Well, over the years I have made the occasional serious blooper on Hyperlipid.
Perhaps the worst of these, to my intense shame, is the acceptance of insulin as a satiety hormone. This is complete bollocks and, thankfully, some deleted-expletive person in obesity research has finally opened my eyes to this. The gift was from Dr Guyenet of course. This is how he convinced me that insulin is not a satiety hormone:
Let's feed some rats standard crapinabag and inject one group with nothing much, one with glargine insulin and another with detemir insulin. But here's the trick. Because we know that hypoglycaemia triggers overeating and the overeating causes weight gain, let's limit the insulin dose to one which does not cause hypoglycaemia... No overeating, active satiety hormone, weight loss...
Because we have been (mis)informed that insulin is a satiety hormone we would expect the insulin-injected rats should eat less, weigh less blah blah blah. What really happens? This does:
I've seen this paper cited as showing insulin can reduce weight gain. By Dr Guyenet no less. Who didn't mention the graphs. Which are core to the paper.
Technically this shows that insulin does bugger all to food intake and fat storage. This is hardly surprising as giving a sub hypoglycaemic dose of insulin will simply attempt to lower blood glucose which will be avoided by reduction of endogenously produced insulin. Total insulin will stay the same. There will be subtleties of peripheral administration vs portal secretion but I guess these are a bit too subtle for this study. There are also fascinating differences in duration of binding of detemir insulin to the insulin receptor vs other insulins. Not surprising as it has a socking great fatty acid tagged on one end but that's another set of stories.
Ah, but what about the effect of detemir insulin on limiting fat gain of rats fed toffeefudgecheescake, aka D12492?
We are talking Fig 3 parts b and e here:
Okay, we're now utterly convinced that insulin limits weight gain. Well, detemir insulin does. Of course glargine insulin doesn't, as Dr Guyenet forgot to mention when citing this paper. It produces a non significant increase in weight over vehicle treated controls.
Just for a giggle, consider changing the grams to kgs on graph e and imagine these rats as humans. Given a group size of 6-8 leading to statistically ns changes in fat mass, would you consider 5kg fat mass gain (a ns change) on glargine, without eating any extra, non significant? Biologically? In dress size? Tee hee.
Now let's look at section e in a little more detail.
The study is very, very carefully set up. The insulin and the D12492 were both started on the same day. It is utterly convincing (to me) that detemir insulin limits weight gain IN THE FIRST 7-10 DAYS of D12492 feeding. From day 10 onwards the fat mass does not change in the control, the detemir or the glargine groups. Not even a trend. A bit like the crapinabag groups demonstrated throughout. In fact, identical to the crapinabag groups. Where's your satiety Guyenet?
Now here's a thought experiment. Let's pretend that all rats were fed D12492 from day 0 to day 10 without injected insulin, so became equally obese with a fat mass of 65 grams, same as the controls on day 10. From day 10 onwards all groups then received their respective insulin or vehicle for four weeks.
Would the fat mass have changed from the 65g starting weight? Of course not, look at the last weeks on graph e. These people are not stupid, though they do like to give that impression.
From this study the follow on question has to be: What is the difference between detemir insulin and either endogenous insulin or glargine insulin during the first 7 days of feeding D12492 to rats?
We all recall from the paper from the Schwartz lab featuring the world's greatest mis-citation expert, that the first few days of sucrose/fat feeding produces an acute inflammatory lesion in the hypothalamus of rats which get fat on D12492. If I had to guess I would suggest detemir insulin limits this injury. How and why cannot be guessed at from this paper but needless to say groups working with gold thioglucose injury have considered what factors influenced hypothalamic injuries. That leads to far out speculation, so I'll limit this post to what Guyenet's citations really do show.
They show that physiological insulin does NOT suppress appetite. Are you surprised? Me neither.
Of course an increased dose of insulin might suppress appetite. But this would need a glucose infusion to maintain life, which would promote DNL in adipocytes and inhibit lipolysis. No hunger while you gain fat. You have to wonder what the point of the above study was, excepting it supports a grant maintaining position and is a self justification for a bizarre mindset.
I also notice Guyenet re-cited this crap. Doesn't he read Hyperlipid????? Giggle... That was a rhetorical question!
Less rhetorical is to ask whether he has actually read the Vanderweele paper at all, particularly Fig 4 of the paper and whether he has reverse engineered said Fig 4 to see the problems with the conclusions of the paper!
Finally he has cited a drug study using an insulin mimetic, not insulin. Well, bully for insulin mimetics. With an insulin mimetic you can mimic lethal doses of insulin without all that inconvenient death. The body does not produce lethal doses of insulin under physiological conditions. If you want to know about physiological doses of insulin within the CNS I can just quote this paper. I feel the authors are being just a teensy weensy bit over the top in their deprecatory attitude to the "centralinsulinisasatietyhormone" brigade. But I can understand why! Here's my fav quote:
"To reduce the likelihood of pharmacological effects of the insulin doses administered, we choose a dose of insulin that is more than 15,000–fold lower than those commonly used for ICV [third ventricle, CSF] insulin infusions"
That's about as rude as you get in Cell Metabolism! You can't use the word "pillock". Drug doses (pharmacologic) of insulin produce drug effects. If you give only physiological dose rates you get physiological effects! Now isn't that amazing?
Oh btw, at physiological levels brain insulin increases peripheral lipogenesis and decreases lipolysis. Did you think insulin would do the opposite through the brain compared to what it does in the periphery?
A more believable scenario is that ATP generation within the brain using glucose metabolism, facilitated by insulin in those areas responsible for energy sensing, does occur. But this combination of glucose and insulin will also store fat, as it should, when it occurs post prandially. Which is exactly what excess energy sensing should signal. Insulin without the glucose is pharmacology, unless you suffer from reactive hypoglycaemia.
BTW I notice over on Woo's blog that there has been some discussion as to whether Dr Guyenet is just dumb or being very deliberately misleading, ie conspiring to mislead. I don't do orchestrated conspiracy theories. I don't really do the financial drive thing either, not for some body who is still as wet behind the ears as Dr Guyenet certainly is. No, for a junior post-doc it has to be:
He has the whole of the knowledge base of the Schwartz lab at his beck and call and the above three citations are the best dross that the Good Doctor can come up with... But still he believes! Stupid.