The proposed research will continue our work in the area of the regulation of fuel metabolism. Lipid energy is transported in the blood in several forms, including chylomicrons and free fatty acids (FFA). Chylomicrons are key elements in the absorption and storage of dietary fat, and also play a role in the pathogenesis of atherosclerosis via the production of remnant particles, but their role as a direct fuel source has not been explored. FFA are the major lipid fuel in the body, and increases in their concentration have been shown to cause insulin resistance, endothelial dysfunction and increases in the production of very low density lipoproteins. FFA are released into the blood through the action of hormone sensitive lipase on triglyceride stores in fat cells. Very little is known about the role of chylomicrons in FFA metabolism, but the potential contribution of chylomicrons to FFA is considerable, especially in people who consume high fat diets. Initial studies indicate that in addition to the role of chylomicrons in fat storage, a portion of chylomicron fatty acids are released as FFA in a process called """"""""spillover"""""""". These studies indicate that the contribution of chylomicrons to FFA is increased in type 2 diabetes. A study of spillover in the splanchnic bed found very high rates of splanchnic spillover in overweight and obese individuals with hypertriglyceridemia. Extremely accurate and precise methods have been developed by the investigator for the measurement of the concentration and specific activity of FFA and chylomicron triglyceride fatty acids in plasma. In addition, a tracer method for accurately determining the kinetics of chylomicrons has been developed. In the proposed studies, the tracer technique will be used to systematically investigate the contribution of chylomicrons to total FFA availability. The technique will be applied to normal subjects at rest and after exercise, as well as subjects with type 2 diabetes mellitus and hypertriglyceridemia. Specifically, these studies will: 1) determine whether weight loss in people with type 2 diabetes reduces spillover from chylomicrons;2) determine whether acute lowering of FFA with insulin infusion reduces spillover in nondiabetic individuals with dyslipidemia;3) determine whether noninsulin-mediated lowering of FFA reduces spillover in diabetic individuals with dyslipidemia, and 4) determine whether obese, insulin-resistant individuals have increased spillover in the splanchnic bed.
Elevated free fatty acids levels (FFAs) in blood are a recognized cause of insulin resistance and may contribute to the development of diabetes, high blood pressure and cardiovascular disease. Dietary fat may contribute to FFAs by a process known as """"""""spillover"""""""", which occurs during fat storage. This work is a comprehensive evaluation of the importance of spillover as a contributor to FFAs.
|Curry, Timothy B; Hines, Casey N; Barnes, Jill N et al. (2014) Relationship of muscle sympathetic nerve activity to insulin sensitivity. Clin Auton Res 24:77-85|
|Miles, John M; Rule, Andrew D; Borlaug, Barry A (2014) Use of metformin in diseases of aging. Curr Diab Rep 14:490|
|Nelson, Robert H; Mundi, Manpreet S; Vlazny, Danielle T et al. (2013) Kinetics of saturated, monounsaturated, and polyunsaturated fatty acids in humans. Diabetes 62:783-8|
|Almandoz, Jaime P; Singh, Ekta; Howell, Lisa A et al. (2013) Spillover of Fatty acids during dietary fat storage in type 2 diabetes: relationship to body fat depots and effects of weight loss. Diabetes 62:1897-903|
|Curry, Timothy B; Somaraju, Madhuri; Hines, Casey N et al. (2013) Sympathetic support of energy expenditure and sympathetic nervous system activity after gastric bypass surgery. Obesity (Silver Spring) 21:480-5|
|Nelson, Robert H; Vlazny, Danielle; Smailovic, Almira et al. (2012) Intravenous niacin acutely improves the efficiency of dietary fat storage in lean and obese humans. Diabetes 61:3172-5|
|Muthusamy, Kalpana; Nelson, Robert H; Singh, Ekta et al. (2012) Effect of insulin infusion on spillover of meal-derived fatty acids. J Clin Endocrinol Metab 97:4201-5|
|Curry, Timothy B; Roberts, Shelly K; Basu, Rita et al. (2011) Gastric bypass surgery is associated with near-normal insulin suppression of lipolysis in nondiabetic individuals. Am J Physiol Endocrinol Metab 300:E746-51|
|Sparks, Lauren M; Ukropcova, Barbara; Smith, Jana et al. (2009) Relation of adipose tissue to metabolic flexibility. Diabetes Res Clin Pract 83:32-43|
|Sparks, Lauren M; Pasarica, Magdalena; Sereda, Olga et al. (2009) Effect of adipose tissue on the sexual dimorphism in metabolic flexibility. Metabolism 58:1564-71|
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