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Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice

L M McShane1, N Irwin1, D O'Flynn2

  • 1SAAD Centre for Pharmacy and DiabetesUniversity of Ulster, Coleraine, Northern Ireland, UK.

The Journal of Endocrinology
|April 22, 2016
PubMed

Insights

Glucagon receptor inhibition and GIP receptor activation show potential for type 2 diabetes (T2DM) treatment. Both approaches, alone or combined, improved glucose control and insulin sensitivity in obese mice without affecting body weight.

Area of Science:

  • Endocrinology
  • Metabolic Diseases

Background:

  • Glucagon receptor (GR) signaling blockade is a potential therapeutic strategy for type 2 diabetes (T2DM).
  • Glucose-dependent insulinotropic polypeptide (GIP) receptor signaling activation also shows promise for T2DM treatment.

Purpose of the Study:

  • To investigate the independent and combined metabolic effects of a GR antagonist (desHis(1)Pro(4)Glu(9)(Lys(12)PAL)-glucagon) and a GIP receptor agonist (d-Ala(2)GIP) in diet-induced obese mice.

Main Methods:

  • Administration of GR antagonist and/or GIP receptor agonist via twice-daily injections in high-fat-fed mice.
  • Assessment of body weight, energy intake, blood glucose, insulin levels, glucagon concentrations, glucose tolerance, insulin sensitivity, and metabolic rate.

Main Results:

  • All treatment regimens significantly decreased blood glucose levels.
  • d-Ala(2)GIP increased plasma and pancreatic insulin levels and enhanced glucose-induced insulin secretion.
  • GR inhibition increased metabolic rate and locomotor activity.
  • All treatments improved glucose tolerance and insulin sensitivity.

Conclusions:

  • Glucagon receptor inhibition, alone or combined with GIP receptor activation, demonstrates therapeutic potential for T2DM.
  • These combined strategies effectively improve glycemic control and insulin sensitivity in a preclinical model of obesity.
Keywords:
GIP receptor agonistdiet-induced obese diabetic miceglucagonglucagon receptor antagonistglucose homeostasisglucose-dependent insulinotropic polypeptide (GIP)insulin secretioninsulin sensitivity

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