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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)191-198
Number of pages8
JournalPharmacogenomics Journal
Volume11
Issue number3
DOIs
Publication statusPublished - 2011 Jun 1

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Cyclosporine
Diabetes Mellitus
Transplantation
Alleles
Insulin
Calcineurin
Glucose
Secretory Vesicles
Tacrolimus
Sirolimus
zinc-binding protein
Insulinoma
Down Syndrome
Single Nucleotide Polymorphism
Zinc
Ions

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Kim, I. ; Kang, E. S. ; Yim, Y. S. ; Ko, S. J. ; Jeong, S. H. ; Rim, J. H. ; Kim, Y. S. ; Ahn, C. W. ; Cha, B. S. ; Lee, H. C. ; Kim, C. H. / A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion. In: Pharmacogenomics Journal. 2011 ; Vol. 11, No. 3. pp. 191-198.
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abstract = "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.",
author = "I. Kim and Kang, {E. S.} and Yim, {Y. S.} and Ko, {S. J.} and Jeong, {S. H.} and Rim, {J. H.} and Kim, {Y. S.} and Ahn, {C. W.} and Cha, {B. S.} and Lee, {H. C.} and Kim, {C. H.}",
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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. / Kim, I.; Kang, E. S.; Yim, Y. S.; Ko, S. J.; Jeong, S. H.; Rim, J. H.; Kim, Y. S.; Ahn, C. W.; Cha, B. S.; Lee, H. C.; Kim, C. H.

In: Pharmacogenomics Journal, Vol. 11, No. 3, 01.06.2011, p. 191-198.

Research output: Contribution to journalArticle

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T1 - A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

AU - Kim, I.

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AU - Yim, Y. S.

AU - Ko, S. J.

AU - Jeong, S. H.

AU - Rim, J. H.

AU - Kim, Y. S.

AU - Ahn, C. W.

AU - Cha, B. S.

AU - Lee, H. C.

AU - Kim, C. H.

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N2 - 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.

AB - 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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