Not listed METABOLIC CONTROL OF BETA-CELL SECRETORY ORGANELLE FUNCTION - COMPELLING EVIDENCE HIGHLIGHTS THE CENTRAL ROLE OF ISLET B-CELL FAILURE IN THE TRANSITION FROM INSULIN RESISTANCE TO TYPE 2 DIABETES (T2D). DEFECTS IN THE B-CELL'S SECRETORY PATHWAY ACCOMPANY T2D ONSET AND INCLUDE CHANGES TO INSULIN TRAFFICKING, REDUCED INSULIN STORAGE, AND IMPAIRED PROINSULIN PROCESSING. THE CELLULAR MECHANISMS UNDERLYING THESE DEFECTS ARE NOT COMPLETELY UNDERSTOOD, YET COULD HAVE CONSIDERABLE THERAPEUTIC VALUE IF B-CELL FUNCTION COULD BE RESTORED. OUR DATA HIGHLIGHT ALTERED ER REDOX HOMEOSTASIS AS A NOVEL MECHANISM THAT CONTRIBUTES TO B-CELL DYSFUNCTION IN HUMAN AND RODENT DIABETES MODELS. USING NOVEL PROINSULIN TRAFFICKING REPORTERS, WE IDENTIFIED A DELAY IN THE ER EXPORT OF PROINSULIN THAT LEADS TO INADEQUATE INSULIN GRANULE PRODUCTION. WE LINKED DELAYED PROINSULIN EXPORT TO HYPEROXIDATION OF THE ER LUMEN AND SHOWED THAT RESTORATION OF ER REDOX HOMEOSTASIS RESCUED PROINSULIN EXPORT AND INSULIN GRANULE FORMATION. THE HYPEROXIDIZED ER ENVIRONMENT MAY INTERFERE WITH PROINSULIN EXPORT BY CONTRIBUTING TO THE FORMATION OF MISFOLDED DISULFIDE-LINKED PROINSULIN OLIGOMERS PREVIOUSLY REPORTED IN HUMAN T2D B-CELLS. ULTIMATELY, THIS PROINSULIN TRAFFICKING DELAY LIMITS THE PRODUCTION OF INSULIN GRANULES, WHICH MAY EXPLAIN THE INCREASE OF PROINSULIN AND LOSS OF INSULIN GRANULES PROMINENT IN T2D. OUR PROPOSED STUDIES ARE DESIGNED TO DEFINE THE MOLECULAR MEDIATORS OF B-CELL ER REDOX CONTROL AND ADDRESS HOW ER HYPEROXIDATION DEVELOPS IN T2D. OUR PRELIMINARY DATA HAVE IDENTIFIED A NOVEL MECHANISM LINKING DEFECTS IN MITOCHONDRIAL AND REDOX METABOLISM WITH CHANGES TO ER FUNCTION IN THE DECLINE OF INSULIN PRODUCTION IN T2D. OUR CENTRAL HYPOTHESIS IS THAT METABOLICALLY SUPPLIED REDUCTIVE REDOX DONORS ARE NECESSARY FOR THE B-CELL'S ER REDOX BUFFERING CAPACITY TO SUSTAIN EFFICIENT PROINSULIN FOLDING FOR INSULIN PRODUCTION. THE GOALS OF THIS PROPOSAL ARE TO ESTABLISH A CRITICAL LINK BETWEEN GLUCOSE METABOLISM AND ER REDOX CONTROL (AIM 1), DEFINE KEY MEDIATORS THAT BUFFER ER REDOX CAPACITY (AIM 2), AND DETERMINE HOW PROINSULIN FOLDING IMPACTS ER REDOX HOMEOSTASIS (AIM 3). $436.0k 6/19/26 Not listed METABOLIC CONTROL OF BETA-CELL SECRETORY ORGANELLE FUNCTION - COMPELLING EVIDENCE HIGHLIGHTS THE CENTRAL ROLE OF ISLET B-CELL FAILURE IN THE TRANSITION FROM INSULIN RESISTANCE TO TYPE 2 DIABETES (T2D). DEFECTS IN THE B-CELL'S SECRETORY PATHWAY ACCOMPANY T2D ONSET AND INCLUDE CHANGES TO INSULIN TRAFFICKING, REDUCED INSULIN STORAGE, AND IMPAIRED PROINSULIN PROCESSING. THE CELLULAR MECHANISMS UNDERLYING THESE DEFECTS ARE NOT COMPLETELY UNDERSTOOD, YET COULD HAVE CONSIDERABLE THERAPEUTIC VALUE IF B-CELL FUNCTION COULD BE RESTORED. OUR DATA HIGHLIGHT ALTERED ER REDOX HOMEOSTASIS AS A NOVEL MECHANISM THAT CONTRIBUTES TO B-CELL DYSFUNCTION IN HUMAN AND RODENT DIABETES MODELS. USING NOVEL PROINSULIN TRAFFICKING