Regulation Of Islet Beta Cell Function By SAD-A,an AMPK-related Kinase

The AMPK-related family of protein kinases, which consist of12kinases, plays a pivotal role in regulating islet β cell metabolism, proliferation, polarity, and insulin secretion, as evidenced by the phenotype of mice with targeted deletion of LKB1, an upstream kinase of AMPK and its related kinases. One of LKB1downstream member is the SAD-A kinase, also known as BRSK2. SAD-A is most closely related to AMPK, and is exclusively expressed in brain and pancreas tissue. However, the role for SAD-A in β cell has not been established. Here we generated mice with conditional deletion of SAD-A gene only in pancreas. Our work show that the SAD-A deficient mice display insulin secretion defect and glucose intolerance. Additionally, SAD-A deletion also causes small islet β cell. In the process, we have identified several downstream targets of SAD-A that mediate these effects. One of the target proteins is GDP-Dissociation inhibitor a (GDIa) which is a negative regulator of insulin secretion by regulating cytoskeletal remodeling. We show that SAD-A directly binds to and phosphorylates GDIa, leading to great enhancement in insulin secretion concurrently with cytoskeletal remodeling. Loss of SAD-A also decreases the β cell size by blocking mammalian target of rapamycin (mTOR) pathway. These results identified a molecular mechanism by which SAD-A regulates β Cell size, insulin secretion, and function.Type2diabetes is characterized by a loss of glucose responsiveness of pancreatic β-cells, which can be restored by GLP-1treatment. However, molecular mechanisms underlying the control of glucose responsiveness in islet β cells remain poorly understood. Using the SAD-A conditional knockout mice, we next investigated a role of SAD-A in glucose responsiveness as a mediator of GLP-1signaling in islet β-cells.We show that SAD-A deficiency in pancreatic islets or global SAD-A knockout impairs GLP-1response, leading to glucose intolerance. Conversely,SAD-A overexpression significantly enhances GLP-1’s effect on glucose-stimulated insulin secretion (GSIS). Consistent with its key role in GSIS, SAD-A is activated by GLP-1through [cAMP]/[Ca2+]-dependent signaling pathways.Together, these findings identify SAD-A as a key regulator of glucose responsiveness by integrating hormonal and metabolic signals to activation of Rho GTPases.