title: Reduction of glucose uptake through inhibition of hexose transporters and enhancement of their endocytosis by methylglyoxal in Saccharomyces cerevisiae.
abstract: Diabetes mellitus is characterized by an impairment of glucose uptake even though blood glucose levels are increased. Methylglyoxal is derived from glycolysis and has been implicated in the development of diabetes mellitus, because methylglyoxal levels in blood and tissues are higher in diabetic patients than in healthy individuals. However, it remains to be elucidated whether such factors are a cause, or consequence, of diabetes. Here, we show that methylglyoxal inhibits the activity of mammalian glucose transporters using recombinant Saccharomyces cerevisiae cells genetically lacking all hexose transporters but carrying cDNA for human GLUT1 or rat GLUT4. We found that methylglyoxal inhibits yeast hexose transporters also. Glucose uptake was reduced in a stepwise manner following treatment with methylglyoxal, i.e. a rapid reduction within 5 min, followed by a slow and gradual reduction. The rapid reduction was due to the inhibitory effect of methylglyoxal on hexose transporters, whereas the slow and gradual reduction seemed due to endocytosis, which leads to a decrease in the amount of hexose transporters on the plasma membrane. We found that Rsp5, a HECT-type ubiquitin ligase, is responsible for the ubiquitination of hexose transporters. Intriguingly, Plc1 (phospholipase C) negatively regulated the endocytosis of hexose transporters in an Rsp5-dependent manner, although the methylglyoxal-induced endocytosis of hexose transporters occurred irrespective of Plc1. Meanwhile, the internalization of hexose transporters following treatment with methylglyoxal was delayed in a mutant defective in protein kinase C.
authors.affiliation: Laboratory of Molecular Microbiology, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Laboratory of Molecular Microbiology, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Dandan
authors.initials: D
authors.lastname: Wei
authors.affiliation: Laboratory of Molecular Microbiology, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.affiliation: Laboratory of Molecular Microbiology, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Izawa
authors.affiliation: Laboratory of Molecular Microbiology, Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011, Japan. Electronic address: y_inoue@kais.kyoto-u.ac.jp.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D011765:Pyruvaldehyde; D043743:Ubiquitin-Protein Ligase Complexes; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; C469287:RSP5 protein, S cerevisiae; D005947:Glucose
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