Paleo Diet, Inflammation and Metformin

I wish life were simple. I guess it is in a way, you live, you die.


But the pesky “in-between” parts, the details can be decidedly non-simple. Heck, they might even be complex! The paleo diet, or more accurately the paleo template, which includes thinking about sleep, lifestyle, photoperiod and socialization, is simple on the surface:

Food: Fish, fowl, meat, roots, tubers, fruits, veggies, and “good fats.”

Sleep: A lot. In the dark. Repeat.

Socialization: Have a solid support network. Don’t Go Ted Kaczynski on us.

Photoperiod: Get up with the chickens, go to bed with the same.

See, simple! Well, until folks want to know how many carbs they need (it depends) if fruit is good or bad (again, it kinda depends) what constitutes “good fats.” These details can get murky, but it’s not that hard to navigate folks through the Paleo Template to help them dial things in for best effect. With that in mind, if you need extra help dialing things in, check out Chris Kresser’s Personal Paleo Code. Be your issue autoimmunity, fat loss or you just want a little hand holding, that program has the goods.

With the infomercial out of the way, we can get down to the things I really want to talk about in this installment: the paleo diet, inflammation and the drug metformin. This will be at once simple, as I’m going to present what I suspect is the root cause of a host of issues related to inflammation, insulin resistance, cancer, autoimmunity and neurodegeneration; namely intestinal permeability (leaky gut in the hippy circles). This is simple in that we may have a common mechanism that underlies all of these conditions. It is complex in that we have a myriad of ways to induce permeable gut and once that happens the ensuing metabolic and immunologic cascades can be tough to keep track of. If you asked me 10 years ago “What’s the cause of all these issues like cancer, diabetes and neurodegeneration?” I’d have hung things squarely on carbohydrates and insulin. But I’ve got to modify things a little: Carbs and insulin are certainly factors, but not in the way we have classically viewed them. With proper vitamin D levels, activity, and in the absence of gut irritating proteins* carbohydrates as a food class may not be damnable. BUT! And please take fracking note of this: if you have a systemic inflammatory condition (most modern folks do), a low-carb paleo diet is likely the best thing you could possibly do to dial down the fires within and get on the road to healing. Folks want to make the world an overly simplistic good/bad, right/wrong false dichotomy. I’ve done it; please do not repeat my mistakes. With that in mind please ALSO hang a sign on this permeable gut story that reads something like “good until further notice.”  Sometimes we need to be willing to burn the house down when new information presents itself. In this case I think we can say that we are adding a wing to the house. The “Insulin Hypothesis” is valid in that it is an effective treatment for a remarkable number of ills. It is weak as a mechanism of causation in many ways.

If you are not familiar with what the paleo diet is and is not, check out this piece I did. Check out other folk’s thoughts on this topic too. Learn, experiment and compare idea. Oh yea, learn to use google too, nifty little tool. I suspect it will catch on…

Now, let’s talk about what inflammation is then I’ll tie in the drug Metformin. Although it’s a “pharmaceutical” it works quite well for type 2 diabetics and I figured out a reason why beyond the simple label information of improving insulin sensitivity.

2012: An Inflammation Odyssey

This needs to be a 30,00ft treatment for inflammation (I know, bummer!) I’m not an immunologist and we really would have only 6 listeners/readers if I went full nut-case on this. But inflammation is important in a lot of things, both “good” and “bad.” Most folks would provide White Hats to things like inflammation related to adaptation to exercise and longevity (yes, you need inflammation and oxidative stress to age effectively), while Black Hats would go to things like cancer, neurodegeneration, insulin resistance and sepsis. Let’s take a look at an overview of the immune system to get a sense of some of the players.


On the left side of this graphic we have cells that make up the innate immune system. They are the first responders to things like exercise induced trauma, infection and exposure to toxicants. I would also put LDL cholesterol in that innate immune system category. That will make sense when we talk about sepsis and lipopolysacharide (LPS) in just a bit. On the right side of the graphic we see elements of the adaptive immune system which is responsible for making antibodies to both foreign invaders (good) and in the case of autoimmunity, our bodies own proteins (bad). What is not represented in the graphic is a dizzying array of cellular communications players including interleukins, prostaglandins, tumor necrosis factor etc. These chemical messengers largely determine whether or not the immune system is on high alert or cruising along peacefully. As an analogy, let’s think about the full immune system like a civil defense force in that if one section of the defense force is on alert or active, ALL elements are on higher alert. This is why we see improvements in allergies on an autoimmune protocol.

Now, it’s well understood that inflammation is elevated in hyperinsulinemia and that this represents a nasty feed forward mechanism. If insulin is high, inflammation increases, insulin sensitivity worsens. In the Zone books insulin is pro-inflammatory in that insulin affects the output of the Delta-5 desaturase pathways in a pro-inflammatory manner. This is certainly true under chronic hyperinsulinemia, but it begs a question: Is the high insulin the CAUSE or an effect? Is high insulin always bad? Interestingly, in acute sepsis, insulin represents a potent, in fact lifesaving ANTI-inflammatory. The poison is in the dose and as with many things, Framework Matters.

Let’s look at a few things we suspect play a role in insulin resistance/hyperinsulinemia:

1-Carbohydrate load


2-Lack of exercise

3-Vitamin D- deficiency

4-Sleep dept


6-Sepsis (infection)

If we time order these issues we see that carbohydrate load, vitamin d deficiency and sedentism may take months or years to manifest as overt hyperinsulinism. If fructose intake is high that time may be dramatically shortened, while sleep dept and stress seem to manifest insulin resistance quite quickly (only a few days.) But sepsis is unique in this list in that it can induce insulin resistance in mere minutes and to such a degree that one could die from metabolic cascades which look eerily similar to type 2 diabetes. Here are two slides from my Paleo Solution Seminar that deal with that paper:


Here is a summary slide of what happens in sepsis (and type 2 diabetes) with regards to metabolic derangement:



High blood glucose, high circulating free fatty acids (FFA’s), glucose spilling out of the liver due to both gluconeogenesis (conversion of amino acids to glucose) and glycogenolysis (release of stored hepatic glycogen).

Now, it’s perhaps worthwhile to back-up and define what sepsis IS. For our purposes its an infection or a situation in which bacterial products (LPS) end up in contact with the blood stream and by extension, the immune system. A great question at this point would be: “How do we get bacteria into our blood stream on a day to day basis?” The answer to that is intestinal permeability. Our gut is full of bacteria, some beneficial, some not, but when we get a dose of LPS (the outer membrane material of some bacteria) our immune system goes into the metabolic cascade described above. Interestingly, one of the first lines of defense against the effects of LPS is actually LDL/HDL cholesterol, which binds to LPS and helps to remove it from circulation. Hence the inclusion of LDL/HDL cholesterol as part of innate immunity. While I was writing this piece I received an email from a chap who nearly died from a septic event. Here are his pre and post sepsis cholesterol numbers:

Been following a strict paleo diet for several years now.  Cholesterol numbers from May 2011:
Total – 226
HDL – 58
TG – 60

Cholesterol while hospitalized, Jan 2012:
Total – 98
HDL – 15
TG – 97

That after HDL is REALLY low and very dangerous. Undergo a septic event with low cholesterol levels and you are likely going to die. As a bonus question that folks can tackle in the comments: What would the effects of LOW GRADE CHRONIC sepsis be on cholesterol levels?

Here is an interesting observation: All of the issues I listed above (sleep debt, fructose etc) have direct impact on immune function and intestinal barrier function. Miss a night of sleep? You experience compromised immunity and an increase in LPS entering the blood stream. Vitamin d is a potent immune modulator, fructose is kinda nasty with regards to endotoxemia.

So, in my book, this gut permeability/endotoxemia/sepsis story lays the foundation for not only metabolic derangement, but also autoimmunity, as Fasaono’s work alludes with celiac disease. Where once intestinal permeability or “leaky gut” was a career death sentence, it is now one of the hottest areas of immunology and clearly an important player in everything from diabetes, to cancer to autoimmunity. So, now that we’ve talked about inflammation, let’s talk drugs, in this case metformin.

