Obesity, Inflammation, and Diabetes

This entry is cross posted from the the SITN Flash, a bimonthly publication written and edited by Harvard graduate students. You can find my piece, as well as archives of previous articles written by many graduate students at the Science in the News website. In 1985, the Centers for Disease Control (CDC) began tracking the prevalence of obesity in the United States. Since then, a clear trend has emerged: obesity is on the rise. The maps below compare obesity levels across the United States in 2004 and 2008:

Obesity 2004 vs 2008

It's clear that the number of people with obesity is growing, and has been as long we have been tracking it. Obesity is defined as having a body mass index (BMI) over 30. BMI is calculated by dividing your weight (in kilograms) by the square of your height (in meters). It is important to note that BMI is by no means a perfect measurement of health - its correlation to body fat can vary depending on one's physiology and genetics - but it is the easiest and least invasive way to assess body fat percentage. More accurate measurements can be achieved by measuring relative buoyancy (fat is less dense than other body tissues) or by looking at tissues with X-ray or MRI, but these methods require special tools and a visit to a doctor [3]. To give you an idea of what obesity by BMI means, someone six feet tall would be classified as obese if they weigh over 220 lbs, someone 5'6" would have to weigh over 185 lbs, and someone five feet tall would be over 150 lbs to be considered obese by this measurement [4].

Obesity affects more than the size of your waistline. If you're wondering why the CDC is tracking obesity, it's because those excess pounds have been linked to several significant health problems, including heart disease, stroke, and some forms of cancer. In fact, one study in 2009 estimated that the direct medical cost of obesity in the US accounted for $147 billion of total health-care spending. Of all the health problems associated with being overweight, one of the most significant and well-studied impact is the increased risk for diabetes. Compare the following maps charting the percentage of adults diagnosed with diabetes from the same time span as the previous maps:

Diabetes Figure.png

The rates of both obesity and diabetes are rising all over the country, and regions with the greatest increases in levels of obesity have corresponding increases in diabetes. In addition to the strong geographical correlation, there is solid evidence for the role of excessive weight in diabetes, but we are only recently beginning to understand the mechanism behind this link.

Diabetes: The Disease

Diabetes mellitus is the Latin name for two conditions in which people are unable to regulate their blood sugar. Blood sugar is comprised of the simple sugar glucose, a product resulting from the breakdown of food that we consume and digest. In healthy people, blood glucose levels are controlled by two competing hormones. When glucose is low (for example, after not eating for awhile), the hormone glucagon is released and causes cells to break down and release their stored glucose. When blood sugar goes up after a meal, the pancreas releases insulin, signaling cells to absorb glucose from the blood and rebuild their stores [5]. Normally, these two processes are finely tuned to make sure cells have sufficient stores of glucose, but are also ready to release it when necessary. In diabetic patients, however, the insulin response is defective, and blood sugar can get dangerously high. In fact, the term diabetes ("passing through" in latin) mellitus ("sweetness") refers to the fact that blood sugar levels are so high that glucose is excreted in urine.

The two forms of diabetes have similar symptoms but have two different root causes. Type 1 diabetes is the result of an inability to produce insulin. Often, this is because the body's own immune cells attack the β-islet cells of the pancreas - the sole producers of insulin. This is an example of an autoimmune disease, and is thought to be unrelated to diet and lifestyle.

Type 2 diabetes is far more common, accounting for nearly 90% of all cases of diabetes, and is the form of the disease that has been linked to obesity. Type 2 diabetics are able to produce insulin, but their cells are unable to respond to it.

Today, diabetes can be effectively managed with the use of synthetic insulin injections, but this requires constant vigilance. If blood sugar levels aren't managed properly, the medical complications can be severe and widespread. Chronic high blood sugar can damage blood vessels, increase a person's risk for heart attacks and stroke by two to four times compared to a non-diabetic person, and can result in significantly higher blood pressure. Blood vessel damage can be so severe that it can lead to blindness and nervous system damage or cut off blood flow to the lower limbs, necessitating amputation [6].

Inflammation, Obesity, and Diabetes

Though aberrant immune responses have long been associated with type 1 diabetes, recent evidence has begun to mount that inflammation and the immune system is also heavily involved in type 2 diabetes. Inflammation is the immune system's normal response to infection. Immune cells called macrophages can detect the presence of bacteria and viruses, and release signals that alert the rest of the immune system to an invading bug. These signals are called cytokines, and they promote an anti-pathogen response by increasing blood flow to the infected tissue, recruiting other immune cells from the blood and activating other, more potent immune cells. These activities result in the characteristic redness, swelling and pain associated with inflammation.

One of the first suggestions that the immune system was involved in type 2 diabetes came in 1993, when researchers at Dana Farber Cancer Institute in Boston, MA noticed an increased production of inflammatory cytokines in obese rats that are prone to diabetes. These cytokines were produced directly by adipocytes, the cells that store fat. Interestingly, when cytokine activity was blocked, these rats became less resistant to insulin and their blood-sugar levels dropped [7].

Since then, the evidence for the role of the immune system in the link between obesity and diabetes has continued to mount. In addition to their role in immunity, macrophages are also involved in maintaining healthy tissues and clearing debris. Macrophages in fat tissue are responsible for cleaning up after adipocytes that have burst and released their fat molecules, but in obese individuals, the increased number of adipocytes can overwhelm macrophages. In the last decade, several published studies showed that obese animals and humans have increased numbers of macrophages in their fat tissue, and that these macrophages were more prone to promote inflammation than the macrophages in non-obese individuals. More recently, the cytokines produced by these macrophages have been shown to have a direct effect on insulin resistance [8].

This research is already leading to potential treatments. Several promising anti-inflammatory drugs are presently undergoing clinical trials, and earlier this year, a study in mice showed that a drug currently used to treat arthritis may help decrease insulin resistance. These drugs may be expensive, however, and may not reach the general public for a long time. Until scientists find an affordable and effective treatment, the best way to prevent diabetes is to maintain a healthy weight. A recent study predicted that if current trends continue, 83 percent of men and 72 percent of women will be overweight or obese by 2020. As good as the science gets, we may not be able to make headway against this disease without changing people's behavior.

References

[1] Centers for Disease Control and Prevention: National Diabetes Surveillance System. Available online at: http://www.cdc.gov/diabetes/statistics/index.htm

[2] http://apps.nccd.cdc.gov/DDT_STRS2/FAQ.aspx

[3] http://en.wikipedia.org/wiki/Body_fat_percentage

[4] http://www.nhlbi.nih.gov/guidelines/obesity/bmi_tbl.htm

[5] http://www.endocrineweb.com/conditions/diabetes/normal-regulation-blood-glucose

[6] http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002194/

[7] G.S. Hotamisligil, et al. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science, 259 (1993), pp. 87-91.

[8] Jerrold M. Olefsky and Christopher K. Glass "Macrophages, Inflammation, and Insulin Resistance." Annual Review of Physiology Vol. 72: 219-246 March 2010

[9] http://clinicaltrials.gov/ct2/results?term=anti-inflammatory+diabetes

[10] Daniel A Winer et al. "B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies." Nature Medicine 17, 610-6187 (2011).