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Diabetes is a genetically heterogeneous disease, for which we are aiming to identify causative genes. Here, we report a missense mutation (c.T1424C:p.L475P) in ZYG11A identified by exome sequencing as segregating with hyperglycemia in a Thai family with autosomal dominant diabetes. ZYG11A functions as a target recruitment subunit of an E3 ubiquitin ligase complex that plays an important role in the regulation of cell cycle. We demonstrate an increase in cells arrested at G 2 /mitotic phase among beta-cells deficient for ZYG11A or overexpressing L475P-ZYG11A, which is associated with a decreased growth rate. This is the first evidence linking a ZYG11A mutation to hyperglycemia, and suggesting ZYG11A as a cell cycle regulator required for beta-cell growth. Since most family members were either overweight or obese, but only mutation carriers developed hyperglycemia, our data also suggests the ZYG11A mutation as a genetic factor predisposing obese individuals to beta-cell failure in maintenance of glucose homeostasis., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

In Thailand, diabetes mellitus is the most significant risk factor for melioidosis, a severe disease caused by Burkholderia pseudomallei. In this study, neutrophils isolated from healthy or diabetic subjects were infected with B. thailandensis E555, a variant strain with a B. pseudomallei-like capsular polysaccharide used here as a surrogate micro-organism for B. pseudomallei. At 2 h post-infection, neutrophil proteins were subjected to 4-plex iTRAQ-based comparative proteomic analysis. A total of 341 proteins were identified in two or more samples, of which several proteins involved in oxidative stress and inflammation were enriched in infected diabetic neutrophils. We validated this finding by demonstrating that infected diabetic neutrophils generated significantly elevated levels of pro-inflammatory cytokines TNFα, IL-6, IL-1β, and IL-17 compared to healthy neutrophils. Our data also revealed that infected neutrophils from healthy or diabetic individuals undergo apoptotic cell death at distinctly different rates, with infected diabetic neutrophils showing a diminished ability to delay apoptosis and an increased likelihood of undergoing a lytic form of cell death, compared to infected neutrophils from healthy individuals. Increased expression of inflammatory proteins by infected neutrophils could contribute to the increased susceptibility to infection and inflammation in diabetic patients in melioidosis-endemic areas.

Diabetes mellitus (DM) and other glucose metabolism abnormalities are commonly observed in individuals with Fanconi anemia (FA). FA causes an impaired response to DNA damage due to genetic defects in a cluster of genes encoded proteins involved in DNA repair. However, the mechanism by which FA is associated with DM has not been clearly elucidated. Fanconi anemia complementation group C (FANCC) is a component of FA nuclear clusters. Evidence suggests that cytoplasmic FANCC has a role in protection against oxidative stress‑induced apoptosis. As oxidative stress‑mediated β‑cell dysfunction is one of the contributors to DM pathogenesis, the present study aimed to investigate the role of FANCC in pancreatic β‑cell response to oxidative stress. Small interfering RNA‑mediated FANCC suppression caused a loss of protection against oxidative stress‑induced apoptosis, and that overexpression of FANCC reduced this effect in the human 1.1B4 β‑cell line. These findings were confirmed by Annexin V‑FITC/PI staining, caspase 3/7 activity assay, and expression levels of anti‑apoptotic and pro‑apoptotic genes. Insulin and glucokinase mRNA expression were also decreased in FANCC‑depleted 1.1B4 cells. The present study demonstrated the role of FANCC in protection against oxidative stress‑induced β‑cell apoptosis and established another mechanism that associates FANCC deficiency with β‑cell dysfunction. The finding that FANCC overexpression reduced β‑cell apoptosis advances the potential for an alternative approach to the treatment of DM caused by FANCC defects.