The autoimmune-inflammatory model of diabesity

macrophage

In this article, I’d like to present a unified model of diabesity. I think it’s helpful to have a “birds-eye view” of how diabesity begins and progresses. It gives us a context for the articles that will follow, each of which will examine specific elements of the model in much more detail.

Two caveats before we dive in. First, remember that all models are imperfect. They’re useful tools, but as the saying goes, a map is never the same as the territory itself.

Second, there is still much about the model I’m going to present that isn’t thoroughly understood. We’re on the bleeding edge here. The science is evolving rapidly, with new articles being published every day. What I’m presenting here is based on my interpretation of the information that is currently available. There are some parts of the model I’m more certain about than others, and I’ll point that out when applicable.

Okay, now that we have that out of the way, take a look at the following diagram. If you click on it a larger version will open in a new window. You might want to print this out or keep it open as we go, because I’ll be referring to it throughout the article.

The model presented in the diagram suggests that diabesity is an autoimmune, inflammatory disorder involving a pathological expression of the innate immune system.

That’s quite a mouthful, so let’s take a closer look at what each part of that statement means.

The innate immune system is the part of the immune system that defends us from infection or foreign substances in a non-specific manner. It’s our first-line of defense against anything the body perceives to be harmful.

Inflammation is the primary response of the innate immune system. In a healthy person, inflammation is temporary and the body eventually returns to homeostasis (“internal balance”). In the case of autoimmunity, however, the body mounts a response against its own cells and tissues and becomes stuck in a continuous loop of chronic inflammation.

Recent research suggests that diabesity is characterized by chronic, low-grade inflammation and a continuous stimulation of the innate immune system. The inflammatory state that accompanies diabesity is not associated with infection or other traditional signs of autoimmunity, and seems to have its own unique features.

If diabesity is an autoimmune, inflammatory disease, the next obvious question is “what causes it?” In a nutshell, the answer is the modern, western lifestyle. Studies clearly show that the incidence of diabesity accompanies its adoption around the world. The features of this lifestyle that have been implicated include:

  • Dietary toxins (primarily refined wheat, fructose and industrial seed oils);
  • Environmental toxins (chemicals like Bisphenol A, pesticides, phthalates, flame retardants, and heavy metals);
  • Micronutrient deficiencies (especially magnesium and vitamin D);
  • Chronic stress (emotional, psychological, physiological);
  • Altered gut microbiota (caused by antibiotic use, poor diet, formula-feeding during infancy);
  • Sedentary lifestyle

Genetics also play a role in diabesity. The evidence suggests, however, that even those with a genetic predisposition to diabesity do not become “diabese” unless they are also exposed to the environmental factors listed above. But genetics likely do explain why some individuals and populations are more likely to develop diabesity when exposed to a modern, western lifestyle.

Environmental factors (together with or independent of genetics) cause both inflammation and obesity, which are both strongly associated with type 2 diabetes (T2DM). But while obesity predisposes people to the metabolic changes characteristic of T2DM, it is not necessarily a feature of diabetes. Evidence is now clear that not all obese people have metabolic dysfunction, and that in some cases, obesity may even protect against metabolic and cardiovascular disease. In this sense obesity may be the body’s attempt to protect against the damage done by a modern lifestyle. (If you’re confused by this, don’t worry – we’ll cover it in more detail later.)

On the other hand, inflammation nearly always accompanies both obesity and diabetes and is independently capable of causing it without overweight – as evidenced by the presence of T2DM in Asian populations that are relatively lean. This explains why thin people can have all of the metabolic problems commonly associated with obesity, including full-fledged T2DM. And in fact these cases of T2DM may be the most severe, because they lack whatever protective adaptation obesity may confer.

Notice that inflammation alone directly contributes to every single metabolic dysfunction associated with diabesity: leptin resistance, impaired fat and glucose metabolism, insulin resistance, and beta-cell destruction. Inflammation can be considered the primary mechanism through which the modern lifestyle and genetics cause diabesity.

Most people are aware that diabetes is characterized by impaired glucose metabolism. What many don’t realize is that diabetes also involves impaired fat metabolism. Fat exists in the body in three primary forms: free fatty acids (FFAs, a.k.a. “non-esterified” fatty acids), triglycerides and phospholipids. Triglycerides and phospholipids are the storage forms of fat. FFAs can be transported in the blood without any carriers.

