A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.

Summary

Using population data, patient iPSC-derived β cells, and in vivo grafts, the study shows INS R6C causes recessive, not dominant, monogenic diabetes. Homozygotes develop early-onset insulin-requiring diabetes with β-cell ER translocation defects, whereas heterozygotes generally do not show increased diabetes risk.

Key Findings

• Homozygous INS R6C individuals develop early-onset insulin-treated diabetes; heterozygous carriers show variable or absent glycemic phenotypes with no population-level enrichment of diabetes.
• Homozygous iPSC-derived β cells accumulate preproinsulin, with reduced insulin content and secretion; heterozygous cells show minimal defects.
• In vivo β-cell transplants from homozygous R6C recapitulate insulin deficiency and respond poorly to GLP-1 receptor agonists; transcriptomics reveal attenuated translation/translocation and ER pathway signatures.
• Evidence supports reclassification of R6C as a recessive loss-of-function variant, informing clinical reassessment of carriers.

Clinical Implications

Genetic counseling for R6C carriers should consider recessive inheritance; heterozygotes may not require enhanced diabetes surveillance. Therapeutic expectations may shift given poor GLP-1RA response in homozygous β cells.

Limitations

• Likely small number of homozygous cases limits precision and generalizability
• Clinical endpoints and long-term outcomes were not systematically assessed; applicability to other INS variants remains uncertain

Future Directions

Expand to larger, multi-ethnic cohorts and additional INS variants; test targeted therapeutics addressing ER translocation stress; develop clinical algorithms integrating population and functional evidence.