The association between Metabolic Syndrome, Type 2 diabetes and Inflammation.
Diabetes is the seventh leading cause of death in the U.S. Even more shocking is the fact that 80% of those who develop type 2 diabetes are obese. Obesity is a factor that initiates a cascade of events such as insulin reistance, type 2 diabetes and inflammation. Studies have shown that abnormal cytokine production specifically over expression of cytokine tumour necrosis factor-alpha (TNF-alpha) leads to insulin resistance. Another name for insulin resistance is metabolic syndrome. Over expression of TNF-alpha is predominantly seen in the obese. In fact studies have shown that after weight loss TNF-alpha expression decreases which lowers insulin resistance.
TNF-alpha over expression causes metabolic syndrome. With the metabolic support not stable, insulin resistance occurs. Metabolic syndrome (insulin resistance) causes a decrease in glucose transport. High amounts of glucose and fatty acids build up in the bloodstream. Long lasting insulin resistance as described leads to type 2 diabetes. This state of insulin resistance not only leads to type 2 diabetes but it promotes inflammation. How does it promote inflammation? Well an adipose tissue hormone called leptin initiates inflammation. Stimulation of leptin is caused through over expression of TNF-alpha and interleukin-6. This is a key link between obesity, insulin resistance and inflammation. Since obesity and diabetes are proinflammatory states, the link to controlling inflammation is by reducing obesity.
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"abnormal cytokine production specifically over expression of cytokine tumour necrosis factor-alpha (TNF-alpha) leads to insulin resistance"
If this is so then, wouldn't the inhibition of TNF-alpha be a possible solution to this disease?
TNF-a does lead to insulin resistance but is one of many pathways that does so. By blocking one pathway there is another pathway that will take over. For example, cytokines and interleukin 6 also lead to insulin resistance. I have a link to show everyone how complex this pathway is and how little we still know about the insulin resistance pathway. http://www.hagedorn.dk/staff/dep458/458profile.html
since there are other pathways that can be taken such as the ROS generation(resistance oxidative stress)inhibition of TNF-alpha is not sufficient enough to control this disease it is only one of the many methods that researchers are still studying.
TNF-alpha and IL-6 are both linked to obesity as studies have shown that they are both present in higher amounts than those who are not obese.
"abnormal cytokine production specifically over expression of cytokine tumour necrosis factor-alpha (TNF-alpha) leads to insulin resistance"
Then why is it that in other inflammatory disorders, such as AS, where TNF-a is also reportedly increased, does insulin resistance not occur? Are they perhaps just linked, or is TNF-a a precursor to insulin resistance in all cases?
It's also strange in general that TNF-alpha is such a player in obesity and insulin resistance because when you read the literature, TNF-alpha often causes cachexia, which is a wasting disease.
It's something to think about...without having done the readings that we've done, I might have suggested giving TNF-alpha to obese people in order to help them lose weight.
A most interesting commentary, Marilyn. One comment in response to your statement that insulin resistance is equivalent to the metabolic syndrome. This is not necessarily the case, and the definition/utlity of the metabolic syndrome continues to be debated amongst the WHO, European Group for the Study of Insulin Resistance, National Cholesterol Education Program, and the International Diabetes Federation. Remember that the metabolic syndrome is a "clustering" of symptoms, of which insulin resistance is only one condition. Other conditions include: visceral obesity (highly associated with increased inflammation); hypertension; hypertriglyceridemia, low HDL, hyperglycemia/impaired glucose tolerance.
Marilyn I found this to be an extremely informative posting. I think it would be interesting to see whether an obese woman would pass on the over expression of TNF-alpha to her children.
kristen that is a very interesting question.i would love to see a study conducted on the possible gentic passing of overexpression in cytokines.but so far there hasnt been any yet.
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