In healthy people, FFAs are burned in the mitochondria soon after release (lipolysis) from storage forms of fat (triglycerides and phospholipids). But in the diabese, inflammation, leptin resistance and oxidative damage impair the mitochondria’s ability to burn fats. The excess FFAs then “spill over” into non-fat tissue like the liver, pancreas and skeletal muscles. FFAs damage these metabolically active tissues because they don’t belong there. This is called lipotoxicity. Lipotoxicity has been shown in several studies to cause insulin resistance and increase the risk of T2DM.

Both inflammation and obesity cause leptin resistance. Leptin is a hormone produced by body fat. It tells the brain to decrease appetite, increase metabolic rate and increase physical activity. As you accumulate more fat, you secrete more leptin. This causes more fat to be burned. But if you become leptin resistant, your brain doesn’t hear your fat telling it that it’s already full. Leptin resistance is almost always present in obesity because it’s a precondition of significant fat gain. It’s impossible to gain more than a few pounds without being leptin resistant.

Leptin resistance and inflammation set the stage for impaired fat and glucose metabolism, which in turn cause insulin resistance – the defining characteristic of metabolic syndrome and T2DM.

Beta-cell destruction, which leads to the decline in insulin production seen in some cases of T2DM, can be caused by several mechanisms. These include genetics, inflammation, autoimmunity (i.e. Type 1.5 or Latent Autoimmune Diabetes in Adults [LADA]), and impaired fat metabolism (lipotoxicity) and glucose metabolism.

And here we arrive at our final destination: full-fledged type 2 diabetes. It is an autoimmune, inflammatory disorder triggered by modern lifestyle, influenced by genetics, and characterized by impaired glucose and fat metabolism and fat hormone resistance. The purpose of this article was to give you a broad overview of all of the elements of the model. In the articles that follow, we’ll look at each of them in much more depth.

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Comments Join the Conversation

  1. Tom Passin says

    I would like to encourage you to improve the graphic model.  The problem is that none of the lines are labeled, but they are a key feature of the model.  It is common for graphs to have unlabeled lines, but those graphs fail to communicate well enough.  Don’t let your diagram  be one of them. It’s especially important for this diagram to be clear and understandable because you are pulling together a lot of key new information, to illustrate a newly developing theory.  It needs to be clear and as expressive as possible.
    In your diagram, we can’t tell if a given line means “leads to”, “causes”, “modifies”, “suppresses”, or something else.

  2. Jesse says

    Related to Tom’s comment, I have been wondering since the beginning why your graphic seems to say that Modern Lifestyle contributes to Genetics.

  3. Tuck says

    I’d expect that the environmental toxins are low on the list of causes, as plenty of folks got diabesity long before the modern toxins became common-place.

    In fact I’d suspect that they’re not required at all to cause diabesity.

  4. Chris Kresser says

    I’ll try to make the arrows more clear – especially related to genetics.  For the rest, the arrows essentially mean “contribute to” or “are a risk factor for”.  The word “cause” might suggest that there’s a causal relationship in every single case, which is rare in the world of diabesity (or in human physiology and health at all).  I will be expanding on all of these relationships in the articles to follow.  I wanted to keep the diagram simple and readable; I had a prior version that was a lot busier but it was very difficult to read (especially for a layperson).

    Jesse: the arrow from lifestyle to genetics is there to suggest that genetic factors are probably only relevant in the presence of environmental factors.  I agree it’s not clear the way it’s depicted right now.

  5. westie says

    Hello Chris. I’m new here and I have to say that I’m here to stay. :)

    This post is very good. You wrote that inflammation can be considered as a primary mechanism through which the modern lifestyle and genetics cause diabesity. I totally agree with that. It really seems to work that way. I’ve spent these few last month puzzling how chronic inflammation develops and what controls the inflammatory responce of the activated immune cells like macrophages. All of this is very interesting.
    I wonder if diabesity is caused by western diet or could it be seen as a lack of some critical elements of the traditional diet? Is western diet poisonous or is it just stupid?

    • Chris Kresser says

      The western diet is toxic and directly contributes to inflammation and obesity, both of which impair glucose and lipid metabolism, cause lipotoxicity and fat hormone resistance, and eventually hyperglycemia and T2DM & metabolic syndrome. The western diet also causes nutrient deficiencies, both because of the low nutrient content of the most commonly consumed foods (flour & seed oils) and because of the “anti-nutrients” in grains, fructose and seed oils. So it’s both poisonous and stupid.

  6. westie says

    Here are some thoughts about the issue.  I don’t know how far from the target they are.
     
    I’ve tried to look western diet from a immunological view. Some authors have suggested that western environment and diet is proinflammatory and that might explain the increase in these diseases you mentioned. If “proinflammatory” is something that gives rise to the inflammation activity of the body then western living isn’t very proinflammatory when we compare it with traditional ones.
     
