A Dash of Salt-Inducible Kinase 1 Keeps Insulin Levels in Check

Abstract

The precise control of insulin release from pancreatic b-cells in response to changes in circulating glucose levels is essential for maintaining metabolic homeostasis. Understanding the pathways coupling insulin secretion to blood glucose levels is critical for the development of new strategies to treat a variety of metabolic disorders, including type 2 diabetes. In this issue of Diabetes, Kim et al.(1) propose a novel regulatory feedback mechanism operating within b-cells that acts to reduce insulin secretion.Within b-cells, cyclic AMP (cAMP) acts as a positive regulator of insulin secretion by both nontranscriptional and transcriptional mechanisms. Increased cAMP levels can directly potentiate insulin granule release, as well as regulate genes involved in b-cell function and survival (2-4). Thus, cAMP levels within b-cells must be tightly regulated in order to ensure proper secretion of adequate amounts of insulin. The importance of cAMP in type 2 diabetes is underscored by the proliferation of incretinbased drugs on the market over the past decade, including glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase-4 inhibitors, which potentiate insulin release by increasing cAMP signaling in b-cells (5). Thus, developing our understanding of the mechanisms controlling cAMP levels in b-cells has great potential to uncover new therapeutic targets for the treatment of type 2 diabetes.The salt-inducible kinases (SIKs), members of the AMPactivated protein kinase family, are negative regulators of cAMP signaling and regulate metabolic processes in various tissues such as the liver and adipose tissue. SIK1 and SIK2 often act as inducible repressors of cAMP signals as they are transcriptional targets of cAMP signaling but can then negatively regulate cAMP-mediated signaling. This negative feedback loop plays a key role in controlling different biological processes, including circadian rhythm (6), the coupling of fasting/feeding states to gluconeogenesis in the liver (7,8), and lipolysis in adipocytes (9).Kim et al.(1) sought to examine the role of SIK1 in glucose homeostasis in mice. The authors observed that SIK1 +/2 mice had reduced blood glucose levels and increased plasma insulin levels compared with wild-type control mice, suggesting that reduced SIK1 levels led to increased insulin release. In order to more directly assess the role of SIK1 in insulin secretion, the authors compared glucose-stimulated insulin secretion (GSIS) from islets isolated from control and SIK1 +/2 mice. Using both static-and perfusion-based GSIS assays, the authors found that SIK1 +/2 islets secreted elevated levels of insulin following glucose stimulation. As SIK1 +/2 islets also displayed elevated cAMP, the authors set out to examine the role of SIK1 in mediating cAMP levels (Fig. 1A).In order to shed light on how SIK1 may be controlling cAMP levels, the authors sought to identify novel substrates of SIK1. Using an in vitro kinase assay, the authors defined a SIK1 phosphorylation consensus sequence and used this to identify p...

Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway

“…The contradictory results lead to the inability to reach a consensus on whether SIK1 can act as a key regulator of gluconeogenesis through the CRTC2/CREB pathway. SIK1 was reported to terminate the cAMP signaling pathway by activating phosphodiesterase 4D (PDE4D) in β cells [ 22 , 23 ]. In view of the important role of the cAMP/PKA/CREB pathway in mediating gluconeogenesis, it would be of interest to investigate if SIK1 activates PDE4 in the liver and further regulates gluconeogenesis.…”