title: Mutations in SLC2A2 gene reveal hGLUT2 function in pancreatic β cell development.
abstract: The structure-function relationships of sugar transporter-receptor hGLUT2 coded by SLC2A2 and their impact on insulin secretion and β cell differentiation were investigated through the detailed characterization of a panel of mutations along the protein. We studied naturally occurring SLC2A2 variants or mutants: two single-nucleotide polymorphisms and four proposed inactivating mutations associated to Fanconi-Bickel syndrome. We also engineered mutations based on sequence alignment and conserved amino acids in selected domains. The single-nucleotide polymorphisms P68L and T110I did not impact on sugar transport as assayed in Xenopus oocytes. All the Fanconi-Bickel syndrome-associated mutations invalidated glucose transport by hGLUT2 either through absence of protein at the plasma membrane (G20D and S242R) or through loss of transport capacity despite membrane targeting (P417L and W444R), pointing out crucial amino acids for hGLUT2 transport function. In contrast, engineered mutants were located at the plasma membrane and able to transport sugar, albeit with modified kinetic parameters. Notably, these mutations resulted in gain of function. G20S and L368P mutations increased insulin secretion in the absence of glucose. In addition, these mutants increased insulin-positive cell differentiation when expressed in cultured rat embryonic pancreas. F295Y mutation induced β cell differentiation even in the absence of glucose, suggesting that mutated GLUT2, as a sugar receptor, triggers a signaling pathway independently of glucose transport and metabolism. Our results describe the first gain of function mutations for hGLUT2, revealing the importance of its receptor versus transporter function in pancreatic β cell development and insulin secretion.
authors.affiliation: From the INSERM UMRS872, Cordeliers Research Center, Université Pierre et Marie Curie, 75006 Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Michau
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Guillemain
authors.forename: Alexandra
authors.initials: A
authors.lastname: Grosfeld
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vuillaumier-Barrot
authors.forename: Teddy
authors.initials: T
authors.lastname: Grand
authors.forename: Mathilde
authors.initials: M
authors.lastname: Keck
authors.forename: Sébastien
authors.initials: S
authors.lastname: L'Hoste
authors.forename: Danielle
authors.initials: D
authors.lastname: Chateau
authors.forename: Patricia
authors.initials: P
authors.lastname: Serradas
authors.forename: Jacques
authors.initials: J
authors.lastname: Teulon
authors.forename: Pascale
authors.initials: P
authors.lastname: De Lonlay
authors.forename: Raphaël
authors.initials: R
authors.lastname: Scharfmann
authors.forename: Edith
authors.initials: E
authors.lastname: Brot-Laroche
authors.forename: Armelle
authors.initials: A
authors.lastname: Leturque
authors.forename: Maude
authors.initials: M
authors.lastname: Le Gall
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D015398:Signal Transduction; D014982:Xenopus laevis
chemical_list: D051273:Glucose Transporter Type 2; D007328:Insulin; C495680:SLC2A2 protein, human; D005947:Glucose
keywords: Carbohydrate Metabolism; Fanconi-Bickel Syndrome; GLUT2; Glucose Transport; Insulin Secretion; Mutant; Pancreatic Islets; Xenopus