Drugs, drugs, drugs!

Metformin was first synthesized in the 1920’s but has gained in popularity since the 1980’s as “the” drug of choice in treating insulin resistant type 2 diabetes. For many, many years the Standard of Care for most GP’s was to administer INSULIN to insulin resistant, type 2 diabetics. You can still find a few MDinosaurs who employ this approach. It’s damn effective at preventing too large a patient load as people die rather quickly due to loss of limbs, infection and the associated end stage buffet that characterizes poorly managed type 2 diabetes. My father was one of these folks and although his compliance sucked (ironic given my background) he did remarkably better after attending a session with a Diabetes Nurse Counselor who recommended he shift to Glucophage (metformin) in lieu of his insulin injections. I offer this up to the folks who bow at the altar of standard of care. Just because it’s common does not mean it’s best or smart. Metformin is one of those rare “good” drugs that seem to provide significant benefit and at relatively little risk and cost. The reason why metformin works so well is it addresses several metabolic issues simultaneously. It blocks the overproduction of glucose from the liver, improves glucose disposal at the muscles (by improving GLUT 4 phosphorylation…slick!) and it improves fatty acid utilization. If you recall from above, that’s a bunch of what goes wrong in sepsis and since I’m arguing that sepsis is a player in insulin resistant diabetes, it’s important there too. So, the other day I was thinking about all this stuff and marveling at what a good little drug metformin is for addressing the issues associated with insulin resistance and it occurred to me: I bet metformin has protective effects on the liver with regards to LPS toxicity. This is what makes LPS so nasty once it initiates metabolic derangement. Lo-and-behold, the literature is thick with examples of metformin’s role in preventing LPS/endotoxemia induced injury:

Metformin has interesting pharmacokinetics in that it is water soluble, yet readily passes through the intestinal epithelium with the aid of transport proteins. I’ve been looking to see if metformin has effects on the tight junctions of epithelial cells (Tight junctions keep cells…well, TIGHT! Loss of tight junctions is part of what happens in celiac disease) And I’ve found material indicating action on kidney and liver epithelial cells, not much with regards to intestinal epithelial cells other than the transport mechanism. It’s an interesting direction that I’ll keep tinkering with and will keep y’all posted if I find anything else of interest.

What does it all MEAN!?

I’m not sure what this means. Yet. I shot this around to several folks in the research circles I keep and they found it pretty interesting. What I’m taking away is the connection between LPS/endotoxemia/metabolic derangement is big. It describes things on both an acute and chronic level, fits with some theories of adaptations to chronic infections (I’ll talk about those soon) and seems to provide a wider, more defensible base than the Insulin Hypothesis. If I have mechanisms that can induce metabolic derangement in a day (sleep deprivation) or minutes (sepsis/endotoxemia) it’s hard to hang the whole story on carbs. But if we live in a world of wacky photoperiods, low activity, chronic stress and inflammation, a low carb paleo diet might just be the ticket. So, please hang on to both baby and bathwater. THINK!

It’s funny, when I was in Seattle a good friend of mine who worked in the Department of Pathobiology said to me “You know, this diabetes epidemic and modern disease will all boil down to some kind of infection or immune response…it’s not going to be carbs, fat or protein.” This was in…oh, 2000. I poo-poo’d the notion and marched along as I saw such amazing improvements in folks with a low-carb paleo diet intervention. For many situations that is indeed the cure (simple) but the cause and how to articulate these nuances to the masses has proven to be decidedly complex.

†-In fact I do not literally mean “go sleep with the chickens.” They are noisy, dirty little avians. This is merely a light hearted attempt to make a point about the benefits of getting up early, going to bed late and generally tracking the rythmicity of the days and nights. Quite a number of folks seem to hang in the wings these days looking to pick-apart any non sequitur.  To such a degree in fact that I feel compelled to include exculpatory clauses like this one, which is oddly reminiscent of the warnings on plastic bags, reminding users that the bag is a “suffocation hazard.”

*See Dr. Mat Lalonde’s upcoming talk at the AHS 2012 for more details on what constituents in Neolithic foods are and are not bedeviling us.



Categories: Anti inflammatory diet, Paleo/Low Carb


Robb Wolf’s 30 Day Paleo Transformation

Have you heard about the Paleo diet and were curious about how to get started? Or maybe you’ve been trying Paleo for a while but have questions or aren’t sure what the right exercise program is for you? Or maybe you just want a 30-day meal plan and shopping list to make things easier? Then Robb Wolf’s 30 Day Paleo Transformation is for you.


      • LibertarianJRT says

        It’s your blog. Write what makes you happy. Obviously pointing out the FUBAR SNAFU that is the current incarnation of the GOP has value to you. You keep the juicy stuff under wraps by and large. You shouldn’t be too discouraged from letting the pressure valve release a little pent up frustration every now and then. Stress release is encouraged for good health. Your off topic “Libertarian leaning” commentary is exactly why I listen to your Podcasts.

        • says

          HA! Thanks man, i do have otehr folks workign here to consider so I’m going to shift some of this into a political blog. Then I can have the illusion I’m making a difference, and not fubar the sitch here for folks to work.

          • says

            Hi Robb, I am a (paleo)MD here in Italy and a libertarian (I am a Ron Paul fan). I love to hear you also are a libertarian…

          • says

            Ciao Andrea! Thank you!Well, not everyone is excited about no war, deficits, hyperinflation and expanded freedom. I’m not sure why not, but they are not.

      • Kris says

        Don’t apologize for your beliefs, Robb. People who dont like the whole You can start their own blogs.

        • says

          Thanks Kris. I do need to consider the other folks associated with the blog. Several folks make their living via the site now and I want to be mindful of that. BUT…I do feel compelled to try to avert the financial catastrophe we are heading towards, one which neither the left leaning liberals nor right leaning religious “conservatives” seem to grasp. So, I might need to start a separate blog to get those ideas out and not muddy the waters here.

          • paleoslayer says

            Presidential candidate Dr. Ron Paul spoke on Health Freedom and the Constitutional rights of Americans to buy and sell natural food, like raw milk, which hasn’t been tainted with chemicals, hormones, or cooked until completely void of nutrients.

            Ron Paul represents the polar opposite of nearly every politician in control of legislation today. Most politicians accept legal bribes (called lobbying) from the big pharmaceutical companies that lead the proliferation of prescription drugs in America, the third leading cause of death. Not only has Ron Paul introduced legislation to repeal the FDA’s prohibition of interstate sales of raw milk, he consistently reminds everyone that Government should not have control over our food choices.

            The loudest applause came when Ron Paul spoke about the regulations on raw milk sales. He explained how the FDA does not “take care of us” but rather interferes with our choices by collaborating with special interests. It’s the drug and insurance companies that keep a stranglehold on the American chronic care management system, which doesn’t cure anything, but rather treats symptoms with dangerous pharmaceuticals.

            How can someone following a paleo lifestyle NOT agree w this?

      • Grafton Prewet SPT says


        I read your book in 2010, and saw Ron Paul speak on the Chico State campus in 2011. I’ve been a Paleolibertarian ever since!

        I’ve heard you mention this paleo/libertarian connection several times, and I’m as interested in it as you are.

        Lots of folks take shortcuts and listen to the culturally appointed “experts”, but paleolibertarians seem to be more independently minded. They have the motivation to question authority and build their own philosophies to act as a compass for their own lives.

        I also love how you said it on Joe Rogan when he asked you why there seems to be such a connection between libertarianism and the paleo community. I don’t want to misquote you, but if I remember correctly, it went something like, “I think its cuz they’re smart.” Classic.

        There’s a good, evidence based book called “Influence: The Psychology of Persuasion” why some people take shortcuts to decision making, and some people don’t. Here’s an overview.

