FAT AND CARBOHYDRATE METABOLISM IN THE LIVER AND SKELETAL MUSCLE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This core research and technology development project has three aims. All are related to the development of new approaches to measuring key fluxes and metabolites important to fat and carbohydrate biochemistry in people. Over the long term, we envision a set of clinical research protocols involving systemic administration of 13C and 2H to determine the kinetics of whole-body glucose production, hepatic fatty acid oxidation, etc., whichare fundamental to understanding the physiology of insulin-resistant states. Simultaneously, organ-specific MR imaging and spectroscopy can be used to probe metabolism in critical organs such as skeletal muscle and liver. Based on our success with stable isotope analysis of metabolism plus our recent progress with magnetization transfer contrast agents (PARACEST agents), this goal can be achieved in experimental animals, and proof-of-concept development will be carried out in human subjects. Specific Aim #1 is to implement and evaluate new metabolic imaging methods in rodent models. Glucose imaging by MRI will be studied in three populations of rats: control animals, hyperthyroid rats, and Zucker fatty rats. By manipulation of nutritional state and glucagon, the concentration and distribution of glucose will be altered in the whole animal. Simultaneous measures of glucose turnover, urea turnover, ketone production, systemic lipolysis and hepatic 13 oxidation will be determined by isotope methods. Specific Aim #2 is to continue development of methods to measure hepatic 13 - oxidation, whole-body lipolysis, gluconeogenesis and hepatic TCA cycle flux in human subjects. The clinical and scientific community wants to be able to routinely measure fatty acid oxidation in the liver. In this Aim of Core 3, methods developed in Core 1 will be extended to patients and volunteers. Hepatic gluconeogenesis and 13 oxidation will be measured in three human populations: fasting, high fat diet, and type 2 diabetes. We have already shown metabolic changes in glucose production pathways in these various metabolic states, some of which are dramatic changes. Finally, specific Aim #3 is to assess intramyocellular fat content and mitochondrial function in skeletal muscle of patients with T2 diabetes. Abnormal intramyocellular fat content, excess hepatic gluconeogenesis, and a widespread defect in mitochondrial function have been postulated among patients with T2D. In calf muscle of fasted control subjects and age matched patients with type 2 diabetes, three measurements will be made: intramyocellular fat content, ATP synthesis rates (by 31p NMR magnetization transfer) and citric acid cycle flux (by 1 H decouple, 13C observe NMR).