- The Huberman Lab Podcast is hosting its first Journal Club episode with Dr. Peter Atiyah.
- A journal club is a practice where students discuss and critique scientific papers.
- Dr. Atiyah will discuss a paper on metformin and its potential role in longevity.
- Dr. Huberman will present a paper on the placebo effect, specifically related to nicotine.
- The episode aims to inform listeners about the discussed papers and how scientists and clinicians analyze research.
- The podcast is separate from Stanford University and aims to provide free science-related information to the public.
- The podcast is sponsored by Helix Sleep and Levels, offering mattress customization and real-time feedback on health, respectively.
- Dr. Atiyah and Dr. Huberman are excited to share their findings and help listeners develop critical thinking skills.

- The speaker discusses their experience with drinking yerba mate and its health benefits
- They talk about a transformative dream they had and the preparation involved
- The speaker then introduces a paper titled "Reassessing the Evidence of a Survival Advantage in Type 2 Diabetics Treated with Metformin Compared with Controls Without Diabetes, a Retrospective Cohort Study"
- They explain the importance of the paper and provide information about metformin and its mechanism of action
- The speaker clarifies the role of metformin in reducing hepatic glucose output in type 2 diabetes
- They provide a simplified explanation of the biochemistry of energy production and metformin's effect on glucose metabolism
- The speaker briefly mentions the failed product Olestero and its side effects.

- Insulin resistance in the muscles is the primary insult in type 2 diabetes.
- Insulin binds to the insulin receptor on muscle cells, triggering a chemical reaction that allows glucose to enter the cell.
- Insulin resistance occurs when intramuscular fat increases, requiring more insulin to trigger glucose transport into the cell.
- Insulin resistance is marked by an increase in insulin levels, not glucose levels.
- Type 2 diabetes progresses to a point where the body becomes resistant to insulin and glucose levels become elevated.
- Accumulation of fat in the muscle, liver, and pancreas exacerbates insulin resistance.
- Metformin is a first-line drug for type 2 diabetes that addresses glucose disposal and hepatic glucose output.
- Other drugs for type 2 diabetes aim to increase insulin production or sensitivity.
- Inactivity, sleep deprivation, hypercortisolemia, and energy imbalance can contribute to insulin resistance.
- Geroprotective agents like metformin target the hallmarks of aging to protect against age-related diseases.

- The study examined the effects of metformin on patients with type 2 diabetes
- It used a registry to match patients on metformin with controls
- Informative censoring was used to exclude certain patients from the study
- The study found a 15% reduction in all-cause mortality in the metformin group
- The results suggest that metformin may have benefits beyond lowering blood glucose levels
- The study has been considered the best evidence for the benefits of metformin

- Keyes and colleagues are redoing the banister analysis due to the high interest in the topic and the upcoming TAME trial.
- They used a larger sample of half a million people from a Danish health registry.
- They created two groups to study: one with people with and without diabetes and another with discordant twins.
- The medication list was not matched between the groups, which is a limitation of the study.
- The study looked at crude mortality rates per thousand person years.
- Adjusting for age, the crude death rate for those on metformin was almost identical between the non-twin and twin groups.

- The study compares death rates between people with diabetes and those without
- The death rate is higher in people with diabetes, even after age adjustment
- The study uses Kaplan-Meier curves to show mortality rates over time
- The curves show that people with diabetes taking metformin have a higher death rate compared to controls
- The shaded areas represent 95% confidence intervals
- Overlapping confidence intervals would indicate no significant difference
- Statistical power is important for determining sample size and detecting significant differences
- Increasing sample size reduces variability in the data set.

- Increasing sample size decreases variation in measurements
- Epidemiological studies rely on large sample sizes to compensate for biases and limitations
- Randomized prospective experiments are expensive and have limitations
- The hazard ratio is a measure of relative risk in studies
- Metformin use in diabetes patients may increase the risk of death
- Adjustments for medications, education, and marital status did not significantly change the results
- Censoring data did not undo the benefits seen in previous studies
- The study suggests that metformin may not fully offset the disadvantages of diabetes

- The Huberman Lab Podcast is hosting a Journal Club episode with Dr. Peter Atiyah.
- Dr. Atiyah will discuss a paper on metformin and its potential role in longevity.
- Dr. Huberman will present a paper on the placebo effect, specifically related to nicotine.
- The episode aims to inform listeners about the discussed papers and how scientists and clinicians analyze research.
- The podcast is separate from Stanford University and provides free science-related information to the public.
- The podcast is sponsored by Helix Sleep and Levels.
- Dr. Atiyah and Dr. Huberman are excited to share their findings and help listeners develop critical thinking skills.
- The speaker discusses their experience with drinking yerba mate and its health benefits.
- They introduce a paper on the effects of metformin on patients with type 2 diabetes.
- Metformin is a first-line drug for type 2 diabetes that addresses glucose disposal and hepatic glucose output.
- The study found a 15% reduction in all-cause mortality in the metformin group.
- Keyes and colleagues are redoing the analysis due to high interest and the upcoming TAME trial.
- The study compared death rates between people with diabetes taking metformin and controls.
- The study suggests that metformin may not fully offset the disadvantages of diabetes.

- The speaker discusses the difficulty of determining the contribution of metformin to health outcomes in sick individuals on multiple medications.
- They mention the challenge of isolating the effects of metformin from other medications and variables.
- The speaker highlights the limitations of epidemiological studies in controlling for all variables and intangible differences.
- They compare the findings of a study on metformin to a previous study on meat consumption.
- The speaker mentions the lack of randomized control trials for metformin and discusses the success of other drugs in animal studies.
- They explain why they stopped taking metformin due to high lactate levels and weak mitochondrial function.
- The speaker briefly discusses their use of berberine as a substitute for metformin.

- Berberine, a supplement similar to metformin, helped buffer blood glucose and reduce feelings of sickness after consuming high-calorie foods
- Berberine caused headaches if not followed by a significant amount of carbohydrates
- Carbose is another glucose disposal agent that prevents glucose absorption and has shown potential health benefits in studies
- Lowering blood glucose may have potential benefits for conditions like dementia
- Regular exercise is the best way to maintain blood glucose levels, but glucose disposal agents can be used as tools
- SGLT2 inhibitors are a class of drugs that have shown promise in managing blood glucose levels and have potential benefits for non-diabetics
- Caloric restriction may not offer a significant survival advantage for humans and is not a practical approach for most people
- Energy balance and overall nutrition may play a greater role in glucose homeostasis than specific macronutrients
- Metformin may have benefits for insulin-resistant individuals, but may not be as effective for insulin-sensitive individuals who exercise regularly
- Short periods of caloric restriction may not have significant longevity benefits, and longer durations may be necessary for any potential benefits

- The speaker discusses the duration and benefits of fasting, mentioning that they used to do 7 days of water-only fasting per quarter.
- They highlight the potential downside of fasting, which is muscle mass loss.
- The speaker emphasizes the lack of biomarkers for measuring the effects of interventions like fasting, which hinders research progress.
- They suggest that more research funding should be allocated to developing biomarkers for aging.
- The speaker shares their approach to reading scientific papers, which involves asking four key questions: the general and specific question being asked, the approach used, the findings, and the conclusion.
- They mention the importance of looking up unfamiliar terms and acronyms when reading papers.
- The speaker discusses the format of papers and the inclusion of supplemental information.
- They express excitement about a particular experimental paper that they discuss, but note that it is not yet published and may undergo changes.

