Diabetes results from failure of beta (β) cells in pancreatic islets to release sufficient insulin to regulate blood sugar in the body. Researchers at Joslin Diabetes Center revealed that the chronically high sugar levels that occur early during the development of diabetes further undermine the ability of beta cells to produce insulin by reducing translation of specific mRNAs that contain the cell’s genetic instructions for making and secreting insulin. Blocking this response to high sugar levels could be a new way to prevent progression of early diabetes or even an effective strategy to improve the function of beta cells implanted in patients to cure diabetes.

The team looked at the impact of sustained elevated glucose levels on β cell mRNA translation across the entire genome using high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells, and then verified specific changes in human islets. They demonstrated that sustained high glucose selectively impairs translation of genes that serve critical roles at almost every step of glucose metabolism–coupled insulin secretion in pancreatic β cells.

The research uncovered a translational regulatory circuit during β cell glucose toxicity that impairs expression of proteins with critical roles in β cell function that may be leveraged to develop new therapeutic strategies for the treatment of diabetes.  

Read the full paper in the Journal of Clinical Investigation.

Joslin authors: Abigael Cheruiyot (lead), Jennifer Hollister-Lock, Brooke Sullivan, Hui Pan, Jonathan M. Dreyfuss, Susan Bonner-Weir, and Jean E. Schaffer (corresponding)

COI: The authors have declared that no conflict of interest exists.

Citation: Cheruiyot A, Hollister-Lock J, Sullivan B, Pan H, Dreyfuss JM, Bonner-Weir S, Schaffer JE. Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion. J Clin Invest. 2023 Nov 30;134(3):e173280. doi: 10.1172/JCI173280. PMID: 38032734; PMCID: PMC10849759.

About Joslin Diabetes Center

Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Part of Beth Israel Lahey Health, Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is affiliated with Harvard Medical School and one of only 18 NIH-designated Diabetes Research Centers in the United States.

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