ChREBP is activated by reductive stress and mediates GCKR-associated metabolic traits

Do iron homeostasis biomarkers mediate the associations of liability to type 2 diabetes and glycemic traits in liver steatosis and cirrhosis: a two-step Mendelian randomization study

“…Although these glycemic traits are well-characterized risk factors for T2D, recent studies indicated that they may have distinct relations with metabolomic signatures and CVD risk [ 57 , 58 ]. However, our sensitivity analysis suggested this paradoxical finding could be driven by rs1260326 ( GCKR ), which encodes glucokinase regulatory protein (GKRP) (a primarily liver-specific protein) and is linked to decreased blood glucose by altering GKRP’s function of suppressing glucokinase activity and enhancing hepatic glycolysis, and concurrently increase total hepatic triglycerides [ 59 ], resulting in the risk allele of rs1260326 (T) decreasing the risk of T2D but increasing liver steatosis [ 30 ], and impacting the overall analyses. Although any effects observed for this GCKR risk variant could be arguably the downstream effects of glucose level variation (i.e., vertical pleiotropy and hence valid), given its high relevance in glucose metabolism, the increased circulating lipids could also arguably as an effect independent of glucose (i.e., horizontal pleiotropy and hence invalid) [ 60 , 61 ].…”