March 28, 2023

The Full Podcast:

So you did a podcast with david sinclair on your channel right before yeah a couple of years ago okay so it was a while ago now because i would be curious if anyone’s grilled them on the metformin study that just came out or like like in general did you talk to him about his metformin use because i know even before the study you weren’t like gung-ho on it to begin

With so like with your initial your initial kind of like perspective of the drug um if it has viability in any context would be you know just interesting for me to know personal interest and then above and beyond that this new data that came out that suggests it’s like heavily implicated in the birth defects in males males yeah so hypospadias yeah we can put a

Link or i can screen share i pulled some stuff up but yeah so i wasn’t a fan of metformin previously uh enable the screenshot yeah let’s see i’ll contextualize this so metformin is a great example like we talked about yes here’s a molecule somewhat derived from plants again there is a derivative of metformin in french lilacs okay um which is essentially a toxin

Like this is a plant defense chemical screen sugar should be on though okay cool the mechanism i’ll say this and then i’ll pull up the study that we were talking about with hypospadias so the mechanism of metformin is super interesting so people think that it’s a complex one inhibitor but it doesn’t inhibit complex one at physiologic concentrations it actually

Does this it’s like really deep biochemistry i did a podcast with uh petra dobermilski from hyperlipid talking about this on my show because i got really into biochemistry so it’s glycerophosphate dehydrogenase which is a part of the it’s a part it’s after glycolysis that regenerates nadh in the early steps of glycolysis like that’s what metformin appears to inhibit

And that’s part of the mechanism functionally what that means is that the good thing about metformin is it shuts down inappropriate gluconeogenesis at the level of the liver in people who are insulin resistant a lot of people think that diabetes is like you eat too much sugar your blood sugar goes high that’s not how it works at all you eat too much sugar and then

Your body is actually making sugar hyperglycemia and diabetes is inappropriate gluconeogenesis by the liver which is the formation of glucose de novo because the liver is insulin resistant so insulin all the studies i’ve seen suggest insulin is not necessarily anabolic it’s anti-catabolic so it stops the flow of like free fatty acids it stops catabolism so do

You think that downstream a lot of insulogenic cascades that lead to growth factor production are kind of very like pro-proliferative like for example gh downstream insulin presence is kind of like critical for the igf-1 for example and some of these growth factors that are you know very very i don’t know like satellite cell proliferative which could then lead to

Increased myonuclear donation which you could then hypothetically hypertrophy those donated myonuclei if you’re a bodybuilder so that’s where the idea of using like high carbohydrate intakes while staying as lean as possible ideally an insulin sensitive and then the implementation of like things to keep you insulin sensitive while you crush a ton of carbs while

Using like exogenous gh with the presence of those carbs drives up igf levels to like crazy amounts and you get like the most hyperplasia and hypertrophy possible so like those kind of cascades um like those don’t seem to be like anti-catabolic they seem to be like the most anabolic and like potentially like cancer driving as well like in that kind of vein do

You still see it as like an anti-catabolic hormone well i mean i think just if we’re talking about insulin action specifically like inherently what it does itself yeah yeah but like downstream yeah there’s a lot of potentially anabolic things okay yeah cool but there’s good studies that show that it’s like anti-catabolic and not necessarily anabolic per se but

Yeah i mean it certainly is part of these like downstream anabolic cascades but there’s so many interesting things in that and what you were just saying but anyway yeah this this idea that that insulin could be involved and that if the if the liver becomes insulin resistant and we can talk about what i think is driving insulin resistance it looks to be broken

Fat cells and this this sort of like impaired adipogenesis like i think insulin resistance most people would agree that insulin resistance aka metabolic dysfunction is starting in the fat cells and then we can talk about why you know like what is causing the fat cells to get broken but broken fat cells appear to be the root cause of metabolic dysfunction but one

Of the downstream effects of that at the level of the liver is well the liver isn’t responding to insulin and you get this gluconeogenesis going out of control and that’s why you get hyperglycemia in diabetes etc pre-diabetes and but metformin blocks that and it probably blocks it by glycerophosphate dehydrogenase which is really fascinating biochemistry and the

Regeneration of nadh in um in glycolysis but what we know is that when you’re in medical school you learn okay you can’t give metformin to somebody if their creatinines more than 1.4 because they’ll get lactic acidosis that’s not a good thing and then recently more and more stuff has come out about metformin and b12 deficiency so what’s going on there it doesn’t

