sitagliptin-phosphate and xenin-25

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.

Topics: Aminopeptidases; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Hypoglycemic Agents; Male; Metalloendopeptidases; Mice; Mice, Inbred C57BL; Neurotensin; O-(Chloroacetylcarbamoyl)fumagillol; Sitagliptin Phosphate; Up-Regulation

Recent studies have characterised the biological properties and glucose-dependent insulinotropic polypeptide (GIP) potentiating actions of an enzymatically stable, C-terminal hexapeptide fragment of the gut hormone xenin, namely Ψ-xenin-6. Given the primary therapeutic target of clinically approved dipeptidyl peptidase-4 (DPP-4) inhibitor drugs is augmentation of the incretin effect, the present study has assessed the capacity of Ψ-xenin-6 to enhance the antidiabetic efficacy of sitagliptin in high fat fed (HFF) mice. Individual administration of either sitagliptin or Ψ-xenin-6 alone for 18 days resulted in numerous metabolic benefits and positive effects on pancreatic islet architecture. As expected, sitagliptin therapy was associated with elevated circulating GIP and GLP-1 levels, with concurrent Ψ-xenin-6 not elevating these hormones or enhancing DPP-4 inhibitory activity of the drug. However, combined sitagliptin and Ψ-xenin-6 therapy in HFF mice was associated with further notable benefits, beyond that observed with either treatment alone. This included body weight change similar to lean controls, more pronounced and rapid benefits on circulating glucose and insulin as well as additional improvements in attenuating gluconeogenesis. Favourable effects on pancreatic islet architecture and peripheral insulin sensitivity were more apparent with combined therapy. Expression of hepatic genes involved in gluconeogenesis and insulin action were partially, or fully, restored to normal levels by the treatment regimens, with beneficial effects more prominent in the combination treatment group. These data demonstrate that combined treatment with Ψ-xenin-6 and sitagliptin did not alter glucose tolerance but does offer some metabolic advantages, which merit further consideration as a therapeutic option for type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Gastrointestinal Hormones; Hypoglycemic Agents; Insulin; Insulin Resistance; Mice; Neurotensin; Sitagliptin Phosphate