Production of Free Fatty Acids From Blood Triglycerides
Condition: Diabetes Mellitus, Type 2; Insulin Resistance; Dyslipidemias
MeSH terms: Diabetes Mellitus, Type 2; Insulin Resistance; Dyslipidemias
Study type: Observational

Summary: 
      The overall hypothesis of these studies is that circulating triglycerides, coming primarily
      from fat in the diet, are an important source of free fatty acids. Free fatty acids are the
      major fat fuel in the body, and when they are elevated in the blood they are thought to raise
      the risk of cardiovascular disease by causing insulin resistance (in some cases leading to
      diabetes), raising blood pressure, and other effects. The investigator will use sophisticated
      methods for tracing triglycerides and free fatty acids in the blood. These methods involve
      the administration of low doses of radioactive and stable isotopes of naturally occurring
      fats. The studies will determine the contribution of triglycerides to free fatty acids in
      normal people and also in people with diabetes.
    

Detailed description: 
      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.
    

Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Volunteers from the region around Rochester, Minnesota who meet the inclusion criteria will
        be recruited.
      
Biospecimen description: 
      Plasma samples obtained during the study are stored for lipid analysis.
    
Keywords: Type 2 Diabetes; Dyslipidemia; FFA; Triglycerides; Tracers