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> Pilot Study on the Effects of Saturated Fatty Acids on Insulin Resistance, Endothelial Dysfunction and Systemic Inflammation
Co-investigators: S. Mitchell Harman, MD, PhD; Arline D. Salbe, PhD; Tinna Traustadóttir, PhD; Frank Gucciardo, PA; Peter D. Reaven, MD; Christos Katsanos, PhD
Recent studies have demonstrated an important role for sub-acute, chronic inflammation in the development of insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). A broad body of data indicates that obesity and high fat or "Western" diets activate sub-acute inflammatory processes in fat, muscle and liver tissue as well as in mononuclear cells. Work from several laboratories indicates that Nuclear Factor-kappa B (NF-kB), an inflammatory master switch for many pro-inflammatory genes and pathways, is activated in fat and liver by obesity and high fat diets. The inflammatory mediators produced by activation of this and other inflammatory signaling pathways promote the development of insulin resistance both locally and at distant sites such as skeletal muscle. These same inflammatory mediators may also increase the risk for CVD. Data indicate that one class of particularly bioactive substances in high fat diets is saturated fatty acids (SFA), which have been shown to activate the innate immune system through toll receptors 2 and 4 and induce NFkB activity and inflammation in several tissues.
Although numerous population studies and cross-sectional cohort studies have shown that dietary intake of SFA is associated with T2DM and CVD, it remains unclear whether this is a direct effect or a consequence of a generally unhealthy diet or lifestyle. Several small clinical studies have demonstrated that lipid infusion over 4-8 hours can substantially raise levels of free fatty acids and inflammatory markers and induce insulin resistance, demonstrating the direct effect of this treatment on tissue glucose metabolism. However, lipid infusion solutions are comprised of a mixture of triglyceride particles, are substantially enriched in polyunsaturated fatty acids and provide a large caloric load. We have speculated that if a diet was specifically enriched in a SFA that was uniquely pro-inflammatory, such as palmitic acid, and is ingested in larger quantities as is often the case in settings of nutritional excess, that a pronounced effect to induce insulin resistance could be established. This may be particularly true when assessing insulin resistance with a gold standard method such as the insulin suppression test, which is also highly reproducible.
This pilot study proposes to test the hypothesis that short-term (24-hour) exposure to a diet enriched in saturated fatty acids, especially palmitic acid, will induce insulin resistance, cause endothelial dysfunction and increase systemic inflammation.
Pilot Study on the Effects of Saturated Fatty Acids on Insulin Resistance, Endothelial Dysfunction and Systemic Inflammation
Principal Investigator: Panayiotis D. Tsitouras, MDCo-investigators: S. Mitchell Harman, MD, PhD; Arline D. Salbe, PhD; Tinna Traustadóttir, PhD; Frank Gucciardo, PA; Peter D. Reaven, MD; Christos Katsanos, PhD
Recent studies have demonstrated an important role for sub-acute, chronic inflammation in the development of insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). A broad body of data indicates that obesity and high fat or "Western" diets activate sub-acute inflammatory processes in fat, muscle and liver tissue as well as in mononuclear cells. Work from several laboratories indicates that Nuclear Factor-kappa B (NF-kB), an inflammatory master switch for many pro-inflammatory genes and pathways, is activated in fat and liver by obesity and high fat diets. The inflammatory mediators produced by activation of this and other inflammatory signaling pathways promote the development of insulin resistance both locally and at distant sites such as skeletal muscle. These same inflammatory mediators may also increase the risk for CVD. Data indicate that one class of particularly bioactive substances in high fat diets is saturated fatty acids (SFA), which have been shown to activate the innate immune system through toll receptors 2 and 4 and induce NFkB activity and inflammation in several tissues.
Although numerous population studies and cross-sectional cohort studies have shown that dietary intake of SFA is associated with T2DM and CVD, it remains unclear whether this is a direct effect or a consequence of a generally unhealthy diet or lifestyle. Several small clinical studies have demonstrated that lipid infusion over 4-8 hours can substantially raise levels of free fatty acids and inflammatory markers and induce insulin resistance, demonstrating the direct effect of this treatment on tissue glucose metabolism. However, lipid infusion solutions are comprised of a mixture of triglyceride particles, are substantially enriched in polyunsaturated fatty acids and provide a large caloric load. We have speculated that if a diet was specifically enriched in a SFA that was uniquely pro-inflammatory, such as palmitic acid, and is ingested in larger quantities as is often the case in settings of nutritional excess, that a pronounced effect to induce insulin resistance could be established. This may be particularly true when assessing insulin resistance with a gold standard method such as the insulin suppression test, which is also highly reproducible.
This pilot study proposes to test the hypothesis that short-term (24-hour) exposure to a diet enriched in saturated fatty acids, especially palmitic acid, will induce insulin resistance, cause endothelial dysfunction and increase systemic inflammation.
| Status: | IRB Approval pending; Funding applications pending |
| Procedures: | At baseline, study participants will give informed consent and be screened by medical history, physical exam, and standard laboratory tests. Each participant will have 5 study visits at one-week intervals. In a randomized, cross-over design, participants will be asked to consume a weight-maintaining diet (STD diet; 20% kcals as protein; 25% fat; 55% carbohydrate) or a liquid diet high in SFA (SFA diet; 65 g fat/m2 body surface area/meal) for 24 hours. Each day of testing, participants will be admitted fasting to the Clinical Research Center of the Carl T. Hayden Veteran's Administration Medical Center in Phoenix, AZ. After 15 minutes of resting, blood samples will be drawn for measures of free fatty acids (FFA), lipids, and markers of systemic inflammation. Participants will then consume a breakfast meal (STD: 20% of daily weight-maintaining calorie needs; SFA: 65 g fat/m2 BSA). Three hours later, participants will undergo testing for endothelial dysfunction using peripheral artery tonometry with the Endo-PAT system. An hour later, participants will undergo testing for insulin resistance using the insulin suppression test. After testing is completed, participants will be discharged to home and asked to return in the following 1-2 weeks to perform the crossover study. |
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