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, arepoorly understood and for this reason a proposed role of mitochondrial dysfunction has attractedconsiderable interest. According to this picture, reduced fatty acid oxidation by mitochondria leads tobuildup of intracellular triglyceride stores, followed by accumulation of byproducts of intracellular fatty acidmetabolism that interfere with insulin signaling. However, in spite of intense scientific and public interest inobesity and type 2 diabetes, this hypothesis is difficult to test because of the limitations of standardmetabolic studies of muscle. New NMR methods have been developed using instruments operating in therange of 1.5 - 3.0 T to noninvasively probe mitochondrial function and intramyocellular triglycerides, butthese methods are difficult to apply because of low signal and relatively poor chemical shift resolution. Ourrecent 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 causesinsulin resistance through accumulation of triglycerides. Mitochondrial function will be assessed by twomethods, the rate of TCA cycle flux measured by oxidation of [2-13C]acetate and by the rate of ATPsynthesis at rest. Intramyocellular lipids will be measured directly by single-voxel 1H NMR spectroscopy. Inthis project we will examine four populations: patients with type 2 diabetes, lean offspring of patients withtype 2 diabetes, patients with type 2 diabetes before and after weight loss, and patients before and afteracute weight gain. If the hypothesis is correct, all patients with type 2 diabetes and lean offspring of diabeticparents should have both abnormal mitochondrial function and excess intramyocellular lipids, whereasweight gain should not cause changes in mitochondrial function. This project requires close interaction withDrs. Cohen and Hobbs (Project 7), Drs. Elmquist and Tamminga (Project 2), and Drs. Parks, Browning andBurgess (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 #
1RL1DK081186-01
Application #
7467558
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
2007-09-30
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$392,500
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; Shang, Ty; Sherry, A Dean et al. (2018) Unveiling a hidden 31 P signal coresonating with extracellular inorganic phosphate by outer-volume-suppression and localized 31 P MRS in the human brain at 7T. Magn Reson Med 80:1289-1297
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2017) 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 78:1657-1666
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2017) Band inversion amplifies31P-31P nuclear overhauser effects: Relaxation mechanism and dynamic behavior of ATP in the human brain by31P MRS at 7 T. Magn Reson Med 77:1409-1418
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; 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) 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; 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

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