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

Published inAmerican Journal of Physiology. Endocrinology and Metabolism, vol. 317, no. 1, p. E25-E41
Publication date2019
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
Funding
  • Swiss National Science Foundation - 146984
  • Swiss National Science Foundation - 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
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Article (Accepted version)
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Identifiers
ISSN of the journal0193-1849
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Creation04/18/2019 10:05:00 AM
First validation04/18/2019 10:05:00 AM
Update time03/15/2023 4:23:41 PM
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