Wednesday, May 15, 2013

A new understanding of Type 2 Diabetes and Cardiovascular disease

A new discovery by scientists at the Harvard School of Public Health has brought us closer to understanding Type 2 Diabetes and the metabolic syndrome.  Adipose Protein 2(aP2), a carrier protein found in adipocytes and macrophages, appears to also act as a signaling molecule that adipocytes secrete to increase glucose production in the liver(1).  This is not the first study showing aP2 to be a contributing factor to Type 2 Diabetes and the metabolic syndrome.  Let's look take a look at some of the other data.

In a study in 1999, disrupting the aP2 gene in mice lead to a 40% drop in basal lipolysis and a 300% increase in the amount of non-esterified fatty acids stored within the fat cells of the mice with aP2 disrupted(2).  This indicates aP2 as a significant, if not the sole, contributor to the increase in fatty acid release from fat cells found in insulin resistance and the metabolic syndrome.  Within fat cells, it appears aP2 is the signal that says, "Enough, no more fat!"  Recall that Lipopolysaccharide (LPS) causes system-wide insulin resistance when it is introduced in to the body.  A  recent study showed that injecting LPS in to the leg of humans lead to muscle insulin resistance and increased lipolysis in fat cells; causing them to leak palmitate, one of the primary fatty acids stored in humans(3).  It is likely that the palmitate was shuttled from the adipocyte by aP2 as aP2 has a 2-3x greater affinity for palmitic acid than does KLBP, the other lipid binding protein found in adipocytes(4).  It appears LPS induced endotexemia is an integral step in the development of Type 2 Diabetes leading to not only muscle and fat cell insulin resistance, but also increased glucose production in the liver.  In addition, blocking aP2 expression in macrophages and adipocytes has been shown to both decrease inflammation as well as protect against insulin resistance(5).  The role of aP2 in the metabolic syndrome does not end there.

The gene for aP2 is also expressed in macrophages, cells of the immune system that engulf invaders in order to neutralize them  Recall from the last LPS blog found here that when LPS attaches to the cell membrane of macrophages that macrophages switch from metabolizing fatty acids to metabolizing glucose.  A byproduct from this switch, succinate, causes the secretion of IL-1Beta which induces insulin resistance in muscle cells and adipocytes.  When exposed to oxidized LDL, macrophages become foam cells and contribute to the accumulation of plaque on blood vessel walls as aP2 becomes the most upregulated gene(6, 7) and macrophages that are aP2 deficient show a reduced capacity to form foam cells(8).  In addition, it is IL-1Beta that signals muscle and fat cells to become insulin resistant and it is this insulin resistance that increases lipolysis in the fat cell and causes it to dump fatty acids, and potentially aP2, in to the bloodstream.

If all of this were not bad enough, high blood glucose causes an increase in monocyte production by bone marrow.  These monocytes move to blood vessel walls and prevent the removal of plaque deposits, which over time would increase plaque accumulation on blood vessel walls.  Reducing blood glucose levels prevents this increased production of monocytes and blood levels of the signaling molecule that causes this over-production of monocytes coincides with the level of coronary artery disease seen in Type 1 Diabetics(9).  This entire story could potentially be the vicious cycle that leads to cardiovasular disease.  Having a liver that over-secretes glucose because it thinks your fighting an infection cannot possibly help attenuate the situation.

When looking at this issue from an evolutionary biology perspective, it seems odd that an immune response would get so out of whack that it would cause these issues in an organism.  When we look at in the proper context, it is absolutely a beneficial trait.  In the vast majority of our time here, fasting blood glucose levels were probably between 80-90mg/dL.  A mild to moderate elevation in a blood glucose level that low is probably not going to lead to sufficient plaque accumulation, certainly not in comparison to the 125mg/dL+ fasting blood glucose seen in Type 2 Diabetics.  In addition, there was probably still sufficient physical activity during infection to prevent major rises in blood and glucose.  A muscle that is insulin resistant is not incapable of burning glucose, it is incapable of using insulin to store it.  Physical activity would still cause translocation of GLUT4 to the muscle cell membrane to take in glucose, the priority is not to prevent muscle from burning glucose it's to prevent circulating glucose from being stored in muscle tissue as it is needed for the immune system.  This would allow the organism to flee in the case of immediate danger while healing from an infection.  Once the infection is healed, it is unlikely that blood glucose levels would rise enough to prevent healing of plaque on blood vessel walls when a person has to actively go out and hunt or gather their food.

