Reduced Insulin Secretion in Protein Malnourished Mice Is Associated with Multiple Changes in the β-Cell Stimulus-Secretion Coupling

The mechanism by which protein malnutrition impairs glucose-stimulated insulin secretion in the pancreatic β-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 β-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 β-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 β-cells of LP mice. All these alterations in the LP group were most likely attributed to higher ATP-dependent K+ (KATP) 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 KATP channel in islets of LP mice. Because β-cell Ca2+ signals depend on electrical activity, intracellular Ca2+ 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 Ca2+ signals was analyzed by confocal microscopy. Islets from LP mice exhibited a decreased level of coupling among β-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 β-cells that might explain the diminished insulin secretion in response to glucose in this malnutrition state. Protein restriction in the diet induces several changes in the signaling events that lead to glucose-stimulated insulin secretion in the pancreatic β-cell.