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Nick Norwitz Profile picture
@nicknorwitz
Jan 6, 2023 • 18 tweets • 7 min read • Read on X
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1/18) 🚨NEW PAPER in @AJCN provides evidence supporting #CIM of #obesity

👉 Glycemic Load >>> Calorie Counting for weight loss

👉 Biomarkers of Low carb diet predict weight

👉Insulin hyper-secreters especially benefit fromlow-carb

Video 👉👉
🧵... Image
2/18) First, and foremost, a big congrats to @AdrianSotoMota and @davidludwigmd for an excellent work!

& of course, for those who have the time, I highly recommend reading the full paper, here: doi.org/10.1016/j.ajcn…

But for those who prefer video or TW thread... HERE WE GO...
3/18) What the researchers did in this paper is perform a secondary analysis of pre-existing data from a 12-month RCT: the DIETFITS trial in which 609 adults aged 18-50 without diabetes were randomized to either a 12 m Low-carb diet (LCD) or low-fa diet (LFD).
4/18) Initial data showed LCD led to more weight loss than LFD at 3 and 6 mo, but that the between group diff in weight loss lost significance at 12 months

This was taken to be evidence against the CIM. However, as this paper reveals, there is more nuance to the story... Image
5/18) One important ? is why significance was lost at 12mo?
2 reasons...

i) Participant dropout. Each group lost ~80 participants, diminishing statistic power

AND

ii) Diet convergence: ‘Carb creep’ in the LCD group (132g/d) + carb drop in the LFD group (213g/d) Image
6/18) Even setting aside the dietary convergence, when missing data was imputed, the LCD group did in fact lose more weight at 12 m than the LFD group at all time points. Image
7/18) Moving on, Fig 2 shows a model of predictors of weight loss ➡️ larger circumferences represent better predictors of weight loss

🍽️🍽️Total fat & Calories were poorer predictors of weight loss

🍩🥭Carbs & GI and sugar are the superior predictors

Consistent with the CIM Image
8/18) In Table are 2 models examining the mediators of weight loss

When you add in Glycemic Load (GL) is added to the model in model 2, GL is highly significant (p=5.7x10-5) and calories (p=0.80) LOSE significance!

Let’s expand on this point... Image
9/18) Many think that LCD works bc it just makes you eat fewer calories, but that it’s actually the drop in calorie intake that’s driving the weight loss. This certainly is a contributing factor but...
10/18) These results show that GL is better than caloric intake at predicting weight loss, which may appear counterintuitive BUT can be made intuitive if you think about the components of Energy balance: Calories in & Calories out...
11/18) The CICO model, when taken in CLINICAL practice, usually focuses on CI because accurately measuring CO accurately is next to impossible (think, NEAT, TEF, body temp, etc.)
12/18) By contrast, if GL influences the hormonal milieu of the body, it dictates NOT ONLY hunger and caloric intake (CI) but also homeostatic mechanisms to maintain energy equilibrium, or tip it one way or another, through CO: NEAT, body temp, etc.
13/18) Simply put, one could actually make the argument that the CIM is actually a superior real-life ‘CICO’ model than the standard cal counting CICO model itself!

LOL If that doesn’t make sense, read ^ again and watch video for completeness
14/18) Other cool data presented in this paper consistent with the results already shared is that, in fig 5, a biomarker of low-carb/GL (TG/HDL) was strongly associated with weight loss whereas a biomarker of fat reduction (LDL+HDL) was not. Image
15/18) Finally, and beautifully, the authors put a bold prediction of the CIM to the test which is that those with higher basal insulin secretion would benefit most for GL reduction. Again, this is b/c in the CIM GL influences insulin to cause fat storage.
16/18) So, if someone naturally is an insulin hyper-secreter, the effect of the model is simply going to be amplified. As a result, those who secrete a lot of insulin probably benefit the most from reducing GL. Is that the case? As it turns out yes!
17/18) Clearly see an interaction b/w GL reduction and basal insulin

As you can see in the back left row, these persons who reduced GL most and were the insulin hyper secreters, lost the most weight! Image
18/18) In summary, this paper provides powerful evidence for two prediction of the CIM: (1) GL > Calories as a predictor of weight loss and (2) insulin hyper secreters benefit most from carb reduction.

Video


Paper
doi.org/10.1016/j.ajcn…

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More from @nicknorwitz

Nick Norwitz Profile picture
Apr 20
🚨 New Genetic Discovery: Why Some People Naturally Eat Less Sugar & Stay Lean 🍫➡️🚫 (link at the end)

Scientists may have just uncovered a hidden biological quirk that makes some people naturally eat less sugar, crave less sugar, and stay lean.

