Role of the Sik2-p35-Pja2 Complex in Pancreatic Beta Cell Functional Compensation

Abstract

Metabolic syndrome and type 2 diabetes are increasingly prevalent global health risks. The transition from glucose intolerance/prediabetes to a diagnosis of diabetes occurs when pancreatic beta cells fail to compensate for the increasing demand for insulin. While mechanisms for increasing beta cell mass have been described, the molecular underpinnings of beta cell functional compensation remain largely unknown. Here we delineate a novel pathway featuring the Ser/Thr protein kinase Sik2 and E3 ubiqutin ligase Pja2 that is harnessed by the beta cell in both rodents and humans to enhance insulin secretion in response to hyperglycemia. Sik2 phosphorylates p35 at Ser91 to trigger p35 degradation by Pja2, which promotes insulin secretion through activation of voltage-dependent calcium channel (VDCC) and calcium ion influx. Loss of Sik2 in beta cells exacerbates high fat diet-induced glucose intolerance due to decreased plasma insulin levels. Sik2 protein accumulates in beta cells of obese models and human obese subjects, and is stabilized upon exposure to high concentration of glucose. Enhanced insulin secretion in islets from obese model mice is reverted by Sik2 knockdown. These findings demonstrate that the Sik2-Pja2-p35 complex is critical for beta cell functional compensation and maintenance of glucose homeostasis.