Project Summary/Abstract The long-term goal of our research is to understand how obesity, specifically upper body obesity (UBO), causes insulin resistance and the other health problems such as Type 2 Diabetes. Our focus has been on how free fatty acid (FFA) release from adipose tissue lipolysis in humans affect the functioning of other tissues (lipotoxicity). The specific aims of this proposal are to: 1) determine whether insulin-resistant UBO have reduced muscle glucose uptake in response to exercise compared with insulin sensitive normal weight control volunteers; 2) assess whether the exercise signaling pathway is intact in insulin-resistant UBO compared with insulin sensitive normal weight control volunteers; 3) measure whether the trafficking of plasma FFA-palmitate into lipid intermediates is altered in insulin resistant UBO compared with insulin sensitive, normal weight control volunteers; and 4) determine whether overnight, modest increases in plasma FFA using an intra-duodenal palm oil infusion impairs exercise-stimulated muscle glucose uptake in insulin sensitive, normal weight volunteers. We will measure exercise-stimulated muscle glucose uptake in vivo and assess some of the muscle signaling proteins involved in GLUT4 translocation in insulin sensitive lean and insulin resistant UBO that are matched for fitness. We will also measure whether raising FFA in a physiological pattern using palm oil reduces exercise-stimulated muscle glucose uptake. Our hypothesis is that the distal steps involved in muscle glucose transport are altered in UBO humans (e.g. exercise-stimulated muscle glucose uptake is also impaired in UBO) and that these defects are responsible for the apparent insulin resistance with regards to muscle glucose uptake. Combined, we believe these studies will offer insights as to why UBO are insulin resistant and provide information on what therapeutic strategies to treat muscle insulin resistance are most promising.
|Effective start/end date||9/30/92 → 3/31/22|
- National Institute of Diabetes and Digestive and Kidney Diseases: $10,148,056.00
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