In a pretty thorough discussion of Otzi, the well preserved mummy of a 45 year old man who lived approximately 5400 years ago, Dr. Stephan Guyenet identifies a few health issues that Otzi experienced.  In addition to having a few of his major arteries calcified, Otzi had several signs of infectious disease including intestinal parasties, Lyme's disease, and an "unknown illness that occurred three times in the four months prior to his death."  Otzi also consumed significant amounts of grain, as evidenced by the belly full of wheat found in his stomach.  We will never know the specifics of Otzi's health, but the fact that there was significant infectious disease prior to his death as well as significant atherosclerosis points to a potential relationship.  Were the calcifications in his arteries accumulated over time or was his level of calcification a snapshot of his poor health at the time of his death?  Evidence points to atherosclerosis being a part of the human condition, is that role as collateral damage from an overactive immune system?  We certainly cannot ignore the effect intestinal parasites may have had on the composition of his gut flora as well.

One of the theories currently being kicked around for our chronic disease epidemic, and the basis for the Paleo diet, is that the storage proteins in grains and legumes as well as the casein found in dairy can cause a molecule called zonulin to open the tight junctions between cells of the intestinal wall.  This allows LPS in to the bloodstream, potentially initiating the above events to fight an infection that doesn't really exist.  There is clinical evidence that the Paleo diet leads to better cardiovascular profiles when compared to a Mediterranean diet(10, 11) as well as better glucose tolerance(12).  The chief difference between the 2 diets is that the Mediterranean diet allows the consumption of grains, legumes, and dairy.  Zonulin is a huge problem for people with Celiac disease because they tend to have high levels of it and the ingestion of gluten causes even higher levels.  Gluten causes the same response in people without Celiac disease, but to a much smaller degree.  In someone with a more robust immune system or who only gets minor doses of these offending proteins, it probably does no significant permanent damage.  This could change with age, however, as the immune system becomes less effective and potential changes in gut flora manifest themselves after  decades of eating foods that may not be suited to a healthy gut

If the triggers do turn out to be the proteins in grains, legumes and dairy; Western civilization is in trouble.  Processed foods are loaded with this stuff; just try to find one without grains (Wheat, corn), legumes (Soy, peanuts), or dairy (Milk, cheeses).  Another potential route for LPS to make it's way in to the bloodstream is via bacterial overgrowth in to the small intestine.  The type of bacteria you need to worry about primarily consume sugars.  Given that the average American eats about 130lbs of sugar annually, it is not unlikely that some of it may feed bacteria that could pose a problem.  At the very least, dumping that amount of sugar in to your bloodstream will negatively impact your ability to remove accumulated plaque from your blood vessel walls.  Over the course of 40-50 years, this could ultimately lead to your demise.


While this new discovery helps give us a mechanistic look at how blood glucose regulation and plaque accumulation on blood vessel walls may go awry in some instances, it still leaves quite a few questions to be answered.  Is this the most common way this process happens?  How do food reward and leptin fit in here?  Why is our brain wired so that we overconsume foods that are bad for us healthwise?  How is the gut flora involved?  Are these issues causes or effects?  None of this changes the fact that overconsumption will more than likely cause the same problems, but is it via the same mechanism or a different one?  Does food overconsumption eventually lead to reaching your genetic capacity to store fat and leaching of fatty acids, and aP2, in to the bloodstream to initiate the same process?  As you can see, whenever we find one answer, 20 more questions pop up.