Mutations in SLC2A2 gene reveal hGLUT2 function in pancreatic β cell development.
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.
['Michau|Aurélien|A|', 'Guillemain|Ghislaine|G|', 'Grosfeld|Alexandra|A|', 'Vuillaumier-Barrot|Sandrine|S|', 'Grand|Teddy|T|', 'Keck|Mathilde|M|', "L'Hoste|Sébastien|S|", 'Chateau|Danielle|D|', 'Serradas|Patricia|P|', 'Teulon|Jacques|J|', 'De Lonlay|Pascale|P|', 'Scharfmann|Raphaël|R|', 'Brot-Laroche|Edith|E|', 'Leturque|Armelle|A|', 'Le Gall|Maude|M|']
D019943:Amino Acid Substitution D000818:Animals D001693:Biological Transport, Active D002454:Cell Differentiation D045744:Cell Line, Tumor D005947:Glucose D051273:Glucose Transporter Type 2 D006801:Humans D007328:Insulin D000078790:Insulin Secretion D050417:Insulin-Secreting Cells D051379:Mice D020125:Mutation, Missense D020641:Polymorphism, Single Nucleotide D051381:Rats D015398:Signal Transduction D014982:Xenopus laevis
Insulin Secretion Mutant Fanconi-Bickel Syndrome Xenopus Glucose Transport GLUT2 Carbohydrate Metabolism Pancreatic Islets