Abstract
Regulated proinsulin biosynthesis, disulfide bond formation and ER redox homeostasis are essential to prevent Type two diabetes. In ß cells, protein disulfide isomerase A1 (PDIA1/P4HB), the most abundant ER oxidoreductase of over 17 members, can interact with proinsulin to influence disulfide maturation. Here we find Pdia1 is required for optimal insulin production under metabolic stress in vivo. ß cell-specific Pdia1 deletion in young high-fat diet fed mice or aged mice exacerbated glucose intolerance with inadequate insulinemia and increased the proinsulin/insulin ratio in both serum and islets compared to wildtype mice. Ultrastructural abnormalities in Pdia1-null ß cells include diminished insulin granule content, ER vesiculation and distention, mitochondrial swelling and nuclear condensation. Furthermore, Pdia1 deletion increased accumulation of disulfide-linked high molecular weight proinsulin complexes and islet vulnerability to oxidative stress. These findings demonstrate that PDIA1 contributes to oxidative maturation of proinsulin in the ER to support insulin production and ß cell health.
Highlights
Type two diabetes mellitus (T2D) is a complex disease caused by multiple genetic and environmental factors with an overarching problem of insufficient insulin to meet the level of insulin resistance (Mokdad et al, 2001; Sladek et al, 2007; Narayan et al, 2007; Støy et al, 2007; Kaul and Ali, 2016)
Immunohistochemistry (IHC) of pancreas tissue sections with antibodies specific for proinsulin/insulin, glucagon and PDIA1 confirmed the absence of PDIA1 in a ß cell-specific manner in the KO mice (Figure 2A–B, compare middle panels)
Numerous in vitro studies demonstrated that Protein disulfide isomerase (PDI) actively engages proinsulin to catalyze disulfide bond formation (Winter et al, 2011; Rajpal et al, 2012; Winter et al, 2002; Wright et al, 2013), there is little information regarding the significance of PDI action in vivo
Summary
Type two diabetes mellitus (T2D) is a complex disease caused by multiple genetic and environmental factors with an overarching problem of insufficient insulin to meet the level of insulin resistance (Mokdad et al, 2001; Sladek et al, 2007; Narayan et al, 2007; Støy et al, 2007; Kaul and Ali, 2016). Disulfide bond formation within secretory proteins occurs during the early stages of protein folding as cysteine residues establish proximity to one another; enzymes can assist catalyzing this process (Bulleid, 2012). Thiol groups on cysteine residues in the active motif are responsible for the oxidoreductase activity, enabling PDI to catalyze both disulfide bond formation as well as disulfide bond isomerization for selective substrates (Hudson et al, 2015; Hatahet and Ruddock, 2007; Freedman, 1995; Wang et al, 2015). The results support the conclusion that therapeutics directed to promote native disulfide bond formation within proinsulin is an attractive strategy to prevent ß cell failure in T2D
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