Written by: Judah Boulet
As we learn more and more about disease states, there tends to be more and more overlap between the pathology of acute inflammatory conditions and the pathology of 21st century chronic disease. At his SUNY New Paltz lecture in February, Robb introduced some correlations between Sepsis and Type 2 Diabetes Mellitus (T2DM). Many moons ago in graduate school, I had looked at both of these conditions separately, under a different guiding principle, so never put the two together, nor had research been done linking the two. Due to time constraints Robb was unable to get deep into the geek speak heart of the matter, however, the general conclusion he drew was that the etiology of both conditions, T2DM and Sepsis, are the same. In order to take a trip down memory lane back to my early 20’s, I can now see the link between the two.
Both sepsis and T2DM are a direct result of the body’s inflammatory response causing the body’s normal metabolic systems to go haywire. The key difference outside of main causality of each condition is the time course of the response. Sepsis is generally an acute condition which can quickly suck the life out of those inflicted. It is the most common cause of mortality in the non-coronary ICU, as the syndrome can progress to a graver condition, septic shock. Obesity, and the potential resulting T2DM, on the other hand are chronic conditions that suck the life out of society, as well as the individual, slowly. In both the diabetic and the septic patient, cardiovascular system dysfunction is the primary cause of morbidity. In both diseases, vascular damage of the endothelium in both small and large blood vessels lead to injuries to multiple organ and tissue structures.
Obesity, and the T2DM which results from it, are now being characterized as diseases of inflammation. Obesity can manifest itself as a low-grade chronic infection, and as a result, a broad inflammatory response (immune response) is generated. Whenever a broad inflammatory response is generated, a plethora of chemical messengers involved with the immune system get released into the bloodstream, some of which are Interleukins 1, 6 and 8 (IL-1, IL-6, IL-8), Tumor Necrosis Factor Alpha (TNF), and C-reactive peptide (CRP).
Adipose tissue, our fat tissue, is what we accumulate as we become obese. Adipose tissue needs to be viewed as a highly active endocrine organ, and not just as a stockpile of excess energy. Adipose tissue secretes a multitude of chemical messengers, called adipokines, which work as messengers throughout the entire body. Some of these messengers are limited to being secreted only by the adipose tissue (ex: leptin), while others are secreted from other sources as well. Two of the adipokines secreted by adipose tissue are TNF and IL-6, which are also secreted by the cells of the immune system to generate an immune response.
While an obese individual’s adipose tissue is actively serving as an endocrine organ secreting various messengers, like TNF, the tissue itself becomes inflamed and macrophages (immune system cells) deposit themselves into the tissue and release their own chemical signals, including IL-8, IL-6, IL-1 and TNF. It is these inflammatory signals that lay the basis for insulin resistance.
Insulin typically binds to a receptor on the cell surface and activates that receptor, akin to someone ringing a doorbell. The receptor causes a response to occur in the cell, via second messengers, which is akin to someone in the house hearing the doorbell. In a normal cell, these second messengers cause something to happen in the cell allowing glucose to enter, or in our doorbell scenario, someone goes and opens the door, letting in whoever is there.
When there are high levels of inflammatory signals, like TNF and IL-6, these second messengers don’t respond. Their actions are blocked by TNF and IL-6. This is akin to the batteries not working in the doorbell. It does not matter how many times the initial stimulus of the receptor happens, no final response will occur-the door does not get open. With no response, the actions of insulin on the cell do not occur, and as a result, there is an increase of glucose and free fatty acids (FFA) in the blood. The cells become resistant to insulin. Another of the pro-inflammatory cytokines mentioned previously, IL-1, also in response to hyperglycemia has a role in regulating insulin secretion. A main issue with Type 2 Diabetes Mellitus is that chronically high glucose levels, due to insulin resistance, leads to an even greater increase of inflammatory mediators, and these mediators have the ability to cause endothelial (vascular) damage.
Insulin resistance is also characterized by hyperactivity of platelets, the parts of the blood which cause blood to form clots, by not only increasing the aggregation and adherence of platelets to the endothelium, however also activating the enzymes and signals in the blood to favor a clotting situation (formation of a thrombus). This also is most likely the direct result of the elevated levels of inflammatory mediators in the bloodstream in the obese patient (IL-1, IL-6, TNF).
In a nutshell, obesity leads to inflammation which leads to insulin resistance which leads to T2DM, meaning more inflammation and a degradation of the cells lining our vasculature, more potential thrombi, which results in widespread cardiovascular and organ issues/malfunctions for the Type 2 Diabetic.
