Intravital imaging of islet Ca2+ dynamics reveals enhanced β cell connectivity after bariatric surgery in mice

Abstract

Bariatric surgery improves both insulin sensitivity and secretion and can induce diabetes remission. However, the mechanisms and time courses of these changes, particularly the impact on β cell function, are difficult to monitor directly. In this study, we investigated the effect of Vertical Sleeve Gastrectomy (VSG) on β cell function in vivo by imaging Ca2+ dynamics in islets engrafted into the anterior eye chamber. Mirroring its clinical utility, VSG in mice results in significantly improved glucose tolerance, and enhanced insulin secretion. We reveal that these benefits are underpinned by augmented β cell function and coordinated activity across the islet. These effects involve changes in circulating GLP-1 levels which may act both directly and indirectly on the β cell, in the latter case through changes in body weight. Thus, bariatric surgery leads to time-dependent increases in β cell function and intra-islet connectivity which are likely to contribute to diabetes remission.

Divergent acute versus prolonged pharmacological GLP-1R responses in adult beta cell-selective β-arrestin 2 knockout mice

“…Values were then corrected for the fact that, in implanted islets, approximately 20% of the imaged islet cross-section is covered by blood vessels. Using this method, we were able to determine the presence of four types of calcium wave activity, in line with earlier studies (Akalestou et al, 2021): islets where we observed activity over 0-25% of corrected area were characterized as type 1, if 26-50% of the islet cross-section was active these were typical of type 2, if 51-75% of the cross-section was active islets displayed type 3 activity and lastly, type 4 activity was assigned to islets where 76-100% of the cross-section was active.…”

“…Islets from these mice were then isolated and used for implantation in the anterior chamber of the eye of WT acceptor mice. This platform supported longitudinal in vivo imaging of calcium responses as previously shown (Akalestou et al, 2021; Salem et al, 2019) at mildly elevated in vivo glucose levels. Experiments were carried out under both chow and HFHS diet conditions, with islet donors and islet acceptors matched for diet type.…”

“…Next, to investigate calcium responses in vivo , a mouse model of the genetically encoded calcium indicator GCaMP6f (36) was crossed with β-arrestin 2 KO mice to generate beta cell-specific GCaMP6f β-arrestin 2 KO and wild type (WT) control mice, and islets from these mice isolated and implanted in the anterior chamber of the eye of WT acceptor mice. This platform supported longitudinal in vivo imaging of calcium responses as previously shown (37, 38) using mildly elevated in vivo glucose levels. Experiments were carried out under both chow and HFHS diet conditions, with islet donors and acceptors matched for diet type.…”

From Isles of Königsberg to Islets of Langerhans: Examining the Function of the Endocrine Pancreas Through Network Science

“…Additionally, trying to decipher the effects of vertical sleeve gastrectomy (VSG) on beta cell function in obese mice, Akalestou et al. have shown that Ca 2+ dynamics as well as the number and strength of connections between beta cells increase within 8-10 weeks post-surgery, which could be attributed to the strong influence of GLP-1 on islet functioning ( 57 ). GLP-1 in physiological picomolar concentrations augments postprandial insulin secretion.…”

Homocysteine Metabolism Pathway Is Involved in the Control of Glucose Homeostasis: A Cystathionine Beta Synthase Deficiency Study in Mouse

“…Functional multicellular Ca 2+ -imaging was performed on isolated islets as previously described [ 17 ]. Correlation analyses were performed between beta-cell pairs and their extracted fluorescent Ca 2+ traces over time in each imaged islet in MATLAB using a custom-made script, as previously described [ 18 ].…”