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bioRxiv · 10.1101/2025.01.09.632106

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

Jacobs, R.·Hernickx, G.·Galland, N.·Balty, C.·Vertommen, D.·Rider, M. H.·Johanns, M.
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Abstract

Obesity and type 2 diabetes (T2D)-linked hyperglycemia, along with their associated complications, have reached pandemic proportions, becoming 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. In the present study, we investigated effects of dual deletion of cytosolic 5-nucleotidase IA (NT5C1A) and NT5C2 in mice. We found that NT5C1A/NT5C2 double-knockout (NT5C-dKO) mice exhibited a hypoglycemic phenotype, displaying enhanced skeletal muscle insulin action and reduced hepatic glucose production. In addition to potential involvement of adenosine monophosphate (AMP)-activated protein kinase (AMPK) in their phenotype, NT5C-dKO mice displayed liver and skeletal muscle proteomic alterations most significantly linked to amino acid metabolism. Our findings support the development of novel anti-diabetic treatments using small-molecule cytosolic 5-nucleotidase inhibitors.

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Jacobs, R., Hernickx, G., Galland, N., Balty, C., Vertommen, D., Rider, M. H., Johanns, M.. 2025-01-13. Combined deletion of cytosolic 5'-nucleotidases IA and II lowers glycemia by improving skeletal muscle insulin action and by lowering hepatic glucose production. https://doi.org/10.1101/2025.01.09.632106

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