The same process occurs with sepsis, however, in a very acute manner. Sepsis is the uncontrolled inflammatory response that usually occurs due to a gram-negative bacterial infection in the blood stream. The pathophysiology of sepsis is not from the pathogen, but is entirely due to the host response. The bacteria release an endotoxin called LPS (lipopolysaccharide) and our immune systems go haywire. LPS triggers a large systemic inflammatory response (lab markers of sepsis include high levels of IL-6, IL-8 and TNF) which if not treated aggressively, could lead to septic shock (body shuts down and you die). Sepsis and septic shock have high mortality rates, 20-35% and 40-60% respectively. The LPS, just as in obesity, triggers an immense inflammatory cascade, including the release of high levels of TNF and IL-6. The TNF response causes massive insulin resistance, and increases in blood glucose and FFA, which, as we described in diabetes, causes a greater increase of inflammatory mediators. This in turn, accentuates the initial problem, which leads to massive endothelial dysfunction and multiple organ dysfunction syndrome (MODS). While the endothelium is turning to mush, the same inflammatory markers are causing a pro-coagulant effect at the endothelium. Sound familiar?
Treatment for sepsis revolves around blocking the widespread inflammatory response, along with aggressively using insulin to lower the hyperglycemic condition. It has been shown that insulin promotes endothelial survival, and that along with tight blood glucose control, has a protective effect on endothelial cells. Protection of the vascular endothelium would decrease organ dysfunction. Sepsis is a condition which is difficult to prevent, so treating symptoms is a necessity. Obesity and T2DM if looking at it from a perspective of controlling inflammation, is a lot easier fix. Prevent the inflammation, maintain insulin sensitivity, and maintain tight glucose control all by eating a diet high in nutrient quality and low in inflammatory properties, and possibly generate a protective effect of the endothelial lining, thereby preventing or lessening the end results of the disease state.
Am J PhysiolEndocrinolMetab. 2007 Mar;292(3):E740-7Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes.
Journal of Leukocyte Biology 2004:75 413-421 The roles of insulin and hyperglycemia in sepsis pathogenesis
Diabetes Care August 2001vol. 24 no. 8 1476-1485 Platelet Dysfunction in Type 2 Diabetes
Blood May 15, 2003 vol. 101 no. 10 3765-3777The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome
Diabetes.1995;44:1323-1327 High-glucose–triggered apoptosis in cultured endothelial cells.
ArteriosclerThrombVasc Biol.2000;20:402-409 Insulin-mediated stimulation of protein kinase Akt: a potent survival signaling cascade for endothelial cells. .
J Clin Invest. 2005;115(5):1111–1119. Inflammation, stress, and diabetes
Circulation.2002; 105: 2-4On Evolutionary Biology, Inflammation, Infection, and the Causes of Atherosclerosis
VitamHorm. 2006;74:443-77.Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells.
J Clin Invest. 1995 May; 95(5): 2409–2415.Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
Judah Boulet is a co-owner and Programming Director at CrossFit Providence. He holds a MS in Pharmacology and Toxicology, teaches high school Chemistry and Biology, and coaches rugby. He also teaches a class in Nutrition, Diet and Health at Merrimack College, where he uses The Paleo Solution as a required reading in his class.
To reverse it type 2’s need to cut the carbs and increase fat. Cutting carbs gets good buy in, increasing protein gets good buy in, but most ppl I’ve tried to help are too afraid of increasing fats. So they get good short term results but eventually fall off the program due to lack of satiety due to lack of fat
Gotta love it. New and exciting news: a Paleo Diet can help avoid chronic disease by reducing inflammation! Love the post Chris.
I was curious about how the two were going to be connected but after reading I have to say very informative article. @ Paleoslayer I have seen the same thing as you with people being scared of fat still. I wont eat fat because its going to kill me but Ill eat the carbs that gave me the disease in the first place that is going to kill me. Very disapointing to watch.
i like avocados and coconut oil, but boy oh boy grass fed butter is manna from heaven. When I first went paleo, i used to have cheat nights- gluten free pizza,and whatnot. I dont even crave that crap anymore.
On the genetic vs. diet only discussion:
My take is that it is both. Probably the original human condition was to have a high insulin response to carbohydrate intake. The 5000 year old corpse called the Iceman had the genes for insulin resistance, as do most non-agricultural or recently agricultural people. It seems that we vary in our “hard-wired” response to carbs in the diet. There seems to have been an evolutionary pressure in agriculture dependent societies for a lessening in insulin response to grain consumption, probably because it conferred an survival advantage in a food resource depleted environment that made grain growing necessary to ward off starvation. However, we are all damaged by the current high carb toxic foods standard western diet, and the huge increase in auto-immune disease and the diseases that are part of the Metabolic Syndrome is proof of this. In any case, the fix is the same–eliminate the Neolithic foods, get rid of the toxic elements in the diet, and do a bit of exercise which will help the insulin resistance.
Robb,
Here is a very interesting MedScape educational e-mail that received today. I recalled reading this article and thought I would pass this along.
http://www.medscape.org/viewarticle/756023?src=emed_case_nl_0
I was a very fit 50yo lifter that came down with pneumonia, bombarded with IV levaquin and solu-medrol, went into sepsis, and for 23 days languished in the ventilator paralyzed by pharmacologies finest. I woke up a month later, an insulin dependent diabetic, steroid myopathy and persistent paralysis. 2 years later and I am walking, off insulin, on metformin, and weaning of many other medications. My lipids are still a mess. But I have been eating Paleo for two years. Not sure it’s helping but I am getting stronger every day.