Production of Free Fatty Acids From Blood Triglycerides
| Status: | Completed |
|---|---|
| Conditions: | High Cholesterol, Endocrine, Diabetes |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Endocrinology |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 10/21/2012 |
| Start Date: | June 2008 |
| End Date: | April 2013 |
| Contact: | John M. Miles, MD |
| Email: | miles.john@mayo.edu |
| Phone: | 507-284-5643 |
FFA Production From Triglyceride-Rich Lipoproteins
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.
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.
Inclusion Criteria:
- Type 2 diabetes
- Atherogenic dyslipidemia
- Obesity
Exclusion Criteria:
- Kidney disease
- Liver disease
- Coronary artery disease
- Retinopathy
- Neuropathy
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