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 μM mannose, metformin corrected experimentally induced deficiencies in the synthesis of glucose₃mannose₉GlcNAc 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 μM 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.