Appear to be related to intrinsic factor but metformin can lead to b12 which is kind of an important b vitamin if you want to make dna and neurons and and not have horrible anemia and like potentially irreversible you know neurologic damage that’s important so we have to get diabetics b12 and watch their their b12 with metformin so it has these bad side effects

Right in some people who who will not make lifestyle change metformin is a life-saving drug and the side effects are worth the risks but this is medicine and in medicine we are pretty good at saying okay watch out for lactic acidosis watch out for b12 and we’ve also known i think the study what about the changes in the microbiome as a result of metformin do you

Think that’s just like a consequence of what it’s doing interaction-wise and that’s ultimately what a downstream outcome is but that’s not like a primary reason why it’s like effective it’s it’s so hard i mean the microbiome is such a black box man yeah do you remember that like what was that big lawsuit um where that lady claimed to make this like magic black

Box and you could put your blood in and it would show oh yeah or whatever they’re there yeah like dude the microbiome is the microbiome is such a black box sorry it’s such a black box um when people say like oh this changes the microbiome and it’s good or bad i’m like i have no idea what that means for the microbiome i can tell like your microbiome changes right

But is it good is it bad who knows dude and and there’s so many different nodes and connections and niches for niches for different organisms in the microbiome it’s crazy so i don’t think we understand the microbiome well enough to clearly say like yes no like these are good microbiome changes bad microbiome changes in general and um yeah so that’s a tough tough

Thing um but i mean look at this study if we’re talking about testosterone so this is 2021 february 20 february 3rd but i mean this is one small study 70 individuals metformin dropping testosterone individuals with newly diagnosed type 2 diabetes so that’s interesting do you hold basic attention token uh what is that it’s the the cryptocurrency that is run through

The brave browser i was just wondering i saw i saw the symbol on your top right section oh no no i’m just using a brave browser oh gotcha okay all right sorry about that i just noticed so um so what they did in this study was they normalized uh their glycemia with insulin for five days so they say 70 men they gave them insulin pump therapy for five days to achieve

Glucose normalization and then they were randomized to either control which is insulin only or metformin for one month and testosterone was measured at baseline randomization one month after treatment and you can see here that when you normalize the testosterone it when you normalize the glycemia testosterone goes up but then you give the metformin and it like kind

Of drops the testosterone significantly in all of the measures with metformin so the reason it went up is because you normalize the glycemia with insulin so nobody’s done a study where they just give metformin to see what the net effect on the testosterone is but this is interesting is there some sort of a an endocrine disruptive effect to this molecule again what

Are the side effects of this molecule there’s definitely a benefit to metformin but we can’t this is the i think the philosophical error that so many people make we can’t just assume that a drug is all good that a plant molecule is all good what’s going on here and now we have this is the science article talking about the study in the animals of internal medicine um

I can’t get past the paywall to see the study i know sci hub failed me yeah you know so you read you read this article and basically they summarize it there’s significantly increased rates of hypospadias which is where the urethra goes to the bottom of the penis rather than out the end of the penis in men taking metformin and they controlled for a lot of different

Things it’s an observational study it’s not an rct but they controlled for a lot of different parts of this saying like okay could it have been something else could have been their diabetes could have been another drug they’re taking and no it really looks like metformin is associated causation is not correlation is not causation but it’s pretty significant now

You know the the absolute risk reduction or the absolute risk increase in this is pretty low but metformin is 86 million people prescriptions so they say here um it’s only affecting the males who were taking metformin while the sperm was being made i found online 64 days for fro spermatogonia production they say 90 days before conception so you can imagine like

If somebody took the metformin not 90 days before conception that’s okay but if you’re making sperm that’s a little bit disrupted because this is some sort of a hormonal disruptor they’re saying significantly increase ra odds of um of genital defects which is a big deal is one of those things i’ve always wondered about as individuals who are using pharmaceuticals

And like epigenetic changes you could pass on to to your children and if it would be like prudent and almost responsible to be coming off of all pharmaceuticals in like the time frame where you have like full sperm production maturation development and impregnation and then making sure your wife is you know doing the proper things as well because like even

For me like i use a five alpha reductase inhibitor for hair loss but i’m aware of the fact that five alpha reductase inhibition and like a pre-pubescent child can lead to like a literal like micro penis i’m not saying that there’s any evidence to suggest that it’s going to pass on to my kid but like i’m worried about it so like i don’t know like coming off of

