Project Grant R01DK139200

14-3-3-ZETA REGULATION OF ISLET HEALTH - ENTER THE TEXT HERE THAT IS THE NEW ABSTRACT INFORMATION FOR YOUR APPLICATION. THIS SECTION MUST BE NO LONGER THAN 30 LINES OF TEXT. PANCREATIC ISLET DYSFUNCTION IS CENTRAL TO TYPE 2 DIABETES MELLITUS (T2DM) PATHOGENESIS AND CONSISTS OF BOTH A-CELL AND B-CELL DYSFUNCTION. THE REGULATION OF A-CELL AND B-CELL HEALTH IS DETERMINED BY A COMPLEX NETWORK OF PARACRINE REGULATORS THAT ARE INCOMPLETELY DEFINED. TO IMPROVE THE TREATMENT AND PREVENTION OF T2DM, IT IS CRITICAL TO HAVE A COMPLETE PICTURE OF A-CELL AND B-CELL REGULATION. WE HAVE IDENTIFIED THE SIGNALING PROTEIN, 14-3-3Z, AS AN IMPORTANT REGULATOR OF B-CELL FUNCTION AND CROSSTALK BETWEEN A-CELLS AND B-CELLS. SPECIFICALLY, RECENT WORK FROM OUR LAB DEMONSTRATES THAT B-CELL 14-3-3Z INHIBITION INCREASES GLUCOSE-STIMULATED INSULIN SECRETION (GSIS) AND ACTIVATES A-CELL ACTIVE GLUCAGON-LIKE PEPTIDE-1 (GLP-1) PRODUCTION AND SECRETION IN MOUSE AND HUMAN ISLETS. IT IS INCREASINGLY EVIDENT THAT A-CELLS PLAY AN IMPORTANT ROLE IN THE POTENTIATION OF GSIS, THEREBY EXPANDING THEIR FUNCTION BEYOND THAT OF THE TRADITIONAL COUNTERREGULATORY ROLE. EFFORTS TO UNDERSTAND THE ROLE OF THE A-CELL IN THE REGULATION OF ISLET FUNCTION HAVE REVEALED BOTH TRANSCRIPTIONAL AND FUNCTIONAL HETEROGENEITY. FURTHER ANALYSIS OF THIS HETEROGENEITY SUGGESTS THAT FUNCTIONALLY DISTINCT A-CELL SUBPOPULATIONS DISPLAY ALTERATIONS IN THEIR HORMONE PROFILE, WITH SOME A-CELLS PRODUCING ACTIVE GLP-1 FROM THE PROGLUCAGON PRECURSOR. WHILE GLP-1 AND GLUCAGON ARE BOTH ABLE TO POTENTIATE GSIS VIA LOCAL ACTIONS MEDIATED BY GLP-1R AND GLUCAGON RECEPTOR EXPRESSED BY B-CELLS, ONLY GLUCAGON STIMULATES HEPATIC GLUCOSE PRODUCTION (HGP). IN EFFECT THEN BY SWITCHING THEIR ENDOCRINE OUTPUT FROM GLUCAGON TO GLP-1, A-CELLS FAVOR GSIS OVER THE STIMULATION OF HGP. HOW PLASTICITY IN A-CELL ENDOCRINE PROFILE IS REGULATED AND HOW IT IMPACTS OVERALL ISLET FUNCTION IS UNKNOWN. THEREFORE, WE WILL TEST THE HYPOTHESIS THAT B-CELL 14-3-3Z REGULATES GSIS BY ENHANCING A-CELL TO B-CELL CROSSTALK. AIM 1 WILL DETERMINE THE ROLE OF A-CELL GLP-1 IN 14-3-3Z REGULATION OF ISLET FUNCTION. TO THIS END, WE WILL ASSESS GSIS IN RESPONSE TO B-CELL 14-3-3Z INHIBITION IN ISLETS FROM WILD-TYPE MICE AND MICE WITH A-CELL-SPECIFIC INABILITY TO PRODUCE GLP-1. AIM 2 WILL DEFINE THE REGULATION OF PLASTICITY IN A-CELL HORMONE PRODUCTION BY B-CELL 14-3-3Z. TO THIS END, WE WILL DEFINE THE REGULATION OF GLP-1+ A-CELLS INDUCED BY B-CELL 14-3-3Z ABLATION AND DETERMINE THE RECEPTOR CLASS RESPONSIBLE FOR ACTIVATION OF A-CELL GLP-1 PRODUCTION.