Hunk, a Serine/Threonine Protein Kinase, Regulates Insulin Secretion from Pancreatic Islets
Authors: Lakshmanan Akshayaa , Rabaglia Mary , Das Rahul , Schueler Kathy , Stapleton Donnie , Simonett Shane , Keller Mark , Attie Allan 
Published: June 2021

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder caused by the failure of the pancreatic β‐cells to secrete sufficient insulin to maintain glucose homeostasis. Genetic factors make a strong contribution to the development of the T2DM. Therefore, identifying and characterizing novel genetic factors that play an important role in β‐cell function is critical to understand the heritability of T2DM. We have recently identified the Hunk (Hormonally Up‐Regulated Neu‐Associated Kinase) gene as a novel regulator of insulin secretion from a mouse genetic screen. Genetic variation near the HUNK gene is associated with T2DM in humans. However, no study has yet been reported on the role of Hunk in pancreatic β‐cells.

We studied the role of Hunk in two model systems; in islets isolated from whole‐body Hunk knockout mice (HunkKO), and in INS1 cells, a rat insulinoma β‐cell line. We observed that compared to wild type (WT) mice, insulin secretion in response to several different secretagogues was elevated in islets from HunkKO mice. This difference in the secretory response between WT and HunkKO islets was larger if the mice were maintained on a western‐style high‐fat/high‐sucrose (HF/HS) diet, suggesting that Hunk may be required for the diet to exert a suppressive effect on β‐cell function.

In contrast to our observations with WT versus HunkKO islets, we observed a very different result in INS1 β‐cells. We transiently overexpressed control Hunk (Hunkcontrol), a catalytically inactive mutant of Hunk that contains a point mutation in the kinase domain (HunkCi), or GFP in INS1 β‐cells; 48 hr later we measured insulin secretion in response to different segretagogues in all three groups of cells. Compared to GFP, cells expressing Hunkcontrol, but not HunkCi, secreted more insulin in response to glucose alone, or a combination of glucose plus fatty acid. This result suggests that the augmented secretory response by Hunkcontrol required Hunk's catalytic activity.

Hunk is known to regulate cellular proliferation in other tissues; e.g., breast cancer. We asked if Hunk controls cellular proliferation in pancreatic islets. β‐cells in adult islets can be induced to proliferate in response to metabolic stress, such as high fat diet. We measured the level of expression for several key cell cycle regulatory genes in islets isolated from WT and HunkKO mice that were maintained on the HF/HS diet for 4 months. In addition, we used the insulin receptor antagonist, S961, to induce a very high degree of insulin resistance that has previously been shown to result in significant β‐cell proliferation. Following one week of S961 infusion, islets were isolated and the expression levels of the cell cycle transcripts were measured. Compared to WT mice, cell cycle expression was not altered in the HunkKO islets when mice maintained on either the HF/HS diet, or when treated with S961. These results suggest that Hunk does not regulate β‐cell proliferation in response to metabolic stress.

Conclusion

We identified Hunk, a Serine/Threonine protein kinase as a novel regulator of insulin secretion from beta cells. We find that for this particular gene, overexpression in a cell line does not yield a result predicted from a knockout in the mouse.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.