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:
2-Lack of exercise
3-Vitamin D- deficiency
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.