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A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

 I Kim  ;  E S Kang  ;  Y S Yim  ;  S J Ko  ;  S-H Jeong  ;  J H Rim  ;  Y S Kim  ;  C W Ahn  ;  B S Cha  ;  H C Lee  ;  C H Kim 
 PHARMACOGENOMICS JOURNAL, Vol.11(3) : 191-198, 2011 
Journal Title
Issue Date
Alleles ; Animals ; Biomarkers, Pharmacological ; Calcineurin Inhibitors ; Cation Transport Proteins/genetics* ; Cell Line ; Cyclosporine/adverse effects* ; Cyclosporine/therapeutic use ; Diabetes Mellitus/etiology* ; Diabetes Mellitus/genetics* ; Glucose/metabolism ; Humans ; Immunosuppressive Agents/adverse effects ; Insulin/secretion* ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Kidney Transplantation/adverse effects* ; Mice ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Mutation ; Rats ; Zinc Transporter 8
SLC30A8 encodes the β-cell-specific zinc transporter-8 (ZnT-8) expressed in insulin secretory granules. The single-nucleotide polymorphism rs13266634 of SLC30A8 is associated with susceptibility to post-transplantation diabetes mellitus (PTDM). We tested the hypothesis that the polymorphic residue at position 325 of ZnT-8 determines the susceptibility to cyclosporin A (CsA) suppression of insulin secretion. INS (insulinoma)-1E cells expressing the W325 variant showed enhanced glucose-stimulated insulin secretion (GSIS) and were less sensitive to CsA suppression of GSIS. A reduced number of insulin granule fusion events accompanied the decrease in insulin secretion in CsA-treated cells expressing ZnT-8 R325; however, ZnT-8 W325-expressing cells exhibited resistance to the dampening of insulin granule fusion by CsA, and transported zinc ions into secretory vesicles more efficiently. Both tacrolimus and rapamycin caused similar suppression of GSIS in cells expressing ZnT-8 R325. However, cells expressing ZnT-8 W325 were resistant to tacrolimus, but not to rapamycin. The Down's syndrome candidate region-1 (DSCR1), an endogenous calcineurin inhibitor, overexpression and subsequent calcineurin inhibition significantly reduced GSIS in cells expressing the R325 but not the W325 variant, suggesting that differing susceptibility to CsA may be due to different interactions with calcineurin. These data suggest that the ZnT-8 W325 variant is protective against CsA-induced suppression of insulin secretion. Tolerance of ZnT-8 W325 to calcineurin activity may account for its protective effect in PTDM.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Kim, Yu Seun(김유선) ORCID logo https://orcid.org/0000-0002-5105-1567
Kim, In Sook(김인숙)
Kim, Chul Hoon(김철훈) ORCID logo https://orcid.org/0000-0002-7360-429X
Ahn, Chul Woo(안철우) ORCID logo https://orcid.org/0000-0003-3733-7486
Lee, Hyun Chul(이현철)
Yim, Yeong Shin(임영신)
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
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