The therapeutic mechanism of action of
methionine aminopeptidase 2 (MetAP2) inhibitors for
obesity-diabetes has not yet been fully defined.
Xenin, a K-cell derived
peptide hormone, possesses an N-terminal Met
amino acid residue. Thus, elevated
xenin levels could represent a potential pharmacological mechanism of MetAP2 inhibitors, since long-acting
xenin analogues have been shown to improve
obesity-diabetes. The present study has assessed the ability of the MetAP2 inhibitor,
TNP-470, to augment the
antidiabetic utility of the
incretin-enhancer
drug,
sitagliptin, in high fat fed (HFF) mice.
TNP-470 (1 mg/kg) and
sitagliptin (25 mg/kg) were administered once-daily alone, or in combination, to diabetic HFF mice (n = 10) for 18 days. Individual
therapy with
TNP-470 or
sitagliptin resulted in numerous metabolic benefits including reduced
blood glucose, increased circulating and pancreatic
insulin and improved
glucose tolerance,
insulin sensitivity,
pyruvate tolerance and overall pancreatic islet architecture. Further assessment of metabolic rate revealed that all treatments reduced respiratory exchange ratio and increased locomotor activity. All
sitagliptin treated mice also exhibited increased energy expenditure. In addition, treatment with
TNP-470 alone, or in combination with
sitagliptin, reduced food intake and
body weight, as well as elevating plasma and intestinal
xenin. Importantly, combined
sitagliptin and
TNP-470 therapy was associated with further significant benefits beyond that observed by either treatment alone. This included more rapid restoration of normoglycaemia, superior
glucose tolerance, increased circulating GIP concentrations and an enhanced pancreatic beta:alpha cell ratio. In conclusion, these data demonstrate that
TNP-470 increases plasma and intestinal
xenin levels, and augments the
antidiabetic advantages of
sitagliptin.