| Summary: | SIRT1 has emerged as a critical regulator of glucose homeostasis and metabolism in the past decade. Glucose homeostasis is tightly regulated by insulin however, the factors affecting insulin release are still incompletely understood. Relatively recent evidence has shown SIRT1 to be a positive mediator of insulin secretion although its mechanism is largely unknown. Therefore, the aim of this study was to determine how SIRT1 regulates insulin release. Using a pancreatic beta cell-specific Sirt1 knockout mouse model (Sirt1BKO), oral glucose challenge revealed a glucose intolerant phenotype with reduced insulin secretion. Isolated Sirt1BKO islets also secreted less insulin without changes to insulin content or islet morphology. Intracellular defects were localized to the mitochondria and showed suppressed bioenergetics negatively affecting downstream glucose-induced calcium influx. This is the first study using a Sirt1BKO mouse model to show novel mitochondrial genes under SIRT1 regulation and when impaired, results in reduced insulin secretion.
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