Abstract
The prevalence of diabetes is increasing rapidly worldwide. A cardinal feature of most forms of diabetes is the lack of insulin-producing capability, due to the loss of insulin-producing β-cells, impaired glucose-sensitive insulin secretion from the β-cell, or a combination thereof, the reasons for which largely remain elusive. Reversible phosphorylation is an important and versatile mechanism for regulating the biological activity of many intracellular proteins, which, in turn, controls a variety of cellular functions. For instance, significant changes in protein kinase activities and in protein phosphorylation patterns occur subsequent to the stimulation of insulin release by glucose. Therefore, the molecular mechanisms regulating the phosphorylation of proteins involved in the insulin secretory process by the β-cell have been extensively investigated. However, far less is known about the role and regulation of protein dephosphorylation by various protein phosphatases. Herein, we review extant data implicating serine/threonine and tyrosine phosphatases in various aspects of healthy and diabetic islet biology, ranging from control of hormonal stimulus-secretion coupling to mitogenesis and apoptosis.
Highlights
The prevalence of diabetes is increasing rapidly worldwide
Each PPP family member can achieve many specific functions, because the protein encoded by a PPP gene represents a catalytic subunit that can interact with a distinct set of substrates and interaction proteins
In vitro studies of islets isolated from such mice demonstrated that decreased b-cell mass was accompanied by decreased proliferation and enhanced apoptosis (Bernal-Mizrachi et al 2010). These results demonstrate that pharmacological inhibition of calcineurin and genetic calcineurin deletion markedly inhibit rodent b-cell proliferation and promote b-cell apoptosis, which should be taken into account when treating patients in the need of immunosuppression
Summary
Pancreatic b-cells are equipped to rapidly sense ambient glycemia. In order for the cells to respond appropriately with insulin secretion, glucose must be metabolized within the b-cells (Hedeskov 1980, Ashcroft & Rorsman 2012). Among other things, in increased production of ATP, leading to an increased ATP:ADP ratio (Detimary et al 1995), which (such as sulfonylurea drugs) closes the ATPsensitive KC (KATP) channels (Ashcroft et al 1984, Cook & Hales 1984). This causes depolarization of the plasma membrane, opening of voltage-dependent Ca2C channels, and influx of extracellular Ca2C. Signaling molecules other than ATP and Ca2C must be involved in glucose sensing in the b-cell, the precise nature by which these complementary signals promote secretion and the KATP-independent signaling pathways activated by glucose have remained elusive. Insulin secretion is a complex process, tuned by many mechanisms, and has been the topic of excellent reviews (Ashcroft & Rorsman 2012, Rorsman & Braun 2013)
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