All medications i guess it’s not a viable strategy for a lot of people that have a necessity clinically but then it kind of like reveals the underlying need for them to probably just fix all their natural stuff to even be in a position to potentially come off the medications to begin with i mean i i think i think do the simple things first do your diet you

Know nutrient-rich diet toxin free diet as much as possible that’s why i’m a fan of organs get organs however you can you know optimize everything but i think it’s reasonable especially for males 90 days before you want to conceive like think about your supplements think about medications you’re on definitely if it’s metformin and let’s just be clear here like

Diabetes is very treatable it’s fixable without medications like we know that this is not controversial like if we could find a way to incept these people and say hey you’re going to wake up and be like i want to make lifestyle changes i’m going to get walking i’m going to get in the sun i’m going to change my diet i’m going to stop eating junk food and get rid of

Coca-cola if if you believe what i believe they get rid of seed oils if you believe what i believe they could eat more red meat more organs more nutrient-rich foods we’re going to fix diabetes like this is fixable and we’re giving people meds and not necessarily within mainstream western medicine saying like hey this is a fixable disease do you want to take meds

Or do you want to do lifestyle somebody says hey i want to take meds great but that’s one of the things i hope to be able to affect in my lifetime is the paradigm that we use now i know this isn’t going to be applicable for the majority of people but like extreme outliers with genetic predispositions like type 1 diabetes or familial hypercholesterolemia and these

Individuals who are put on certain medications to manage things that their genetics have essentially or i don’t know some autoimmune thing that happened when they were like a baby or like however the stuff manifests itself those kind of people are kind of like need to be on medications to prevent certain things from happening so like when they’re about to have a

Kid is there like some sort of i don’t know like what do they need to be mindful of do you think they just go like bite the bullet and stay on their stuff like i know that’s not maybe not a question you should be you need to answer but i don’t know it’s just an interesting paradigm everyone is so individual right like i mean a type 1 diabetic is not going to be on

Metformin they’re going to be on insulin they’re completely different things they don’t get like enhanced glucose control with metformin above and beyond like where they can lower their insulin dose though it’s pretty rare i mean i i haven’t you know worked a lot of diabetics maybe they’re incorporating it but i you know type 1 diabetics at least in the beginning

Are not insulin resistant so that’s the mechanism of it foreign they’re not getting inappropriate gluconeogenesis they’re not secreting any insulin because the pancreas is attacked by here we are back to autoimmune disease and i’ll say this which is quite interesting there are case studies these are small case studies of young kids doing dietary interventions

Specifically a carnivore diet there’s a group in hungary that’s a pretty intense group and pretty strict but they’ve published case reports of reversing type one diabetes and a 9 year old kid and i think a 10 year old kid when they caught it early and they did this elimination diet granted many people would see a carnivore diet is pretty intense but it argues

Like is there an autoimmune component to some cases of type 1 diabetes that could be affected positively by changing diet this is why it’s important to ask these questions i would speculate probably like i like that’s just my you know layman’s perspective but like i would think things like you know hashimoto’s thyroiditis if you get in front of it before it’s

Like totally destroyed like you can obviously retain function but if you just let it disintegrate itself through like autoimmune attack over years and years like eventually the organ can only withstand so much like damage to a point that it’s like non-functional presumably so if you’re a type one diet or going to be a type one diabetic like it’s at least one of my

Friends who’s a type one diabetic it didn’t happen he didn’t notice it until he was like in his teens so like presumably when you’re a kid like actually i don’t know maybe that’s wrong i would have to revisit the situation to actually ask them the context but presumably this is like a progressive thing that’s happening something internally is like i don’t know

Attacking your pancreas presumably unless your immune system yeah and then at some point you you know i don’t know destroy enough beta cells that you no longer have any function but if you got in front of it then maybe you could have prevented it happening in the first place seems reasonable right and then the question becomes what is triggering the autoimmunity

That’s why i got interested in carnivore all right and so the hypothesis which many people would disagree with but i think is fascinating that i’ve kind of been captivated by for the past few years is are some of these plant chemicals triggering autoimmunity in some people who knows but we asked the question

Transcribed from video
Paul Saladino On The New Controversial Metformin Study And Diabetes By More Plates More Dates