    I think that chronic activation of inflammatory markers  (NFkB, COX-2 etc.) isn’t caused by proinflammatory living environment or food. It is a result of proinflammatory phenotype of innate immunity and we should solve what drives the development of this phenotype over the tolerant one.
     
    Traditional diets and living environments have been lot of immune stimulating than modern ones. So traditional environment and food can be seen “proinflammatory” or “immune activating” and that is something that has led to the development of tolerant innate immunity system and simultaneous absence of western disease.

    • Chris Kresser says

      If “proinflammatory” is something that gives rise to the inflammation activity of the body then western living isn’t very proinflammatory when we compare it with traditional ones.

      I strenuously disagree and will present evidence to the contrary throughout the series. Wheat, processed & refined foods, industrial seed oils and fructose are all pro-inflammatory (this is easily measured), as are modern environmental toxins that weren’t present in the traditional environment.

  7. chuck says

    I have not read that obesity causes leptin resistance. I have read  that leptin resistance causes hunger>obesity. I have read that fructose may be the sole cause (Lustig) of leptin resistance or inflammation of the hypothalamus. So i think the arrow from obesity to leptin resistance might be piling on.
    I see obesity as a result and less of a cause. I would put it further down with dietary poisons higher up.
     

    • Chris Kresser says

      Obesity does cause leptin resistance, via lipotoxicity and inflammatory cytokines secreted by adipose tissue (body fat). I’ll discuss this in a future post.

      • says

        There are two schools of thought here: obesity causing leptin (and insulin resistance) and the opposing view. Consider the work of Gerald Reaven (Stanford) in your next post!

  8. Jesse says

    Seems like by the end of the series you might want to repost that diagram but with sources cited for each of the arrows… It seems to be causing confusion at the moment.

  9. Chris Kresser says

    Jesse: as I said, the diagram is meant to provide a broad, general overview of a developing theory.  It’s not intended to be a document that stands on its own.  I will be developing each section in detail as we go.  In fact, each section could easily be an entire series (or book) in its own right.  But my goal is to make this accessible to the broadest possible audience, so I have to leave some things unsaid.

  10. jehona says

    Dear Cris Kresser! I m writing a research paper on a high fat diet and insulin resistance and I m confused on the mechanism. How does it really work in the cellular level! Please email me if you can help at echobklyn@gmail.com

  11. Mandy says

    So how does one reduce inflammation? (I am not a medical professional. I am trying desperately not to develop diabetes as all my relatives have.)

    • Chris Kresser says

      In short, by avoiding everything that causes inflammation. I’ve written about the main culprits in several other articles in this series.

  12. andy says

    HI Chris,

    Thx for another great post.
    When I get most of my energy from fats and cut most of the carbs, I get bad body odour expecially frmo the armpit (not bad breath). Whilst I cut fat and most energy comes from carbs , the body odour disappears, and I dont need to wash my armpits for even a week.
    DO you think my mitochondira is not able to metabolise fatty acids.

    Also , in not healthy people , is that innability to metabolise fatty acids due to high insulin level, which inhibits fatty acid metabolism and transport (Acyl CoA via carnitine shuttle) acros mittochondria membrane??

  13. Namby says

    Chris, I’ve suspected this for a long time. Type 1 is autoimmune. So is Type 1.5. Type 2 involves inflammation. Now, if we are to hypoethesize that they’re all autoimmune, could we possibly make a case that they owe their origins to “gut permeabiilty”. In other words, a “leaky gut” precipitated most likely by gluten (wheat, barley and rye)? I realize that HFCS, plant oils, transfats, fatty acid imbalance, and junk foods that are high in carbohydrates all play a role here. But perhaps the leaky gut precipitates all this, as it seems to in all autoimmune diseases? Perhaps we’re not ready to make that leap yet but I tend to think that food toxins (wheat, fructose, and PUFA) are the biggest contributors in causing T2DB.

  14. Adrian says

    Hi Chris,

    Dr. Doug McGuff in ‘Body By Science says that insulin itself is inflammatory, and that increased elevated insulin in the blood causes inflammation that results in damage to the arteries… Maybe you should include that in your diagram.

  15. Denise says

    Hi there, after being recently diagnosed type2 diabetes 4 yrs after gestational I am really interested to learn more about how we can reverse this leptin resistance or maybe trigger it to work as in the case of insulin resistance metformin is prescribed for that but ive developed fluid retention and 3ltrs water a day isnt flushing and assisting my system. So i need to go back and review but would like to know what blood tests are available to test the leptin theory as my body has become resistant to fat and weight loss.

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