How inflammation makes you fat and diabetic (and vice versa)

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.

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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