Mechanisms of Metabolic Dysfunction in Type 2 Diabetes

Summary

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

Top Publications

  1. pmc Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle
    J 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
  2. pmc Selective inhibition of ATPase activity during contraction alters the activation of p38 MAP kinase isoforms in skeletal muscle
    Jeffrey J Brault
    Department of Kinesiology, East Carolina University, Greenville, North Carolina, USA
    J Cell Biochem 114:1445-55. 2013

Research Grants

  1. CELLULAR MECHANISMS OF INSULIN RESISTANCE IN HUMANS
    Gerald I Shulman; Fiscal Year: 2013
  2. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  3. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  4. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  5. Systems Biology Investigation of Muscle Exercise Metabolism in Diabetes
    Nicola Lai; Fiscal Year: 2013
  6. Mechanism of Insulin Resistance in the Aged.
    Kitt F Petersen; Fiscal Year: 2013
  7. Palmitate Metabolism and Insulin Resistance
    CRAIG LAWRENCE KIEN; Fiscal Year: 2013
  8. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
  9. Pathogenesis of the Metabolic Syndrome
    W Timothy Garvey; Fiscal Year: 2013
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle
    J 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...
  2. pmc Selective inhibition of ATPase activity during contraction alters the activation of p38 MAP kinase isoforms in skeletal muscle
    Jeffrey 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...

Research Grants30

  1. CELLULAR MECHANISMS OF INSULIN RESISTANCE IN HUMANS
    Gerald I Shulman; Fiscal Year: 2013
    ..It is anticipated that the results of these studies will yield important new insights into the causes of insulin resistance, which will lead to new therapies for T2DM. ..
  2. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  3. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  4. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  5. Systems Biology Investigation of Muscle Exercise Metabolism in Diabetes
    Nicola Lai; Fiscal Year: 2013
    ..Simulations with the validated computational models will help to identify hypotheses that can be tested with efficient experimental designs. ..
  6. Mechanism of Insulin Resistance in the Aged.
    Kitt F Petersen; Fiscal Year: 2013
    ....
  7. Palmitate Metabolism and Insulin Resistance
    CRAIG LAWRENCE KIEN; Fiscal Year: 2013
    ..The proposed study will examine biochemical and molecular mechanisms for how a high saturated fat diet versus a low saturated fat/high monounsaturated fat diet alters the action of the hormone, insulin, in skeletal muscle. ..
  8. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  9. Pathogenesis of the Metabolic Syndrome
    W Timothy Garvey; Fiscal Year: 2013
    ..These data will predictably identify new diagnostic biomarkers for insulin resistance and T2DM, and advance our understanding of molecular mechanisms underlying human insulin resistance. ..
  10. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..