Abstract
Zinc is integral for β-cell function in glycaemic control. Intracellular zinc concentrations are regulated by buffering and membrane transportation mediated by the ZIP (14 paralogues; SLC39A) and ZnT (10 paralogues; SLC30A) families of transporters, which flux zinc into and out of the cytosol, respectively. The predominantly β-cell-specific paralogue ZnT8 (SLC30A8) uptakes zinc into granules, where it is essential for normal insulin maturation and exocytosis. Deregulation of zinc and its transporters is associated with β-cell dysfunction and Type 2 Diabetes development: the non-synonymous polymorphism rs13266684 in SLC30A8 confers differential zinc transporting efficiencies and is linked to disease risk, and many type 2 diabetic patients and animal models of diabetes present with hypozincaemia. We hypothesised that ZIP transporters are coordinated with ZnT8 to mediate β-cell zinc content, phenotype and function in response to the hyperglycaemia and hypozincaemia present in Type 2 Diabetes. We used a systematic approach to identify Slc39a1 in rodent, and SLC39A6, SLC39A7, SLC39A9, SLC39A13 and SLC39A14 in human and rodent as potentially biologically important for β-cell phenotype and function. We showed that both prolonged stimulation and extracellular zinc depletion, representative of hyperglycaemia and hypozincaemia in vivo, respectively, lower the zinc content of MIN6 β-cells and disrupt expression of multiple Slc39a paralogues and zinc-responsive markers for β-cell identity. Moreover, we demonstrated that ZIP6 and ZnT8 are involved in maintaining β-cell zinc content, survival and identity in response to zinc depletion, and identified potential co-regulation of ZnT8, ZIP6 and ZIP9 by the major β-cell transcription factor PDX-1. Critically, these data show that ZIP6 and ZnT8 are involved in maintaining β-cell zinc homeostasis and that stresses present in Type 2 Diabetes induce loss of β-cell zinc, which may alter cellular phenotype and reduce survival.Date of Award | 2019 |
---|---|
Original language | English |
Awarding Institution |
|
Supervisor | Christer Hogstrand (Supervisor), Mark Peakman (Supervisor) & Wolfgang Maret (Supervisor) |