UBC Theses and Dissertations
Role of the caspase and calpain families in mediating pancreatic beta cell dysfunction and death in type 2 diabetes Kennedy, Michael Alex Ander
Type 2 diabetes is characterized by an inability to maintain normoglycemia due to impairments in both insulin secretion and action. The impaired capacity of the pancreatic beta cell to secrete sufficient concentrations of insulin directly contributes to the worsening glycemic control. High concentrations of glucose and free fatty acids have been shown to be deleterious for pancreatic beta cell function and viability. Increased availability of glucose and free fatty acids may also contribute to the aggregation of islet amyloid polypeptide (IAPP) and formation of islet amyloid, a commonly observed pathology in type 2 diabetes associated with decreased beta cell viability. The mechanism(s) mediating the continuum of declining pancreatic beta cell function towards increased pancreatic beta cell death under conditions of increased glucose and free fatty acid availability are not completely understood. Insight into the pathways contributing to pancreatic beta cell dysfunction and death could provide avenues for therapeutic strategies aimed at improving glycemic control in type 2 diabetes. In this thesis, the role of the calpain and caspase families in mediating the toxic effects of IAPP, glucose and free fatty acids in the pathogenesis of impaired beta cell function and viability were assessed. The propensity of IAPP to aggregate in vitro was greatly influenced by an increased availability of the peptide and a neutral pH, replicative of conditions observed during increased glucose and free fatty acid availability. The toxicity of the IAPP aggregates was not found to be solely dependent upon the activation of either the caspase or calpain family. However, culture of the pancreatic beta cell line INS-1 in elevated glucose concentrations was found to increase secretory vesicle release under nonstimulatory conditions in a caspase-dependent manner. Additionally, fatty acid-induced pancreatic beta cell death was found to be dependent upon activation of the caspase but not the calpain family and was evident only at increased glucose concentrations. These results implicate a role for the caspase family in mediating the deleterious effects of increased glucose and free fatty acid availability upon beta cell function and viability. The beta cell function and viability in patients with type 2 diabetes may potentially benefit from strategies aimed at inhibiting caspase activity or reducing free fatty availability.
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