- The paper discusses how our beliefs about drugs can impact their effects on us at a biological level
- Belief effects are different from placebo effects and can shift psychology and physiology
- Examples of belief effects include how stress affects performance and how beliefs about food can impact hunger levels
- The study focuses on belief effects of nicotine, which is known to improve cognitive performance
- Nicotine enhances signal-to-noise ratio in the brain, increases dopamine release, and improves attention and focus

- Stimulant drugs can enhance the function of the ventromedial prefrontal cortex circuit in children with ADD and ADHD
- Other methods, such as nutrition and playtime, can also help improve symptoms without drugs
- Nicotine can enhance focus in the brain and provide muscle relaxation in the body
- A study used fMRI to measure brain activity in smokers who vaped different doses of nicotine
- Participants were unaware that they all received the same low amount of nicotine
- Subjective feelings matched what participants were told about the nicotine dose
- Activation of the thalamus and other regions involved in attention were observed during a task
- The study provides insights into the impact of nicotine on brain function.

- The study examined how beliefs about nicotine strength affect brain activation and performance on a task.
- Activation in attention-related areas of the brain scaled with the perceived nicotine strength.
- The belief effect changed the way the brain responded to nicotine.
- The connection between the thalamus and ventral medial prefrontal cortex showed a dose-dependent response based on belief.
- The study is the first to look at dose dependence of belief effects.
- The study did not include a control group with no nicotine.
- The study found that beliefs about nicotine strength did not modulate the reward response in the brain.
- The sample size of the study was relatively small.
- The findings suggest that beliefs about nicotine strength can impact physiological responses to nicotine.

- Difficulty of determining metformin's contribution to health outcomes in sick individuals on multiple medications
- Challenge of isolating metformin's effects from other medications and variables
- Limitations of epidemiological studies in controlling for all variables
- Comparison of metformin study to previous meat consumption study
- Lack of randomized control trials for metformin and success of other drugs in animal studies
- Speaker's personal experience with metformin and use of berberine as a substitute
- Benefits and drawbacks of berberine and carbose as glucose disposal agents
- Potential benefits of lowering blood glucose for conditions like dementia
- Importance of exercise in maintaining blood glucose levels
- Potential benefits of SGLT2 inhibitors for managing blood glucose levels
- Lack of significant survival advantage with caloric restriction
- Role of energy balance and overall nutrition in glucose homeostasis
- Effectiveness of metformin for insulin-resistant individuals but not insulin-sensitive individuals who exercise regularly
- Potential benefits of fasting and downside of muscle mass loss
- Need for biomarkers to measure effects of interventions like fasting
- Importance of asking key questions when reading scientific papers
- Impact of beliefs on drug effects at a biological level
- Examples of belief effects on stress, food, and nicotine
- Nicotine's effects on cognitive performance and brain function
- Study on belief effects of nicotine and its impact on brain activation and performance on a task
- Dose dependence of belief effects on brain activation and connection between thalamus and ventral medial prefrontal cortex
- Lack of control group and small sample size in the study
- Impact of beliefs about nicotine strength on physiological responses to nicotine.

- The belief in the amount of nicotine consumed can impact the reward pathways in the brain
- The study was conducted on smokers, who were constantly coughing during the fMRI scans
- Naive individuals may be more susceptible to the belief system regarding the effects of nicotine
- The experiment has implications for drugs, behavioral interventions, vaccines, and psychoactive drugs
- Beliefs about the effects of a drug can impact the brain's reaction to it
- GLP-1 agonists may have a central impact on appetite reduction, but belief is necessary for it to be effective
- Belief effects can also impact the perception of side effects and the effectiveness of a drug
- Medical students may develop symptoms of the diseases they learn about, leading to a warped sense of prevalence
- The study highlights the importance of belief in the effects of drugs and medical conditions.

- The speaker enjoys learning from the person across the table
- They plan to meet again in Austin
- The speaker asks the audience to subscribe to their YouTube channel and podcast on Spotify and Apple
- They mention the sponsors of the podcast
- They discuss the benefits of supplements and mention their partnership with Momentus Supplements
- They promote their Neural Network newsletter and social media accounts
- They thank the audience for their interest in science.

