Tuesday, July 24, 2018

Insulin makes you hungry (1)

TLDR: The function of insulin is the inhibition of lipolysis. In the brain. In the periphery.

If you want to think about the central effects of insulin you could do a great deal worse than working through this paper:

Brain insulin controls adipose tissue lipolysis and lipogenesis

It is jammed full of exquisite quotes:

"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 [intra cerebro ventricular] insulin infusions (Air et al., 2002; Brief and Davis, 1984; Rahmouni et al., 2004)"

and

"An ICV (5 μl/h) or MBH [medial basal hypothalamus] (0.18 μl/h per side) infusion with either vehicle (artificial cerebrospinal fluid (aCSF) (Harvard Apparatus, Holliston, MA) or insulin (ICV 30μU; MBH 2 μU; Humulin R, Lilly) was started and maintained for 360 min"

and

"Both ICV and MBH insulin administration markedly suppressed the rate of appearance (Ra) of glycerol under basal and clamped conditions indicating that brain insulin, and more specifically MBH insulin signaling, suppresses lipolysis (Figs. 1B and C)"

and

"Hyperinsulinemia [systemic] induced by a 3 mU · kg−1 · min−1 clamp decreased the Ra glycerol by about 65% compared to a 1 mU · kg−1 · min−1 clamp in vehicle infused animals (Fig. 1C). Thus, at the doses administered, brain insulin infusion inhibited lipolysis to a similar extent as that achieved with peripheral hyperinsulinemia"


Here it is in pictures.

What does a CNS infusion of insulin do to lipolysis, at what are purported to be physiological dose rates? Obviously, it does exactly what peripheral insulin does, but using minuscule amounts; it suppresses lipolysis:

















Of course, you have to ask how physiological is this "physiological" infusion rate? Insulin in the brain is thought to be derived from insulin secreted by the pancreas, so we are at liberty to ask what level of plasma insulin would produce a comparable level of suppression of lipolysis. The answer is an hyperinsulinaemic clamp of 3mU/kg/min, as in the above quote. That will be a clamp of somewhere around 70microU/ml clinically (3.5ng/ml in the paper), the sort of level of systemic insulin a healthy human might produce following a meal of real food, it's the column on the right of the graph:

















Obviously the fall in lipolysis results in depressed FFA levels during the central insulin infusion, as you might expect:






















The researchers didn't check the fall in FFAs from the peripheral 3mU/ml/kg clamp but I would expect it to be comparable to the central infusion level fall, glycerol appearance was equally suppressed by the central and peripheral administrations.

So one question (among many) is: Does this fall in plasma FFA levels result in hunger?

Oddly enough there are relatively few studies where humans have had experimental cannulae inserted in to either their cerebral ventricles or directly in to their ventomedial hypothalamus for insulin infusion. Ok, there are none.

But there are plenty of studies where humans have had systemic hyperinsulinaemic euglycaemic clamps performed. What is rare is to ask what the effect of such a clamp might be on hunger. Which brings us to another gem of a paper, this one from Woo. And it's good.

Peter

3 comments:

Slobodan Jovic said...

*A sharp beep indicating that AI has started recording
Mr. Slobodan's personal log for March 17th 2071(Tuesday), primary teacher at Newton Centre elementary school, Massachusetts.

Finally the new government initiative to help size-unfortunate kids is starting in our school too. I have just been informed by a colleague that it will be applied to all our kids regardless of their weigh or age.
The miracle of modern science "DBII" stands for Direct Brain Insulin Injection will induce satiety in the kids brains, additionally the amount of snacking and random eating at night will decrease dramatically.
The projections they have shown us indicate that in just 5 years we will cut the need for hover seats for the over 200 pound kids by half.

This morning I will have the kids park in a triangle shape with their hover seats and we will join our hands in a pyramid shape over our foreheads and say thanks to FDA for saving us.
Then I will give a small introductory lecture about the Food Reward Hypothesis to my 5th graders and the 6th graders will start learning about the tragic history of our species and the horrors of animal products whose victims they are today.

The epigenetic changes caused by animal flesh consumption in the 20th and early 21st century permanently damaged our mitochondria and are the reason for today’s epidemic of size-unfortunate kids.

We can only be thankful to the grain industry for providing the majority funding to the pharmaceutical companies in search of a cure.
Questions were asked about why Insulin can’t just be added to drinking water like statins but I am not knowledgeable enough to answer that.
Anyways, here come the kids, may the pyramid guide us, end log.

bill said...

"... introductory lecture about the Food Reward Hypothesis ..."
Isn't it the Food Reward Axiom?

Slobodan Jovic said...

@bill

I guess it should have been.