1798-P: Chronic Administration of a Long-Acting Glucagon Analogue Results in Enhanced Insulin Secretory Activity in a Directly-Observed Murine Model

Abstract

Aims: GLP-1 (GLP-1R) and glucagon (GCGR) receptor co-agonists are in development to treat type 2 diabetes. The effect of chronic GCGR agonism on weight loss is well-documented, but its direct influence on islet function remains poorly understood. We investigated the effects of a long-acting glucagon analogue G778 on pancreatic islet calcium dynamics. Methods: C57Bl/6 (n=9 per group) mice with diet-induced obesity (DIO) received daily subcutaneous injections of G778 100nmol/kg or saline (and calorie restricted to achieve weight matching) for 40 days. All mice had syngeneic islets with beta-cell specific expression of the calcium fluorophore GCaMP6f implanted in the anterior chamber of the eye, providing a direct, longitudinal readout of beta-cell function in vivo using confocal microscopy. Such islets were tested in vitro to measure the effects of G778 on whole islet calcium dynamics. Another experiment measured the effects of G778 administration on oxygen consumption in a CLAMS system. Results: G778 produced a small but significant rise in energy expenditure (EE) in mice. At 40 days, there was non-significant difference in body weight loss between the saline and G778-treated groups (0.9g ±1.1 vs. 3.4g ±0.7 p=0.07), but a marked improvement in glucose tolerance in mice treated long term with the glucagon analogue (15 min glucose on a 2mg/kg IPGTT 15.9 mmol/L vs. 9.2 mmol/L p<0.001). Islet readouts over the course of the experiment revealed that glucagon receptor agonism was able to restore calcium activity of islets in DIO mice in vivo. In vitro findings confirmed that G778 promoted calcium waves of longer duration and heightened connectivity above 7mM glucose (p=0.05). Summary: Our data suggest that the glucagon element of a glucagon/GLP-1 analogue contributes to weight-loss partly through an elevation in EE but also has independent effects on insulin secretory function, promoting more robust and sustained beta-cell calcium responses. Disclosure K. Suba: None. Y.S. Patel: None. A. Martin Alonso: None. R. Scott: None. J.S. Minnion: None. I. Leclerc: Consultant; Spouse/Partner; Sun Pharmaceutical Industries Ltd. Research Support; Spouse/Partner; Servier. B. Owen: None. W. Distaso: None. T.M. Tan: None. K. Murphy: None. S. Bloom: None. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd. V. Salem: None. Funding Diabetes UK (15/0005317)