        I’m a big fan of what you are doing trying to put together with a paleo-based community of healthcare professionals. As a student of physical therapy I’d love to get on board.

        Why am I a paleolibertarian? Cuz my brain works gooder! Duh.

        I liked the post btw.


  1. gygez says

    Great post Robb.
    Would there be a significant increase in TC and HDL levels during a low grade infection?
    For the past ten years I have been trying to figure out what has been causing intermittent bouts of fatigue and muscle fasciculations. Doctors tend to throw up their hands and send me away. As a general rule these episodes start with an infection(sinus) and a course of antibiotics. The muscular symptoms persist for a couple of weeks to months after the infection symptoms are gone. Lately I have been wondering about antibiotic use, intestinal permeability and LPS.
    Could LPS be causing neurological problems?
    I should also mention I have had gut problems since I was young and contracted E. coli O157:H7.
    Iv’e been eating a paleo diet per your recommendations for over two years. I am having still having trouble with fat loss.
    Blood work from last Dec. ’11 TC 336 TRI 57 HDL 129.
    I’m 27 5’11 176lbs athlete when I don’t feel like crap.
    Could antibiotics be causing a leaky gut on top of an ongoing sinus infection, allowing for the trans-location of LPS into the blood stream which in turn affects neurological function?
    I could go into more detail but I wanted to try and keep it short.
    Any thoughts would be appreciated.
    Thanks, keep up the great work.

    • says

      My husband gets sinus infections following a cold.

      He has found BlisK12 remarkably effective. He uses the BlisK12 Fresh Breath Kit. This is the best one to use. It has a powerful antibiotic mouthwash. Follow this up by sucking on the probiotic lozenges.

      They clear his sinus infection in a day or two. I guess the bacteria track back up to the paranasal sinuses. They probiotic bacteria crowd out the nasties and have an anti-viral effect as well.

      Try nz online pharmacy Blis K12 fresh breath kit

      (free delivery world wide)

  2. Melissa says

    This could also prove a connection between adhd and leaky gut. People with adhd tend to have very low cholesterol which might indicate chronic sepsis. Probably applies to other ‘neurological’ conditions too.

  3. Devon says

    Thanks for posting. I appreciate you addressing Metformin. As someone with PCOS and resistance to weight despite NO measurable insulin resistance I have taken Metformin. I immediately slimmed down to a good weight for me (okay, an awesome weight. . . I never felt so sexy in my life—again, despite NO measurable insulin resistance- I had very stable blood sugars and a LOW amount of insulin). Unfortunately, once I started low carbing, metformin became intolerable (vomiting a couple hours after I took it). Another lesson I learned the hard way is that you become uninsurable for 7 years because “you have diabetes” (insurance companies don’t understand) after having used a diabetes drug for an offlabel use. I’m also curious from a paleo perspective how much of a concern b12 is in the face met. Nonetheless, it was a wonder drug for me when it came to moving off weight loss, and in a way that no expected to have an effect (the doctor specifically said it wouldn’t do anything for me since I wasn’t insulin resistant). I suspect that it works in ways we don’t yet understand. Perhaps I’m silly to continue looking for a “natural” (read: insurance doesn’t give a sh&t) metformin, but until insurance companies understand offlabel uses I think I’ll have to stay away.
    Thanks for the information Robb!

      • Devon says

        Thanks Barb. I’ve been reticent to try it, based on somewhat credible, apparently well-reasoned information I’ve found (see below). Perhaps you recommend it based on a different perspective/information. Nonetheless, I’m not sure that further working on insulin sensitivity will be helpful as I have no indication of a lack of sensitivity. (Blood sugars never get above 120, in fact rarely above 105, and that’s all with a LOW fasting insulin (insulin resistance means it takes a lot of insulin to make your blood sugars normal), suggesting that sensitivity here isn’t my problem, even though that is a a very common problem for PCOSers. I am beginning to suspect leptin resistance may be among the culprits, but I’m not exactly sure how to proceed. . . I don’t understand the reasoning behind Kruse’s leptin reset or how one can evaluate if it actually is working (nor does it seem significantly different than what I already do minus morning protein gluttony). Any advice/insight welcome.

        See below for some vanadyl sulfate information:

        Vanadium: (Bis-Glycinato Oxovanadium Complex, BGOV, Vanadyl Sulfate)

        Vanadyl Sulfate is a more common and available form of Vanadium than BGOV. There appears to be no safe and effective dose of Vanadyl Sulfate. Doses shown in studies to be effective for insulin resistance and glucose tolerance are all 100mg or more. Yet, there is concern that 10mg may cause kidney toxicity. I could not find dose information for BGOV, but it is thought to be less toxic.

        At any rate, Vanadium supplements may not be very effective in patients with PCOS who are not yet diabetic. In one study, oral vanadyl sulfate improved insulin sensitivity in NIDDM but not in obese non-diabetic subjects.

    • Deanna says

      Hi Devon,

      As someone who has been diagnosed with PCOS for several years, and has been on Metformin for ALL of them AND IS INSURED – here is what worked for me with insurance companies. I went through an insurance broker (that may have helped) and had him attached an explanation with my app about my Metformin use being given to treat PCOS and that I wasn NOT a diabetic. I have never been without health insurance. Hope it works for you!

  4. Jaime says

    I have been interested in metformin for a while and was excited to see this post. I am one of the success stories…used to be on metformin for PCOS pre-paleo, and when I began eating low-carb paleo with some ALA, biotin, and chromium thrown in, my insulin levels and high CRP became optimal within months. Metformin has many useful applications, and if it did help heal intestinal permeability, that would be an awesome discovery. Despite the drug’s prevalance and many uses, I haven’t met a person with cancer yet who knows about metformin, nor a ketogenic diet for that matter, or whose doctor suggested it to improve insulin sensitivity and decrease the rate of tumor growth. If in that setting, it still hasn’t been widely accepted, how would it be embraced for use with permeability issues when most doctors don’t even accept that “leaky gut” exists? Maybe the bottom line should be emphasized, which is, low-carb paleo increases insulin sensitivity and improves gut permeability, thus putting you at better odds during an illness. With that approach, there are none of the folate and B12 issues with Metformin and no issues getting an Rx from a doctor. That is unless there’s something Metformin accomplishes that a low-carb paleo diet (maybe with supplementation for the permeability) cannot, and if that’s what you are saying, Robb, could you clarify?

    • says

      I think metformin could be great to get things rolling, but low carb paleo does all the good, without any of the bad (for the long haul). Looks like I’ll be speaking with Gary Taubes, Peter Attia and some other folks at a wing ding in Reno regarding low-carb and cancer. Should be good, I believe the video will be freely available.

      • says

        At my last visit to my Endo (a brilliant man, BTW!) he mentioned that FINALLY there are going to be trials with cancer and metformin. Specifically for those that have quit smoking.
        The idea is that the metformin can also inhibit the growth of a cancerous tumour is inhibited because of the reduction in horomones that stimulate growth. (Including insulin.)
        Unfotunately the drug is so cheap that one can understand all the foot-dragging on conducting a clinical trial…

        • says

          I am taking metformin as part of a clinical trial. I have recently finished treatments for breast cancer and have been on metformin for a year. I am starting the paleo diet tomorrow, so I wanted to research whether or not it’s safe with the metformin. I am happy to read anyone’s comments!

  5. Phil Bear says

    Excellent post – my eyes only glazed over a couple of times, forcing me to back up and reread slowly.

    Love the note at the end.
    Warning: this bag of peanuts may contain peanuts.

  6. Björn S says

    Great article :)

    I may have overlooked it but I couldn’t find why is post-sepsis cholesterol so low? Is it used up by the immune system?

  7. Garry says

    Great stuff! But be honest: you had to spell check ‘Kaczynski’, didn’t you? 😉

    Years from now, the role of the gut (especially a leaky one) in health and disease will be much clearer, and we’ll look back and say ‘Damn, we didn’t know Jack back then’. This is important work, so please keep writing about it.

