Insulin2^Q104del (Kuma) mutant mice develop diabetes with dominant inheritance

Area of Science:

• Genetics
• Endocrinology
• Animal Models

Background:

• Insulin gene mutations are a known cause of monogenic diabetes, often leading to permanent neonatal diabetes.
• Establishing reliable animal models is crucial for understanding diabetes pathogenesis and testing therapies.

Purpose of the Study:

• To generate a novel animal model for permanent early-onset diabetes using genome editing.
• To characterize the phenotype and underlying mechanisms of the generated mouse model.

Main Methods:

• Genome editing using CRISPR/Cas9 to introduce a specific mutation (p.Q104del) in the Insulin2 (Ins2) gene.
• Phenotypic analysis of mutant mice, including hyperglycemia assessment, insulin level measurement, and islet morphology evaluation.
• Electron microscopy to examine beta-cell ultrastructure and insulin granule characteristics.

Main Results:

• A novel Kuma mutant mouse model with a dominant mode of inheritance for hyperglycemia was successfully generated.
• Mutant mice exhibited non-obese hyperglycemia from 3 weeks of age, reduced insulin protein levels, and impaired insulin granule formation.
• Islet size and mass were reduced in Kuma mutant mice, and hyperglycemia was reversible with insulin administration.

Conclusions:

• The Kuma mutant mouse presents a novel model of permanent early-onset diabetes caused by an insulin mutation.
• This model mimics key aspects of human monogenic diabetes and is suitable for investigating islet transplantation and other diabetes therapies.