Tuesday, September 03, 2024

Protons (77) Shulman PUFA and insulin sensitisation. Or not. Or so.


Over in the comments to the last post on metformin and Shulman's lab, Tucker pointed out that Shulman was an author (penultimate, so a senior author) on Nowotny et al's 2013 paper

Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans

which starts its discussion with the controversy about whether PUFA, particularly from soybean oil,  induce insulin resistance or insulin sensitivity. The most contradictory paper they cite is Xiao et al from 2006. In my head I think of this as the Hot Chocolate or the Cocoa study, which I discussed here as pure Protons in a cup of hot chocolate:

Differential effects of monounsaturated, polyunsaturated and saturated fat ingestion on glucose-stimulated insulin secretion, sensitivity and clearance in overweight and obese, non-diabetic humans

The two studies have diametrically opposite conclusions and this is an obvious opportunity for insight.

To me, it contradicts Protons, so let's go! Sadly, as Tucker points out, the chance for insight is completely missed by the Shulman group. They settled for PUFA -> insulin resistance. They lack the Protons perspective.

Equally sadly I have no handy mental label for the Nowotny/Shulman paper, probably because it produces no confirmation bias induced dopamine release in my head. My bad.

So let's compared the two.

The Cocoa study fasted obese subjects for 12 hours then fed them almost nothing but fat (with just a little carbohydrate) in small aliquots over 28-30 hours depending on how you read the methods. These subjects, by the time they started their hyperglycaemic clamp, had been either fully fasting or running their metabolism on the study fat, for approaching forty hours. In the control section of the study there were minimal calories supplied throughout, just a little carbohydrate in each drink. We can consider our control section to be, of necessity, in the functional insulin resistance of (very mild) starvation.

They are in a functional, very physiological, insulin resistance which is essential secondary to fasting or a fat based metabolism.

In Nowotny/Shulman their subjects were fasted for 10 hours in the aftermath of three days of a "high carbohydrate" eating period. By the start of the study period the subjects might have been ready for breakfast but they will have had absolutely no need (with a liver still full of glycogen) for the physiological insulin resistance adaptation to an absence of carbohydrate food intake such as would be necessitated by 40 hours of near fasting.

Subjects either drank 900kcal of soybean oil, started a 6h infusion of ~900kcal of intravenous soybean oil (Intralipid) or, for the control group, a 6h infusion containing approximately 54kcal of glycerol, ie mild fasting of 16h in total for the controls. Glycerol is primarily used by the liver for gluconeogensis so it will be a bit like the carbohydrate from the drink in the Cocoa study.

So Nowotny/Shulman  only looked at soybean oil vs nothing on a deliberately carbohydrate based metabolism of their mildly fasted control group. After carb loading to ensure a glucose based metabolism.

And soybean oil triggered insulin resistance. Glycerol didn't. QED, PUFA cause insulin resistance, directly. Diacylglycerols blah blah and all that crap as a mechanism, which is what the study seems to have been all about.

But the soybean oil was only being compared to a fully primed glucose based metabolism. Using an hyperinsulinaemic clamp and glucose supply to normoglycaemia.

In the Cocoa study the various fats were being compared to what was approaching a 40 hour fast. These subjects were already physiologically insulin resistant.

Adding more fat will (at approximately the correct 24h metabolic requirement for calories) either increase or decrease the degree of fasting insulin resistance based on Protons, the F:N ratio and reverse electron transport derived ROS.

Here PUFA cause a decrease in the physiological insulin resistance of 40 hours of fasting. Saturated fat augments it. MUFA is neutral:

















You have to be very, very careful about what you are comparing to what.

Without thinking through the methods sections you could easily be forgiven for believing that the Nowotny/Shulman paper shows that PUFA cause insulin resistance. Possibly uniquely.

They clearly do, compared to to glucose. But they are *less* effective than saturated fats in performing the essential metabolic function of resisting insulin when glucose is in short supply. Shulman missed this, despite having Xiao point it out (*sarcasm warning*) in words of one syllable. PUFA are insulin sensitising when compared to whatever FFAs an obese person has available after nearly 40 hours of fasting.

Peter

Afterthought: The Cocoa SFA group required just under 40μmol/kg/min of glucose to maintain 20mmol/l in their plasma. The PUFA group needed about 55μmol/kg/min of glucose.

Given an infinite supply of donuts, which state would result in you eating the most?

Mmmmmm PUFA. The fat that makes you fat. By limiting insulin resistance.

7 comments:

  1. Nice. I didn't connect Xiao with this. So why does aspirin cure insulin resistance? (Another Shulman paper...)

    And Ω-3 PUFA seems to also, although I will await your protons perspective there...

    Will post/send those papers when I get to my computer.

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  2. Peter, protons and membrane potential, reverse electron transport, source of ROS, all is fine, but I couldn't accept the F/N ratio concept. It's negligible, sorry. You know my explanation via NADP+ flow. And I also see H2O2 as insulin analogue, it elevates oxygen supply via IDH2/CO2, elevates glucose intake, which is in accordance with elevated ROS caused by LA. It's lactate that slow down PDH complex, and DNL that slow down TCA cycle and fat oxidation., which can lead to HIF1A activation if not acetylated. My bias.
    Jaromir

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  3. ''S fine Jaromir. The views will eventually converge. I don't stress...

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    1. Ok, I wonder about the timeframe. Mouse take 8 days to correct change in LA intake, rat take 8 weeks to correct LA intake, how long it takes human to correct LA intake change? 10 years? How many cells will be harmed before it starts to work? How the correction is controlled? Via pathologic insulin sensitivity?

      In this paper overfeeding people with 50% more calories as fat has no effect on DNL. So the protection aginst LA can be turned on only by carbs. In this paper carbohydrates overfeeding takes 5 days to activate "protective" DNL action (resistance). So is the need for carbs intake the effect of LA to limit LA fat intake?

      DNL is not as protective as it looks. DNL strongly correlates with hepatic glucose production, looks like it's regulated the same way, via lack of AMPK action. Glucose activates glucose production, counterintuitive, possible liver protection.

      https://doi.org/10.1172/JCI118342

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  4. Replies
    1. I'm Confused? Are both these papers looking at insulin resistance in muscle? I don't think you can define insulin resistance via insulin secreted. Muscle, liver, adipose can all have different states of sensitivity - and much will depend on the feeding history and accumulated tissue damage.

      So if the contradiction mattered, wouldn't that mean that farm animals and lab rates would lose weight on high LA diets? Just not what we see?

      So I think what I'm seeing is that insulin sensitivity in the muscle depends on the glycogen already in storage - in both the muscle and liver? (Muscles hold a lot more glycogen than the liver - and muscles need glucose to produce glycogen. The liver can hold both glycogen and some fats. Muscles can also store a tiny amount of energy in ketones.

      What is important to know - insulin resistance in adipose tissue is what you want if you want to lose weight - and by that point, both muscle and liver are already resistant.

      Another point - if someone is keto-adapted and they end up in major surgery - on a drip - tube fed - blood glucose spikes - the MDs freak out - pump insulin - are confused as to what is happening.

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  5. Hi Karl

    The feature in the papers (Xiao vs Nowotny) that both are looking is glucose disposal whole body. I would expect most is going in to muscle but the same ability (saturates) or lack of ability (PUFA) to resist insulin will be going on in adipocytes too. Crucial for fat gain if a relatively small contribution to total glucose disposal.

    Chronic ketoadaptation obviously suppresses the mechanism for glucose induced insulin secretion but neither study would involve this phenomenon. Xiao particularly stated that they avoided ketosis and it's not even on the radar of the Nowotny group at Yale.

    Peter

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