  8. Stephanie says

    I saw a talk recently by Ken Struhl of the Harvard school of medicine where he was looking at cancer and cancer stem cells and did some testing with metformin. I believe he found that metformin was effective at killing the cancer stem cells. I think this had something to do with it affecting some inflammatory pathway. Anyways, not sure if he’s published this stuff yet but may be worth looking into. Everything is related it seems.

    • metformin is poison says

      Yep! Medicare is a bread winner for Bristol Myers Squibb!
      This is going to be the natural selection for baby boomers. Harvard grads are well known to be bought off.
      Have fun with Metformin, I’m sure it’s a more fun diet drug than chemo!

  9. Luke Terry says

    Interesting post.

    I can see clearly the case for clinical benefit with metformin. However, having done a tour of duty as a nutritionist in an MD/endocrinologist’s office, I saw a lot of the side effects that Jaime describes above, often when metformin was stacked with avandia or other diabetes drugs. So was it the metformin, or was it interaction with other compounds? Drug interactions follow a logarithmic progression as more drugs are introduced, so I’ll bet it was the interactions, but still.

    Worthy of note, metformin’s a very old drug (1922), and as such it hails from the era where most drugs came from plants. Metformin is no exception, it was culled and cultivated chemically from the diverse array of biomolecules found in galegae officinalis, the stinky, pungent herb known as goat’s rue. Goat’s rue has a long history of being used for similar purposes. The problem is, no pharmaceutical can make a billion dollars on goat’s rue, so no one studies it.

    Of even greater promise is the ayurvedic herb, gymnema sylvestre, also known as the ‘sugar destroyer.’ It has compared well against metformin in small clinical trials, even offering better results in changing body composition for the better than metformin, and also far fewer occurences of the side effects Jaime described above.

    The bottom line: there are few instances where synthetic chemists can outperform millions of years of plant evolution in the production of safe, effective therapeutic agents. Metformin, while still pretty darn good as far as drugs go, is still likely not as good as several naturally occurring substances from the plant world.

  10. gygez says

    Do you know of any blood-work which test specifically for LPS toxicity?
    Or what the next best indicator might be.
    With the help of a naturopath, I am hoping to get to the bottom of this very soon.
    Thanks for the reply earlier.

  11. Joe says

    “Friends, sepsis is a bigger cluster phøk than the Republican Party front runners, and that is saying something.”

    Yeah, that’s smart, Robb. Piss off roughly half your audience. How that helps the Paleo movement I DO NOT KNOW.


    • steve says

      Whew, thx for the quote. I was starting to go crazy rereading the post looking for the political commentary… that I wasn’t finding. And regardless about how you feel about reading it here, it is kinda true. The resultant buyers remorse with each lead change the past 6-9 months really shows how confused the base is.
      Consequently, I credit my libertarian transformation (from GOP) to my exposure to crossfit/paleo. Something about that bucking conventional “wisdom” and critical thinking thing that just makes you start seeing crap as crap. It’s all kinda interwoven to me…

      • Joe says

        I’m a classical (emphasis on “classical”) liberal (I know, close, but no cigar), but it’s nice to not have to grapple with politics on a health blog. There’s few places left where one can hide from politics these days.

        Anyway, thanks again.

        • says

          You bet. i do feel compelled to start a political blog where I can try (vainly I suspect) to push the Classical Liberal agenda. Maybe I can rope you over to that when it’s rolling.

          • Joe says

            Count me in, Robb. It’s not that I don’t enjoy political discussion, it’s that I don’t enjoy it on a health & fitness blog.

            I don’t think most people even know what classical liberalism is. The word “liberal” has been so corrupted of late.

            So, if you’re serious about the new blog, consider me “roped.”

          • says

            Right on Joe! It is wacky…almost Orwellian NewSpeak how Liberal was co-opted and completely changed from the original meaning.

          • Ronin says


            I gotta disagree with the idea that your life-philosophy/politics have no place here on YOUR blog because it might annoy some segment of your readership.

            Last time I checked this site and your podcast were free (and thank you very much).

            You provide what you wish to provide, and I give it my time and attention. You have a self directed mission of evangelizing (sorry for the term) for the health and happiness of millions of folks you don’t know and will never meet. If part of the “payment” you receive is the chance to parlay a bit of your cache’ to advocate your point of view on any subject you deem fit, rock on!

            You want to get your points across in a new blog, how do you think your readership will compare? Your diverse captured audience wont be there, just the choir.

            I think Joe is completely out of line on this. If the vito litmus test your blog is offending your readers, then stop the endless Crossfit bashing. HQ may well be dorked up beyond all belief, but there are thousands of really good folks who are trying to do right by their clients and also have a Crossfit sign on their door.

            But I hope you don’t. It’s funny, and hopefully inspires Box owners to maybe take a hard look at programming and the other issues you often raise.

            Good on you and thanks for your good work.

          • Butte Bill says

            When asked about politics I reply that my mom had a political blog for four years during which time she wrote nothing. “If you can’t say anything nice…”

  12. Gail says

    I was on Metformin for Type 2 Diabetes and hated it. I had horrible symptoms of low blood sugar while maintaining blood glucose levels that averaged 180. The better I ate, the worse I felt. I dropped the Metformin and cholesterol meds, continued to exercise, and switched to a low-carb, more or less Paleo diet (no HFCS, wheat, but some rice, dairy). My blood sugar is steadily drifting downward (30-40 lower) even as I eat slightly more carbs. I expect the trend to continue or accelerate now that I am settling in to my new life-style and eating style. The improvement happened in spite of experimenting with diet, travel, holidays, and illness. Beginning A1C: 9.6. On Metformin: 8.0. Going moderately Paleo; 7.0 (so far).
    I still have elevated blood sugar in the morning. I would guess that is related to liver issues. But Metformin didn’t help. But it is going down with the diet change.
    After not eating wheat, I now find that I react very badly to it. My experience would support the idea that gut permeability is the real cause of my problems.
    If only I had ignored my mother and not eaten a healthy low-fat diet for the last 40+ years.

  13. Salima says

    Hi Robb—thanks for this post! I have a burning question about Metformin that none of my doctors have been able to answer. I have PCOS and was on 1000 mg of Metformin for seven years. For the first six years on the drug, my diet was pretty awful. In the seventh year I started eating paleo and felt dramatic physical improvements (energy & overall health). I eventually went off the Metformin altogether—exactly a year ago—and now manage the PCOS with diet and exercise, and feel great.

    My question is: I realized that Metformin had a dramatic negative impact on my thought process. For me, whether I was eating paleo or not, Metformin acted almost like an ADHD drug. Some people would have said it had a mood “stabilizing” effect, but for me, it seemed to cut me off from my emotions and from a considerable amount of my own abstract thinking. I didn’t feel like “me” at all, and made decisions that also weren’t reflective of “me.” I am an author and artist, and had trouble accessing much of my creativity.

    It’s been very frustrating to ask doctors about this and be dismissively told that I’m either imagining things or that there’s no answer for it. I’ve spoken to many other people for whom Metformin has had major mood-altering effects so I know I’m not alone.

    Could it be because Metformin cut down on the cortisol in my bloodstream? You also mentioned it blocking overproduction of glucose from the liver, and am wondering if this could be related to cortisol? Or something else? Also, my endo did tell me that I am not “that insulin resistant,” but did not elaborate.

    I would love to know what you think.

  14. zane says

    Robb, do you still do one on one consults? Or is that up to your team members?
    If so how would I contact you directly.

  15. says

    Instead of putting everyone on Metformin (or at least making everyone interested in this drug through this article), I’d suggest something else. I come from Greece, and there we have goats and sheep, not as many cows. If goats eat “goat’s rue” (Galega officinalis) and fenugreek when grazing, then the active ingredient of Metformin, called galegine and found in these two plants, it will be present at some degree in the goat’s milk, and maybe offal.