REPORTERS, WE IDENTIFIED A DELAY IN THE ER EXPORT OF PROINSULIN THAT LEADS TO INADEQUATE INSULIN GRANULE PRODUCTION. WE LINKED DELAYED PROINSULIN EXPORT TO HYPEROXIDATION OF THE ER LUMEN AND SHOWED THAT RESTORATION OF ER REDOX HOMEOSTASIS RESCUED PROINSULIN EXPORT AND INSULIN GRANULE FORMATION. THE HYPEROXIDIZED ER ENVIRONMENT MAY INTERFERE WITH PROINSULIN EXPORT BY CONTRIBUTING TO THE FORMATION OF MISFOLDED DISULFIDE-LINKED PROINSULIN OLIGOMERS PREVIOUSLY REPORTED IN HUMAN T2D B-CELLS. ULTIMATELY, THIS PROINSULIN TRAFFICKING DELAY LIMITS THE PRODUCTION OF INSULIN GRANULES, WHICH MAY EXPLAIN THE INCREASE OF PROINSULIN AND LOSS OF INSULIN GRANULES PROMINENT IN T2D. OUR PROPOSED STUDIES ARE DESIGNED TO DEFINE THE MOLECULAR MEDIATORS OF B-CELL ER REDOX CONTROL AND ADDRESS HOW ER HYPEROXIDATION DEVELOPS IN T2D. OUR PRELIMINARY DATA HAVE IDENTIFIED A NOVEL MECHANISM LINKING DEFECTS IN MITOCHONDRIAL AND REDOX METABOLISM WITH CHANGES TO ER FUNCTION IN THE DECLINE OF INSULIN PRODUCTION IN T2D. OUR CENTRAL HYPOTHESIS IS THAT METABOLICALLY SUPPLIED REDUCTIVE REDOX DONORS ARE NECESSARY FOR THE B-CELL'S ER REDOX BUFFERING CAPACITY TO SUSTAIN EFFICIENT PROINSULIN FOLDING FOR INSULIN PRODUCTION. THE GOALS OF THIS PROPOSAL ARE TO ESTABLISH A CRITICAL LINK BETWEEN GLUCOSE METABOLISM AND ER REDOX CONTROL (AIM 1), DEFINE KEY MEDIATORS THAT BUFFER ER REDOX CAPACITY (AIM 2), AND DETERMINE HOW PROINSULIN FOLDING IMPACTS ER REDOX HOMEOSTASIS (AIM 3). $433.3k 6/4/25 Not listed METABOLIC CONTROL OF BETA-CELL SECRETORY ORGANELLE FUNCTION - COMPELLING EVIDENCE HIGHLIGHTS THE CENTRAL ROLE OF ISLET B-CELL FAILURE IN THE TRANSITION FROM INSULIN RESISTANCE TO TYPE 2 DIABETES (T2D). DEFECTS IN THE B-CELL'S SECRETORY PATHWAY ACCOMPANY T2D ONSET AND INCLUDE CHANGES TO INSULIN TRAFFICKING, REDUCED INSULIN STORAGE, AND IMPAIRED PROINSULIN PROCESSING. THE CELLULAR MECHANISMS UNDERLYING THESE DEFECTS ARE NOT COMPLETELY UNDERSTOOD, YET COULD HAVE CONSIDERABLE THERAPEUTIC VALUE IF B-CELL FUNCTION COULD BE RESTORED. OUR DATA HIGHLIGHT ALTERED ER REDOX HOMEOSTASIS AS A NOVEL MECHANISM THAT CONTRIBUTES TO B-CELL DYSFUNCTION IN HUMAN AND RODENT DIABETES MODELS. USING NOVEL PROINSULIN TRAFFICKING REPORTERS, WE IDENTIFIED A DELAY IN THE ER EXPORT OF PROINSULIN THAT LEADS TO INADEQUATE INSULIN GRANULE PRODUCTION. WE LINKED DELAYED PROINSULIN EXPORT TO HYPEROXIDATION OF THE ER LUMEN AND SHOWED THAT RESTORATION OF ER REDOX HOMEOSTASIS RESCUED PROINSULIN EXPORT AND INSULIN GRANULE FORMATION. THE HYPEROXIDIZED ER ENVIRONMENT MAY INTERFERE WITH PROINSULIN EXPORT BY CONTRIBUTING TO THE FORMATION OF MISFOLDED DISULFIDE-LINKED PROINSULIN OLIGOMERS PREVIOUSLY REPORTED IN HUMAN T2D B-CELLS. ULTIMATELY, THIS PROINSULIN TRAFFICKING DELAY LIMITS THE PRODUCTION OF INSULIN GRANULES, WHICH MAY EXPLAIN THE INCREASE OF PROINSULIN AND LOSS OF INSULIN GRANULES PROMINENT IN T2D. OUR PROPOSED STUDIES ARE DESIGNED TO DEFINE THE MOLECULAR MEDIATORS