Insulin vs. fat metabolism FTW

Insulin is there to grow fat tissue for the obesity epidemic, not replenish glycogen after yoga.

Teaser: insulin-induce hypoglycemia can get deadly quite fast, and there is no equivalent for the effects of insulin on fat.  However, the effects of insulin on fat are 100 times more powerful.

Background: Hormone sensitive lipase (HSL) responds to insulin by inhibiting lipolysis.  It halts fat burning.  It got its name because it’s THEE most hormone-sensitive lipase in the body.  The hormone about which we are speaking is of course insulin.  And the enzyme, or at least one of the enzymes as it were, is HSL.  To be clear, it takes very little insulin to inhibit HSL.  Just a dollop, in fact.

Effect of very small concentrations of insulin on forearm metabolism.  Persistence of its action on potassium and free fatty acids without its effect on glucose.   (Zierler and Rabinowitz, 1964)

Expt 1.  Since we’re all about jabbing people with insulin lately, let’s get at it again.  Jab someone with about 100 uU (/min*kg), and muscle and fat vacuum glucose out of the blood.  Same goes for potassium; and adipose gets all stingy too… it stops releasing and starts storing fat.  This is “healthy,” and its part of why people say insulin, and by extension carbohydrate, causes lean people grow fat tissue.

What do you think would happen in an insulin resistant obese crowd.  Less glucose vacuuming, but scrooge adipose will still responds with gravitas, by saving more and spending less?  Likely.  HSL is like the little piggy’s straw house.  The strong young wolf can blow it down.  The COPD emphysema wolf can blow it down…  because it’s made of straw.


Thus, insulin causes lean people to grow fat tissue, and it causes obese people to grow more fat tissue.

In other words, with regard to common obesity, being resistant to insulin means postprandial hyperglycemia; you can’t handle sugars proper.  but it’ll still make you fat(ter).

Expt 2. The interesting part.  Try jabbing healthy people with 10x less insulin.  Looks like IR obesity!  Adipose gets stingy, potassium scrams, but no effect on glucose uptake.

In the figure below: A-DV is muscle; A-SV is adipose.  Glucose uptake into fat & muscle is unaffected by a low dose of insulin.glucose on 10uU

Second figure: with the same dose, adipose goes on a budget SAVE MORE SPEND LESSFAs on 10 uU

Conclusion.  In a healthy person, (eg, healthy person), even very low doses of insulin cause fat growth.  This isn’t an issue of high vs. low glycemic issue.  The insulin dose used in this study was less than that expected from a respectable low glycemic index meal.  This is probably why the glycemic index hasn’t cured the obesity epidemic.  On the other hand, dietary fat doesn’t stimulate insulin…  just sayin’

Furthermore, perhaps glucose uptake into adipose promotes fat storage under certain conditions, but it’s clearly neither necessary nor essential.  Insulin can Miracle Grow fat mass without affecting glucose uptake one iota.  I imagine the abundance of 3C precursors simply isn’t “the limiting factor.”  And it works just as good with Whole Foods Low GI pa$ta and Wonderbread.buttressed

Translation: insulin buttresses fat growth.  and it doesn’t matter how much.  FYI this probably seems nonsensical at first: carbs stimulate insulin in order to dispose of said carbs, like a logical feedback mechanism.  Perhaps.  But said insulin cares far more about fat than said carbs.  On a scale of 1 to 10 (ie, putting things into “perspective”): insulin is there to grow fat tissue for the obesity epidemic, not replenish glycogen after yoga.

 

 

Part II.

Dose-dependent effect of insulin on plasma free fatty acid turnover and oxidation in humans (Bonadonna et al., 1990)

There are a lot of data in this paper, but here are the relevant points:

Infuse insulin at various rates.  In the lowest infusion rate, the only aspect of glucose metabolism to respond is hepatic glucose production (second line; HGP declines from 2.0 to 1.34 at the lowest dose):glc turnover

WRT low dose insulin on glucose metabolism: liver responds, not skeletal muscle.  Skeletal muscle doesn’t even look at glucose until insulin infusion reaches 250 – 500 uU, which is probably why back in ’64 they saw absolutely no effect at 10 uU.  At 100 uU they saw an effect, but according to these data, it was likely due solely to liver, because skeletal muscle doesn’t seem to care until levels exceed 250 uU (it’s an infusion rate, not an absolute concentration.  But that’s neither here nor there).  To be clear, 10 uU insulin infusion doesn’t affect glucose metabolism (1964).  period.  100 uU modestly affects it (1964), and this is probably so modest because only liver is helping out (1990).  At 500 uU, full scale attack on blood glucose.

