Early Cardiac Mitochondrial Dysfunction in the Nile Rat model of Type 2 Diabetes

  • Author / Creator
    Schneider, Jillian F
  • The pathological events initiating diabetic cardiac changes in response to chronic hyperglycemia and hyperinsulinemia remain unclear. Due to the high metabolic activity of the heart, and its sensitivity to acute changes in oxygen and substrate flux, mitochondrial dysfunction has been proposed as a potential early indicator of diabetic cardiac disease. We hypothesize that mitochondrial changes in cardiac tissue will precede the onset of hyperglycemia in the Nile grass rat (NR), a model of spontaneous Type 2 diabetes. Male NRs were fed standard rodent chow (Prolab 2000) or a high fibre low fat diet (Mazuri Chinchilla). Hearts were studied at 2, 6, 12 (echo only) and 18 months. Mitochondrial dysfunction was assessed in permeabilized cardiac fibres utilizing the OROBOROS Oxygraph-2k high-resolution respirometry system. Four protocols were applied, including two states: LEAK state (non-phosphorylating, ADP-free) and the oxidative phosphorylation state, measuring oxygen consumption coupled to the phosphorylation of ADP to ATP. We used substrates feeding electrons into Complexes I (NADH-pathway), II (Succinate pathway) or IV of the electron transport system. Mitochondrial metabolism for fatty acids octanoylcarnitine, palmitoylcarnitine, and acetylcarnitine was similarly assessed. Additional testing included citrate synthase activity, glycated hemoglobin A1c, plasma insulin levels, and transthoracic echocardiography. Echocardiography results were suggestive of mild diastolic dysfunction at 12 months of age. Hyperglycemia and elevated %HbA1c were noted in Prolab-fed animals after 6 months, preceded by hyperinsulinemia detectable at 2 months. High resolution respirometry results showed an increase in the flux control ratio of Complex IV and citrate enzymatic assay results suggest an increase in mitochondrial content in Prolab-fed animals at 2 months. This preceded the onset of hyperglycemia, but not hyperinsulinemia. Other dietary and aging-related changes were noted in mitochondrial LEAK and OXPHOS capacities per mg permeabilized fibres at 6 and 18 months, and an increase in fatty acid β-oxidation (FAO) for medium-chain fatty acids was observed at 6 months. These results suggest that mitochondrial functional changes are detectable prior to the onset of hyperglycemia in the NR, and these dysfunctions coincide with the onset of hyperinsulinemia.

  • Subjects / Keywords
  • Graduation date
    Fall 2017
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.