OF B-CELL ER REDOX CONTROL AND ADDRESS HOW ER HYPEROXIDATION DEVELOPS IN T2D. OUR PRELIMINARY DATA HAVE IDENTIFIED A NOVEL MECHANISM LINKING DEFECTS IN MITOCHONDRIAL AND REDOX METABOLISM WITH CHANGES TO ER FUNCTION IN THE DECLINE OF INSULIN PRODUCTION IN T2D. OUR CENTRAL HYPOTHESIS IS THAT METABOLICALLY SUPPLIED REDUCTIVE REDOX DONORS ARE NECESSARY FOR THE B-CELL'S ER REDOX BUFFERING CAPACITY TO SUSTAIN EFFICIENT PROINSULIN FOLDING FOR INSULIN PRODUCTION. THE GOALS OF THIS PROPOSAL ARE TO ESTABLISH A CRITICAL LINK BETWEEN GLUCOSE METABOLISM AND ER REDOX CONTROL (AIM 1), DEFINE KEY MEDIATORS THAT BUFFER ER REDOX CAPACITY (AIM 2), AND DETERMINE HOW PROINSULIN FOLDING IMPACTS ER REDOX HOMEOSTASIS (AIM 3). $449.9k 6/27/24 Not listed METABOLIC CONTROL OF BETA-CELL SECRETORY ORGANELLE FUNCTION - COMPELLING EVIDENCE HIGHLIGHTS THE CENTRAL ROLE OF ISLET B-CELL FAILURE IN THE TRANSITION FROM INSULIN RESISTANCE TO TYPE 2 DIABETES (T2D). DEFECTS IN THE B-CELL'S SECRETORY PATHWAY ACCOMPANY T2D ONSET AND INCLUDE CHANGES TO INSULIN TRAFFICKING, REDUCED INSULIN STORAGE, AND IMPAIRED PROINSULIN PROCESSING. THE CELLULAR MECHANISMS UNDERLYING THESE DEFECTS ARE NOT COMPLETELY UNDERSTOOD, YET COULD HAVE CONSIDERABLE THERAPEUTIC VALUE IF B-CELL FUNCTION COULD BE RESTORED. OUR DATA HIGHLIGHT ALTERED ER REDOX HOMEOSTASIS AS A NOVEL MECHANISM THAT CONTRIBUTES TO B-CELL DYSFUNCTION IN HUMAN AND RODENT DIABETES MODELS. USING NOVEL PROINSULIN TRAFFICKING REPORTERS, WE IDENTIFIED A DELAY IN THE ER EXPORT OF PROINSULIN THAT LEADS TO INADEQUATE INSULIN GRANULE PRODUCTION. WE LINKED DELAYED PROINSULIN EXPORT TO HYPEROXIDATION OF THE ER LUMEN AND SHOWED THAT RESTORATION OF ER REDOX HOMEOSTASIS RESCUED PROINSULIN EXPORT AND INSULIN GRANULE FORMATION. THE HYPEROXIDIZED ER ENVIRONMENT MAY INTERFERE WITH PROINSULIN EXPORT BY CONTRIBUTING TO THE FORMATION OF MISFOLDED DISULFIDE-LINKED PROINSULIN OLIGOMERS PREVIOUSLY REPORTED IN HUMAN T2D B-CELLS. ULTIMATELY, THIS PROINSULIN TRAFFICKING DELAY LIMITS THE PRODUCTION OF INSULIN GRANULES, WHICH MAY EXPLAIN THE INCREASE OF PROINSULIN AND LOSS OF INSULIN GRANULES PROMINENT IN T2D. OUR PROPOSED STUDIES ARE DESIGNED TO DEFINE THE MOLECULAR MEDIATORS OF B-CELL ER REDOX CONTROL AND ADDRESS HOW ER HYPEROXIDATION DEVELOPS IN T2D. OUR PRELIMINARY DATA HAVE IDENTIFIED A NOVEL MECHANISM LINKING DEFECTS IN MITOCHONDRIAL AND REDOX METABOLISM WITH CHANGES TO ER FUNCTION IN THE DECLINE OF INSULIN PRODUCTION IN T2D. OUR CENTRAL HYPOTHESIS IS THAT METABOLICALLY SUPPLIED REDUCTIVE REDOX DONORS ARE NECESSARY FOR THE B-CELL'S ER REDOX BUFFERING CAPACITY TO SUSTAIN EFFICIENT PROINSULIN FOLDING FOR INSULIN PRODUCTION. THE GOALS OF THIS PROPOSAL ARE TO ESTABLISH A CRITICAL LINK BETWEEN GLUCOSE METABOLISM AND ER REDOX CONTROL (AIM 1), DEFINE KEY MEDIATORS THAT BUFFER ER REDOX CAPACITY (AIM 2), AND DETERMINE HOW PROINSULIN FOLDING IMPACTS ER REDOX HOMEOSTASIS (AIM 3). $449.9k 6/27/24