AKT1 Regulates Endoplasmic Reticulum Stress and Mediates the Adaptive Response of Pancreatic ? Cells.

ABSTRACT: 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 ? cells. Using a mouse model with inducible ?-cell-specific deletion of the Akt1 gene (?A1KO mice), we showed that AKT1 is involved in high-fat-diet (HFD)-induced growth and survival of ? cells but is unnecessary for them to maintain a population in the absence of metabolic stress. When unchallenged, ?A1KO mice presented the same metabolic profile and ?-cell phenotype as the control mice with an intact Akt1 gene. When metabolic stress was induced by HFD, ? cells in control mice with intact Akt1 proliferated as a compensatory mechanism for metabolic overload. Similar effects were not observed in ?A1KO mice. We further demonstrated that AKT1 protein deficiency caused endoplasmic reticulum (ER) stress and potentiated ? cells to undergo apoptosis. Our results revealed that AKT1 protein loss led to the induction of eukaryotic initiation factor 2 ? subunit (eIF2?) 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 ?-cell response and suggest that ER stress induction is responsible for this effect of AKT1.

SUBMITTER: Peng Z 

PROVIDER: S-EPMC7225563 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature