Category Archives: liver

The Fates of Pyruvate

As mentioned in the previous blog, obligatory glycolytic cells lack the apparatus (eg, mitochondria) to fully oxidize fuels down to CO2 and water. Thus, they can’t run on fatty acids, ketones, or beta-hydroxybutyrate. During prolonged starvation, there’s always some glucose in the blood, so they survive.

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Recommended textbook: Stipanuk or Gropper.

Glucose -> glycolysis -> pyruvate: then to lactate or the mitochondria, depending on the context. Skeletal muscle has mitochondria, but if you’re exercising hard, glycogen to lactate produces more energy faster than glycogen to pyruvate to mitochondria. Blood lactate increases in this context. During prolonged starvation, lactate is a valuable precursor for gluconeogenesis, so many tissues release lactate instead of oxidizing pyruvate.

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Low carb diet. NAFLD.

An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans (Mardinoglu et al., 2018)

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Critique and analysis.

They did two very small (n=10 & n=7) 2-week long studies of low carb, high protein. Carb/fat/protein was 4/72/24 compared to 20/42/18 at baseline. There was no control group, so the results were compared to baseline.

 

 

Lots of pro’s and con’s on this one… but for that, head over to Patreon! Five bucks a month for full access and there are many other options. It’s ad-free and you can cancel if it sucks 🙂

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20% off some delish stocks and broths from Kettle and FireHERE.

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else.

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Is gluconeogenesis demand-driven? answer: it depends (#context strikes again!)

Context #1. The easiest way to explain gluconeogenesis (GNG) is how it relates to starvation. If you’re not eating food, your brain still needs a steady supply of fuel. Mostly glucose at first (ketones come later), but since you’re not eating anything, glucose comes from hepatic GNG (huge potential supply*) or glycogenolysis (limited supply). *One of the precursors for GNG, glycerol, comes from stored fat (which you’ll die of something else before you run out of stored fat bc GNG).

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In this case, it is mostly true that GNG is demand-driven.

 

If you’re interested in this, more HERE.

 

Context #2. Protein (which also contains GNG precursors) doesn’t acutely increase glucose. But you might think protein does convert to glucose via GNG but protein also induces a splash of insulin which is why blood glucose doesn’t rise. Read this blog post at least up to the awesome Fromentin study: “8% of the blood glucose produced under optimal gluconeogenic conditions came from dietary protein.” But also check out the Conn & Newburgh studies. And Gannon.

 

 

This is usually the reason recreational keto dieters say they can be high protein, which either ends up looking like PSMF or it’s probably not very ketogenic (which doesn’t really matter in this #context; protein is restricted in therapeutic ketogenic diets).

#BenignDietaryKetosis #BDK

 

 

For the rest of this article (or if you just like what I do and want to support it) head over to Patreon! Full access for a measly five bucks a month and there are many other options. It’s ad-free and you can cancel if it sucks 🙂

Also, I’m open to suggestions, so please don’t hesitate to leave a comment or contact me directly at drlagakos@gmail.com.

Affiliate links: still looking for a pair of hot blue blockers? Carbonshade  is offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERETrueDark is running a pretty big sale HERE.  BLUblox just upped their game with their 550‘s.
If you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else

calories proper

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Context #3. the mouse doctor is in 🙂

Context #3b. Chronic high protein.

Context #4. Random thoughts on animal foods.

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Ketones, Cancer, and the NLRP3 Inflammasome

“Check ‘em all. Do the work. There’s no room for cherry-picking here.

LOOK THE GIFT HORSE IN THE MOUTH”

A few years back, researchers discovered the pseudo-ketone beta-hydroxybutyrate suppressed the NLRP3 inflammasome (Youm et al., 2015). NLRP3 is notorious for aggravating gout symptoms, so it was like: “Yay! A potentially clinically relevant use for ketone supps!” (I think there might be other applications as well, but that’s for another blog post).

Ketones, NLRP3, and IL-1b

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It’s thought that NLRP3 is around during active flares, so gout sufferers would stay on their regular meds and take ketone supps as needed – this is important because from what I understand, gout flares really suck, some people get them frequently, and ketone supps aren’t covered by insurance [yet?].

 

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Fixing your rhythms makes everything better. Here’s how.

Full article open to everyone over at Patreon! <- link

What’s more anti-cancer than ‘shrooms and isothiocyanates?

CIRCADIAN RHYTHMS

Affiliate discounts: if you’re still looking for a pair of hot blue blockers, Carbonshade  is offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERE. If you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like the taste, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS.

Caffeine, large meals, and bright light in the evening induce circadian misalignment. That’s why these are better suited earlier in the day.

Caffeine reduces sleep pressure (which is supposed to start low in the morning and peak shortly after sunset) and delays melatonin onset (Burke et al., 2015). After dinner, make it a decaf or just pass.

 

Caffeine is an adenosine antagonist, and the accumulation of adenosine in the brain throughout the day is thought to be a chemical mediator of sleep pressure. Caffeine also delays and reduces melatonin, which increases your sleep needs, or at least time in bed/darkness.

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FOOD PROFILE

Hey Fam, announcement: I’m moving to Patreon soon — will still post about 4-5 articles per month with at least 1 open to the public. The rest will be for Patrons. I’m still trying to figure it out and I’m open to suggestions!

 

I loved this – when describing the two study diets, which differed markedly in carb content (10% vs. 53%), the authors said they were similar in energy, protein, and “FOOD PROFILE,” meaning low-processed, lower-glycemic foods.

Non-industrial foods.

Hunger-free Diet(s).

BOOM!

Visceral adiposity and metabolic syndrome after very high-fat and low-fat isocaloric diets: a randomized controlled trial (Veum et al., 2016)

 

What happens when you give up industrial foods and start following a Hunger-free Diet (regardless of carbz)?

 

 

EVERYBODY LOSES WEIGHT

 

 

And le saturated fat? Industrial foods are the problem, not saturated fat. One group went from 48 to 31 grams per day (LFHC), the other group went from 42 to 81 (VLCHF): all metabolic parameters improved in both groups.

 




 

Even their livers shrank:

 

 

My only qualm: everyone lost a bit of muscle. NOT SURPRISING when you cut calories & protein and don’t exercise. Protein dropped by about ~25 grams in both groups. When you cut calories, you need to up protein or start lifting heavy shit otherwise you’ll lose muscle. The ketonez won’t help.

 

 

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GLP-101

Insulin secretion happens pretty quickly after a meal, in part, due to nutrients and gut-derived incretins like GLP-1.  GLP-1 secretion only happens with a meal, so the insulinemic response to oral glucose is greater than that to i.v. glucose:

 

 

Part 2. The liver sees WAY more insulin than peripheral tissues when this happens.  And it’s probably that way for a reason; ie, perhaps you need more insulin to shut down hepatic glucose output than to stimulate muscle glucose uptake and shut down lipolysis, etc.

 

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Autophagy

Caloric restriction (CR) activates autophagy.  Intermittent fasting (IF) is basically kind-of-like the opposite of CR.  I’m not knocking IF.  The animal studies of autophagy, based on “chronic nutrition depletion,” more accurately reflect CR which results in decreased body weight or metabolic rate.   IF generally includes refeeds, resulting in weight maintenance.  Also, in the few human studies on it, weight loss (CR) but not fasting (IF) has been shown to induce autophagy.

If you’re actually losing weight over the long-term with an IF protocol, and thus are CR by definition, then I suspect you may be autophaging, too (yeah yeah, I know, that’s not really how autophagy works, but you get the picture).

Disclaimer: I’m relatively autophagy-agnostic; not really confident racing to maximize it is a great thing based on Human Studies.

Book: Autophagy in Health and Disease

 

autophagy-image

 

Exhibit A: autophagy in skeletal muscle

Tl;dr: “a little exercise is a better than a lot of fasting”

A1) Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle (Moller et al., 2015)

The protocol: participants either fasted for 36 hours or received a glucose infusion before and during exercise (cycling at 50% max for an hour).

“In the present study, we demonstrate that short-term aerobic exercise activates autophagic signaling through ULK1 in human skeletal muscle, independently of nutrient background.”

They really should’ve stressed that the deck was stacked to show fasting activated autophagy… 36 hours of fasting is pretty long but it had no effect.

 

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Circadian arrhythmia in different types of obesity

This study was pretty interesting.

Three groups of women:

1) normal weight

2) gynoid obesity (stores more fat in hips & butt), defined by WC/HC < 0.85

3) android obesity (stores more fat in belly, which is rare in women), defined by WC/HC > 0.85

 

First, we get confirmation that insulin sensitivity (IS) is better in morning than evening.  But then we get these interesting glucose tolerance curves:

 

circadian-glucose-tolerance

 

Fat stored in your hips & butt is thought to be healthier than that stored in your belly region.  This is confirmed here.  Gynoid obesity, while exhibiting an attenuated AM/PM difference, was able to restore euglycemia by the end of the experiment at both time points.  Ie, gynoid obesity selectively improved IS in the evening.

 




 

Android obesity, which is more nefarious than gynoid (also confirmed here), had a similar though not as robust effect in the evening but deteriorated IS in the morning.

One potential interpretation: it’s better to have a little extra fat stored in your hips and butt than to be lean or have belly fat.  However, I have a qualm with that interpretation.  Healthy people show a robust circadian difference in glucose tolerance.  Just as insulin resistance (IR) is an accepted physiological phenomenon observed in some ketogenic dieters, I view this circadian difference, also, as physiological.

 

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Alcohol on keto

This article isn’t about alcohol tolerance.  It’s about your liver.

Tl;dr: with a basic knowledge about alcohol metabolism and ketoadaptation, drinking on keto gives me pause.

It might be nothing, but it gives me pause.

Alcohol is metabolized primarily by alcohol dehydrogenase, producing acetaldehyde and reducing equivalents as NADH.  This pathway produces energy.

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