- Belief in the amount of nicotine consumed affects reward pathways in the brain
- Study conducted on smokers experiencing coughing during fMRI scans
- Naive individuals more susceptible to belief system about nicotine effects
- Experiment has implications for drugs, interventions, vaccines, and psychoactive drugs
- Beliefs about drug effects impact brain's reaction
- GLP-1 agonists for appetite reduction require belief for effectiveness
- Belief affects perception of side effects and drug effectiveness
- Medical students may develop symptoms of diseases they learn about
- Importance of belief in drug effects and medical conditions highlighted
- Speaker enjoys learning from person across table
- Plan to meet again in Austin
- Audience asked to subscribe to YouTube channel and podcast on Spotify and Apple
- Sponsors of podcast mentioned
- Benefits of supplements discussed, partnership with Momentus Supplements mentioned
- Promotion of Neural Network newsletter and social media accounts
- Audience thanked for interest in science.

In this journal club episode, my guest is Stanford and Johns Hopkins-trained physician, Dr. Peter Attia, M.D., who is also the host of The Drive podcast and the author of the bestselling book "Outlive: The Science & Art of Longevity."
We each present a scientific paper and discuss the findings' strengths, weaknesses and actionable takeaways.
First, we discuss an article that addresses whether taking the drug metformin can enhance longevity. Then, we discuss an article on belief effects (similar to placebo effects), showing how the effects of a drug on the brain and cognition depend on one's belief about the dose of the drug taken, not the actual dose.
Our conversation also highlights how to read, interpret and critique scientific studies. This episode ought to be of interest to those curious about health and longevity, medicine and psychology and for anyone seeking to better understand how to read and digest scientific findings.
For the full show notes, including articles, books, and other resources, visit hubermanlab.com.
Thank you to our sponsors
AG1: https://drinkag1.com/huberman
Helix Sleep: https://helixsleep.com/huberman
Levels: https://levels.link/huberman
InsideTracker: https://insidetracker.com/huberman
Momentous: https://livemomentous.com/huberman
Timestamps
00:00:00 Dr. Peter Attia, Journal Club
00:03:27 Sponsors: Helix Sleep & Levels
00:06:11 Dreams
00:12:36 Article #1, Metformin, Mitochondria, Blood Glucose
00:19:47 Type 2 Diabetes & Causes, Insulin Resistance
00:25:30 Type 2 Diabetes Medications, Metformin, Geroprotection, Bannister Study
00:36:19 Sponsor: AG1
00:37:15 TAME Trial; Demographics, Twin Cohort
00:44:27 Metformin & Mortality Rate
00:51:28 Kaplan-Meier Mortality Curve, Error Bars & Significance, Statistical Power
01:01:17 Sponsor: InsideTracker
01:02:23 Hazard Ratios, Censoring
01:09:00 Metformin Advantage?, Variables, Interventions Testing Program
01:16:02 Berberine, Acarbose, SGLT2 Inhibitors
01:23:48 Blood Glucose & Energy Balance; Caloric Restriction, Aging Biomarkers
01:32:22 Tool: Reading Journal Articles, 4 Questions, Supplemental Information
01:38:10 Article #2, Belief Effects vs. Placebo Effect
01:45:22 Nicotine Effects
01:51:07 Nicotine Doses & Belief Effects, fMRI Scan
02:00:07 Biological Effects, Dose-Dependent Response & Belief Effects
02:05:14 Biology & Beliefs, Significance, Dopamine Response, Non-Smokers
02:10:57 Dose-Dependence & Beliefs, Side Effects, Nocebo Effect
02:19:06 Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous, Neural Network Newsletter, Social Media
Title Card Photo Credit: Mike Blabac
Disclaimer

Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life.

I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.

Today marks the first Journal Club episode between myself and Dr.

For any of you that are not familiar with Dr.

Peter Atiyah, he is a medical doctor and MD, who is an expert in all aspects of health and lifespan.

He is the author of a bestselling book entitled, "'Outlive'", which is a phenomenal resource on all things healthspan and lifespan.

And he is the host of the very popular podcast, The Drive, where he interviews various experts in all domains of medicine and scientists as well.

Today, Peter and I hold our first online collaborative journal club.

