AKT1 regulates endoplasmic reticula stress and mediates adaptive response of pancreatic β-cells.

Isoforms of protein kinase B (also known as AKT) play important roles in mediating insulin and growth factor signals. Previous studies have suggested that the AKT2 isoform is critical for insulin-regulated glucose metabolism, while the role of the AKT1 isoform remains less clear. This study focuses on the effects of AKT1 on the adaptive response of pancreatic beta cells. Using a mouse model with inducible beta-cell-specific deletion of the Akt1 gene (beta A1KO mice), we showed that AKT1 is involved in high-fat-diet (HFD)-induced growth and survival of beta cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, beta A1KO mice presented the same metabolic profile and beta-cell phenotype as the control mice with an intact Akt1 gene. When metabolic stress was induced by HFD, beta cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in beta A1KO mice. We further demonstrated that AKT1 protein deficiency caused endoplasmic reticulum (ER) stress and potentiated beta cells to undergo apoptosis. Our results revealed that AKT1 protein loss led to the induction of eukaryotic initiation factor 2 alpha subunit (eIF2 alpha) signaling and ER stress markers under normal-chow-fed conditions, indicating chronic low-level ER stress. Together, these data established a role for AKT1 as a growth and survival factor for adaptive beta-cell response and suggest that ER stress induction is responsible for this effect of AKT1.