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

The precise control of insulin release from pancreatic β-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 β-cells that acts to reduce insulin secretion.

Within β-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 β-cell function and survival (2–4). Thus, cAMP levels within β-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 incretin-based 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 β-cells (5). Thus, developing our understanding of the mechanisms controlling cAMP levels in β-cells has great potential to uncover new therapeutic targets for the treatment of type 2 diabetes.

The salt-inducible kinases (SIKs), members of the AMP-activated 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^+/− 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^+/− mice. Using both static- and perfusion-based GSIS assays, the authors found that SIK1^+/− islets secreted elevated levels of insulin following glucose stimulation. As SIK1^+/− 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 potential target proteins in silico that could then be confirmed by in vitro kinase assay. Using this approach, the authors identified phosphodiesterase 4D (PDE4D) as a substrate of SIK1 and provided multiple pieces of evidence that phosphorylation by SIK1 activates PDE4D, thus promoting the degradation of cAMP and reducing insulin secretion. These findings were corroborated by a recent study in another excitable cell type, cardiomyocytes, where PDE4D was part of a negative feedback loop buffering cAMP levels (10).

Taken together, this work delineates a novel pathway controlling GSIS in mouse β-cells where SIK1 phosphorylation of PDE4D leads to reduced cAMP levels and decreased insulin secretion (Fig. 1B).

These findings are not without controversy as they contradict many aspects of a recent study demonstrating a role for SIK2 in promoting insulin secretion (11). Using an inducible β-cell–specific SIK2 knockout model, Sakamaki et al. (11) found that SIK2 ablation in β-cells results in reduced insulin secretion and glucose intolerance. In contrast to Kim et al. (1), Sakamaki et al. found that the pan-SIK inhibitor HG-9-91-01 decreased GSIS in wild-type islets and HG-9-91-01 had no effect on SIK2-null islets, suggesting that only SIK2, not SIK1 or SIK3, plays a role in GSIS. The reason for the differences in results is not clear. A direct head-to-head comparison of inducible β-cell–specific knockouts of SIK1 and SIK2 would certainly be informative, as Kim et al. cannot eliminate the possibility of a developmental defect in SIK1^+/− islets or that SIK1 acts in other cell types within the islet, such as α- or δ-cells. However, the ultimate answer will potentially come from studies on isolated human islets and samples from diseased human pancreas.

The study by Kim et al. (1) raises several questions. Clearly, it will be important to reconcile the roles of SIK1 and SIK2 in coupling cAMP and Ca²⁺ signals to GSIS. In addition, the relative contributions of PDE4D, protein kinase A, and CREBP-regulated transcription coactivators in regulating cAMP signaling in β-cells remain to be clearly defined. As well, the mechanism(s) controlling SIK1 and SIK2 expression, stability, and activity in β-cells also remains to be elucidated, and it will be interesting to examine any changes in the expression of these kinases in diseased human pancreas. Finally, given that SIKs are known to regulate class IIa histone deacetylases (HDACs) (12), and that class IIa HDACs play a role in β-cell specification (13), it will be interesting to explore if SIK-mediated regulation of HDACs plays a role in β-cells.

Overall, the studies by Kim et al. (1) and Sakamaki et al. (11) open up several avenues for future study that can have important implications for the development of treatments for human metabolic disorders. While the role of cAMP in GSIS was proposed more than 50 years ago through the study of how glucagon-mediated signaling stimulates insulin secretion (14,15), our understanding of the network of pathways controlling cAMP signaling in β-cells continues to evolve.