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

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Glucokinase (GCK) is a key enzyme regulating glucose metabolism in the liver and pancreatic beta-cells.
• Two major GCK isoforms, hepatic and pancreatic, differ in exon 1, but their functional distinctions are unclear.

Purpose of the Study:

• To investigate the functional impact of isoform-specific GCK overexpression on beta-cells.
• To determine the in vitro and in vivo effects of hepatic and pancreatic GCK isoforms.

Main Methods:

• Utilized a beta-cell-targeted gene transfer vector for isoform-specific GCK overexpression.
• Assessed glucose uptake, beta-cell proliferation, fasting glucose levels, and intraperitoneal glucose tolerance tests (IPGTT) in vitro and in vivo.
• Analyzed human GCK sequences for variant and mutation distribution.

Main Results:

• Pancreatic GCK possesses a unique nuclear localization signal, leading to distinct subcellular distribution.
• Overexpression of both GCK isoforms similarly enhanced glucose uptake and beta-cell proliferation in vitro.
• Both hepatic and pancreatic GCK overexpression promoted beta-cell proliferation in mice without altering glucose homeostasis.
• GCK variants were disproportionally found in exon 1, while MODY2 mutations were concentrated in later exons.

Conclusions:

• The two major GCK isoforms exhibit functional conservation despite differences in subcellular localization.
• Isoform-specific GCK overexpression demonstrates similar effects on beta-cell function and proliferation.
• Exon 1 differences do not significantly impair the primary metabolic functions of GCK isoforms.