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Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion

Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells... Full description

Journal Title: Endocrinology (Philadelphia) 2016-12, Vol.157 (12), p.4534-4541
Main Author: Syring, Kristen E
Other Authors: Boortz, Kayla A , Oeser, James K , Ustione, Alessandro , Platt, Kenneth A , Shadoan, Melanie K , McGuinness, Owen P , Piston, David W , Powell, David R , O'Brien, Richard M
Format: Electronic Article Electronic Article
Language: English
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Publisher: United States: Endocrine Society
ID: ISSN: 0013-7227
Link: https://www.ncbi.nlm.nih.gov/pubmed/27754787
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5133349
title: Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion
format: Article
creator:
  • Syring, Kristen E
  • Boortz, Kayla A
  • Oeser, James K
  • Ustione, Alessandro
  • Platt, Kenneth A
  • Shadoan, Melanie K
  • McGuinness, Owen P
  • Piston, David W
  • Powell, David R
  • O'Brien, Richard M
subjects:
  • Abridged Index Medicus
  • Animals
  • Body Weight - genetics
  • Cation Transport Proteins - genetics
  • Cation Transport Proteins - metabolism
  • endocrine system
  • endocrine system diseases
  • Female
  • Glucagon-Secreting Cells - metabolism
  • Glucose - pharmacology
  • Glucose Intolerance - genetics
  • Glucose Intolerance - metabolism
  • Insulin - metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells - metabolism
  • Islets of Langerhans - drug effects
  • Islets of Langerhans - metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Rapid Communication
  • Sex Factors
  • Zinc Transporter 8
ispartof: Endocrinology (Philadelphia), 2016-12, Vol.157 (12), p.4534-4541
description: Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.
language: eng
source:
identifier: ISSN: 0013-7227
fulltext: no_fulltext
issn:
  • 0013-7227
  • 1945-7170
url: Link


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titleCombined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion
creatorSyring, Kristen E ; Boortz, Kayla A ; Oeser, James K ; Ustione, Alessandro ; Platt, Kenneth A ; Shadoan, Melanie K ; McGuinness, Owen P ; Piston, David W ; Powell, David R ; O'Brien, Richard M
creatorcontribSyring, Kristen E ; Boortz, Kayla A ; Oeser, James K ; Ustione, Alessandro ; Platt, Kenneth A ; Shadoan, Melanie K ; McGuinness, Owen P ; Piston, David W ; Powell, David R ; O'Brien, Richard M
descriptionPolymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.
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subjectAbridged Index Medicus ; Animals ; Body Weight - genetics ; Cation Transport Proteins - genetics ; Cation Transport Proteins - metabolism ; endocrine system ; endocrine system diseases ; Female ; Glucagon-Secreting Cells - metabolism ; Glucose - pharmacology ; Glucose Intolerance - genetics ; Glucose Intolerance - metabolism ; Insulin - metabolism ; Insulin Secretion ; Insulin-Secreting Cells - metabolism ; Islets of Langerhans - drug effects ; Islets of Langerhans - metabolism ; Male ; Mice ; Mice, Knockout ; Rapid Communication ; Sex Factors ; Zinc Transporter 8
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descriptionPolymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.
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titleCombined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in Glucose-Stimulated Insulin Secretion
authorSyring, Kristen E ; Boortz, Kayla A ; Oeser, James K ; Ustione, Alessandro ; Platt, Kenneth A ; Shadoan, Melanie K ; McGuinness, Owen P ; Piston, David W ; Powell, David R ; O'Brien, Richard M
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5endocrine system
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8Glucagon-Secreting Cells - metabolism
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20Rapid Communication
21Sex Factors
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notesResearch in the laboratory of R.M.O. was supported by the National Institutes of Health (NIH) Grant DK92589. Research in the laboratory of O.P.M. was supported by NIH Grants DK043748 and DK078188. Research in the laboratory of D.W.P. was supported by the NIH Grant DK085064. The Vanderbilt Hormone Assay and Analytical Services Core, Islet Procurement and Analysis Core and Cell Imaging Shared Resource are all supported by the NIH Grant P60 DK20593 (to the Vanderbilt Diabetes Research Training Center) and the NIH Grant DK59637 (to the Vanderbilt Mouse Metabolic Phenotyping Center). K.E.S. was supported by the Vanderbilt Molecular Endocrinology Training Program Grant 5T32 DK07563.
abstractPolymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8 haploinsufficiency is protective against the development of T2D in obese humans. SLC30A8 is predominantly expressed in pancreatic islet β-cells, but surprisingly, multiple knockout mouse studies have shown little effect of Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion (GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic islets. We hypothesized that functional compensation by the Slc30a7 isoform, which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We therefore analyzed the effect of Slc30a7 deletion alone or in combination with Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and reducing the glucose-stimulated increase in plasma insulin levels, hepatic glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected islet morphology and increased the ratio of islet α- to β-cells. However, deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply that ZnT8 may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.
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pmid27754787
doi10.1210/en.2016-1573
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