    I know that mainstream Paleo is anti-dairy and all, but I believe this comes from the cow situation in the US (casein/lactose), while in Greece we never had problems with goat/sheep dairy (different casein, lactose goes away in our yogurt after a day’s fermentation, cheese too). In Greece, I know of no one who is lactose-intolerant.

    Anyways, what I suggest really is that maybe people should start going back to consuming more meat/dairy from goats/sheep, and have these animals actually eating the plants they are expecting to eat on their original environment (not just grass or whatever they feed them in the US, even when pastured). Basically, Paleo for goats, will bring health to the ones consuming the goats too. No need for drugs in that case. The active ingredient will be found on the goat itself.

    I know I’m overreaching a bit here, but it’s something possible to do if farms were more aware of all that.

      • says

        Thank you Rob, much appreciated. :)

        BTW, I just checked, and there are some supplements made from goat’s rue, which have the active ingredient galegine in them. So even without a prescription for Metformin, someone could order a goat’s rue (or fenugreek) supplement, legally. The tricky part is that these supplements are suggested only for women who can’t lactate, while they increase breast size (mammary gland) to non-mothers. Taking that pill might get messy, at least for men… So I think the safest way to get some of that blood sugar reducer ingredient is via the goat dairy/offal method.

        • Devon says

          Thanks for this information! And if I ever get that goat farm I’ve dreamed of, I’ll try out some goat’s rue feed. . . that stuff grows like crazy around here.

    • Peter says

      The A2 casein in sheep and goat dairy may be a key difference. I heard an interview on Sean Croxton’s show with Keith Woodford, professor of agribusiness in New Zealand, proponent of A2 milk, and author of The Devil in the Milk. He’s got a database of papers on health problems related to BCM-7 and believes that many of the problems attributed to cow dairy are actually problems with the BCM-7 from A1 casein.

  16. says

    Very good post Robb! I have been reading your work and listening to your podcasts over a year now up and I have to say I really appreciate all of the work you are doing to help people navigate their health!
    The Paleo Template (I actually really appreciate the terminology here!) is exactly what we all need to be the healthy human beings we are built to be!
    I really see the general disregard for how our bodies are supposed to function (including moving much more than we do, eating what we can hunt and gather, and sleeping as we need it – not on a forced schedule) as the biggest problems in being healthy. I also appreciate the fact that yourself and others in the Ancestral Health community are searching for how to create health (as opposed to fighting disease) through understanding how the body is supposed to work. Anyone can find disease – it is more important to find and express health!
    My practice is predicated on helping people express their health – when they are looking, feeling, and performing better they display less pain/disease.
    Keep up the amazing work Robb!

  17. Rita says

    I have been diagnosed with Leaky Gut and have been taking l-glutamine 3 x’s / day for over a month. I have been taken off of all gluten as well as I have the gene for celiac too. I have developed tons of food allergies and am eating paleo. How long does it typically take to heal leaky gut. I would be very interested in this answer. I have been working on all this since late December but have only been completely gluten-free for about 3 weeks. Before that, I had removed all foods that I have sensitivities to. I am still not losing weight although by body composition has changed some. Lost 4 lbs of fat but gained 3lbs of lean body mass. Thanks!

      • Rita says


        Update: I still haven’t lost much “weight”. However, my body comp is changing.

        I see a dietician every 2 weeks who measures my body fat (using a machine that reminds me of an eeg machine because she puts leads on my hand and foot on the same side).

        Anyway, the last time I saw the dietician, I had lost another 6 lbs of fat and gained 5 more lbs of lean body mass. She said as quickly as I add muscle, I could be a body builder. Not really my thing but I think that was a compliment.

        I was also very dehydrated at a cellular level (intracellular) and I have gained 3 liters at the intracellualar level.

        My dietician told me to stop worrying about the scale as well because there are obvious improvements in my body composition.

        I have been working on this since the day after Christmas so it’s nice to see something finally happening!

        I finished my l-glutamine and since I quit eating ALL grains (rice doesn’t agree with me and never has), my bloating has gone away. I also quit eating beans.

        In addition, about half of my meat is grass-fed beef, I have been ordering thru the US Wellness Meats website. I already have half a hog in my freezer that is not. I just ordered chicken and butter as well.


  18. Amy B. says

    Friggin’ awesome stuff, Robb.

    Two questions – and I’m jumping on the opportunity to ask them here, b/c they’ve been in my head for a while.

    Regarding inflammation:

    I read a ton of blogs, websites, and listen to a ton of podcasts related to health and nutrition. Everyone seems to be jumping on this “inflammation” bandwagon. All I hear is “inflammation is at the root of all disease.” While I believe inflammation is *related* to most of our modern chronic conditions, I’m starting to get annoyed when I hear inflammation bandied about all over the place b/c I feel like people are trying to say inflammation is *causing* all these conditions. Maybe I’m wrong, but I’m no slouch in the biochem area, and if you ask me, inflammation is the *result* of these conditions. That is, you’re not diabetic or have heart disease because you’re inflamed; *you’re inflamed because your body’s derailed!* Yes? No? I don’t think that clearing up inflammation will “cure” or reverse these conditions; I think reversing the conditions (whether via a Paleo diet or medication) makes the inflammation subside. I dunno…maybe I’m getting worked up too much. It just sounds to me like people have the causation backward. (Or if they don’t, they need to be more careful with how they phrase things!)

    2. “Lack of exercise” as one of the causes of insulin resistance: In your opinion (which I cannot tell you how much I respect and value!) do you think we should say “lack of MUSCLE,” instead? I realize that cardio-type exercise (even just walking) can use glucose and glycogen during and maybe even for some amount of time after the exercise stops, but it seems like the more *muscle* mass you have, the better you’d handle glucose and insulin b/c of the GLUT-4 transporters. Besides just wanting to build muscle mass now while I’m young so I’ll be able to get out of a chair under my own power when I’m 80, the benefits of muscle mass are obviously a better physique for purely aesthetic purposes. BUT, thinking of this insulin sensitivity issue also helps me push harder with the weights at the gym. I’m operating under the assumption that the more muscle mass I can build (within reason…not looking to be a ripped freak or anything), the better my glucose and insulin handling will be. (I hate to say it this way, but the more muscle mass I build, the more carbs I’ll be able to “tolerate,” if that makes any sense.) Maybe we should say “lack of muscle-building exercise?”

    I dunno…I’m getting an MS in nutrition now and really love understanding this stuff. Lots of “lightbulb” moments every time I learn something new and make a big connection.

    Thanks for your insights, Robb. You rock!

    • says

      Thanks for the kind words.
      1-I DO think we can largely hang our hats on inflammation, as in the cell signaling and immune activity related to inflammation. The follows type 2 diabetes, Alzheimer’s etc. The sepsis story is so damn compelling in that we see this process in an acute fashion, then we see this happening to a lower degree with chronic issues. This ties together autoimmunity AND metabolic derangement. it might be wrong, there might be a nuance here I’m missing, but it sure looks this way to me. if you see a different route here let’s get a blog post from you and hash this out! i love being wrong… because then I get to be right once I realize my mistake.

      2-Yes and no. Do we want more muscle mass? Almost always “yes” but we DO need to sensitize that muscle with some activity. i sit so damn much working that I really think I am not turing on that non-insulin mediated glucose transport enough, or frequently enough, despite carrying a good bit of muscle.think about the Frank Booth paper on exercise and gene expression. So, yea, not all exercise is created equal, we DO want muscle and I think we do need some basal activity level to keep it insulin sensitive and utilizing fatty acids for at rest energy.

    • hoggle says

      I agree about inflammation being overhyped. I personally have ZERO inflammation, hs crp of. 3…underweight yet I experience hyperglycemia.

