Mechanisms of Metabolic Dysfunction in Type 2 Diabetes
Principal Investigator: Robert W Wiseman
Abstract: DESCRIPTION (provided by applicant): Skeletal muscle is the primary pathway of glucose disposal in the body through glucose uptake, storage as glycogen, and/or oxidation. Hence the development, progression and treatment of type 2 diabetes (T2D) are intimately related to the regulation of energy metabolism in muscle. We propose to apply iterative computational modeling in conjunction with both in vitro and in vivo experimentation to uncover the integrated control of energy metabolism in muscle and determine how its regulation is altered in disease (T2D). We will develop computer models of muscle energy metabolism by utilizing the substantial foundation of software and data resources that we have established. Models will be parameterized and validated based on kinetic time- course experiments using purified mitochondria and in vivo 31P-magnetic resonance spectroscopy. Data will be obtained from male Wistar rats (normoglycemic) and the Goto Kakizaki rat model of T2D (hyperglycemic) to identify functional differences between these groups. We will determine how whole body glucose disposal is altered in T2D by coordination of the pathways of glucose and fatty acid uptake and disposal (glycogen synthesis, glycogenolysis, fatty acid oxidation, TCA cycle, and oxidative phosphorylation) using experimental protocols defined by the modeling effort. Our goal is to quantitatively describe and understand the regulation of skeletal muscle oxidative metabolism in both healthy and T2D animals. Furthermore, thorough understanding of the mechanism of action of exercise, the putative targets influenced by exercise may generate new approaches to prevention of the disease and potentially identify new targets for diabetes treatment.
Funding Period: 2012-04-15 - 2013-08-31
more information: NIH RePORT
- Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscleJ P J Schmitz
Computational Biology, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
Am J Physiol Cell Physiol 304:C180-93. 2013..100-200 ms, respectively) as a result of accumulation of glycolytic intermediates downstream of PFK during contractions...
- Selective inhibition of ATPase activity during contraction alters the activation of p38 MAP kinase isoforms in skeletal muscleJeffrey J Brault
Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA
J Cell Biochem 114:1445-55. 2013..These observations suggest that an energetic signal may trigger phosphorylation of the p38γ isoform and also may explain how contractions differentially activate signaling pathways...
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