Chronic fructose renders pancreatic beta-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling

Bartley, Clarissa; Brun, Thierry; Oberhauser, Lucie; Grimaldi, Mariagrazia; Molica, Filippo; Kwak, Brenda; Bosco, Domenico; Chanson, Marc; Maechler, Pierre

doi:10.1152/ajpendo.00456.2018

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Title		Chronic fructose renders pancreatic beta-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling
Authors		Bartley, Clarissa Brun, Thierry Oberhauser, Lucie Grimaldi, Mariagrazia Molica, Filippo Kwak, Brenda Bosco, Domenico Chanson, Marc Maechler, Pierre show all authors [1 - 9]
Published in		American Journal of Physiology. Endocrinology and Metabolism. 2019, vol. 317, no. 1, p. E25-E41
Abstract		Fructose is widely used as a sweetener in processed food and since then is associated with metabolic disorders, such as obesity. However, the underlying cellular mechanisms remain unclear, in particular regarding the pancreatic beta-cell. Here, we investigated the effects of chronic exposure to fructose on the function of insulinoma cells and isolated mouse and human pancreatic islets. Although fructose per se did not acutely stimulate insulin exocytosis, our data show that chronic fructose rendered rodent and human beta-cells hyper-responsive to intermediate physiological glucose concentrations. Fructose exposure reduced intracellular ATP levels, without affecting mitochondrial function, induced AMPK activation and favored ATP release from the beta-cells upon acute glucose stimulation. The resulting increase in extracellular ATP, mediated by pannexin1 channels, activated the calcium-mobilizer P2Y purinergic receptors. Immunodetection revealed the presence of both pannexin1 channels and P2Y1 receptors in beta-cells. Addition of an ectonucleotidase inhibitor or P2Y1 agonists to naïve beta-cells potentiated insulin secretion stimulated by intermediate glucose, mimicking the fructose treatment. Conversely, P2Y1 antagonist and pannexin1 inhibitor reversed the effects of fructose, as confirmed using pannexin1-null islets and by the clearance of extracellular ATP by apyrase. These results reveal an important function of ATP signalling in pancreatic beta-cells mediating fructose-induced hyper-responsiveness.
Keywords		Pancreatic islet — Insulin secretion — Fructose — AMPK — ATP — Pannexin — Purinergic receptor
Identifiers		DOI: 10.1152/ajpendo.00456.2018 PMID: 30912960
Full text		Article (Accepted version) (1.1 MB) - Free access Appendix (1 MB) - Free access
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de chirurgie Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique
Research groups		L'athérosclérose (665) Mitochondries et sécrétion d'insuline (671) Mucoviscidose et jonctions communicantes (229) La transplantation d'îlots de Langerhans (623)
Projects		FNS: 146984 FNS: 166625
Citation (ISO format)		BARTLEY, Clarissa et al. Chronic fructose renders pancreatic beta-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling. In: American Journal of Physiology. Endocrinology and Metabolism, 2019, vol. 317, n° 1, p. E25-E41. doi: 10.1152/ajpendo.00456.2018 https://archive-ouverte.unige.ch/unige:116616