title: Sustained treatment with a stable long-acting oxyntomodulin analogue improves metabolic control and islet morphology in an experimental model of type 1 diabetes.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: N
authors.initials: N
authors.lastname: Irwin
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: V
authors.initials: V
authors.lastname: Pathak
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Pathak
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
authors.affiliation: Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004435:Eating / Q000187:drug effects; D005768:Gastrointestinal Hormones / Q000494:pharmacology*; D005934:Glucagon / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D053772:Oxyntomodulin; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism
chemical_list: C000607531:(Ser2)Oxm(Lys38-gamma-Glu-PAL); D001786:Blood Glucose; D005768:Gastrointestinal Hormones; D007004:Hypoglycemic Agents; D007328:Insulin; D053772:Oxyntomodulin; D005934:Glucagon
keywords: diabetes; glucose tolerance; insulin secretion; islet; oxyntomodulin (Oxm); streptozotocin; β-cell