Permanent Neonatal diabetes-causing Insulin mutations have dominant negative effects on beta cell identity

Area of Science:

• Endocrinology
• Genetics
• Cell Biology

Background:

• Permanent neonatal diabetes mellitus (PNDM) is a severe form of diabetes caused by beta cell failure.
• Heterozygous mutations in the insulin (INS) gene are a known genetic cause of PNDM.

Approach:

• Investigated beta cell failure mechanisms in two PNDM patients with distinct INS mutations.
• Utilized human embryonic stem cells (hESCs) with INS mutations to study proinsulin processing and endoplasmic reticulum (ER) homeostasis in vitro.
• Transplanted patient-derived stem cell-derived beta (SC-beta) cells into NSG mice to assess in vivo function and identify dominant-negative effects.

Key Points:

• INS mutations lead to the accumulation of misfolded proinsulin and impaired proinsulin processing.
• These mutations disrupt ER homeostasis, causing beta cell loss and functional decline.
• Observed beta cell dedifferentiation, marked by altered marker expression, in addition to apoptosis.

Conclusions:

• INS mutations contribute to PNDM through both established (apoptosis) and novel (dedifferentiation) mechanisms.
• Understanding these pathways is crucial for developing targeted therapies for PNDM.
• Highlights the critical role of ER homeostasis in maintaining beta cell function and mass.