For those of you that aren't familiar with what a journal club is, a journal club is a common practice in graduate school and or medical school, whereby students get together to discuss 1 or 2 papers, to critique those papers, and to really compare their own conclusions of those papers with the conclusions of the authors and to highlight any key takeaways.

Peter and I have been wanting to do a journal club together for a very long time.

And we decided to do that journal club and to record it for you.

So today you will be sitting in on the first Huberman-Attiyah Journal Club.

By the way, it could just have easily been called the Attiyah-Huberman Journal Club.

First, Peter is going to discuss a paper on metformin, which is a drug that many people are interested in for its potential role in longevity.

He's going to compare that paper to previous findings on metformin.

And by the end of that discussion, he will advise as to whether or not he himself would take metformin and whether or not other people might be well-advised or ill-advised to take metformin based on the data in that paper and at this time.

Then I present a paper which is about the placebo effect.

I have to imagine that most of you have heard of the placebo effect, but What's interesting about the paper that we discussed today is that it shows that the placebo effect can actually follow a dose response.

It actually is the case that you can scale the degree of placebo effect depending on whether or not you're thinking you're taking low doses, moderate doses or high doses of a particular drug.

And the particular drug that's discussed in the paper that I cover is nicotine.

So for those of you that are interested in cognitive enhancement by way of pharmacology, or frankly, for people who are simply interested in how our beliefs can shape our physiology, I think you'll find that discussion to be very interesting.

So by the end of today's episode, you will not only have learned about 2 novel sets of findings, 1 in the realm of longevity as it relates to metformin, and another in the realm of neurobiology and placebos or placebo effects, but you will also learn how a journal club is conducted.

I think you'll see in observing how we parse these papers and discuss them, even arguing in them at times, that what scientists and clinicians do is they take a look at the existing peer-reviewed research and they look at that peer-reviewed research with a fresh eye asking, does this paper really show what it claims to show or not?

What I know is for certain is that by the end of today's episode, you will learn a lot of science.

You'll learn a lot about health practices, some of which you may want to apply or avoid, and you'll learn a lot about how science and medicine is carried out.

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.

It is however, part of my desire and effort to bring 0 cost to consumer information about science and science related tools to the general public.

In keeping with that theme, I'd like to thank the sponsors of today's podcast.

Helix Sleep makes customized mattresses to give you the best possible night's sleep.

Now, sleep is the foundation of mental health, physical health, and performance.

When we are sleeping well and enough, mental health, physical health, and performance all stand to be at their best.

1 of the key things to getting a great night's sleep is to make sure that your mattress is tailored to your unique sleep needs.

Helix Sleep has a brief two-minute quiz that if you go to their website, you take that quiz and answer questions such as, do you tend to sleep on your back, your side of your stomach, do you tend to run hot or cold in the middle of the night, maybe you don't know the answers to those questions, and that's fine.

At the end of that two-minute quiz, they will match you to a mattress that's ideal for your sleep needs.

I sleep on the Dusk, a D-U-S-K mattress, and when I started sleeping on a Dusk mattress about 2 years ago, my sleep immediately improved.

So if you're interested in upgrading your mattress, go to helixsleep.com slash Huberman, take their 2 minute sleep quiz, and they'll match you to a customized mattress for you.

And you'll get up to $350 off any mattress order and 2 free pillows.

Again, if interested, go to helixsleep.com slash Huberman for up to $350 off and 2 free pillows.

Today's episode is also brought to us by Levels.

Levels is a program that lets you see how different foods and behaviors affect your health by giving you real-time feedback using a continuous glucose monitor.

1 of the most important factors impacting your immediate and long-term health is the way that your body manages its blood glucose, or sometimes referred to as blood sugar levels.

To maintain energy and focus throughout the day, you want to keep your blood glucose steady without big spikes or dips.

Using levels, you can monitor how different types of foods and different food combinations, as well as food timing and things like exercise combine to impact your blood glucose levels.

