Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2

Area of Science:

• Genetics
• Metabolic Diseases
• Molecular Biology

Background:

• The rs58542926C >T (E167K) variant in the TM6SF2 gene is linked to nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D).
• The specific impact of the TM6SF2 rs58542926 variant on glucose metabolism remains unclear.

Purpose of the Study:

• To investigate the association between the TM6SF2 rs58542926 variant and T2D, with a focus on sex-specific effects.
• To elucidate the underlying mechanisms of TM6SF2's role in glucose metabolism using a mouse model.

Main Methods:

• Sex-stratified analysis of the rs58542926C >T variant and T2D in human cohorts.
• Utilized an E167K knockin (KI) mouse model to assess glucose tolerance.
• Examined the interaction between TM6SF2 and IRE1α signaling in the liver of KI mice.

Main Results:

• The E167K variant showed a significant association with T2D, predominantly in males.
• Male KI mice displayed impaired glucose tolerance, while female KI mice did not.
• Male KI mice exhibited dysregulated IRE1α signaling in the liver, indicating ER stress.

Conclusions:

• The TM6SF2 E167K variant contributes to glucose intolerance, with a pronounced effect in males.
• This suggests a sex-specific role for TM6SF2 in glucose homeostasis and ER stress pathways.