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How Inflammation Makes You Fat and Diabetic (And Vice Versa)


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In the previous article in this series, I argued that diabesity is an autoimmune, inflammatory disorder. In this article, we’re going to review the evidence linking inflammation to obesity and type 2 diabetes (T2DM) and learn why inflammation may be the single-most important mechanism driving the diabesity epidemic.

The inflammation-diabesity connection is a hot topic in the scientific literature. A Pubmed search for “inflammation diabetes obesity” turns up more than 1,800 articles. The association between these conditions has been known for decades. In fact, more than 100 years ago high doses of salycilates – a class of anti-inflammatory compounds which includes aspirin – were used to treat T2DM. In 1876, a physician named Ebstein found that sodium salycilate could make the symptoms of diabetes completely disappear. (In case you’re wondering why doctors don’t use this therapy today, it fell out of favor due to the serious side effects caused by high doses of salicylates.)

Though the association between inflammation and diabesity is well-known, questions remain. Does diabesity cause inflammation, or does inflammation cause diabesity? How and why does the body initiate an inflammatory response to diabesity? Does obesity itself cause inflammation, or is inflammation caused by something secondary to obesity (like high blood sugar or triglycerides)?

I’m going to try to answer those questions in this article. Let’s dive in.

How Inflammation Causes Diabesity

There are several lines of evidence that inflammation directly causes obesity and diabetes.

First, inflammation has been shown to precede the development of diabesity. Elevated levels of inflammatory cytokines predict future weight gain, and infusion of inflammatory cytokines into healthy, normal weight mice causes insulin resistance.

The idea that inflammation precedes diabesity is supported by the observation that humans with other chronic inflammatory conditions are at higher risk of developing T2DM.

For example, about one-third of chronic Hepatitis C patients develop T2DM, and those with rheumatoid arthritis are also at higher risk.

Second, inflammation begins in the fat cells themselves. Fat cells are the first to be affected by the development of obesity. As fat mass expands, inflammation increases. One mechanism for this may be dysfunction of the mitochondria (the “power plant” of our cells) caused by the additional stress obesity places on cellular function. Another mechanism may be oxidative stress. As more glucose is delivered to the fat cells, they produce an excess of reactive oxygen species (ROS) which in turn starts an inflammatory cascade within the cell.

Third, inflammation of the fat tissue causes insulin resistance, which is the primary feature of T2DM. TNF-α, a cytokine (small protein) released during the inflammatory response, has been repeatedly shown to cause insulin resistance. Several other proteins involved with inflammation, such as MCP-1 and C-Reactive protein, have also been shown to cause insulin resistance.

Fourth, inflammation of the brain (specifically the hypothalamus) causes leptin resistance, which often precedes and accompanies insulin resistance and T2DM. Leptin is a hormone that regulates appetite and metabolism. It does this through its effect on the hypothalamus. When the hypothalamus becomes resistant to leptin, glucose and fat metabolism are impaired and weight gain and insulin resistance result.

Finally, inflammation of the gut causes leptin and insulin resistance. This may occur via an increase in lipopolysaccharide (LPS), an endotoxin produced by Gram-negative bacteria in the gut. LPS has been shown to cause inflammation, insulin resistance in the liver and weight gain.

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How Diabesity Causes Inflammation

Up until relatively recently, fat was considered an inert tissue with no biological activity. The idea was that it was just, well, there. It didn’t do much other than store excess energy.

We now know, however, that fat tissue is a metabolically active endocrine organ that secretes hormones and inflammatory cytokines such as IL-6 and TNF-α. The metabolic activity of fat is the key to understanding its role in diabesity.

Why would obesity cause inflammation? There are two basic theories. The first is that obesity-induced inflammation is actually a protective mechanism that prevents the body from losing mobility or fitness. Fat storage is an anabolic process, which means it builds up the organs and tissues. Inflammation, on the other hand, is a catabolic process. Catabolism breaks down organs and tissues. It’s possible that the activation of catabolism via inflammation is the body’s attempt to keep weight within acceptable bounds. Evidence that experimentally induced local inflammation in fat tissue improves insulin resistance and causes weight loss supports this theory.

