The human glomerular podocyte is a novel target for insulin action.
Microalbuminuria is significant both as the earliest stage of diabetic nephropathy and as an independent cardiovascular risk factor in nondiabetic subjects, in whom it is associated with insulin resistance. The link between disorders of cellular insulin metabolism and albuminuria has been elusive. Here, we report using novel conditionally immortalized human podocytes in vitro and human glomeruli ex vivo that the podocyte, the principal cell responsible for prevention of urinary protein loss, is insulin responsive and able to approximately double its glucose uptake within 15 min of insulin stimulation. Conditionally immortalized human glomerular endothelial cells do not respond to insulin, suggesting that insulin has a specific effect on the podocyte in the glomerular filtration barrier. The insulin response of the podocyte occurs via the facilitative glucose transporters GLUT1 and GLUT4, and this process is dependent on the filamentous actin cytoskeleton. Insulin responsiveness in this key structural component of the glomerular filtration barrier may have central relevance for understanding of diabetic nephropathy and for the association of albuminuria with states of insulin resistance.
Coward
Richard J M
RJ
Academic and Children's Renal Unit, University of Bristol, Southmead Hospital, Bristol, UK BS10 5NB.
Welsh
Gavin I
GI
Yang
Jing
J
Tasman
Candida
C
Lennon
Rachel
R
Koziell
Ania
A
Satchell
Simon
S
Holman
Geoffrey D
GD
Kerjaschki
Dontscho
D
Tavaré
Jeremy M
JM
Mathieson
Peter W
PW
Saleem
Moin A
MA
D000199:Actins / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003599:Cytoskeleton; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects
D000199:Actins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; D005947:Glucose