But fatty acids are obliterated with 5 – 50 x less:FA turnover

It worked with 10 uU in ’64, and it worked just as well with 100 uU in ’90.  (FYI the first paper was published in 1964; this one in 1990).

Furthermore, in the table above glucose metabolism was progressively affected with increasing insulin concentrations.  Not so much with FAs:FA suppression

FA flux is rapidly and completely shut down with a dollop of insulin.  Indeed, it is obliterated.  Giving more insulin doesn’t do anything, because, well, when you blow down a straw house, it tends to stay down.

 

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  • Miodrag Mili?

    Epic post, funny per usual, amazing papers (deserved to be stored in case somebody destroys internet)

    So …. it looks like Rosedale is right…. u need to reduce protein too if you want to go down, since such low doses make lipolysis turned of ?

  • John

    In terms of carbohydrate load, where do you think the threshold is for enough insulin to inhibit fatty acid oxidation? Is it possible that a low-carb diet (roughly 50 carbs a day) inhibits fatty acid oxidation as much as a typical western diet, rendering the advantage to a low-carb diet simply less fuel storage due to less insulin rather than that phenomenon coupled WITH fatty acid oxidation? Then, there seems to be a substantial difference between ketogenic diets and low-carb diets in terms of energy expenditure and weight regulation — is that, indeed, correct? If so, is it only ketosis that harnesses both the minimal storage of fuel AND maximum fatty acid oxidation due to so little insulin? Is that the cut-off where you can release fatty acids?

    • Hi John,
      Thanks for the comment, and that’s a great question.
      My best guess: there probably is a threshold, but it will depend on a lot of things; eg, physical activity, dietary protein levels, nutrient timing, etc. I think fatty acid oxidation will be higher on low carb vs. SAD regardless, due to both lower insulin and higher fat intake. But from the data abve, all we know is lipolysis shuts down with minimal insulin. If your 50 grams of CHO are all at one sitting, for example, it might be a completely different picture.
      Best,
      Bill

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  • Thomas Hemming Larsen

    Expt 2 is really interesting.

    • Most studies looking at resistance exercise, high vs low carb, are acute – usually just 1 training session and a meal, then measurements of muscle protein synthesis, breakdown, etc.

      “gaining muscle on a ketogenic diet can be difficult for anyone”

      I think a lot of this can be mitigated with ? dietary protein & calories… might lower ketones, might not if combined with ??? exercise.

      • Thomas Hemming Larsen

        Good point. I figured it would be impossible to find.

        Hehe, I should have seen that one coming 🙂 The verdict is still out on CBL vs. ketosis…

  • George

    After almost-pure fat feeding, there’s a slight increase in insulin, but it’s followed by a drop
    http://ajcn.nutrition.org/content/75/4/767/T1.expansion.html
    It’s hard to see how this keeps fat in adipocytes much more than the basal insulin did. Yet oxidation of fat will not differ much between fasting and fat-feeding – the fed fat is sparing the stored fat
    https://www.dropbox.com/s/500oew1a48a4uwa/woodyatt1921.pdf?dl=0

    My hunch is that insulin control of lipolysis dominates when glucose and/or protein is fed, because insulin is plentiful and proportionate then – a decent signal – but that the effect of insulin has to be supported by other mechanisms in fasting or fat-feeding. Insulin is simply not the best way of communicating to adipocytes how much fat is incoming, when there is no carbohydrate or protein with the fat. Yet Woodyatt’s examples show that oxidation of stored fat is very closely (inversely) matched to intake of dietary fat. The insulin response to fat can’t provide the sensitivity needed.
    B-OHB receptors on adipocytes inhibit lipolysis, as does FGF21; somatostatin and parasympathetic responses to fat feeding may modulate glucagon secretion in low-insulin states; however, experiments that describe responses to pure-fat feeding or carbohydrate-free, low protein meals are pretty sparse in the literature.
    This might tell us something (89% fat, 11% protein), but I’m not sure what the basal insulin here really means.
    https://www.dropbox.com/s/ug8ahcsgf5nfagg/Allik%20HF%20vs%20HC%202004.pdf?dl=0

  • Rob Coberly

    Useful article, well referenced, thanks. Responding to say how fun it was to read – love all the metaphors in that early paragraph. Especially “scrooge adipose will still responds with gravitas, by saving more and spending less” HA, gravitas!