Bryan J Gonz\u00e1lez et al. Commun Biol. 2022.<\/p>\n\n\n\n
Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of \u03b2-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A.
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HNF1A-deficient \u03b2-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation. Knockout of CACNA1A and SYT13 reproduce the relevant phenotypes. In HNF1A deficient \u03b2-cells, glibenclamide, a sulfonylurea drug used in the treatment of HNF1A-MODY patients, increases intracellular calcium, and restores insulin secretion. While insulin secretion defects are constitutive in \u03b2-cells null for HNF1A, \u03b2-cells heterozygous for hypomorphic HNF1A (R200Q) mutations lose the ability to secrete insulin gradually; this phenotype is prevented by correction of the mutation. <\/p>\n\n\n\n
Our studies illuminate the molecular basis for the efficacy of treatment of HNF1A-MODY with sulfonylureas, and suggest promise for the use of cell therapies.<\/p>\n\n\n\n
https:\/\/pubmed.ncbi.nlm.nih.gov\/35918471\/<\/a><\/p>\n\n\n\n (Chooselife is interested in the Calcium Status of Cells, not proposed drugs)<\/p>\n\n\n\n