  19. pj says

    As a diabetic who has control his blood sugars very successfully with diet a Low Carb Paleo approach as I now see that some like to stuff Paleo carbs down their throat and still feel Grok, oh yes my point, I found Metformin to be a very useful ingredient/drug in my daily diet, but metformin is not created equally. Gloucage is the best and rarely covered by insurance plans anymore and the cheap genric stuff made overseas is poorly produced so it may take a while to find the tablet that works best. A study I read in Jan linked Metformin with anti-aging.

    • paleoslayer says

      I believe there is a new brand called Glumetza. Its basically an extended-release (ie:once daily) version of glucophage. It should be covered by insurance as its not interchangeable w the generics. Worth a shot.

  20. TandooriChicken says

    Hey Robb, great article.

    I was wondering if you had any handy resources or info regarding wheat/gluten, gut permeability, and their relationship to seasonal allergies. I know removing gluten from my diet before allergy season really makes things easier for me, but I’m looking for a way to easily explain it to my mom. Thanks in advance.

      • Kevin says

        Shocked me when I dropped Gluten,
        44 years of torturous allergies just melted away into an occasional sneeze or itch. Soy products have some disastrous effects on me too. I think the book “Dangerous Grains” was the keystone for me. “Wheat belly” looks like another good one. This year allergies have been a bit worse, but they hit when i was getting over a flu, I’m concluding that ties in with an aggravated immune system. The Flu being just a different antagonist.

  21. Janknitz says

    Side effects from Metformin vary from person to person.

    I have PCOS and my low carb “almost Paleo” diet (I still permit high fat dairy products) made me feel a lot better, but my fasting blood glucose and HbA1C numbers were still too high.

    I added Metformin and the FBG’s are in the 80’s and low 90s now, HbA1C is now 5.2 (whoo Hoo!), without any other dietary changes.

    Personally,Metformin keeps me “honest” on low carb because I have rather dramatic GI side effects if I overdo the carbs.

    The insulin resistance has been an issue for me from childhood–I had terrible hypoglycemia. I was quite thin. When I started menses it was clear from the beginning that things were amiss. I did not gain significant weight until my mid thirties following major fertility treatments to conceive my first child (ivf). Low carbing and Metformin 12 years ago brought me a big surprise–child number two. Unfortunately I stopped Metformin (and low carb diet) after her birth and my body has suffered the results.

    Although dietary changes, helped, I have also benefitted greatly from the addition of Metformin to stave off a diagnosis of full-blown diabetes and for my overall health.

  22. Jenny says

    Rob- don’t get me started on how backwards the medical community is on this issue. I have PCOS and have been through years of infertility treatment including in-vitro fertilization. Now 2 months into a paleo diet and my cycles are regular for the first time ever. I’ve got 12 people now on this way of eating. The successes are amazing. I’m going to send you a write up soon on the whole pcos issue and overcoming it.

    • says

      We’ve seen shocking beenfits on the fertility side of things, for both men and women. Metabolic, and autoimmune issues are addressed. Keep us posted!

  23. Marc says

    All politics aside and only concerning humor: even if you ARE a republican and you don’t see the humor in the “party frontrunner statement ” , you have serious sense of humor issues. That is what needs “grappling” with. Wish these damn sticks-in-the-mud would lighten up…….. It may even help their stress levels

    • paleoslayer says

      Yeah, laughter is the best medicine. people who take things too seriously are ppl who lack a sense of humor and are easily offended. They are also dogmatic. Which means they are loathe to change their beliefs, even in the face of contradictory evidence.
      And if you analyze WHY ppl are offended, its bc there is usu an element of truth to it. If you call me a fatso, im not gonna be offended bc im 5’11 and 165 lbs. (perhaps not if you call me a ‘pencil-necked girly man’)

      As a Canadian, one thing I always admired about the USA was the first amendment. What is freedom if not one’s ability to express one’s thoughts without fear of censure or punishment? What’s next? thought crimes?

  24. Martin says

    And what about plain old sugar? What if the Katavans started to add just large amounts of sugar to their otherwise perfect(?) diet?

    Would it first cause intestinal permeability, infection and only then insuline resistance?

  25. Martin says

    You might be right Rob, and if you are then you should get a Nobel prize. But if you are right it’s not good news to the Paleo. Why? Because if it all boils down to some kind of infection then some kind antibiotic or other medicine will do. Why bother eating the right stuff then? It would be good news to the pharma industry.

  26. CanadianArcticPaleo says

    Hey Robb,

    I always love reading your posts – thx for this one!

    Make sure your fourthcoming little guy gets the sleep he deserves!!!….I probably didn’t need to say that lol but it must be hugely fucking important for babies neural development eh

  27. Gary says


    Thanks for this post. Your insights are assisting very many of us who are wrestling with understanding more about these intertwined conditions. I’m now getting why my seasonal allergic response went off the card after a tetanus and shingles innoculation incident to a physical exam 3 weeks ago.

    Migrated into paleo diet/lifestyle over the past year–burned off 30+ lbs, 62yrs, 6′, now at 175 and slowly drifting down. Chol@228, hdl@69,ldl@152,tri@36, glucose, random@101. No A1C#, trying to understand the blood sugar # when my carb intake is as restricted as it is.

    Thanks for your work.

  28. Elizar says

    Hey Robb have you taken any blood tests? I would like to see what your blood work is like in terms of meeting all the nutrients(vitamins, minerals, protein, lipids, carbs)

  29. kris says

    I had a lot of difficulty on metformin: difficulty breathing, palpitations, chest pain and insomnia. After doing some research, I found that many people found it intolerable and suffered the same symptoms. Side effects sites are starting to list possible liver and kidney damage as a concern also. There are similar pharmaceuticals that have been shown to have serious heart side effects. I believe avandia, a similar drug was taken off the market for causing heart failure and stroke. Although these drugs have an obvious positive effect on blood sugar levels, I wouldn’t be surprised if they eventually becomes as controversial as statins for their negative side effects. I don’t understand why they are generally viewed as being so safe.

    I believe also that infection may be key in immunity and disease. There are even books written years ago, touting certain antibiotics curing diseases such as scleroderma. Of course most doctors view this as bs.

  30. Jason says

    One thing leaped out for me at the very beginning of your post: you list the four components of the paleo template as containing photo period, and not exercise. Have you changed your mind recently on priorities, or have I misunderstood something from your book? I always thought it was clean food, appropriate exercise, adequate sleep, and no chronic stress. Is photo period really more important to long term health than appropriate exercise?

  31. Martin says

    One thing I’m not sure about the is directionality of the relationship between systemic inflammation and insulin resistance.

    Would sugar alone, when added to an otherwise optimal diet (e.g. that of Katavans) also first cause the leaking gut causing inflamation causing insulin resistance? Or could it be that insulin resistance causes inflamation?

    Phinney and Volek agree in their book that the occurrance of systemic inflamation and insuline resistance strongly correlate, but the causation arrow is not that straightforward. First of all, they mention that insulin has anti-inflamatory effects: “insulin decreases gene expression of several inflammatory transcription factors in leukocytes inducing a broad spectrum anti-inflammatory effect” also “insulin sensitizing drugs have been shown to exert anti-inflammatory effect” and “thus as long as cells are responsive to insulin, inflammation remains in check”. But then they add: “just as insulin resistance induces inflammation, several studies have implicated inflammatory mediatos in promoting insulin resistance”. Finally they try to define inflammation as “the net effect of repeated exposures to substances that trigger an immune response”. Gluten is then mentioned as one such substance (obviously) but they put forward a hypothesis: “In an insulin resistant state, such as metabolic syndrome, the substance constantly irritating the body is carbohydrate”. And they seem to provide an explanation: “carbohydrate ingestion and acute hyperglycemia activate a host if inflammatory […] pathways. Some of which include: stimulation of NAPDH oxidase, superoxidase generation by leukocytes, TNF-a production and activation of NF-kB”.

