Sustained treatment with a stable long‐acting oxyntomodulin analogue improves metabolic control and islet morphology in an experimental model of type 1 diabetes

Abstract

AIM: To assess the therapeutic benefits of regulatory peptides other than insulin, which have to date received limited consideration in the context of type 1 diabetes. METHODS: We assessed the effects of subchronic administration of the stable, oxyntomodulin (Oxm) analogue, (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL], for 28 days in streptozotocin (STZ)-induced insulin-deficient diabetic mice. RESULTS: Twice-daily injection with (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL] significantly countered the excessive food and fluid intake in STZ-induced diabetic mice, and maintained normal body weight. Lean body mass was normalized, whilst fat mass was significantly increased compared with control STZ-induced diabetic mice. In addition, circulating glucose was significantly reduced by the Oxm analogue, whilst plasma and pancreatic insulin concentrations were increased and glucagon decreased by day 28. Plasma lipid profile was normalized by (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL] administration and circulating amylase was not significantly altered by induction of diabetes or Oxm analogue therapy. This was associated with significantly improved glucose tolerance and insulin secretion. Peripheral insulin sensitivity was also significantly improved by Oxm analogue treatment. Histological examination of pancreata showed beneficial elevations of total islet and β-cell area, associated with an increase in the number of smaller-sized islets. Further analysis revealed enhanced islet cell proliferation relative to apoptosis in Oxm analogue-treated mice. CONCLUSION: These studies emphasize the potential of stable Oxm-based peptides, such as (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL], as therapeutic agents for insulin-deficient type 1 diabetes.