Skeletal muscle plays a central role in systemic carbohydrate metabolism by oxidizing or storing glucose. The mechanisms of reduced glucose clearance by skeletal muscle, the hallmark of type 2 diabetes, are poorly understood and for this reason a proposed role of mitochondrial dysfunction has attracted considerable interest. According to this picture, reduced fatty acid oxidation by mitochondria leads to buildup of intracellular triglyceride stores, followed by accumulation of byproducts of intracellular fatty acid metabolism that interfere with insulin signaling. However, in spite of intense scientific and public interest in obesity and type 2 diabetes, this hypothesis is difficult to test because of the limitations of standard metabolic studies of muscle. New NMR methods have been developed using instruments operating in the range of 1.5 - 3.0 T to noninvasively probe mitochondrial function and intramyocellular triglycerides, but these methods are difficult to apply because of low signal and relatively poor chemical shift resolution. Our recent observations on healthy volunteers indicate that both limitations will be substantially improved at 7 T. The project will focus on the hypothesis that abnormal function of skeletal muscle mitochondria causes insulin resistance through accumulation of triglycerides. Mitochondrial function will be assessed by two methods, the rate of TCA cycle flux measured by oxidation of [2-13C]acetate and by the rate of ATP synthesis at rest. Intramyocellular lipids will be measured directly by single-voxel 1H NMR spectroscopy. In this project we will examine four populations: patients with type 2 diabetes, lean offspring of patients with type 2 diabetes, patients with type 2 diabetes before and after weight loss, and patients before and after acute weight gain. If the hypothesis is correct, all patients with type 2 diabetes and lean offspring of diabetic parents should have both abnormal mitochondrial function and excess intramyocellular lipids, whereas weight gain should not cause changes in mitochondrial function. This project requires close interaction with Drs. Cohen and Hobbs (Project 7), Drs. Elmquist and Tamminga (Project 2), and Drs. Parks, Browning and Burgess (Project 6).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Linked Research project Grant (RL1)
Project #
5RL1DK081186-05
Application #
8106278
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Laughlin, Maren R
Project Start
2007-09-30
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$377,381
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2017) Band inversion amplifies 31 P-31 P nuclear overhauser effects: Relaxation mechanism and dynamic behavior of ATP in the human brain by 31 P MRS at 7 T. Magn Reson Med 77:1409-1418
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) Efficient (31) P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T. Magn Reson Med :
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) A simple approach to evaluate the kinetic rate constant for ATP synthesis in resting human skeletal muscle at 7 T. NMR Biomed 29:1240-8
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2015) Amplification of the effects of magnetization exchange by (31) P band inversion for measuring adenosine triphosphate synthesis rates in human skeletal muscle. Magn Reson Med 74:1505-14
Marin-Valencia, Isaac; Hooshyar, M Ali; Pichumani, Kumar et al. (2015) The ratio of acetate-to-glucose oxidation in astrocytes from a single 13C NMR spectrum of cerebral cortex. J Neurochem 132:99-109
Ren, Jimin; Yang, Baolian; Sherry, A Dean et al. (2015) Exchange kinetics by inversion transfer: integrated analysis of the phosphorus metabolite kinetic exchanges in resting human skeletal muscle at 7 T. Magn Reson Med 73:1359-69
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2015) (31)P-MRS of healthy human brain: ATP synthesis, metabolite concentrations, pH, and T1 relaxation times. NMR Biomed 28:1455-62
Ren, Jimin; Lakoski, Susan; Haller, Ronald G et al. (2013) Dynamic monitoring of carnitine and acetylcarnitine in the trimethylamine signal after exercise in human skeletal muscle by 7T 1H-MRS. Magn Reson Med 69:7-17
Ren, Jimin; Dean Sherry, A; Malloy, Craig R (2013) Noninvasive monitoring of lactate dynamics in human forearm muscle after exhaustive exercise by (1)H-magnetic resonance spectroscopy at 7 tesla. Magn Reson Med 70:610-9
Szatmari, Istvan; Iacovino, Michelina; Kyba, Michael (2010) The retinoid signaling pathway inhibits hematopoiesis and uncouples from the Hox genes during hematopoietic development. Stem Cells 28:1518-29

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