      • Martin says

        Sure it’s confusing. The good thing is that in the end I don’t have to care if I understand it or not. You are in a much more difficult position. In a way, it’s your job to figure those things out :-) All I need to do is live a healthy life and for that the arrow of causality is irrelevant :-)

  32. liv says

    Hey, Robb, 2 things regarding Metformin and kidneys:

    Metformin slows down renal cystogenesis in ADPKD (via activating the good ol’ AMPK)

    And Metformin significantly decreased the urine albumin excretion rate with none of the expected changes in renal hemodynamics, probably due to its favorable effects on blood pressure, lipid profile, metabolic control, and insulin resistance.

  33. Trace says

    Robb, It relevant to applaude the anti-gluconeogenesis properties of metformin while in a dysfunctional insulin resistant state, but what about with respect to a low, low carb diet that requires effecient gluconeogenisis in order to convert from a carb dependent metabolism to a fat burning machine. Q. Wouldn’t metformin impair that effeciency?

  34. says


    Exquisite commentary!!!! The data for triple negative breast cancer, colon, post-surgery breast CA and metformin are very compelling, as you alluded.

    In the past, I loved your stories at the nutri cert showing infertility reversal when you had 12 women all pregnant at once with Xfit, omega-3 and the anti-inflammatory paleo (LC) diet. Also being a pharmacist, I’ve loved the story of the two pharmacists with fatty liver who reversed it in one month with paleo. I think you HIT IT. I also believe infertility, PCOS, fatty liver and ALL WESTERN DISEASES are congruent examples of greatly impaired intestinal permeability and subsequent inflammation-immunity issues which lead to a state of broad-spectrum organ insulin resistance (IR) and sick-euthyroid syndrome/hypercortisolism/GH-deficiency.

    Although metformin is one of good, badassed pharmaceutical (I’d concur), however it is not without a couple of issues:
    –diarrhea related to an osmotic gap (it kicks out Ca++ and Mg++ in the intestinal cells), affects small bowel overgrowth, motility, or changes in gut flora
    –duration and dose related B12 deficiency within 1-2 months (prevents absorption of protein-bound B12 and intrinsic-factor B12 in the ileum)
    –lowers cortisol by blocking 3-beta-HSD (which is good in PCOS, lowering testosterone) but for those adrenally compromised, maybe be problematic
    –hypoglycemia (markedly with lower energy intake and/or exercise and/or other insulin sensitizing drugs or herbals)
    –AMPK activation leads to decreased DPP-IV activity (DPP-IV inactivates GLP-1, an incretin which increases insulin secretion and BG lowering effects); Celiacs generally appear to have less DPP-IV activity. DPP-IV also breaks down specifically gluten and casein.
    –in healthy men, metformin will lower Total T and Free T (naturally in insulin resistant men, because T is flat-lined/negligible, it does RAISE Total T and Free T); see below links.
    –being water-soluble, any renal/kidney function reduction will increase blood levels of the drug which if it accumulates can lead to lactic acidosis which is 50% fatal (conditions that reduce kidney function: dehydration, dehydrated high intensity exercise, dehydrated endurance training, binge alcohol, chronic high alcohol, kidney disease, heart failure, certain drugs, etc)
    –appears to be ineffective for low BMI and/or low-moderate insulin resistance

    (sorry for the long email/spam)
    I do love the mechanism of Metformin; AMPK activation is the prime regulator of oxidative capacity, fuel switching, remodeling of oxidative muscle fibers and BAT, immunity, cholesterol transport, as well as energy balance.

    AMPK activators all mimic exercise! Exercise sets off two things, per the literature: AMPK and PPAR-delta activation. PPAR-d activation (receptor independent) actually will turn on AMPK pathways, and vice versa.

    A number of foods, drugs, lifestyles changes that you advise and think highly of also turn on both expression of PPAR-δ and AMPK:
    –DHA + EPA
    –vitamin D
    –brief, intense exercise
    –endurance exercise
    –routine low to moderate exercise
    –intermittent starvation, ketone bodies, ketosis

    The below nutraceuticals also activate PPARδ-AMPK in studies…
    –berberine FYI trumps metformin (!!) (also has beneficial antimicrobial effects, sibo; may also decrease DPP-IV activity)
    –hydroxytyrosol (olive extract or oleuroperin which breaks down to HT; apparently hundred times AMPK activation than AICAR)
    –corsolic acid (e.g. banaba leaf extract, apparently spectacular; DFH GlucoSupreme, the paleo company)
    –ursolic acid (holy basil, rosemary; Zyflamend hexane-free)
    –rho iso-alpha acids/SKRMs (Insinase, by Metagenics; MetalloShield has higher doses and activates metallothienien which excretes cadmium, mercury arsenic lead etc without affecting endog Zn, Mg, etc)
    –bitter melon (triterpenoids)
    –PQQ (quinone)
    –dietary carotenoids
    –fiber (PGX, low GI carbs, etc)
    –medium chain triglycerides (MCT oil)
    –sterculic oil
    –phytanic acid (grassfed meat, dairy, seafood)
    –EGCG (green tea)
    –(anything that reduces cortisol/IR and increases GH like phosphatidyl serine, adaptogens, eleutheros, rhodiola, holy basil; GH is low and cortisol high in most IR states)

    These do too.. couple of WADA, IOC banned research chemicals (AICAR, GW1516 — but FYI these cause cancer in lab animals).


  35. Ananda says

    I am a vegetarian and have NEVER eaten meat, even as a child. I have recently become ill due to environmental toxins, malnutrition and an immune deficiency. The Paleo diet is very appealing and I currently eat that way except for the meat, which I substitute with tofu and maybe once a month I have rice or corn. After reading your article about reduced inflammation and speaking with a “paleo friend” I would like to go 100% paleo. Do you have any tips for incorporating meat, fish, poultry into my diet? In the past even small bites would make me VERY ill.

    • says

      I’d stick with fish and poultry initially, cook your food well and youo might include some digestive enzymes like NowFoods: super enzymes to help get the digestion rolling. Keep us posted!

  36. Amy says

    Thanks, Robb, for explaining innate vs. adaptive immunity. This is the least painful explanation I’ve seen to date (and I’ve been looking). Much appreciated!

  37. Bryan says

    Our chickens go to bed at 10pm and get up at 3am…makes me want to throttle them more than wanting to rise with them :)

  38. Mariah says

    Happy to seem some good new about Met. I’ve been paleo for over 2 yrs now and was diagnosed PCOS about the same time I made the switch(from vegan). Despite CF +ultra-low carb Paleo, for 2 years my body comp just wouldn’t shift- I couldn’t get rid of the belly fat, even though I was a “thin PCOS”. Went on Metformin 2000mg a day (on a 140lb body) in January and am losing inches, finally. I was SO resistent to go on the drug.. it took them a year to convince me because I hate putting anything chemical in my body. I just kept thinking I could solve it with Paleo+Exercise. I’ve now become a convert. I have SO Much more energy all around on this medication, and it has given me increased energy even when I’m operating on less than 50g carb a day, plus CFing, plus being in law school. It’s great to see someone in the Paleo community talking some good talk about this drug!

  39. Linda says

    I got a little lost in the political talk, but I think when Robb is elected President after solving the health care crisis with The Paleo Solution – no one is going to care!

