HIF-1α/FOXO1 axis regulated autophagy is protective for ß cell survival under hypoxia in human islets.

ABSTRACT

ß cells suffer from hypoxia due to the rapid metabolic rate to supply insulin production. Mechanistic study of ß cell survival under hypoxia may shed light on the ß cell mass loss in type 2 diabetes mellitus (T2DM). Here, we found that the expressions of LC3 and p62/SQSTM1, two key autophagy regulators, were significantly higher in ß cells than that in non-ß endocrine cells in both non-diabetic and T2DM human pancreases, and the autophagy process was accelerated upon Cobalt Chloride (CoCl2) treatment in ex vivo cultured primary human islets. Meanwhile, CoCl2 induced the upregulation of FOXO1 in human islets, where HIF-1α played a key role. CoCl2 treatment caused the increase of ß cell apoptosis, yet inhibiting autophagy by Chloroquine or by FOXO1 knockdown further aggravated apoptosis, suggesting that FOXO1-regulated autophagy is protective for ß cell survival under hypoxia. Immunofluorescence staining showed that LC3 and p62/SQSTM1 expressions were significantly decreased in T2DM patients and negatively correlated with HbA1c, indicating that the autophagy capacity of ß cells is impaired along with the progression of the disease. Our study revealed that HIF-1α/FOXO1 regulated autophagy benefits ß cell survival under hypoxia and autophagy dysregulation may account for ß cell mass loss in T2DM. BRIEF SUMMARY: Our study revealed that HIF-1α/FOXO1 regulated autophagy benefits ß cell survival under hypoxia and autophagy dysregulation may account for ß cell mass loss in T2DM.