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In the present study, we showed that the expression of <jats:italic>Nadk<\/jats:italic> and <jats:italic>Nadk2<\/jats:italic> transcripts and NADP(H) content were lower in islets of 80\u2010week\u2010old (<jats:italic>aged<\/jats:italic>) mice than those of 8\u2010week\u2010old (<jats:italic>young<\/jats:italic>) mice. This was associated with diminished oral glucose tolerance of old mice and the glucose\u2010stimulated insulin secretion (GSIS) response of islets. Knockdown (KD) of <jats:italic>Nadk<\/jats:italic> or <jats:italic>Nadk2<\/jats:italic> gene expression in NIT\u20101 cells impaired glucose\u2010stimulated insulin secretion. Metabolomic analysis revealed that <jats:italic>Nadk<\/jats:italic> KD specifically affected purine metabolism in glucose\u2010stimulated cells. The levels of 5\u2010aminoimidazole\u20104\u2010carboxamide ribonucleotide (AICAR) were higher in KD cells than in the non\u2010targeting control (NTC) cells. Phosphorylation of AMP\u2010activated protein kinase (AMPK) was elevated in glucose\u2010treated KD cells compared to that of NTC cells. Increased AICAR level and AMPK\u03b1 phosphorylation were observed in the glucose\u2010stimulated islets of the aged mice. Genetic and pharmacological inhibition of AMPK promoted glucose\u2010stimulated insulin release by KD cells and the aged mouse islets. It is likely that NADK is modulatory to AMPK activation in pancreatic \u03b2\u2010cells and to their GSIS response. Enhanced AICAR formation in KD cells was accompanied by significantly increased conversion from inosine monophosphate (IMP) in a tetrahydrofolate (THF)\u2010dependent manner. Folate supplementation augmented the GSIS response of KD cells and aged mouse islets. 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