    I am a critical care physician and found this write-up to be quite interesting. I deal with sepsis, severe sepsis, and septic shock patients daily. These patients (and any patients under stress of illness, really) become hyperglycemic and we put them on IV insulin to control blood glucose levels. Studies have shown this improves outcomes. However, since adapting a paleo diet over 6 months ago, I cannot help but wonder if we are, indeed, making our patients SICKER with trying to overfeed them. We try to prevent malnutrition to help keep immune function intact and help with wound healing. However, I believe the typical “tube feed” macronutrient ratio is something like 15:1 carb:protein. (I apologize, I cannot recall the fats.) There have been studies showing mild improvement in outcomes by adding Omega-3s, but other studies haven’t been so great. However, to my knowledge there has never been a study with a paleo-type of anti-inflammatory diet. (Why would there be….pharmaceutical companies make no money from preventive medicine…) Am I making my patient sicker by pumping their guts full of carbs then pumping their veins full of insulin?? We do not keep critical care patients on metformin – they are taken off their oral hypoglycemics until they are taking an oral diet again. However, IV insulin does not address the insulin resistance issue. Once again, I am torn here after reading something on Robb’s site. On one hand, this is useful information that could potentially change the future of healthcare. On the other hand, I now have to go to pubmed and read more. :)

  40. Edison says


    I have a question regarding this part of your article:

    “I received an email from a chap who nearly died from a septic event. Here are his pre and post sepsis cholesterol numbers:

    Been following a strict paleo diet for several years now. Cholesterol numbers from May 2011:
    Total – 226
    HDL – 58
    TG – 60″

    If he had been on a strict paleo diet for several years, then he would likely not have a leaky gut leaving him susceptible to sepsis, right?

    Why would someone get sepsis if they are following a strict paleo diet, especially if they had been following the diet strictly for several years???

    And, you say, ” a low carb paleo diet might just be the ticket.”

    Confused. I feel I might be missing something here.

    • says

      You get acute sepsis when you get a cut, infection etc. It happens all the time. Impacted tooth. In the past (and occasionally still) people die from this. this is in contrast to chronic, low grade sepsis from leaky gut, periodontal disease etc.

  41. Mindy says

    Thanks for the post….and thanks to those who commented also! I have been Primal for almost 2 years. I also have PCOS. Blood sugars have never been too high, but metformin has seemed to help a lot in regulating my cycles. In the past two years I went off Metformin to test things out, yet as soon as I went off, my cycles got out of whack again and the acne returned. I recently read in Primal Body, Primal Mind that diabetic drugs get in the way of the leptin communication so I thought I would go off it once more to see how things go. It’s been too short of time to now yet. After reading the possible good that Metformin can bring I almost wonder if I should go back on it…yet after reading the comments, there seems to be some natural supplements out there with a similar benefit. I guess all I can do is try and see. It would be great to have regular cycles, no acne and the final 10 lb weight loss without taking Metformin. At least from my experience, Metformin has always made my digestion MUCH more sensitive and touchy.

  42. says

    Robb — Your Libertarian Leanings are well appreciated, as is your dietary “willingness” to learn.

    It cannot be denied — The list of Super-Centenarians is growing (American having the most) and in each case there is NO dietary rhyme or reason to their longevity — save that they all drank water from the “crick” at some point in their lives and that they ALL have used Western Medicine (including anti-biotics).

    If we combine the best of practices (dietarily and when needed medically) then maybe some of us will see 90 (and be healthy) rather than dying at 75 or 80 — maybe some of us who’d reach 90 on the SAD diet would reach 110, given a balanced combination of both.

    For Paleo Folk who are anti-western medicine (like I was) just wait ’till a loved one has a debilitating disease or is in an accident — idealism should never replace common sense.

    Political Rant: Banking was founded on commodities, Slaves produced commodity produce, the greatest destroyer of the environment is related to commodity growth or extraction (minding), the greatest destroyer of our herbivorous food stock (our meat) has been mono-farming of commodities — silt destruction of rivers and mining or paper waste has destroyed our salmon runs (et al fish).

    The Paleo Diet, becoming a Localvore, and free-markets (wheres vote with their dollars and not at the state monopolized ballot box) is the surest path to individual liberty and a healthy environment.

  43. Charles Knouse says


    at the risk of adding noise, I want to thank you for your blog and work; I think you’re doing really important, ground-breaking work, and I gotta tellyuh…I think you are NAILING it. And I’m a doc who has tried it all, although I’ve tried my best to avoid foisting mainstream stupidity onto patients…and I have reluctantly had to abandon vegetarianism. I do have a crazy idea for you to consider someday: how about a version of the Paleo diet that doesn’t include killing animals, but simply using their milk for protein? No, I don’t mean American heat-killed-denatured-toxic dairy, I mean goat/sheep/maybe cow raw milk/yogurt/cheese…(and none of that %($#@!!! soy or almond crap)…

    One of my best friends was a mouth-foaming Republican for years, to my dismay, but then – because he has a brain and even uses it – he made this huge switch to Ron Paul and Libertarianism, and I have followed him; the logic is inescapable. Humans are basically irrational animals, we got a long way to go yet, but I believe the only way forward is COMPLETE freedom, which means complete self-responsibility as well. How could ANY Republican object to that? I say piss on anybody who doesn’t like it LOL.

  44. Pasi says

    I’m first time here. Lot of interesting stuff in your blog! Thanks! :) This quote is indeed very strong: “You know, this diabetes epidemic and modern disease will all boil down to some kind of infection or immune response…it’s not going to be carbs, fat or protein.”

  45. David O' says

    Rob – pretty sure i have leaky gut for the last 10 odd years – was on a course of strong antibiotics for 9 months and have not felt right since. Also got meningitis in Nov 11. Recovered well but have episodes when i feel like crap.
    Have started an 80% paleo diet[no grains, some dairy, some alcohol] in the last month. Going strict as of today. What else would you suggest to help heal the gut??
    Am a crossfiter and have 3 young kids[youngest 5weeks old] so not much quality sleep/recovery – adrenal fatigue??
    Any help appreciated!

  46. Jen C says

    Robb, great blog! LOVE that you covered this topic here! I have Hashimoto’s and am being treated for hypothyroidism. Also have low cortisol levels. Was also just diagnosed as insulin resistant and put on Metformin. I’m sure it’s all related. :-) The GOOD news is, I am on board with low carb, love exercise, and I have no problems sleeping. What’s your thought on high intensity exercise while taking Metformin though? I love CrossFit, but am concerned about the lactic acidosis warnings with this drug.

    • says

      Jen- it’s a good question and I do not have a ready answer. I’ll say this however, given your medical issues I’d lift weights and do LOw intensity activity. Better for a variety of reasons. Keep me posted!

  47. Lola says

    Hello Robb,

    I really love your article, thanx for all the information. I have been on paleo diet for over a year, which totally messed up my metabolism. I have developed serious Insulin Resistance, after each carbs I have huge headache and Im very dizzy. I started taking alpha lipoic acid, which is the first thing that really helps me. No headache, no dizziness with carbs. But there is one thing that really worries me. I also have now Hypothyreosis, with what ALA is not suggested. Is there any specific dosage that would already worsen my state? Or should I just skip it all (though I don’t really want since in other ways I feel better when taking it).Thanx for helping me.

  48. Mer says

    As a paleo demigod not sure how often you’re able to check old posts, but I’m glad I had something that put me at ease in regards to metformin.

    I was diagnosed “lean PCOS” (5’5″, 123 lbs) a few months ago and keep trying to dig down to the root of it all. Pretty scared for my 2Hr OGTT tomorrow as I eat a fairly ketogenic version of paleo (almost doubling my caloric intake of old, lost a bit of weight and can see my muscles now), worried that I’ll get a false positive per another of your posts. On the bright side, perhaps if I do get a metformin script I can potentially expect some OK results for my gut according to this research(though broth/gelatin helped a lot). Also worried about the lactic acidosis with my HIIT/Tabata routine that I love.

  49. Greg says


    I’ve had a horrible chronic exhaustion issue for 12 years. I was an ultra runner, gym manager, navy dive team leader, but at 42 it all went into the crapper and I became unable to recover, from anything. LCHF ketosis fixed me right up last Feb, felt 100%, began lifting heavy weights and sprinting, and my body responded with glorious recovery. But it only lasted a few months, ugh! I began adding back some rice and potato, but no joy.

    My FBG is in the 110 range, daytime and post meal readings are lower. My 23andme DNA test displayed diabetes as my greatest risk. I’m experimenting with metformin. Do you think driving my FBG below 90 will help get my energy and recovery back?

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