I started using levels a little over a year ago and it gave me a lot of insight into how specific foods were spiking my blood sugar and then leaving me feeling tired for several hours afterwards, as well as how the spacing of exercise and my meals was impacting my overall energy.

And in doing so, it really allowed me to optimize how I eat, what I eat, when I exercise, and so on, such that my blood glucose levels and energy levels are stable throughout the day.

If you're interested in learning more about levels and trying a continuous glucose monitor yourself, go to levels.link slash Huberman.

Right now, Levels is offering an additional 2 free months of membership.

Again, that's levels.link, L-I-N-K slash Huberman to get 2 free months of membership.

And now for my journal club discussion with Dr.

This is something that you and I have been wanting to do for a while.

And it's basically something that we do all the time, which is to peruse the literature and find papers that we are excited about for whatever reason.

And oftentimes that will lead to a text dialogue or a phone call or both.

But this time we've opted to try talking about these papers that we find particularly exciting in real time for the first time as this podcast format.

First of all, so that people can get some sense of why we're so excited about these papers.

We do feel that people should know about these findings.

And second of all, that it's an opportunity for people to learn how to dissect information and think about the papers they hear about in the news, the papers they might download from PubMed if they're inclined.

And also just to start thinking like scientists and clinicians and get a better sense of what it looks like to pick through a paper, the good, the bad, and the ugly.

So we're flying a little blind here, which is fun.

I'm definitely excited for all the above reasons.

No, this is, you and I have been talking about this for some time and, you know, actually we used to run a journal club inside the practice where once a month 1 person would just pick a paper, and we would go through it in kind of a formal journal club presentation.

We've gotten away from it for the last year just because we've been a little stretched thin.

I think it's something we need to resume, because it's a great way to learn.

People probably ask you all the time, because I know I get asked all the time, hey, what are the do's and don'ts of interpreting scientific papers?

And I think the 2 papers we've chosen today illustrate 2 opposite ends of the spectrum.

You're going to obviously talk about something that we're going to probably get into the technical nature of the assays, the limitations, et cetera.

And the paper, ultimately, I've chosen to present, although I apologize, I'm surprising you with this up until a few minutes ago, is actually a very straightforward, simple epidemiologic paper that I think has important significance.

I had originally gone down the rabbit hole on a much more nuanced paper about ATP binding cassettes in cholesterol absorption.

But ultimately, I thought this 1 might be more interesting to a broader audience.

By the way, I got to tell you a funny story.

And in this dream, you were obsessed with making this certain drink that was like your elixir and it had all of these crazy ingredients in it.

But the 1 thing I remembered when I woke up, because I forgot most of them, I was really trying so hard to remember them, 1 thing that you had in it was do like you had to collect a certain amount of do off the leaves every morning to put into this drink it was so but it's like

just sounds like something that I would do

and and so but here's the best part you had you had like a thermos of this stuff that had to be with you everywhere.

And all of your clothing had to be tailored with a special pocket that you could put the thermos into so that you were never without the special Andrew drink.

And again, you know how dreams, when you're having them, seem so logical and real?

And then you wake up and you're like, that doesn't even make sense.

Like why would he want the thermos in his shirt?

Like that, I would warm it up like, you know, all these, but, but boy, it was a realistic dream and there were lots of things in it, including do spa special do off the leaves every morning.

In fact, in its many forms, usually the loose leaf.

I don't tend to drink it out of the gourd.

My dad's Argentine, so that's where I picked it up.

I started drinking it when I was like 5 years old or younger, which I don't recommend people do.

Don't drink the smoked versions either, folks.

I think that was potentially carcinogenic.

But this thing that you describe of carrying around the thermos close to the body, if you are ever in Uruguay, or if you ever spot grown men in a restaurant anywhere in the world carrying a thermos with them and to their meals and hugging it close, chances are they're Uruguayan and they're drinking yerba mate.

It's supposed to be good for your digestion.

I don't carry the thermos, but I do drink mate every day.

And I'm gonna start collecting dew off the leaves.

