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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin

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A novel AKT2 gene variant (p.Pro50Thr) significantly increases fasting insulin levels and type 2 diabetes risk, particularly in Finnish individuals. This finding sheds light on glucose homeostasis mechanisms.

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Area of Science:

  • Genetics
  • Metabolic Disorders
  • Molecular Biology

Background:

  • Understanding genetic factors influencing glycemic traits and type 2 diabetes risk is crucial.
  • The AKT2 gene is implicated in monogenic glycemic disorders.

Purpose of the Study:

  • To identify novel coding association signals for glycemic traits.
  • To characterize mechanisms influencing type 2 diabetes risk.

Main Methods:

  • Exome array genotyping and exome sequencing in up to 39,339 normoglycemic individuals.
  • Analysis of 109,215 exome array variants and 390,225 exome sequence variants.
  • Cellular studies to assess protein function.

Main Results:

  • A novel association was found between the AKT2 p.Pro50Thr coding variant and fasting insulin (FI).
  • The low-frequency AKT2 allele increases FI by 12%, is prevalent in Finns, and associated with increased type 2 diabetes risk.
  • Cellular studies revealed a partial loss of function for the AKT2-Thr50 protein.

Conclusions:

  • The study extends the allelic spectrum of AKT2 coding variants linked to glucose homeostasis disorders.
  • Variants within AKT2's pleckstrin homology domain exhibit bidirectional effects on glycemic traits.