Molecular and Metabolic Evidence for Mitochondrial Defects Associated With β-Cell Dysfunction in a mouse model of Type 2 Diabetes

  1. Hongfang Lu,
  2. Vasilij Koshkin,
  3. Emma M. Allister,
  4. Armen V. Gyulkhandanyan and
  5. Michael B. Wheeler (michael.wheeler{at}
  1. Departments of Physiology and Medicine, Faculty of Medicine, University of Toronto, Toronto, Canada


    Objective: The inability of pancreatic β-cells to appropriately respond to glucose and secrete insulin are primary defects associated with β-cell failure in type 2 diabetes. Mitochondrial dysfunction has been implicated as a key factor in the development of type 2 diabetes; however a link between mitochondrial dysfunction and defective insulin secretion is unclear.

    Research Design and Methods: We investigated the changes in islet mitochondrial function and morphology during progression from insulin resistance (3 week-old), immediately prior to hyperglycemia (5 week-old) and after diabetes onset (10 week-old) in transgenic MKR mice compared to control. The molecular and protein changes at 10 weeks were determined using microarray and iTRAQ proteomic screens.

    Results: At 3 weeks MKR mice were hyperinsulinemic but normoglycemic and β-cells showed negligible mitochondrial or morphological changes. At 5 weeks MKR islets displayed abrogated hyperpolarization of mitochondrial membrane potential (ΔΨm), reduced mitochondrial Ca2+ uptake, slightly enlarged mitochondria and reduced glucose-stimulated insulin secretion. By 10 weeks, MKR mice were hyperglycemic, hyperinsulinemic and β-cells contained swollen mitochondria with disordered cristae. β-cells displayed impaired stimulus-secretion coupling including reduced hyperpolarization of ΔΨm, impaired Ca2+-signaling, and reduced glucose-stimulated ATP/ADP and insulin release. Furthermore, decreased cytochrome c oxidase-dependent oxygen consumption and enhanced oxidative stress were observed in diabetic islets. Protein profiling of diabetic islets revealed that 36 mitochondrial proteins were differentially expressed, including inner membrane proteins of the electron transport chain.

    Conclusions: We provide novel evidence for a critical role of defective mitochondrial oxidative phosphorylation and morphology in the pathology of insulin resistance-induced β-cell failure.


      • Received January 28, 2009.
      • Accepted October 28, 2009.
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