Some other time we can talk about dreams.

Recently I've been doing some dream exploration.

I've had some Absolutely transformative dreams for the first time in my life 1 dream in particular that it has that allowed me to feel something I've never felt before and has Catalyzed a large number of important decisions in a way that no other experience Waking or sleep has ever impacted me and this was drug-free Etc.

And do you think you could have had that dream?

We don't have to get into it if you don't want to talk about it now, but was there a lot of work you had to do to prepare for that dream to have taken place?

At least 18 months of intensive analysis type work with a very skilled psychiatrist, but I wasn't trying to seed the dream.

It was just I was at a sticking point with a certain process in my life.

And then I was taking a walk while waking and realized that my brain, my subconscious, was going to keep working on this.

I just decided it's going to keep working on it.

And then 2 nights later, I traveled to a meeting in Aspen and I had the most profound dream ever, where I was able to sense something and feel something I've always wanted to feel as so real within the dream.

Woke up, knew it was a dream and realized this is what People close to me that I respect have been talking about but I was able to feel it and therefore I can actually access this in my waking life that it was it was it was absolutely transformative for me Anyway, sometime I can share more details with you or the audience, but for now, we should talk about these papers.

This one's, this is a pretty straightforward paper.

So, we're going to talk about a paper titled, Reassessing the Evidence of a Survival Advantage in Type

Diabetics Treated with Metformin Compared with Controls Without Diabetes, a Retrospective Cohort Study.

This is by Matthew Thomas Keyes and colleagues.

Bannister published a paper that I think in many ways kind of got the world very excited about metformin.

And I'm sure many people have heard about this paper, even if they're not familiar with it, but they've heard the concept of the paper.

And in many ways, it's the paper that has led to the excitement around the potential for Jiro protection with metformin.

And I should probably just define for the audience what gyroprotection means.

And probably also, sorry to interrupt, what metformin is just for the uninformed.

So metformin is a drug that has been used for many years, Depends where it was first approved, I think, was in Europe.

But call it directionally 50-plus years of use as a first-line agent for patients with type 2 diabetes.

So this is a drug that's been around forever, trade name Glucophage, or brand name.

The mechanism by which Metformin works is debated hotly.

But what I think is not debated is the immediate thing that metformin does, which is it inhibits complex 1 of the mitochondria.

So again, maybe just taking a step back, so the mitochondria, as everybody thinks of those, is the cellular engine for making ATP.

So the most efficient way that we make ATP is through oxidative phosphorylation, where we take either fatty acid pieces or a breakdown product of glucose once it's partially metabolized to pyruvate.

We put that into an electron transport chain, and we basically trade chemical energy for electrons that can then be used to make phosphates onto ADP.

So it's, you know, you think of everything you do eating is taking the chemical energy and food, taking the energy that's in those bonds, making electrical energy in the mitochondria, those electrons pump a gradient that allow you to make ATP.

To give a sense of how primal and important this is, if you block that process completely, you die.

So everybody's probably heard of cyanide, right?

Cyanide is something that is incredibly toxic even at the smallest doses.

Cyanide is a complete blocker of this process.

And if my memory serves me correctly, I think it blocks complex 4 of the mitochondria.

I don't know if you recall if it complex 3 or complex 4.

Justin Marchegiani I know a lot about toxins that impact the nervous system, but I don't know a lot about poison.

But if ever you want to have some fun, we can talk about all the dangerous stuff that animals make and insects make and how they kill you.

Yeah, like detrototoxin and all these things that block sodium channels.

I really geek out on this stuff because it allows me to talk about neuroscience, animals, and scary stuff.

So we could do that sometime for fun, maybe at the end if we have a few moments.

So something like cyanide that is a very potent inhibitor of this electron transport chain will kill you instantly.

People understand that, of course, a drop of cyanide and you would be dead literally instantaneously.

So metformin works at the first of those complexes.

I believe there are 4, if my memory serves correctly, 4 electron transport chain complexes.

But of course, it's not a complete inhibition of it.

