In this research study, investigators will test the effects of an approved medication for diabetes,Liraglutide, to reduce insulin resistance that develops from eating a diet high in saturated fats.
The specific aim of this study is to determine the ability of subacute liraglutide administration to protect against dietary lipid induced peripheral insulin resistance in non-diabetic subjects who have normal glucose tolerance. Recent data from our laboratory and others suggest that high fat meals, enriched with saturated fatty acids (SFA) in particular, have a unique and profound ability to induce rapid (in ≤ 24 hr) and profound onset of insulin resistance in humans. This is presumably mediated in part through delivery of lipids and lipid products generated during postprandial lipolysis into non-adipose tissue. This unique model therefore provides an excellent platform to test agents for their ability to inhibit dietary induced insulin resistance. As we and others have demonstrated the ability of GLP-1 receptor agonists to markedly suppress postprandial lipid elevations and to modify lipid metabolism, we hypothesize that liraglutide may be an effective agent to inhibit development of dietary induced insulin resistance.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
97
Subcutaneous injection by patient
Subcutaneous injection daily
Carl T. Hayden VA Medical Hospital
Phoenix, Arizona, United States
Whole Body Insulin Sensitivity (insulin suppression test)
An insulin suppression test will be measured before and approximately 3 weeks after each treatment phase. Key time frames for assessing steady state plasma glucose will be between 150 and 180 minutes during the insulin suppression test
Time frame: 3 weeks
Postprandial lipid changes (area under the curve difference in triglyceride,total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.
The major endpoints will be the area under the curve difference in triglyceride and free fatty acids between treatment arms on test day 1 and 2 following a standard meal. Other postprandial lipids will include total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.
Time frame: 3 weeks
Postprandial changes in glucose metabolism (total and incremental area under the curve differences in glucose, insulin and glucagon)
total and incremental area under the curve differences in glucose, insulin and glucagon between treatment arms
Time frame: 3 weeks
Changes in adipose tissue insulin signaling pathway activation (compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation)
Adipose tissue biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.
Time frame: 3 weeks
subcutaneous adipose tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
Adipose tissue biopsy samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.
Time frame: 3 weeks
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skeletal muscle tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
skeletal muscle tissue samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.
Time frame: 3 weeks
Adipose tissue inflammation measures (e.g., interleukin (IL)-6, and -8, adiponectin, TNF-alpha, nuclear factor-kappa b, gene and protein expression)
Adipose tissue biopsy samples will be used to compare inflammation measures in placebo and liraglutide treatment phases.
Time frame: 3 weeks
Skeletal muscle inflammation measures (e.g., IL-6,8, TNF-alpha, nuclear factor-kappa b gene and protein expression)
skeletal muscle tissue samples will be used to compare inflammation measures in placebo and liraglutide treatment phases
Time frame: 3 weeks
Adipose tissue arteriole function (vasodilation measurement)
Adipose tissue biopsy samples will be used to isolate arterioles and measure ex vivo vascular function in placebo and liraglutide treatment phases.
Time frame: 3 weeks
Changes in skeletal muscle insulin signaling pathway
skeletal muscle biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.
Time frame: 3 weeks