Disclosure(s): I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose
Blinded Abstract: Incretin receptor agonists including GLP1 are used extensively to treat type 2 diabetes, and restore both insulin secretion and sensitivity. To explore how GLP1 agonism impacts islet β-cell Ca2+ dynamics in vivo we engrafted islets expressing the calcium indicator GCaMP6f into the anterior eye chamber (ACE) of control, diet- or genetically-induced hyperglycemic mice. Following engraftment (21 weeks-post-surgery), islet Ca2+ was monitored by confocal imaging through the front of the eye in anesthetized animals at day 0, 1 and 7. In control animals, Ca2+waves emanated from “leader” β-cells at the islet periphery. Islets from High-fat-High-sucrose (HFHS) diet-treated mice, or animals heterozygous for a hypomorphic Gck allele (C57BL6/J-Gcktm1(mCard)/Rutt; GckKI+, Salazar et al, unpublished), displayed lower connectivity (0.89±0.02 control mice, n=8 islets, 5 mice; vs 0.48±0.3 HFHS, n=9 islets, 6 mice; vs 0.58±0.2 GckKI+, n=5 islets, 4 mice respectively). Intraperitoneal exendin-4 (1 nmol/kg) administration at day 8 increased connectivity in HFHS and GckKI+ mice compared to vehicle injection at day 7 (HFHS 0.42±0.3 vs 0.86±0.02, n=7 islets, 6 mice p< 0.05; GckKI+0.45±0.12 vs 0.81±0.11, n=4 islets, 4 mice p< 0.05), but was without effect in control mice. Notably, Exendin-4 reengaged a highly-connected “hub” population to restore islet-wide Ca2+ dynamics. Interestingly, the in vivo responses to GLP1R agonists were more marked than those observed in isolated islets, suggesting that additional mechanisms, possibly including neuron-mediated signal relay. In summary, GLP1R agonism improves islet-wide Ca2+ dynamics in vivo in a metabolic and genetic model of type 2 diabetes. Further studies will be required to explore the mechanisms involved.
