| Nearly 2 million Canadians are treated for diabetes and its associated complications at a cost of roughly 9 billion dollars (US) per year. Approximately 90% of these patients suffer from type 2 diabetes mellitus, which is characterised by peripheral insulin resistance and a relative insufficiency of insulin secretion from pancreatic β-cells. Currently the most common drug therapies for type 2 diabetes mellitus are only partially effective in preventing the long term complications of the disease and also present dangerous side effects (i.e. hypoglycaemia) and often become ineffective at later stages. To better understand the mechanisms regulating insulin secretion, the present thesis investigates the machinery controlling electrical excitability and insulin secretion from β-cells.; The work presented here identifies the expression of a number of voltage-dependent K+ (Kv) channel homologues in insulin secreting cells. The Kv2.1 channel in particular is identified, using molecular and pharmacological approaches, as an important mediator of K+ currents in β-cells. In the β-cell, these channels open in response to glucose-dependent membrane depolarisation and act to repolarise action potentials, limiting Ca 2+ entry and insulin secretion. Importantly, antagonism of these channels stimulates insulin secretion in a glucose-dependent manner, and may therefore form the basis for future therapies of type 2 diabetes mellitus.; Since Kv channels, particularly Kv2.1, are potent glucose-dependent regulators of insulin secretion, the present thesis also investigates the possibility that physiological modulators of insulin secretion regulate β-cell Kv channels. Three modes of regulation were identified: interaction with exocytotic peptides (SNAP-25), hormonal (GLP-1), and temperature dependence. This work has contributed to our knowledge of factors controlling β-cell electrical activity and insulin secretion. It also suggests that Kv2.1 may be a useful target for the development of therapeutics for treatment of type 2 diabetes mellitus. |
