Exendin-4 improves β-cell function in autophagy-deficient β-cells.

Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.

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