1/5) A paper just published in Gastroenterology found that people with mutations in a gene coding for a carbohydrate-digesting protein called “sucrase-isomaltase” had:
✅Lower intake of added sugar
✅Lower BMI
✅Improved metabolic health

But here’s the kicker: there may be a way to hack this system, even if you weren’t born with these lucky genetics 👀…

#SugarCravings #Metabolism #NutritionScience #GLP1 #FunctionalFood #Genetics #HealthHackImage
2/5) Researchers found that people with a Sucrase-isomaltase mutation that reduces this protein’s function not only consumed less sugar but also experienced better metabolic health overall.

🍭 Voluntarily ate less sugar
🥤 Drank less sugary fluids
🔁 AND released more GLP-1 in response to sugarImage
3/5) The whole metabolic cascade isn’t fully understood yet, but another key player might be acetate, a molecule that increased in both the mice and humans with this mutation.

Researchers suspect this acetate signals the brain and nervous system to boost GLP-1 levels and curb sugar cravings.

And here’s something else really fascinating part: the more sugar a food contained, the less people with this mutation liked it—compared to those without it!
Read 5 tweets
Nick Norwitz Profile picture
Apr 19
'Lettuce' Be Honest: Fiber Isn’t Always the Answer🥬🤥(Refs linked in letter at the end) 🧵

1/6) We’ve been told for years that fiber is a must-have for gut health—that without it, your microbiome will crumble faster than a stale bran muffin.

But what if I told you… you don’t actually "need" fiber?

But before you throw your kale smoothie at the screen, let’s break down the science—because the truth about fiber is way more complex than a simple 'good' or 'bad.'

#fiber #microbiome #guthealth #educational #SCFA #ketodiet #carnivore #plantbased #metabolism #metabolichealth
2/6) Fiber & Inflammation🔥🥬

Some people argue that fiber-rich foods are anti-inflammatory. But that’s not entirely true.

For example, a landmark randomized controlled trial published in Cell found that some people were inflammatory responders to dietary fiber. Reading from the paper, “Taken together, these data suggest divergent immune system responses to the high-fiber intervention, with high-inflammation participants exhibiting broad increases in steady-state immune activation.”

To be clear, this was NOT the majority of participants.

And it's also worth noting that those with lower microbiome diversity tended to be the inflammatory responders, raising the 🤔hypothesis🤔 that there might be protocols by which one could train-up a microbiome such that it responds with a healthier anti-inflammatory response to fiber...

It’s possible.

But the fact remains that some people have a pro-inflammatory response to fiber that could have negative health consequences and contribute to or exacerbate chronic disease.Image
3/6) Fiber & Microbiome Diversity🥬🤔

One point that is often raised is that fiber depletion or elimination will decrease microbiome diversity, a presumed marker of good health. This is fair speculation at a population level. However, there are deeper nuances.

First, microbes in the gut can feed off more than just fiber and eating a low-fiber diet doesn’t necessarily lead to decreased diversity.

For example, in one impressively comprehensive case study, a man who had been on a carnivore diet for 4 years had his microbiome compared to that of omnivores and, reading from the study, “[T]he comparison showed surprising results. The carnivore’s gut microbiome did not stand out regarding α- and β-diversity, indicating that it did not lack richness or diversity when compared to its omnivore counterparts.”

And “Our study indicates that adherence to a carnivorous diet does not cause detrimental changes in the gut microbiome. Instead, it suggests that the effects on the gut microbiome are due to the combined influences of dietary regime and lifestyle, rather than meat consumption alone. Further research is needed to identify which components of the carnivore diet could act as prebiotics in the absence of plant-derived prebiotics and maintain gut health over time.”

Granted, this is a case study. But even an N = 1 it’s sufficient to make the point that even complete fiber elimination for 4 years doesn’t starve off the microbiome.Image
Read 6 tweets
Nick Norwitz Profile picture
Apr 13
What if all *autoimmune diseases* were stemming from the same source, from a seed planted 2 Billion years ago that’s just beginning to flower? 🔥🤔🧵

1/6) That might sound wild—but it’s actually the central thesis of a perspectives paper published in @Nature, which proposes that many autoimmune diseases may be driven by the failure of a relationship that began 2 billion years ago: the one between your body and your mitochondria.

For me, this idea carries personal weight since I suffered from debilitating inflammatory bowel disease, which went into remission on a ketogenic diet.

I’ve seen others similarly put IBD, lupus, multiple sclerosis, and rheumatoid arthritis into remission with lifestyle change.

And I desperately want to know how it works.

But enough chit chat, the paper is entitled: “A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.” (PMID: 38326590).

This thread will explain it in simple terms, but with nuance. 🧵👇

(link to more at the end)

Potentially of interest to:
@ChrisPalmerMD #BrainEnergy
@thegarybrecka @joerogan - Discussed Autoimmune Disease on Epi #2304. I agree with Gary, "God [metaphorically or literally speaking, depending on your beliefs], didn't make a mistake." And THIS might be what we are missing
@hubermanlab @R_Mohr @bryan_johnson because of relationship to circadian rhythms
@MitoPsychoBio because #mitochondria
@AdrianSotoMota @drmarkhyman @MatthewNehsMD @drericwestman @JEverettLearned @AKoutnik @lowcarbGP because I know they will
And Ht/ @davidludwigmd who passed me the paper that inspired this thread, newsletter & upcoming video
#autoimmunity #inflammation #mitochondria #metabolichealth #metabolismImage
2/6) What is "Mitochondrial Endosymbiosis?"

About 2 billion years ago, a cell consumed another, smaller bacteria-like cell (technically it was an Asgard archaeon). That second, smaller cell didn’t get digested and pooped out, but integrated into the larger one.

This is what’s meant by “endosymbiosis.”

And, you guessed it, that smaller cell was the precursor to our very own mitochondria, the engine and the powerhouse of most of the cells in your body and the center of your metabolism.

But your mitochondria are far more than just little engines.

They are also informational hubs and communication stations, signaling all over your body to cue and coordinate near infinite pathways and processes.

And how mitochondria do this derives, at least in part, from their foreign origins. Truly, mitochondria retain many of the signatures of their foreign origins that mark them much like bacteria or viruses and apart from other components of “you.”

The authors write, “we can also consider mitochondria as a pseudobacterium ‘bricked in’ behind the mitochondrial outer membrane.”Image
3/6) A Break in Endosymbiosis Triggers Autoimmunity

And your body’s immune system is great at recognizing the “other” – foreign invaders.

Mitochondria, for the most part, are shielded within cells and so don’t get targeted and attacked. However, the body can selectively release mitochondrial components or mitochondria-derived signaling molecules to trigger certain events.

In the authors’ words, “[T]he endosymbiotic origin of mitochondria marks them apart from the rest of the cell in a way that can be co-opted to produce key messages pertaining to cell fate.”

For example, in response to cell stress, mitochondria can release proteins from the intermembrane space, like cytochrome C, to trigger a form of organized cell death called apoptosis. Mitochondria also retain their very own mitochondrial DNA (mtDNA), separate from the DNA in your cells’ nuclei.

And the release of this DNA can also trigger immune reactions. In some cases, the inner portion of mitochondria can swell, and components can literally herniate out (illustrated below) of the mitochondria, pushing components including mtDNA, and triggering an immune/inflammatory reaction.Image
Read 6 tweets
Nick Norwitz Profile picture
Apr 7
🚨FINALLY! The Lean Mass Hyper-Responder 1 Year Data Just Dropped!🚨
jacc.org/doi/10.1016/j.…

🫀Most participants showed NO OR MINIMAL or progression of coronary plaque
🫀Neither ApoB nor LDL exposure predicted plaque progression
🫀But plaque predicted plaque progression, leading to the conclusion and Title:

1/10) 🧵This thread will give you some high-level points, direct you to more information, and tell you how 🫵YOU🫵 can help change “the science”

(🔗 links at the end!)

ht/ @realDaveFeldman @AdrianSotoMota @Metabolic_Mind @janellison @bschermd @BudoffMd @khurramn1Image
2/10) Necessary Background

Colleagues and I have spent the last several years studying what happens to cholesterol levels in people who adopt very low-carbohydrate ketogenic diets

🤔Most don’t see increases in cholesterol.

🤔Many even see decreases.

👉However, some see their LDL cholesterol (LDL-C) levels rise so high that most doctors think it’s “inconceivable.”

These special individuals are called ‘lean mass hyper-responders’ (LMHR) because they are, as a population, generally lean and healthy.

In fact, our prior meta-analysis of 41 human RCTs (PMID: 38237807) showed that the leaner a person is, the higher their LDL-C tends to rise on a low-carbohydrate diet trials.
🧈🧈🧈🧈This study also showed that having a BMI < 25 kg/m2 was >5X as powerful as being in the top quartile of saturated fat intake for predicting LDL-C change.

So, this is certainly far more interesting than a ‘blame-the-butter’ story …Image
3/10) We followed 100 LMHR and near- LMHR, having mean BMI 22.5 kg/m2 and mean LDL-C = 254 mg/dl, with high resolution coronary CT angiography.

