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Progressive ER stress over time due to human insulin gene mutation contributes to pancreatic β-cell dysfunction, islet inflammation and compensatory responses

ABSTRACT: Heterozygous human INS gene mutations are known to promote ER stress, leading to β-cell dysfunction and neonatal diabetes. Recent literature challenged the long-standing notion that neonatal diabetes occurs due to ER stress-induced β-cell apoptosis. Importantly, mechanisms of β-cell failure during the disease progression and why the other wild-type (WT) INS allele is unable to function still remain unclear. Here, our computational modelling studies, short-term and long-term expression studies in β-cells revealed the presence of ER stress, organelle changes and insulin processing defects, resulting in decreased insulin secretion but not insulin secretory capacity. By nine weeks of expression of mutant INS, dominant negative effects of mutant INS were evident and β-cell insulin secretory capacity declined. INS+/C109Y patient-derived β-like cells and single cell RNA-Sequencing analyses then revealed compensatory upregulation in genes involved in insulin secretion, processing and inflammatory response. Our results provide deeper insights into the mechanisms of β-cell failure during INS mutation-mediated diabetes disease progression. Decreasing CHOP-10, sXBP1 or inflammatory response could be avenues to restore the function of the remaining WT INS allele.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141319 | GEO | 2021/10/03

REPOSITORIES: GEO

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