Dietary dipeptide γ-glutamyl valine (γ-EV) activates AMPK and improves glucose homeostasis in db/db mice.

This study investigates the therapeutic potential of γ-glutamyl valine (γ-EV) in 4 week-old male db/db mice, a well-established model for type 2 diabetes. Mice were fed an AIN-93 G diet and administered γ-EV (500 mg/kg body weight) via drinking water for 3 weeks. Blood, liver, muscle, and intestinal tissues were collected to assess blood glucose, peptide bioavailability, liver function, glycogen levels, protein expression, and transcriptomic changes. γ-EV was bioavailable in circulation (2.07±1.59 μM) and significantly improved food efficiency (+79%, P<.0001), despite reduced calorie intake (-27%, P<.0001). Treated mice exhibited markedly reduced polyuria and water intake (-80%, P<.0001), and showed substantial reductions in blood glucose under both fasted (-76%, P<.0001) and non-fasted (-29%, P=.0054) conditions. Although γ-EV increased the hepatosomatic index (+66%, P<.0001), serum ALT levels remained unchanged (P=.0765), indicating no hepatotoxicity. RNA-seq revealed 1308 differentially expressed genes in the liver and 147 in the jejunum, with 26 genes overlapping between the two. Key upregulated GO terms included fatty acid metabolism (jejunum) and oxidoreductase activity (liver). Hepatic p-AMPKα levels increased (+86%, P=.0137) alongside decreased liver glycogen (-79%, P<.0001), suggesting γ-EV induces beneficial catabolic signaling. Overall, γ-EV shows promise as an anti-diabetic peptide.