A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.

Area of Science:

• Genetics
• Metabolic Diseases
• Molecular Biology

Background:

• Type 2 diabetes (T2D) is a global health concern with rising costs.
• Identifying genetic factors influencing T2D risk is crucial for therapeutic development.

Purpose of the Study:

• To identify genetic variations associated with T2D in Latino populations.
• To explore the therapeutic potential of identified genetic variants.

Main Methods:

• Genome-wide analysis of protein-coding variation in 8,227 T2D cases and 12,966 controls of Latino descent.
• In vitro and human tissue studies to assess the functional impact of a novel IGF2 variant.
• Phenotypic examination of variant carriers.

Main Results:

• A novel variant in the IGF2 gene was identified, associated with a ~20% reduced risk of T2D.
• This variant disrupts IGF2 splicing, leading to reduced expression of IGF2 isoform 2 in an allele-dosage-dependent manner.
• Reduced IGF2 isoform 2 expression in adipose tissue correlated with lower T2D incidence and glycated hemoglobin levels.

Conclusions:

• Reducing IGF2 isoform 2 expression presents a potential therapeutic strategy for T2D.
• The identified variant shows no adverse effects on other health or reproductive parameters.
• This finding has implications for T2D treatment beyond the studied population.