Diabetes mellitus is an epidemic in the United States and the world. Type 2 diabetes, the most prevalent form of diabetes, is commonly associated with insulin resistance that often precedes the onset of overt hyperglycemia. Here we propose to further develop and employ a PET-scanning-based methodology to measure glucose transport in skeletal muscle, heart and other tissues under normal and insulin-resistant states. The method has two components: a radiopharmaceutical and a mathematical model. Specifically, we have developed a new radiopharmaceutical 18F-labeled 6-fluoro-6-deoxy-D-glucose ([18F]6FDG) so that the bio- and kinetic distribution of the compound can be quantitatively measured with positron emission tomography (PET). [18F]6FDG, unlike 2-fluoro-2-deoxy-D-glucose ([18F]2FDG) that is commonly used in PET studies, lacks a hydroxyl on carbon 6, and hence is transported but not phosphorylated. The new model relates the PET-measured time-course of radioactive glucose analogs, [18F]6FDG and [18F]2FDG, to the fluxes, transport capacities, phosphorylation and concentrations of glucose. Our overall objective is to validate and apply methodologies for the in vivo quantification of glucose transport, phosphorylation and interstitial and intracellular concentrations in skeletal muscle, heart and brain in normal and abnormal conditions. We use biochemical analyses, in vitro transporter assays, in vivo animal models, PET scanning and mathematical models. We will also perform preclinical and clinical PET studies. Importantly, the PET scan data will enable us to calculate the effect of insulin and other agents on the rate of glucose transport in the above tissues in normal and disease states. The goal is to establish a method that can be used in vivo in humans to determine influx and efflux rates of glucose, intracellular and interstitial concentrations of glucose, the phosphorylation rate of glucose, and most importantly, the maximal glucose transport capacity (Vmax) from the time-series of PET images following sequential injections of [18F]6FDG and [18F]2FDG. Determination of insulin-stimulated glucose transport will provide insight into mechanisms underlying abnormal glucose metabolism in diabetes and will enable monitoring the progression of the disease and its response to specific treatments. Hence, progress on this grant proposal will significantly contribute to our ability to evaluate and optimally manage patients at the individual level.

Public Health Relevance

The goal of this project is to establish a method for measuring glucose (sugar) transport and metabolism that can be safely used in humans. It will provide insights into abnormal glucose metabolism in diabetes that could lead to better maintenance of the level of glucose in the blood thereby reducing damage to kidneys, eyes, nerves and blood vessels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK082423-04
Application #
8322155
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Laughlin, Maren R
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$334,680
Indirect Cost
$121,508
Name
Case Western Reserve University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Su, Kuan-Hao; Chandramouli, Visvanathan; Ismail-Beigi, Faramarz et al. (2014) Dexamethasone-induced insulin resistance: kinetic modeling using novel PET radiopharmaceutical 6-deoxy-6-[(18)F]fluoro-D-glucose. Mol Imaging Biol 16:710-20
Muzic Jr, Raymond F; Chandramouli, Visvanathan; Huang, Hsuan-Ming et al. (2014) Human radiation dosimetry of 6-[18F]FDG predicted from preclinical studies. Med Phys 41:031910
Muzic Jr, Raymond F; Chandramouli, Visvanathan; Huang, Hsuan-Ming et al. (2011) Analysis of metabolism of 6FDG: a PET glucose transport tracer. Nucl Med Biol 38:667-74
Huang, Hsuan-Ming; Ismail-Beigi, Faramarz; Muzic Jr, Raymond F (2011) A new Michaelis-Menten-based kinetic model for transport and phosphorylation of glucose and its analogs in skeletal muscle. Med Phys 38:4587-99