Startseite The two major glucokinase isoforms show conserved functionality in β-cells despite different subcellular distribution
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The two major glucokinase isoforms show conserved functionality in β-cells despite different subcellular distribution

  • Brian Lu , Miguel Munoz-Gomez und Yasuhiro Ikeda EMAIL logo
Veröffentlicht/Copyright: 23. März 2018
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 399 Heft 6

Abstract

Glucokinase (GCK) is crucial to regulating glucose metabolism in the liver and in pancreatic β-cells. There are two major GCK isoforms, hepatic and pancreatic GCKs, which differ only in exon 1. However, the functional differences between the two GCK isoforms remain poorly understood. Here, we used a β-cell-targeted gene transfer vector to determine the impact of isoform-specific GCK overexpression on β-cells in vitro and in vivo. We showed that pancreatic GCK had a nuclear localization signal unique to the pancreatic isoform, facilitating its nuclear distribution in β-cells. Despite the difference in subcellular distribution, overexpression of GCK isoforms similarly enhanced glucose uptake and β-cell proliferation in vitro. Overexpression of hepatic or pancreatic GCK also similarly enhanced β-cell proliferation in normal diet mice without affecting fasting glucose and intraperitoneal glucose tolerance tests (IPGTT). Our further study on human GCK sequences identified disproportional GCK amino acid variants in exon 1, while mutations linked to maturity onset diabetes of the young type 2 (MODY2) were disproportionally found in exons 2 through 10. Our results therefore indicate functional conservation between the two major GCK isoforms despite their distinct subcellular distribution.

Keywords: β-cell; glucokinase; isoform

Acknowledgments

The authors would like to thank the Mayo Clinic Graduate School of Biomedical Sciences Initiative for Maximizing Student Development for supporting our Ph.D. trainees.

  1. Funding: This work was supported by NIH GM (R43 GM112316), Vann Family Fund in Diabetes Research, Kieckhefers Foundation, Paul A. and Ruth M. Schilling Medical Research Endowment Fund, and Mayo Clinic Center for Regenerative Medicine (to Y.I.), and Mayo Clinic Graduate School of Biomedical Sciences (to B.L.), and Initiative for Maximizing Student Development (IMSD, to B.L.).

  2. Conflict of interest statement: No potential conflicts of interest relevant to this article are reported.

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Supplemental Material:

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0109).

Received: 2018-1-8
Accepted: 2018-3-8
Published Online: 2018-3-23
Published in Print: 2018-5-24

©2018 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Hodgkin lymphoma cell lines: to separate the wheat from the chaff
  4. The AGO proteins: an overview
  5. Research Articles/Short Communications
  6. Protein Structure and Function
  7. Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation
  8. The two major glucokinase isoforms show conserved functionality in β-cells despite different subcellular distribution
  9. Functional characterization of the mouse Serpina1 paralog DOM-7
  10. Cell Biology and Signaling
  11. CD45RO regulates the HIV-1 gp120-mediated apoptosis of T cells by activating Lck
  12. Silencing of MED27 inhibits adrenal cortical carcinogenesis by targeting the Wnt/β-catenin signaling pathway and the epithelial-mesenchymal transition process
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https://doi.org/10.1515/hsz-2018-0109
Schlagwörter für diesen Artikel
β-cell; glucokinase; isoform

Artikel in diesem Heft

  1. Frontmatter
  2. Reviews
  3. Hodgkin lymphoma cell lines: to separate the wheat from the chaff
  4. The AGO proteins: an overview
  5. Research Articles/Short Communications
  6. Protein Structure and Function
  7. Structural changes at the myrtenol backbone reverse its positive allosteric potential into inhibitory GABAA receptor modulation
  8. The two major glucokinase isoforms show conserved functionality in β-cells despite different subcellular distribution
  9. Functional characterization of the mouse Serpina1 paralog DOM-7
  10. Cell Biology and Signaling
  11. CD45RO regulates the HIV-1 gp120-mediated apoptosis of T cells by activating Lck
  12. Silencing of MED27 inhibits adrenal cortical carcinogenesis by targeting the Wnt/β-catenin signaling pathway and the epithelial-mesenchymal transition process
  13. HDAC1 knockdown inhibits invasion and induces apoptosis in non-small cell lung cancer cells
  14. Hepatitis B virus X protein promotes proliferation of hepatocellular carcinoma cells by upregulating miR-181b by targeting ING5
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