The second theory is that obesity-induced inflammation is simply a malfunction that was never selected against in human evolution. Obesity and its related disorders have been extremely rare throughout human history, and have only become common in the past 40 years. The surplus of modern, processed foods that accompanies diabesity is also a relatively new phenomenon. It’s possible that the stresses of obesity are similar enough to the stresses of an infection that the body reacts to obesity in the same way it would to an infection: via inflammation. Supporting this theory is evidence that the same intracellular, inflammatory stress pathways are activated in both obesity and infection.

Whichever theory is correct (and they probably both are, to some extent), it’s clear that diabesity causes inflammation. Insulin and leptin resistance impair glucose metabolism. When fat cells become insensitive to insulin, they can’t store any more glucose and hyperglycemia results. Excess sugar in the blood causes glycation, a process where a sugar molecule binds to a protein or a fat, and leads to the formation of advanced glycation endproducts (AGEs). AGEs are inflammatory and are associated with T2DM.

Obesity also contributes to inflammation by up-regulating certain genes involved with the inflammatory response. These genes control the expression of white blood cells called macrophages that play a key role in inflammation. As the concentration of macrophages in the fat tissue increases, the release of inflammatory byproducts such as TNF-α, IL-6 and MCP-1 also increases. This means that the more fat tissue you have, the more inflammation it will produce.

Putting It All Together

Collectively, these findings are consistent with the theory I presented in the last article that obesity is an autoimmune, inflammatory disorder.

As we’ve seen, inflammation is both the cause and the result of diabesity. Once obesity and/or insulin resistance have been established, each can further stimulate the production of inflammatory cytokines, forming a vicious cycle of inflammation and diabesity.

It follows, then, that the key to preventing and treating diabesity is reducing inflammation. Unfortunately, few clinicians treating diabesity today understand this. Focusing exclusively on regulating blood sugar and fat hormones without addressing other potential causes of inflammation is bound to produce inferior results.

What are these “other causes” of inflammation? In a phrase: the modern lifestyle. Specifically, dietary triggers (fructose, wheat and industrial seed oils), stress, poor sleep, gut dysbiosis and environmental toxins all cause inflammation on their own. When combined together, they are an explosive mix.

We’ll talk about each of those factors in future articles. For now, the takeaway is that inflammation is probably the single most important mechanism driving the diabesity epidemic. Keep this in mind as we discuss the lifestyle factors that contribute to diabesity, because almost all of them relate back to inflammation in some way.

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Join the conversation

  1. Dear Prof. Chaussade,

    You are the perfect example of a Marie Curie fellow. Could you please share your experience?

    Best wishes,
    Dr. Nelly Kumanova

  2. Any idea how to stop this inflammation happening and in time line to reduce weight and keep the weight avoiding this LTB4 molecules ?

    • Yes. Drink kava. It is a powerful anti-inflammatory which is also safe. I have been drinking kava every day for the past six months and in that time my BMI dropped from 30 to 27. It is expensive, but you don’t need much. A therapeutic daily dose could run as little as $13 a month.

  3. There has been an increase in Obesity in the past 40 yrs. So has there been an increase in GMO’S. Are GMO’S the reall fat and Diabetes trigger?

