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adiponectinmouseIn the last article we learned that type 2 diabetes (T2DM) is characterized by chronic inflammation. We also learned that while inflammation often precedes the development of obesity and T2DM, obesity and T2DM contribute to inflammation – creating a vicious cycle of metabolic damage.

In this article we’re going to review the complex and sometimes murky relationship between body weight and type 2 diabetes. There’s a strong association between obesity and T2DM in the scientific literature, and it doesn’t take a rocket scientist to determine that there might be a connection between the two.

But some obese people never develop T2DM, and and some type 2 diabetics are extremely lean. Even more strangely, recent research suggests that obesity may actually protect certain people from developing T2DM.

How do we make sense of this? Let’s find out.

How obesity causes type 2 diabetes

As I explained in the previous article, body fat isn’t just a lump of inert tissue. It’s a metabolically active endocrine organ that secretes inflammatory cytokines and hormones, both of which have profound effects on our physiology.

It has long been known that T2DM is a disease of impaired glucose metabolism. But what is less commonly known is that T2DM is also characterized by impaired fat metabolism. And recent research suggests that this is one way that obesity contributes to type 2 diabetes.

The first step in this process is an abnormal gain of fat mass, usually caused by overconsumption of wheat, fructose, industrial seed oils or other dietary toxins. As fat mass increases, more leptin is secreted. (Remember, leptin is the hormone that tells the brain to decrease appetite, increase metabolic rate and increase physical activity.) Chronically high levels of circulating leptin cause leptin resistance. It’s like leptin is banging on the brain’s door, but the brain has its headphones on and can’t hear leptin knocking.

Leptin resistance causes free fatty acids (FFA) to spill over into tissues other than fat cells, such as the liver, pancreas and heart. This starts a chain reaction of inflammation and toxicity, because fat does not belong in these tissues and damages them when present.

Also, obesity causes excessive growth of fat tissue in two ways: it makes the fat cells larger (hypertrophy) and increases their number (hyperplasia). These overgrown fat cells become unstable and eventually rupture, releasing their fat content and causing further inflammation as the body attempts to clean up the dead or dying fat cells.

The end result of this “lipotoxicity” and inflammation is insulin resistance, which as you know is the defining feature of type 2 diabetes and the metabolic syndrome.

Not all obese people get diabetes

At one point it was assumed that all obese people were at higher risk for developing T2DM. But in recent years, research has proven that assumption to be untrue. We now know that a subset of obese people are “metabolically healthy”, which means that their fasting glucose, triglycerides, and other metabolic markers are normal. This population, referred to as the metabolically healthy obese (MHO) are at no higher risk for type 2 diabetes or cardiovascular disease (CVD) than their metabolically healthy lean counterparts.

Early studies suggested that up to 1 in 3 obese people were metabolically healthy. But these studies used either insulin resistance or the presence of metabolic syndrome (which includes 3+ risk factors) alone to determine metabolic health. But a newer study that used a stricter definition of metabolic health (the absence of any risk factor known to contribute to T2DM) found that the percentage of metabolically healthy obese is much lower: only 6%.

Though the number of MHO is much lower than was once assumed, it’s still true that a small subset of obese people 1) does not develop type 2 diabetes or metabolic syndrome, and 2) is not at higher risk for cardiovascular disease.

How might that be possible?

Not all obesity is created equal

The most honest answer to that question is, “we still don’t really know”. But there are a few possibilities.

The first is that not all obesity is the same. There are two main areas where we store fat: under the skin (subcutaneous) and in the abdominal cavity (abdominal or visceral). Visceral fat (a.k.a. “beer gut”, “spare tire”, and “wheat belly“) is distinguished from subcutaneous fat by a large waist circumference and waist-to-hip ratio. As it turns out, the amount of visceral fat you have is far more important than body-mass index (BMI) in predicting whether you’ll develop type 2 diabetes or metabolic syndrome.

Let’s take a step back and look at why obesity develops in the first place. You might be surprised to learn that obesity is actually a healthy response to high blood sugar. High blood sugar is extremely toxic. The conversion of glucose to fat is the body’s attempt to protect the liver, brain and other vital organs from glucose poisoning. But this mechanism only works for so long. Eventually the fat cells can’t accommodate any more glucose, and metabolic dysfunction sets in.

Subcutaneous fat has a much larger capacity to store the converted glucose as fat, given its much larger size and distribution throughout the body. This may explain why it appears to be protective against metabolic syndrome, and why men, who possess a smaller amount of subcutaneous fat than women, tend to more easily develop “beer gut” or “wheat belly”.

Visceral fat, on the other hand, is not only a smaller storage depot than subcutaneous fat, it is highly active from a metabolic point of view. It is associated with a higher production of inflammatory cytokines, and it is more susceptible to lipolysis. Visceral fat cells are also subject to sudden pressure variations (cough, physical exercise, etc.) that cause them to rupture more easily than subcutaneous fat cells. And as we saw earlier in this article, ruptured fat cells cause inflammation.

All of this explains why visceral fat is an independent predictor of insulin sensitivity, impaired glucose tolerance, high blood pressure and high cholesterol and triglycerides. That means even if you have a relatively low BMI, you’re at much higher risk for T2DM and cardiovascular disease if you’ve got a lot of visceral fat. It also means that even if you have a high BMI, if you don’t have a lot of visceral fat you may not be at higher risk.

A second factor in determining whether obesity protects against or causes type 2 diabetes is levels of a hormone called adiponectin. Early studies suggested that high adiponectin levels protect against obesity, and it was observed that adiponectin levels were inversely correlated with BMI. But later studies found that increased levels of adiponectin in mice led to remarkable weight gain – that wasn’t accompanied by high blood sugar or other metabolic abnormalities. In fact, the mice with high adiponectin levels are up to 5 times fatter than the control mice, but they still don’t develop type 2 diabetes.

This suggests there may be something about adiponectin that protects against the metabolic abnormalities that cause T2DM, and that adiponectin levels may be another explanation for why some obese people don’t develop diabetes.

A third explanation for the MHO phenotype may be genetics. I’m going to leave it at that for now, because this article is already getting very long, and I will be devoting an entire future article to the contribution of genetics to diabesity.

Metabolically “healthy” obese still isn’t healthy

As we saw above, the MHO are not at higher risk of developing type 2 diabetes or heart disease. However, there’s more to health than normal triglycerides and blood sugar. A group of researchers recently found that the MHO who don’t have T2DM and CVD die at the same rate as those that do. The MHO are at higher risk for cancer and death from any cause than the non-obese, and they are also at higher risk for dying from traumatic injuries.

This highlights the negative impact of excess weight alone. What’s more, weight loss still improves insulin sensitivity and fasting insulin levels in obese people that are metabolically healthy.

Although nearly 1 in 3 Americans are obese today, it hasn’t always been this way. Overweight and obesity have only become common in the last 40 years in the U.S., and is virtually unheard of in traditional hunter-gatherer societies. Leanness is the natural human state, and obesity is a sign that something has gone wrong.

That’s why I think it’s still a good idea for the overweight and obese to lose weight, provided they do it in a responsible way that doesn’t include severe caloric restriction (which won’t work in the long-term anyways, and can actually predispose towards increased weight gain in the future). Given the non-metabolic problems that characterize obesity – such as impaired mobility, joint problems, reduces sexual function, psychological and social status, etc. – all obese individuals will benefit from losing weight.

In part 2 we’re going to discuss the mirror reflection of the metabolically healthy obese phenotype: the “metabolically unhealthy non-obese”, a.k.a. the “skinny diabetic”.

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