Combined deletion of cytosolic 5'-nucleotidases IA and II lowers glycemia by improving skeletal muscle insulin action and lowering hepatic glucose production.

Obesity and type 2 diabetes (T2D)-linked hyperglycemia, along with their associated complications, have reached pandemic proportions, constituting a major public health issue. Genetic deletion or pharmacological inhibition of purine nucleotide-metabolizing enzymes has emerged as a potential strategy for treating diseases. We previously showed that cytosolic 5'-nucleotidase II (NT5C2)-deficient mice were protected against high-fat diet (HFD)-induced insulin resistance. This study investigated the effects of dual deletion of cytosolic 5'-nucleotidases IA (NT5C1A) and II (NT5C2) in mice. We found that NT5C1A/NT5C2 double-knockout (NT5C-dKO) mice exhibited mild hypoglycemia, associated with enhanced skeletal muscle insulin action and reduced hepatic glucose production. This phenotype was accompanied by liver and skeletal muscle proteomic alterations notably related to amino acid metabolism, besides the potential involvement of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Our findings support the development of novel anti-diabetic treatments using small-molecule cytosolic 5'-nucleotidase inhibitors.