  4. What tests would determine if a person had local inflammation in fat tissue?

  5. interesting blog proved right 5 yrs later LTB4 causes macrophage–mediated inflammation and directly induces insulin resistance in obesity
    Pingping Li#1,3, Da Young Oh#1, Gautam Bandyopadhyay1, William S. Lagakos1, Saswata Talukdar1, Olivia Osborn1, Andrew Johnson1, Heekyung Chung1, Michael Maris1, Jachelle M. Ofrecio1, Sayaka Taguchi1, Min Lu1, and Jerrold M. Olefsky1,31Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093# These authors contributed equally to this work.
    Chronic inflammation is a key component of obesity–induced insulin resistance and plays a central role in metabolic disease. In this study, we found that the major insulin target tissues, liver, muscle and adipose tissue exhibit increased levels of the chemotactic eicosanoid LTB4 in obese high fat diet (HFD) mice compared to lean chow fed mice. Inhibition of the LTB4 receptor, Ltb4r1, through either genetic or pharmacologic loss of function results in an anti–inflammatory phenotype with protection from systemic insulin resistance and hepatic steatosis in the setting of both HFD–induced and genetic obesity. Importantly, in vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways in macrophages, promoted de novo hepatic lipogenesis, decreased insulin stimulated glucose uptake in L6 myocytes, increased gluconeogenesis, and impaired insulin–mediated suppression of hepatic glucose output (HGO) in primary mouse hepatocytes. This was accompanied by decreased insulin stimulated Akt phosphorylation and increased Irs1 and Irs2 serine phosphorylation and all of these events were Gαi and Jnk dependent. Taken together, these observations elucidate a novel role of LTB4/Ltb4r1 in the etiology of insulin resistance in hepatocytes and myocytes, and shows that in vivo inhibition of Ltb4r1 leads to robust insulin sensitizing effects.
    insulin resistance;

  6. Cute coin word diabesity. What do you call a young kid who is not fat with diabetes? Call him obese too? Does “daiabesty” cause inflammation or vice versa? Well son inflammation is triggered. It doesnt just happen out of nowhere. Therefore inflammation is always the result of something else.

  7. Please stop using the term DIABESITY!! It’s implying the two always go together and they don’t… and it’s not a recognized medical term. My father has not been even close to overweight a day in his whole life, very physically active and he still developed type 2 diabetes… and he doesn’t think its that serious because he’s skinny, if he was fat then it would be serious (he actually said that). Skinny people are at risk as well. Yes, if you eat poorly you’re more likely to be obese, but to use terms like diabesity is to give thin people a false sense of security! My mother has been obese for decades, and does not have it but my skinny father does, go figure… maybe genetics… or maybe trying to watch her weight she made better choices more often (but still took in too many calories and did not burn enough, she is very inactive). I just don’t think the terms adds anything to the discussion and at worst is harmful.

  8. I think I have insulin resistance but I am not diabetic. I eat low gi, no gluten, no sugar, all that. Nothing touches it. Exercise makes the inflammation go up. I don’t know what the source of inflammation is. Is it insulin resistance? I feel like I have hypoglycemia a lot. Less carbs I eat the worse the weight is. I have been gaining weight for one year and doctors just say eat less. I have tried eating less and less and all that happens is I am hungry and psychotic.

    • I get mentally affected by eating less and less food and carbs. I am thinking of doing Ray Peat’s protocol. There is a definate disregulation of something causing my inflammation as I have to be on steroids to remain sane and not flat on my back. Of course the steroids put up the blood sugar. The trouble with doctors nowadays they don’t seem to be very good at diagnosing, just drawing blood.

    • Repy to Kristen.

      You will not be hungry when you eat less if the glucose in your food (fruits, leafy green vegetables, beans (not canned), whole grain, oats, quinoa, nuts and seeds IS CONTROLLED BY SOLUBLE FIBER !!!!. That is the key to increase “satiety”. Stable blood glucose keeps the hypothalmus “happy”. and I founded with diabetics that works and they do eat less ‘AUTOMATICALLY” without feeling DEPRIVED (hypothalmus happy). and lose excess weight automatically.
      Yes, you should EAT LESS; but that applies to the REFINED processed food, sugars, and starches, but EAT MORE of the fruit and vegetables and to KEEP FULL YOU MUST ADD HIGH SOLUBLE FOOD, LIKE OATS AND BEANS.
      Because the plant food is HIGH IN NUTRIENTS AND LOW IN CALORIES.

