title: Reduced insulin secretion in protein malnourished mice is associated with multiple changes in the beta-cell stimulus-secretion coupling.
abstract: The mechanism by which protein malnutrition impairs glucose-stimulated insulin secretion in the pancreatic beta-cell is not completely known but may be related to alterations in the signaling events involved in insulin release. Here, we aimed to study the stimulus-secretion coupling of beta-cells from mice fed with low-protein (LP) diet or normal-protein (NP) diet for 8 wk after weaning. Patch-clamp measurements in isolated cells showed that beta-cells from LP mice had a resting membrane potential that was more hyperpolarized than controls. Additionally, depolarization and generation of action potentials in response to stimulatory glucose concentrations were also impaired in beta-cells of LP mice. All these alterations in the LP group were most likely attributed to higher ATP-dependent K(+) (K(ATP)) channel activity in resting conditions and lower efficiency of glucose to induce the closure of these channels. Moreover, a Western blot analysis revealed higher protein levels of the sulphonylurea receptor of the K(ATP) channel in islets of LP mice. Because beta-cell Ca(2+) signals depend on electrical activity, intracellular Ca(2+) oscillations were measured by fluorescence microscopy in intact islets, indicating a lower response to glucose in the LP group. Finally, cell-to-cell synchrony of Ca(2+) signals was analyzed by confocal microscopy. Islets from LP mice exhibited a decreased level of coupling among beta-cells, which was probably due to the low expression levels of connexin 36. Therefore, low-protein diet leads to several alterations in the stimulus-secretion coupling of pancreatic beta-cells that might explain the diminished insulin secretion in response to glucose in this malnutrition state.
authors.affiliation: Instituto de Bioingeniería and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Universidad Miguel Hernández, 03202 Elche, Spain. ivanq@umh.es
authors.forename: Sergi
authors.initials: S
authors.lastname: Soriano
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Laura
authors.initials: L
authors.lastname: Marroquí
authors.forename: Eva
authors.initials: E
authors.lastname: Tudurí
authors.forename: Elaine
authors.initials: E
authors.lastname: Vieira
authors.forename: Andressa G
authors.initials: AG
authors.lastname: Amaral
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Batista
authors.forename: Alex
authors.initials: A
authors.lastname: Rafacho
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Boschero
authors.forename: Angel
authors.initials: A
authors.lastname: Nadal
authors.forename: Everardo M
authors.initials: EM
authors.lastname: Carneiro
authors.forename: Ivan
authors.initials: I
authors.lastname: Quesada
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D018753:Diet, Protein-Restricted / Q000009:adverse effects; D004044:Dietary Proteins / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D025802:Electric Capacitance; D005215:Fasting / Q000378:metabolism / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018408:Patch-Clamp Techniques; D011502:Protein-Energy Malnutrition / Q000378:metabolism* / Q000473:pathology; D055571:Secretory Pathway / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical
chemical_list: D004044:Dietary Proteins; D007328:Insulin; D005947:Glucose