Conclusions
In this model, the C43G proinsulin mutation does not impair glucose homeostasis or cause significant loss of β-cell mass. This model might be useful for identifying potential therapeutic targets for proper trafficking of intracellular insulin or for maintenance of β-cell mass in early-stage diabetic patients.
Methods
Islets from adult transgenic zebrafish expressing GFP-tagged human proinsulin mutant C43G (C43G-GFP) or wild-type human proinsulin (Cpep-GFP) were analyzed histologically across a range of ages. Blood glucose concentration was determined under fasting conditions and in response to glucose injection. Insulin secretion was assessed by measuring circulating GFP and endogenous C-peptide levels after glucose injection.
Results
The majority of β-cells expressing C43G proinsulin showed excessive accumulation of C43G-GFP in the ER. Western blotting showed that C43G-GFP was present only as proinsulin, indicating defective processing. GFP was poorly secreted in C43G mutants compared with controls. Despite these defects, blood glucose homeostasis was normal. Mutant fish maintained β-cell mass well into maturity and secreted endogenous C-peptide. Conclusions: In this model, the C43G proinsulin mutation does not impair glucose homeostasis or cause significant loss of β-cell mass. This model might be useful for identifying potential therapeutic targets for proper trafficking of intracellular insulin or for maintenance of β-cell mass in early-stage diabetic patients.