    • The problem is that everyone is treated like everyone else. The truth is that everyone is uniquely different. What works for one person just doesn’t work for everyone. You have to find the diet that works best for you; maybe you should be eating whole grains and avoiding meats. Experiment.

  9. People tend to think those who are “thin” aren’t Fat. Enter the phenomenon known as “skinny fat”.

    I see “thin” people quite a bit…that are surprised after I measure their Body Fat that it’s 25+%. Both Men AND Women.

    So these type 2s that you see that don’t LOOK Fat…doesn’t mean they aren’t.

  10. You talk about “diabesity,” but the correlations between fatness and diabetes are not direct or even understood. How do you explain the 25% of Type II diabetes who’ve never been fat, and the fact that only 20% of fat people develop diabetes? To speak as if there’s a 1:1 correlation just doesn’t represent reality.

      • My Mom has never been overweight a day in her life and developed Type 2 in her late sixties. I have never understood this but I did notice that she was on a soda pop kick the year that she developed Type2. To my knowledge, of her 7 surviving brothers and sisters none of them had Type2. Breast cancer and lung cancer and osteoporosis but no diabetes. Now, at 56, I have been diagnosed with pre-diabetes. Am very confused as to what is going on.

        • Sudden type 2 in menopause caused by stress, which can be from the stress of low hormones as was my case. Started bi est progesterone and testosterone plus ndt. Voila! No more diabetes or blood sugar swings. BP went down too. Doctors are quick to hand out pills like metformin and clonidine and ssri’s. I didn’t need any of those I needed hormones.

    • There are a group of people that have the ability to regenerate beta cells and those that can’t. The ones that can’t are the ones that become diabetic and it doesn’t matter on their size. Obesity though does increase insulin resistance/inflammation and then high levels of insulin are required to bring down the glucose levels. Insulin is proving to be a higher risk factor for other disease than the high blood sugar. Cancer is tied to the high levels of insulin. Another interesting observation is that as blood sugar stays elevated bacteria and yeast such as Candida proliferate. Candida is prevalent in all cancer diagnosed patients. In theory as candida increases the waste from it and other pathogens create an even more acidic and anaerobic condition creating a perfect environment for cancer to grow.

  11. I recently switched to a vegan diet which I’m trying for 90 days to clear out my system. I have all the symptoms of inflammation discussed, pain in joints, digestive problems when I eat wheat, hypertension, and my blood sugar was elevated at last exam. I need to get this under control NOW. So I’m curious to find out what role tomatoes and legumes play in inflammation, since they are a core component of a vegan diet. Thank you.

  12. I can not get the doctor to trace why I have had high inflammation, and growing obesity for years and now am developing type 2 diabetes according to the HBaic test.
    I get terrible pain in the adipose tissue on my thighs which I think is down to the whole lot of inflammation in my body. I have Hashimotos and Addison’s but my sug conars might have been deranged for a while. My fasting sugars are still okay but i can not seem to control my health with diet. Even though I eat lots of fresh unprocessed foods i suffer with iron, folate, B12, vitamin D and zinc deficiency, and copper excess. I feel if I could get the inflammation down i would be much healthier, my A{R like ferritin would come down and let my body use iron as serum, and I might get healthier.
    Chris you mention certain food groups, I am fully gluten free, but I have never had any trouble with the nightshades, been eating them all my life wihtout any issues.
    I am housebound and often have to be in bed so ill and breathless with exertion. Nobody can seem to help me. The diabetes is a recent event.
    Could you please suggest anyhing I could request from the doctor or any tests I could suggest?
    thanks in case.

    • You have so many of the symptoms I suffer with. Please research DAO Deficiency resulting in Histamine Intolerance (HIT). The high copper rings a bell because DAO uses copper to reproduce. Low DAO = high copper.

  13. I have metobolic syndrome. Would like follow ups on blog. Thanks
    Doing alot of what has been suggested prior to blog.