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

Brian Lu, Miguel Munoz-Gomez, Yasuhiro H Ikeda

Research output: Contribution to journalArticle

2 Citations (Scopus)

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. 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 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.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StateAccepted/In press - Mar 23 2018

Fingerprint

Glucokinase
Protein Isoforms
Glucose
Exons
Cell proliferation
Liver
Cell Proliferation
Gene transfer
Nuclear Localization Signals
Glucose Tolerance Test
Nutrition
Medical problems
Metabolism
Fasting
Conservation
Diet

Keywords

  • glucokinase
  • isoform
  • β-cell

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

Cite this

The two major glucokinase isoforms show conserved functionality in β-cells despite different subcellular distribution. / Lu, Brian; Munoz-Gomez, Miguel; Ikeda, Yasuhiro H.

In: Unknown Journal, 23.03.2018.

Research output: Contribution to journalArticle

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N2 - 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. 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 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.

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