Abstract
Several small guanosine triphosphatases (GTPases) from the Ras protein superfamily regulate glucose-stimulated insulin secretion in the pancreatic islet β-cell. The Rho family GTPases Cdc42 and Rac1 are primarily involved in relaying key signals in several cellular functions, including vesicle trafficking, plasma membrane homeostasis, and cytoskeletal dynamics. They orchestrate specific changes at each spatiotemporal region within the β-cell by coordinating with signal transducers, guanine nucleotide exchange factors (GEFs), GTPase-activating factors (GAPs), and their effectors. The Arf family of small GTPases is involved in vesicular trafficking (exocytosis and endocytosis) and actin cytoskeletal dynamics. Rab-GTPases regulate pre-exocytotic and late endocytic membrane trafficking events in β-cells. Several additional functions for small GTPases include regulating transcription factor activity and mitochondrial dynamics. Importantly, defects in several of these GTPases have been found associated with type 2 diabetes (T2D) etiology. The purpose of this review is to systematically denote the identities and molecular mechanistic steps in the glucose-stimulated insulin secretion pathway that leads to the normal release of insulin. We will also note newly identified defects in these GTPases and their corresponding regulatory factors (e.g., GDP dissociation inhibitors (GDIs), GEFs, and GAPs) in the pancreatic β-cells, which contribute to the dysregulation of metabolism and the development of T2D.
Highlights
Pancreatic islet β-cells release the hormone insulin in response to elevated blood glucose concentrations, especially after meals, via a process called glucose-stimulated insulin secretion (GSIS) [1,2]
The Rho, Arf, and Rab families of small guanosine triphosphatases (GTPases) are required for this biphasic pattern of insulin release from the β-cell, overseeing the actin cytoskeletal remodeling, which is required for mobilizing the insulin granules to their docking/fusion sites at the inner plasma membrane (PM) for regulated release of insulin into the circulation [14,15]
We summarize the evidence for the role of different small GTPases in the islet insulin secretory process, including actin cytoskeletal rearrangement, vesicle trafficking, and vesicle fusion
Summary
Pancreatic islet β-cells release the hormone insulin in response to elevated blood glucose concentrations, especially after meals, via a process called glucose-stimulated insulin secretion (GSIS) [1,2]. The metabolism of glucose induces a plethora of signaling events, which change the ATP/ADP ratio, trigger the closure of ATP-sensitive potassium channels, and depolarize the plasma membrane (PM). The insulin secretory process is biphasic [10,11,12]; the first phase, lasting 10 min, is associated with rapid and robust insulin secretion, whereas the second phase is associated with a less robust level of secretion but continues as long as elevated glucose levels persist [13].
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