Basic Research Study to Examine the Relation Between Muscle Insulin Resistance and Lipid Production in the Liver.

Basic Research Study to Examine the Relation Between Muscle Insulin Resistance and Lipid Production in the Liver.

The purpose of this study is to examine the pathophysiology of insulin resistance and the relation to the metabolic syndrome in humans.

In this study insulin resistant (IR), young offspring of parents with type 2 diabetes (18-46 years) and healthy, lean elderly individuals (65-90 years) will undergo 1H/13C MRS measurements of liver and muscle lipid and glycogen content before and after a high carbohydrate meal challenge. Hepatic de novo lipogenesis will be determined as the incorporation of deuterium, from deuterium labeled water (2H2O), into plasma triglycerides 5. These metabolic studies will be performed in 3 sets: Study Part 1: Resting, Study Part 2: After 1 bout of exercise and Study part 3: After 6 weeks of exercise training. Since intra-abdominal obesity has been postulated to be at the core of the metabolic derangements and directly responsible for the atherogenic dyslipidemia associated with the metabolic syndrome, the investigators will also measure intra-abdominal fat content by magnetic resonance imaging (MRI).

Participants will engage in a single bout of elliptical exercise for 45 minutes (3X15 spaced by 5 minutes rest) at baseline. Subjects will be studied before and after this one bout to measure hepatic de novo lipogenesis. Participants will then take part in six weeks of exercise training on an elliptical trainer 3 times per week each time for 45 minutes. Hepatic de novo lipogenesis will be compared pre and post to examine wether improving muscle glucose uptake will decrease hepatic de novo lipogenesis as the glucose is taken up by muscle and not directed to the liver.

At the baseline assessment, de novo lipogenesis will be assessed by giving a high carbohydrate meal and heavy water to drink. Muscle glycogen and lipid contents pre- and post meal will be measured using 1H/13C MRS and de novo lipogenesis will be assessed from the heavy water incorporation into blood lipid in samples collected overnight.

At the 6 weeks assessment, de novo lipogenesis will be assessed by giving a high carbohydrate meal and heavy water to drink. Muscle glycogen and lipid contents pre- and post meal will be measured using 1H/13C MRS and de novo lipogenesis will be assessed from the heavy water incorporation into blood lipid in samples collected overnight.

Inclusion Criteria: Body Mass Index < 29 kg/m2 No regular exercise routine Non-smokers Absence of systemic and organ disease. Exclusion Criteria: Hematocrit < 35 vol% History of claustrophobia Ferromagnetic implants Regular exercise regimen Not weight stable Any significant hematological, neurological, musculoskeletal or endocrine disease (including diabetes mellitus) Any significant cardiovascular condition, including confirmed CAD and prior cardiovascular events Taking coumadin as anticoagulant therapy.

Rabol R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13705-9. doi: 10.1073/pnas.1110105108. Epub 2011 Aug 1.

Flannery C, Dufour S, Rabol R, Shulman GI, Petersen KF. Skeletal muscle insulin resistance promotes increased hepatic de novo lipogenesis, hyperlipidemia, and hepatic steatosis in the elderly. Diabetes. 2012 Nov;61(11):2711-7. doi: 10.2337/db12-0206. Epub 2012 Jul 24.