Insulin-mediated pseudoacromegaly in a patient with severe insulin resistance: association of defective insulin-stimulated glucose transport with impaired phosphatidylinositol 3-kinase activity in fibroblasts.
The purpose of this study was to clinically and biochemically describe an insulin resistant patient with insulin-mediated pseudoacromegaly and in addition, to examine the molecular cause responsible for the defective insulin-stimulated glucose transport in cultured fibroblasts derived from the patient. The patient was a 64 year old female with severe insulin resistant diabetes mellitus, requiring up to 200 U insulin per day, associated with typical acromegaloid characteristics including increased hand and foot size, macroglossia and development of coarse facial features. Pituitary magnetic resonance imaging as well as multiple GH and IGF-1 measurements were normal. In cultured fibroblasts derived from the patient, (i) insulin-stimulated glucose transport, (ii) the subcellular distribution of GLUT1 glucose transporters, (iii) insulin-stimulated IRS-1-immunoprecipitable phosphatidylinositol (PI) 3-kinase activity, as well as (iv) protein expression of the small GTP-binding protein Rab4 was determined. The results indicate, that insulin's ability to stimulate glucose transport is defective in the patients fibroblasts although the GLUT1 content in the plasma membrane was increased by 34% when compared to control cells. Furthermore, the IRS-1 dependent activation of PI 3-kinase was reduced by 39.6% after incubation with 10 nM insulin for 5 min. Interestingly, immunodetection of the small GTP-binding protein Rab4, which is believed to be involved in the regulation of glucose transporter vesicle targeting to the plasma membrane, revealed a marked reduction of the expression of Rab4 protein in a total membrane fraction by 57.4%. In conclusion, in fibroblasts of a patient with clinical and biochemical evidence of pseudoacromegaly, the defective insulin-stimulated glucose transport was associated with impaired insulin-stimulated PI 3-kinase activity, which may contribute to the severe insulin resistant state of this patient.
D000172:Acromegaly / Q000209:etiology* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D019204:GTP-Binding Proteins / Q000032:analysis; D051272:Glucose Transporter Type 1; D006801:Humans; D007163:Immunosorbent Techniques; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000276:immunology; D020695:rab4 GTP-Binding Proteins