We followed them to see whether, and to what degree, plaque accumulated in the arteries of these individuals with extremely high LDL-C.
Read 11 tweets
Nick Norwitz Profile picture
Apr 3
Why do some people with crazy high LDL-C and ApoB develop no plaque in their arteries, while others – including those with far lower LDL and lower ApoB – do develop plaque? 🫀🤔(link 🔗 at the end) 🧵...

1/6) We know this is a phenomenon. So, let’s tackle one possible explanation centered around the following term: Transcytosis...

#LDL #ApoB #LMHR #LEM #Cholesterol #HeartHealth #CholesterolCode cc @realDaveFeldman @AdrianSotoMotaImage
2/6) Transcytosis, Made Simple🫀🤔
Your arteries are lined by cells called endothelial cells. Endo- means within, as these cells are within the tube that composes your blood vessels. A coronary plaque grows when cholesterol-containing particles, including LDL particles, slip through the endothelial barrier and begin to seed a plaque.

But HOW do cholesterol-containing particles penetrate the endothelial barrier? It’s not like a healthy endothelial barrier is coarse chicken wire. It’s rather tightly knit.
That’s where “transcytosis” comes into the picture.

Transcytosis is the process whereby a cell – in this case, the endothelial cells lining your arteries – sucks up something from outside (here, an LDL particle containing cholesterol), passes that something through its interior, and then out the other side.

By way of analogy, think of your artery wall like an exclusive nightclub. Some particles get waved in VIP-style. Others get stuck outside. But what if LDL wasn’t just passively slipping through a hole in the wall, but was actually being escorted through by a bouncer? That is - more or less - transcytosis.Image
3/6) Your Coronary Epiphany! 🫀💡
Now, given this perspective, you may have just made a connection or had a coronary epiphany!
People often talk about the process of plaque development in a manner that suggests the more cholesterol-containing particles you have in the blood, the more that end up getting inside your artery wall and getting trapped there – in a rather linear fashion.

Let me be clear, this idea that more cholesterol containing particles in your blood automatically equals more flow of these particles into your artery walls (and more coronary artery disease) is a MASSIVE ASSUMPTION and likely incorrect, or at least incomplete.

Instead, transcytosis is an active, regulated process...Image
Read 6 tweets
Nick Norwitz Profile picture
Mar 29
🧠Saffron for Depression: The Science, the Studies, and the Recipes🧠

1/5) What if I told you that the kitchen spice – Saffron – could treat depression?

It may sound too good to be true, but that claim is supported by a growing pile of human randomized controlled trials (RCTs) and sensible biological mechanisms.

I’m going to share two of these studies, explain the neuroscience, and direct you to more learning.

This golden spice really might be the next big thing in mental health!

References are in the newsletter linked at the end. #saffron #depression #mentalhealthImage
2/5) Saffron vs SSRI (RCT)
This double-blind randomized controlled trial compared 6 weeks of saffron supplementation (30mg/d) vs Prozac (fluoxetine), a commonly prescribed selective serotonin reuptake inhibitor (SSRI).

Impressively, the saffron performed equal to the fluoxetine!

You can see the results over 6 weeks here, with the Hamilton Rating Scale for Depression dropping in lock step between the treatments.

The absolute decrease in both treatments was >12. What does that number mean?

Well, in clinical trials, there’s a key distinction between a “statistically significant” difference and a “clinically significant” difference. A “statistically significant” difference means there was a detectable numeric difference, as in over time or between groups. Conversely, a “clinically significant” difference means that size of the change was detectable and meaningful for the patient.

Now while it’s somewhat arbitrary, a clinically meaningful change in this depression scale is ~5 points, which means a ~12-point drop is impressive and is clinically substantial!

Note on Side Effects: One presumed advantage of saffron is that it could have fewer side effects than prescription medications. In this first small pilot trial, there is an apparent trend to lower side effects in the saffron group vs SSRI. To see that table, click on the link at the end of this thread.Image
3/5) Saffron for Mental Health - Meta-Analysis
Rather than working through another 20+ studies, I want to share with you excerpts from a meta-analysis of 23 RCTs conducted on saffron for mental health, including depression and anxiety:
👉 [M] eta-analysis found a significant and large positive effect size for saffron reducing symptoms of depression in comparison with placebo.
👉When compared with antidepressants medications, there was no significant difference between saffron and medications.
👉Meta-analysis of studies that investigated the effect of saffron as an adjunct to pharmacotherapy reported a large significant benefit from saffron supplementation.

In simpler terms:
👉Saffron’s effect alone with large and positive for mental health
👉Saffron performed as well as commonly prescribed medications
👉Saffron provided additional benefit when stacked on prescription medications

Effects on anxiety were similar.Image
Read 5 tweets

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