title: Novel stable isotope analyses demonstrate significant rates of glucose cycling in mouse pancreatic islets.
abstract: A polymorphism located in the G6PC2 gene, which encodes an islet-specific glucose-6-phosphatase catalytic subunit, is the most important common determinant of variations in fasting blood glucose (FBG) levels in humans. Studies of G6pc2 knockout (KO) mice suggest that G6pc2 represents a negative regulator of basal glucose-stimulated insulin secretion (GSIS) that acts by hydrolyzing glucose-6-phosphate (G6P), thereby reducing glycolytic flux. However, this conclusion conflicts with the very low estimates for the rate of glucose cycling in pancreatic islets, as assessed using radioisotopes. We have reassessed the rate of glucose cycling in pancreatic islets using a novel stable isotope method. The data show much higher levels of glucose cycling than previously reported. In 5 mmol/L glucose, islets from C57BL/6J chow-fed mice cycled ∼16% of net glucose uptake. The cycling rate was further increased at 11 mmol/L glucose. Similar cycling rates were observed using islets from high fat-fed mice. Importantly, glucose cycling was abolished in G6pc2 KO mouse islets, confirming that G6pc2 opposes the action of the glucose sensor glucokinase by hydrolyzing G6P. The demonstration of high rates of glucose cycling in pancreatic islets explains why G6pc2 deletion enhances GSIS and why variants in G6PC2 affect FBG in humans.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt School of Engineering, Nashville, TN.
authors.forename: Martha L
authors.identifier: http://orcid.org/0000-0001-8846-267X
authors.initials: ML
authors.lastname: Wall
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Lynley D
authors.initials: LD
authors.lastname: Pound
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt School of Engineering, Nashville, TN.
authors.forename: Irina
authors.initials: I
authors.lastname: Trenary
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN.
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Brien
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt School of Engineering, Nashville, TN Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN j.d.young@vanderbilt.edu.
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Young
mesh_terms: D000818:Animals; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000378:metabolism*; D007553:Isotope Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse; D005947:Glucose