Chronic fructose renders pancreatic β-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling
| Autor: | Brenda R. Kwak, Filippo Molica, Thierry Brun, Mariagrazia Grimaldi, Clarissa Bartley, Domenico Bosco, Lucie Oberhauser, Pierre Maechler, Marc Chanson |
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| Rok vydání: | 2019 |
| Předmět: |
AMPK
0301 basic medicine Physiology Endocrinology Diabetes and Metabolism AMP-Activated Protein Kinases ddc:616.07 Connexins Mice Receptors Purinergic P2Y1 chemistry.chemical_compound Adenosine Triphosphate 0302 clinical medicine Insulin-Secreting Cells Insulin Secretion ddc:616 ddc:618 ddc:617 Chemistry Insulin secretion Apyrase Purinergic receptor Pannexin Receptors Purinergic P2Y Purinergic P2Y Receptor Agonists Signal Transduction medicine.medical_specialty Nerve Tissue Proteins Fructose Pancreatic islet Islets of Langerhans 03 medical and health sciences Physiology (medical) Internal medicine medicine Extracellular Animals Humans ddc:612 Mice Inbred C57BL ATP Glucose 030104 developmental biology Endocrinology Purinergic P2Y Receptor Antagonists 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Physiology. Endocrinology and Metabolism, Vol. 317, No 1 (2019) pp. E25-E41 |
| ISSN: | 1522-1555 0193-1849 |
| Popis: | Fructose is widely used as a sweetener in processed food and is also associated with metabolic disorders, such as obesity. However, the underlying cellular mechanisms remain unclear, in particular, regarding the pancreatic β-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 β-cells hyper-responsive to intermediate physiological glucose concentrations. Fructose exposure reduced intracellular ATP levels without affecting mitochondrial function, induced AMP-activated protein kinase activation, and favored ATP release from the β-cells upon acute glucose stimulation. The resulting increase in extracellular ATP, mediated by pannexin1 (Panx1) channels, activated the calcium-mobilizer P2Y purinergic receptors. Immunodetection revealed the presence of both Panx1 channels and P2Y1 receptors in β-cells. Addition of an ectonucleotidase inhibitor or P2Y1 agonists to naïve β-cells potentiated insulin secretion stimulated by intermediate glucose, mimicking the fructose treatment. Conversely, the P2Y1 antagonist and Panx1 inhibitor reversed the effects of fructose, as confirmed using Panx1-null islets and by the clearance of extracellular ATP by apyrase. These results reveal an important function of ATP signaling in pancreatic β-cells mediating fructose-induced hyper-responsiveness. |
| Databáze: | OpenAIRE |
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