinemia here.) Here's the rundown on LIRKO:
- Hyperglycemic -- fasting and postprandial
- Hyperinsulinemic -- fasting and postprandial
- Normal glucose transport into muscle and adipocytes
- A pancreas that just doesn't quit
- Livers that suffer over time
- Normal weight
- Normal (slightly lower) intake
- Lower circulating NEFA
LIRKO should be a fat mouse by any version of TWICHOO. The hyperinsulinemia is caused by the hyperglycemia, that in this case is caused by unrestrained gluconeogenesis as the liver does not "see" insulin at all. This is a "simple" KO mouse to understand, and it should absolutely be a porker if TWICHOO had any validity. The latest TWICHOO X.0 hangs its hat pretty much unequivocally on IR causing obesity by inducing hyperinsulinemia. This is a rather considerable switch from postprandial insulin spikes leading to hyperinsulinemia but I can only work with what Taubes is claiming today. LIRKO is the test mouse for this version. Fail.
How about non-genetically modified humans? Well, it was a small study, but it was in a metabolic ward and the macros were varied quite widely. Grey & Kipnis. Here's a seminal blog post on this study as relates to Gary Taubes and the "good science" tome GCBC: GCBC Reference Check ~ Part IV of ? ~ Kipnis. Sure, these women were already obese, but if hyperinsulinemia caused fat accumulation or prevented fat breakdown, then this is your study. Incidentally it is among those dismissed by Taubes & Attia as not looking at a low enough carb diet. This is (a) in conflict with Taubes citing Kipnis in GCBC , and (b) not entirely correct as the weight loss phase involved essentially zero fat (sugar) diet vs. zero carb with steady weight loss despite wildly fluctuating insulin. Yeah, they didn't measure body composition, but do you really think there would be substantial differences on the iso-protein diets?
The mechanism by which hyperinsulinemia is purported to promote obesity is rather simple. Because of that, results in the LIRKO and studies like G&K are impossible to ignore. Folks like Peter/Hyperlipid make valiant attempts to explain them away making up ever more convoluted scenarios and misrepresenting facts, but in the end it comes back to this. In G&K we had women who were obese, thus clearly susceptible to insulin's evil actions on their fat cells. They failed to respond as TWICHOO claims. QED.