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Comparison of stability, cellular, glucose-lowering and appetite supressing effects of oxyntomodulin analogues

Aisling M Lynch1, Nupur Pathak1, Yasmin E Flatt1

  • 1SAAD Centre for Pharmacy and Diabetes, Biomedical Sciences Research Institute, University of Ulster, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK.

European Journal of Pharmacology
|September 24, 2014
PubMed

Insights

Modified oxyntomodulin (Oxm) peptides show promise for obesity-diabetes treatment. Several analogues demonstrated resistance to dipeptidyl peptidase-4 (DPP-4) degradation and beneficial effects on glucose and insulin levels in mice.

Area of Science:

  • Biochemistry
  • Endocrinology
  • Pharmacology

Background:

  • Oxyntomodulin (Oxm) has therapeutic potential for obesity and diabetes.
  • Rapid inactivation by dipeptidyl peptidase-4 (DPP-4) limits Oxm's clinical use due to its short half-life.

Purpose of the Study:

  • To synthesize and evaluate novel Oxm analogues for enhanced DPP-4 stability and biological activity.
  • To assess the therapeutic potential of these stable Oxm analogues in preclinical models of metabolic disease.

Main Methods:

  • Six Oxm analogues were synthesized, including modifications at position 2 and a PAL conjugate.
  • DPP-4 stability, cAMP production in receptor-transfected cells (GLP-1-R, GIP-R, Glucagon-R), and insulinotropic activity in BRIN BD11 cells were assessed.
  • In vivo studies in normal mice and receptor knockout models evaluated glucose homeostasis, insulin levels, and appetite suppression.

Main Results:

  • Analogues (Aib(2))Oxm, (d-Ser(2))Oxm, and (d-Ser(2))Oxm-Lys-γ-glutamyl-PAL exhibited resistance to DPP-4 degradation.
  • Stable analogues stimulated cAMP production via GLP-1 receptors and showed insulinotropic effects.
  • In vivo, stable Oxm analogues lowered glucose excursion, increased insulin levels, and suppressed appetite, with (d-Ser(2))Oxm-Lys-γ-glutamyl-PAL showing persistent effects.
  • GLP-1 receptor signaling was crucial for the glucose-homeostatic actions of the most promising analogues.

Conclusions:

  • Enzymatically stable Oxm-based peptides, particularly those with position 2 modifications, hold significant therapeutic promise for treating obesity and diabetes.
  • These modified peptides offer improved pharmacokinetic properties and potent glucose-lowering and appetite-suppressing effects.
  • Further development of these stable Oxm analogues could lead to novel treatments for metabolic disorders.
Keywords:
AnalogueFood intakeGlucose homoeostasisInsulin secretionOxyntomodulin

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