It's just kind of a weak blocker of that.

So the net effect of that is that it changes the ratio of adenosine monophosphate to adenosine diphosphate.

What's less clear is why does that have a benefit in diabetics?

Because what it unambiguously does is Reduces the amount of glucose that the liver puts out so hepatic glucose output is 1 of the fundamental problems That's happening in type 2 diabetes.

You may recall I think we talked about this even on previous podcast You and I sitting here with normal blood sugar have about 5 grams of glucose in our total circulation.

Think about how quickly the brain will go through that within minutes.

So the only thing that keeps us alive is our liver's ability to titrate out glucose.

And if it puts out too much, for example, if the glucose level was consistently 2 teaspoons, you would have type 2 diabetes.

So the difference between being metabolically healthy and having profound type 2 diabetes is 1 teaspoon of glucose in your bloodstream.

So the ability of the liver to tamp down on high glucose output is important.

Is it fair to provide this overly simplified summary of the biochemistry, which is that when we eat, the food is broken down, but the breaking of bonds creates energy that then our cells can use in the form of ATP.

And the mitochondria are central to that process.

And that metformin is partially short-circuiting the energy production process.

And so even though we are eating, when we have metformin in our system, presumably there is going to be less net glucose.

We're chewing, we're digesting, but less of that is turned into blood sugar glucose.

I mean it's not it's not depriving you of ultimately storing that energy.

What it's doing is changing the way the body partitions fuel.

That's probably a better way to think about it to be a little bit more accurate.

So for example, like it's not depriving you of the calories that are in that glucose.

that's not- That was the Olestero approach.

Olestero folks, for those of you who don't remember, by the way, if you ever ate this stuff, you'd remember, because it was a fat that was not easily digested.

It had sort of analogous to plant fiber or something like that.

So it was being put into potato chips and whatnot.

And the idea was that people would simply excrete it.

And I don't know what happened, except that people got a lot of stomach aches.

The anal seepage is what really did that product.

Only a physician, because after all, Peter's a clinician, a physician, an MD, and I'm not, could find an appropriate term to describe.

When you have that much fat malabsorption, you start to have accidents.

It was either that or the diaper industry was going to really take off.

That's why you don't hear about a Lester.

It's considered a perfect first line agent for people with type 2 diabetes.

So again, what's happening when you have type 2 diabetes?

The primary insult probably occurs in the muscles.

Everybody hears that term, what does it mean?

Insulin is a peptide, it binds to a receptor on a cell.

So let's just talk about it through the lens of the muscle because the muscle is responsible for most glucose disposal.

High glucose is toxic, we have to put it away, and we want to put most of it into our muscles.

When insulin binds to the insulin receptor, tyrosine kinase is triggered inside.

So Just ignore all that, but a chemical reaction takes place inside the cell that leads to a phosphorylation, so ATP donates a phosphate group, and a transporter, just think of like a little tunnel, like a little straw, goes up through the level of the cell, and now glucose can freely flow in.

So I'm sure you've talked a lot about this with your audience.

Things that move against gradients need pumps to move them.

Glucose is moving with its gradient into the cell.

It doesn't need active transport, but it does need the transporter put there.

I mean, I certainly know active and passive transport as it relates to neurotransmitter and ion flow, But I'd never heard that when insulin binds to a cell that literally a little straw is placed into the membrane

The glucose doesn't need a pump to move it in Because there's much more glucose outside the cell than inside So it's just but the energy required is to move the straw up to the cell.

So what happens is, as, and Gerald Schulman at Yale did the best work on elucidating this, as the intramuscular fat increases, And by intramuscular, I mean intracellular fat.

Triacyl and diacylglycerides accumulate in a muscle cell.

And all of a sudden, I'm making these numbers up.

If you used to need 2 units of insulin to trigger the little transporter, now you need 3.

See all Huberman Lab transcripts on Applepodcasts

Journal Club with Dr. Peter Attia | Metformin for Longevity & The Power of Belief Effects