Endocrine Abstracts

Glucagon receptor KO mice are resistant to the clinical manifestations of diabetes induced by streptozotocin (STZ) and retain normal glycaemic control and glucose tolerance. In the present study the effects of chronic (18 days) once daily i.p. administration of two different glucagon receptor antagonists (GRA); desHis¹Pro⁴Glu⁹-glucagon (GRA-1) and its related acylated peptide desHis¹Pro⁴Glu⁹(Lys¹²PAL)-glucagon (GRA-2) were investigated in groups of male (n=8) high fat fed (45% fat) STZ-induced (125 mg/kg) diabetic mice. Food intake, body weight, blood glucose and plasma insulin were measured at regular intervals. At the end of the study period an oral glucose tolerance test, insulin sensitivity test and analysis of metabolic rate was performed. Terminal plasma glucagon concentrations and pancreatic insulin content were also measured. GRA-1 and GRA-2 showed no significant improvement in STZ-induced weight loss over the course of the study, however both peptides delayed STZ-induced glucose elevations (P<0.05) on day 3. No significant differences were found in non-fasting blood glucose on day 18 between the STZ-treated and both GRA treated groups. In comparison to STZ-treated controls (Area under curve AUC_0-60min 749.5±152.8): GRA-1 (530.2±188.6) and GRA-2 (510.9±184.9) significantly (P<0.05) improved oral glucose tolerance in STZ-induced diabetes, producing a 30% reduction in the overall glucose excursion. Both GRA-1 and GRA-2 significantly (P<0.05) enhanced the hypoglycaemic effects of insulin by 1.36-fold (Area above curve AAC_0-60min 1471±144.6) and 1.29-fold (1396±112.8), compared with STZ-treated controls (1079±165.5). Energy expenditure was also significantly increased (P<0.001) in both GRA treatment groups compared with STZ-treated controls. GRA-2 significantly enhanced (P<0.001) pancreatic insulin content (0.85 μg/g tissue) versus STZ-treated controls (0.02 μg/g; P<0.001). In conclusion, novel glucagon receptor antagonist peptides improved glycaemic control and partially protected against STZ-induced type 1 diabetes in mice.

Disclosure: Proof of Concept (PoC106) funding from Invest NI. DEL PhD Studentship award.