Metformin-stimulated mannose transport in dermal fibroblasts.
The biguanide drug metformin stimulates AMP-activated protein kinase, a master regulator of cellular energy metabolism, and has antihyperglycemic activity due to attenuation of gluconeogenesis in hepatocytes and 2-fold stimulation of glucose transport by skeletal muscle. Here we identify a metformin-stimulated d-mannose transport (MSMT) activity in dermal fibroblasts. MSMT increased mannose uptake 1.8-fold and had greater affinity for mannose than basal mannose transport activity. It was attributed to robust stimulation of a transporter expressed weakly in untreated cells. MSMT was not explained by greater glucose transporter activity because metformin unexpectedly decreased transport of 2-deoxy-d-glucose and 3-O-methyl-d-glucose by fibroblasts. Effective inhibitors of MSMT retained specificity for the 3-, 4-, and 6-OH groups of the mannose ring but not the 2-OH group. Thus, MSMT could be strongly inhibited by glucose and 2-deoxy-d-glucose even though the latter was not a good transport substrate. MSMT was significant because in the presence of 2.5 microm mannose, metformin corrected experimentally induced deficiencies in the synthesis of glucose(3)mannose(9)GlcNAc(2)-P-P-dolichol and N-linked glycosylation. MSMT was also identified in congenital disorder of glycosylation types Ia and Ib fibroblasts, and metformin acted synergistically with 100 microm mannose to correct lipid-linked oligosaccharide synthesis and N-glycosylation in the Ia cells. In conclusion, metformin activates a novel fibroblast mannose-selective transport system. This suggests that AMP-activated protein kinase may be a regulator of mannose metabolism and implies a therapy for congenital disorders of glycosylation-Ia.
Shang
Jie
J
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Lehrman
Mark A
MA
D019325:3-O-Methylglucose / Q000493:pharmacokinetics; D001692:Biological Transport; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism; D008358:Mannose / Q000378:metabolism / Q000493:pharmacokinetics*; D008687:Metformin / Q000494:pharmacology*; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010693:Phloretin / Q000494:pharmacology; D010695:Phlorhizin / Q000494:pharmacology; D012867:Skin / Q000378:metabolism*; D013997:Time Factors; D014415:Tunicamycin / Q000494:pharmacology
D007004:Hypoglycemic Agents; D009004:Monosaccharide Transport Proteins; D014415:Tunicamycin; D019325:3-O-Methylglucose; D008687:Metformin; D003847:Deoxyglucose; D010695:Phlorhizin; D005947:Glucose; D008358:Mannose; D010693:Phloretin