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Translational Programming of Beta-cells in Response to Glucose Toxicity

Award Number: R01DK138605
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Translational Programming of Beta-cells in Response to Glucose Toxicity - ABSTRACT Control of insulin biosynthesis in beta-cells occurs primarily at the level of translation of the insulin mRNA. An acute rise in glucose levels stimulates insulin translation by a process that involves binding of proteins to the 5' untranslated region of the insulin mRNA. Simultaneous translational upregulation of other secretory granule proteins also contributes to glucose-stimulated insulin secretion and provides evidence that beta-cells coordinately regulate translation of functionally related mRNAs. By contrast, exposure of beta-cells to sustained high glucose suppresses glucose-stimulated insulin translation and secretion. The mechanisms responsible for dysregulation of insulin translation and whether the deleterious effect of chronic high glucose impacts translation of other proteins are not known. This project will test the hypothesis that glucose toxicity leads to early alterations in mRNA-specific beta-cell translation that are mediated by intrinsic properties of mRNAs and by dynamic remodeling of the ribosome itself. Furthermore, we propose this programmatic translational dysregulation contributes to impaired glucose-stimulated insulin secretion. Knowledge gained from this study has the potential to identify novel therapeutic targets for prevention of progressive beta-cell failure in diabetes and for optimizing functionality of ex vivo generated beta-cells for cell replacement therapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $707,452 )
2025	2025	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/14/2025	NON-COMPETING CONTINUATION	$707,452
														Subtotal = $707,452

Issue Date FY: 2024 ( Subtotal = $724,053 )
2024	2024	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/1/2024	NEW	$724,053
														Subtotal = $724,053

Grand Total All Awards = $1,431,505

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Translational Programming of Beta-cells in Response to Glucose Toxicity

Award Number: R01DK138605

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/02/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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