Wednesday, April 24, 2013

LPS, insulin resistance, and obesity...An update

A new study in the journal Nature has opened up a new understanding in the relationship between obesity, inflammation and insulin resistance that could also have a larger impact on how we view weight loss, and more importantly health and well being.  The study, published in Nature in March of 2013, has lead to a shift in my line of thinking.  Recall from this blog that when Lipopolysaccharide (LPS) manages to find it's way in to your bloodstream via a leaky gut, it induces system-wide insulin resistance.  It seemed as though this would be a good strategy to conserve glucose for the brain, but this new study in Nature implies a different reason.

LPS, fuel selection, and cellular communication

The study, located here, identifies a metabolite called succinate as a signaling molecule in immune cells called macrophages that causes them to increase secretion of the inflammatory molecule IL-1B(1).  Succinate levels increase because macrophages shift their metabolism from oxidative phosphorylation (Fat burning) to aerobic glycolysis (Sugar burning) when LPS attaches to receptors on the plasma membrane.  This would increase macrophage activity as glycolysis produces energy much more rapidly than oxidative phosphorylation, something you want when a foreign invader enters you bloodstream.  Theoretically speaking, when succinate increases IL-1B, it is telling the rest of your cells that glucose is needed to fight the infection rather than for being stored for later muscular contraction.  Perhaps the relationship between inflammation and insulin resistance is simply communication between body systems (Immune and musculoskeletal) to partition resources(glucose) to the more pressing need(fighting an infection). 

This doesn't prevent muscles from burning glucose as physical activity causes glucose transporters to bring in glucose to muscles cells.  What it does is block insulin from increasing glucose uptake in to resting muscles as insulin's primary function is to store glucose as glycogen for later use.  Basically, it shouldn't directly impact the use of glucose by muscles, but it will indirectly impact the use of glucose in muscle by preventing the storage glucose for later use during recovery.  Click here for a not-as-sciencey rundown of this. This is not to say there is no benefit to the brain in this scenario, but since the signal originates from the immune system we should focus there.

When the scientists blocked succinate production with the anti-epilepsy drug vigabatrin, they were able to inhibit expression of IL-1B, cutting down the level of inflammation.  High IL-1B levels are seen in many diseases including diabetes.  Let's take a look at some of my older blogs and see where this all fit's in to the obesity/diabetes discussion.

Previous Type 2 diabetes discussion

Recall from here and here that Type 2 diabetics and people prone to obesity tend to have a higher percentage of Type IIx muscle fibers and a lower percentage of Type I fibers. There are 3 basic muscle fiber types: Type I, Type IIa, and Type IIx.  The type I fibers burn primarily fat, the IIa fibers burn primarily glycogen, and the IIx fibers burn primarily ATP as they do not tend to store much energy in the form of fat or glycogen to recharge ATP.  However, the Type II muscle fiber types can convert in to one another with physical activity or a lack of it.  When a person becomes sedentary over long periods of time, the IIa fibers begin converting to IIx fibers as their need to store glycogen to recharge ATP stores is not needed because they are not used.  When a person begins using the IIx fibers more with physical activity, they convert in to the IIa fibers as they begin to store more glycogen.  This leaves them with more room to store glycogen which gives the glucose from excess carbohydrate consumption a place to go.  However, this point is moot if LPS is inducing system-wide insulin resistance by partitioning glucose to the immune system and away from muscle cells.

This causes a double-edged sword scenario.  On the one hand, having a higher percentage of Type II muscle fiber types means a larger portion of your musculature uses glucose as a fuel supply.  In a trained state this is beneficial but in an untrained state you have a larger percentage of muscle fibers that don't use energy.  The problem is, as discussed in the first blog mentioned in the above paragraph, high insulin levels are what cause the IIa fibers to convert to IIx fibers.  Since the IIx fibers are the most insulin resistant of the muscle fibers, LPS induced system-wide insulin resistance can force adaptation in a way that will just make you progressively more insulin resistant, even when you are no longer directly dealing with LPS in the blood. As such, high levels of LPS need to be dealt with and avoided altogether if fixing insulin resistance is your goal.  However, we still have the other edge of that sword to deal with.

Since people who are prone to diabetes and obesity have a higher percentage of Type II muscle fibers, this means they also have a lower percentage of Type I muscle fibers.  Recall that the Type I muscle fibers burn primarily fat.  If LPS is inducing insulin resistance to spare glucose for the immune system, this means muscle is going to have to metabolize fat.  The problem here is that a lower proportion of Type I muscle fibers means a reduced ability to metabolize fat.  This effect, coupled with a decreased ability to suppress fatty acid release from adipose tissue(2) could be why we see something that is common in people with Type 2 diabetes, high levels of triglycerides in the blood.  We also see an accumulation of triglycerides in tissues that should not have high triglyceride levels such as muscle and liver tissue(2).  In people with a higher percentage of Type I muscle fibers, this may not be a concern as they are more equipped to metabolize fat and the Type I fibers are the most sensitive to insulin. This could help explain why they are less likely to contract Type 2 diabetes.


As you can see, having LPS in your bloodstream is far from an ideal scenario.  It has been hypothesized that the consumption of grains and dairy can increase the likelihood of LPS making it's way in to the bloodstream via a leaky gut.  This could potentially be one of the reasons a Paleo diet has been shown to improve glycemic control at a rapid rate, much faster than a Mediterranean diet (Paleo lowered FBG by 23 mg/dL in 10 days vs 0mg/dL for Mediterranean diet)(3).  The primary difference between these 2 diets is that the Paleo diet is grain, legume and dairy free while the Mediterranean diet is not.  In this particular study, they did not measure IL-1B levels and in other studies they measured CRP levels with no significant change (4).  Given the results of the recent study in Nature, perhaps measuring IL-1B  in a study comparing the Paleo diet with the Mediterranean diet can give us an answer to these questions and bring us closer to understanding more of the mechanisms that underlie insulin resistance and Type 2 diabetes.