- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01612234
Saturated Fat Versus Monounsaturated Fat and Insulin Action
Palmitate Metabolism and Insulin Resistance
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Palmitic acid (PA), impairs insulin sensitivity in skeletal muscle, and replacing PA in the diet with oleic acid (OA), a monounsaturated fatty acid (FA), may be beneficial. The first objective of this project is to understand the effects on lipid metabolism and skeletal muscle lipid composition, insulin signaling, and inflammatory signaling of two common variations in FA composition of the diet: (1) The typical intake of North America where PA and OA are present in equal proportions (HI PA diet). (2) The Mediterranean FA composition in which PA is much lower and OA much higher (HI OA diet). PA may induce insulin resistance in skeletal muscle cells via its accumulation in lipids within muscle cells and via activation of inflammatory signaling. The second objective of this project is to assess the hypothesis that a high intake of PA will down-regulate its own one-carbon (initial) oxidation, leading to increased inflammatory signaling and decreased insulin signaling. However, there is literature evidence that FA may induce defects in insulin signaling, if FA are not completely oxidized; therefore, the third objective is to assess the hypotheses that a high PA diet may decrease complete oxidation of FA and possibly accelerate initial FA oxidation. A double-masked, cross-over trial of the effects of a high PA diet versus a high OA/low PA diet in 16 overweight or obese subjects and 16 lean subjects (aged 18 - 40 yr) will be conducted to investigate the following Specific Aims:
- To test the hypothesis that increased intake of PA will cause a decreased rate of [1-13C]-PA oxidation and will be associated with: (a) increased inflammatory signaling, within the muscle and by peripheral blood mononuclear cells; (b) Decreased insulin signaling as characterized by decreased, whole body, peripheral insulin sensitivity (euglycemic/hyperinsulinemic clamp) and, in skeletal muscle, decreased phospho-AKT (Ser473), increased phospho-IRS-1 (Ser636/Ser639), decreased tyrosine phosphorylation of IRS-1, and decreased membrane content of GLUT4.
- To test the hypothesis that increased intake of PA will cause less complete mitochondrial fatty acid oxidation, perhaps associated with dysfunction of the TCA cycle and increased reactive oxygen species formation. This hypothesis will be tested by measuring whole body and muscle (upper limb) relative rates of oxidation of [13-13C]-PA and [1-13C]-PA and by determining the serum profile of acylcarnitines, the urine concentrations of organic acids, and muscle concentrations of protein carbonyls.
- To test the hypothesis that a high PA diet will lead to less complete oxidation of FA, less insulin signaling in skeletal muscle in response to a test meal, less whole body insulin sensitivity, increased dysfunction of the TCA cycle, and greater reactive oxygen species formation compared to the results obtained in obese versus lean humans.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Vermont
-
Burlington, Vermont, United States, 05401
- The Unversity of Vermont Clinical Research Center at Fletcher Allen Health Care
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- healthy young adults,
- 18 - 40 years of age
Exclusion Criteria:
- regular aerobic exercise training,
- dyslipidemia, and
- type 2 diabetes or insulin resistance
Study Plan
How is the study designed?
Design Details
- Primary Purpose: PREVENTION
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: High palmitate or high oleate diet.
This is a solid food diet in which vegetable oils are used to create a dietary fat composition similar to the average American/Western diet in which palmitic and oleic acid are ingested in approximately equal amounts (high palmitate diet) or a composition similar to the Mediterranean Diet (low palmitate, high oleate, using hazelnut oil as the source of fat).
There are no interventions other than the diet itself.
|
High palmitate diet composition: Fat, 40.4% kcal; palmitic acid, 16.0% kcal; oleic acid,16.2%
kcal.
High oleate diet composition: Fat, 40.1% kcal; palmitic acid, 2.4% kcal; oleic acid, 28.8% kcal
|
EXPERIMENTAL: high palmitate or high oleate diet
This is a solid food diet in which vegetable oils are used to create a dietary fat composition similar to the average American/Western diet in which palmitic and oleic acid are ingested in approximately equal amounts (high palmitate diet) or a composition similar to the Mediterranean Diet (low palmitate, high oleate, using hazelnut oil as the source of fat).
There are no interventions other than the diet itself.
|
High palmitate diet composition: Fat, 40.4% kcal; palmitic acid, 16.0% kcal; oleic acid,16.2%
kcal.
High oleate diet composition: Fat, 40.1% kcal; palmitic acid, 2.4% kcal; oleic acid, 28.8% kcal
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Whether increased palmitate balance (as measured by intake and the rate of [1-13C]-PA oxidation) causes increased insulin resistance and increased inflammatory signaling by peripheral blood mononuclear cells
Time Frame: up to 4 yr
|
Insulin sensitivity, inflammatory signaling, palmitate balance, and incomplete oxidation of palmitate in lean and obese young adults.
|
up to 4 yr
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
We will examine the link between palmitate intake and balance and oxidative stress measured using muscle and peripheral blood markers of oxidative stress and antioxidant responses.
Time Frame: up to 4 yr
|
activation of c-Jun N-terminal kinase (JNK) and heme oxygenase 1 in skeletal muscle in response to the diets.
|
up to 4 yr
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Craig L. Kien, M.D, Ph.D., The University of Vermont
Publications and helpful links
General Publications
- Kien CL, Everingham KI, D Stevens R, Fukagawa NK, Muoio DM. Short-term effects of dietary fatty acids on muscle lipid composition and serum acylcarnitine profile in human subjects. Obesity (Silver Spring). 2011 Feb;19(2):305-11. doi: 10.1038/oby.2010.135. Epub 2010 Jun 17.
- Kien CL, Bunn JY, Stevens R, Bain J, Ikayeva O, Crain K, Koves TR, Muoio DM. Dietary intake of palmitate and oleate has broad impact on systemic and tissue lipid profiles in humans. Am J Clin Nutr. 2014 Mar;99(3):436-45. doi: 10.3945/ajcn.113.070557. Epub 2014 Jan 15.
- Kien CL, Bunn JY, Tompkins CL, Dumas JA, Crain KI, Ebenstein DB, Koves TR, Muoio DM. Substituting dietary monounsaturated fat for saturated fat is associated with increased daily physical activity and resting energy expenditure and with changes in mood. Am J Clin Nutr. 2013 Apr;97(4):689-97. doi: 10.3945/ajcn.112.051730. Epub 2013 Feb 27. Erratum In: Am J Clin Nutr. 2013 Aug;98(2):511.
- Kien CL, Bunn JY, Poynter ME, Stevens R, Bain J, Ikayeva O, Fukagawa NK, Champagne CM, Crain KI, Koves TR, Muoio DM. A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults. Diabetes. 2013 Apr;62(4):1054-63. doi: 10.2337/db12-0363. Epub 2012 Dec 13.
- Kien CL, Matthews DE, Poynter ME, Bunn JY, Fukagawa NK, Crain KI, Ebenstein DB, Tarleton EK, Stevens RD, Koves TR, Muoio DM. Increased palmitate intake: higher acylcarnitine concentrations without impaired progression of beta-oxidation. J Lipid Res. 2015 Sep;56(9):1795-807. doi: 10.1194/jlr.M060137. Epub 2015 Jul 8.
- Kien CL, Bunn JY, Fukagawa NK, Anathy V, Matthews DE, Crain KI, Ebenstein DB, Tarleton EK, Pratley RE, Poynter ME. Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-sensitive genes. J Nutr Biochem. 2015 Dec;26(12):1599-606. doi: 10.1016/j.jnutbio.2015.07.014. Epub 2015 Aug 1.
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Other Study ID Numbers
- R01DK082803 (NIH)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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