Lipotoxicity disrupts incretin-regulated human β cell connectivity
David J. Hodson, … , Stephen J. Hughes, Guy A. Rutter
David J. Hodson, … , Stephen J. Hughes, Guy A. Rutter
Published September 9, 2013
Citation Information: J Clin Invest. 2013;123(10):4182-4194. https://doi.org/10.1172/JCI68459.
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Research Article Endocrinology

Lipotoxicity disrupts incretin-regulated human β cell connectivity

Abstract

Pancreatic β cell dysfunction is pathognomonic of type 2 diabetes mellitus (T2DM) and is driven by environmental and genetic factors. β cell responses to glucose and to incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are altered in the disease state. While rodent β cells act as a coordinated syncytium to drive insulin release, this property is unexplored in human islets. In situ imaging approaches were therefore used to monitor in real time the islet dynamics underlying hormone release. We found that GLP-1 and GIP recruit a highly coordinated subnetwork of β cells that are targeted by lipotoxicity to suppress insulin secretion. Donor BMI was negatively correlated with subpopulation responses to GLP-1, suggesting that this action of incretin contributes to functional β cell mass in vivo. Conversely, exposure of mice to a high-fat diet unveiled a role for incretin in maintaining coordinated islet activity, supporting the existence of species-specific strategies to maintain normoglycemia. These findings demonstrate that β cell connectedness is an inherent property of human islets that is likely to influence incretin-potentiated insulin secretion and may be perturbed by diabetogenic insults to disrupt glucose homeostasis in humans.

Authors

David J. Hodson, Ryan K. Mitchell, Elisa A. Bellomo, Gao Sun, Laurent Vinet, Paolo Meda, Daliang Li, Wen-Hong Li, Marco Bugliani, Piero Marchetti, Domenico Bosco, Lorenzo Piemonti, Paul Johnson, Stephen J. Hughes, Guy A. Rutter

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Figure 7

Species specificity of incretin action on coordinated β cell activity.

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Species specificity of incretin action on coordinated β cell activity. (...
(A) β cells within islets from ND animals display highly coordinated Ca2+ oscillations in response to 11 mM glucose (G11), and synchronicity is not affected by 20 nM GLP-1. Conversely, an HFD disrupts G11-stimulated coordinated β cell activity, but this is restored by the application of incretin. Top panel: representative Ca2+ traces. Bottom panel: heatmap depicting minimum (0) to maximum (100) for each cell. (B) Bar graph demonstrating that the mean percentage of significantly correlated cell pairs is restored to ND values during the application of GLP-1 to islets derived from HFD-fed animals (**P < 0.01 versus before GLP-1 application, Kruskal-Wallis test; n = 8 islets from at least 4 animals). (C) GLP-1–stimulated insulin secretion (G11; 11 mM glucose), as measured using ZIMIR, is subtly improved by an HFD (**P < 0.01 versus ND, Mann-Whitney U test; n = 12 islets from 4 animals). (D) Duty cycle (i.e., time spent in the active phase) is 2-fold higher during the application of GLP-1 to islets from ND animals (**P < 0.01 versus before GLP-1 application; Mann-Whitney U test; n = 4 recordings). (E) As for B, except for the exogenous application of palmitate to islets from animals fed an ND (**P < 0.01 versus before GLP-1 application; Kruskal-Wallis test; n = 8 islets from 6 animals). (F) Representative traces from control- and palmitate-treated islets. (G) As for D, except for the exogenous application of control (BSA plus NaOH) to islets from animals fed an ND (**P < 0.01 versus before GLP-1 application; Mann-Whitney U test).