Targeting SGK1 in diabetes.
Compelling evidence is accumulating indicating a pathophysiological role of the serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in the development and complications of diabetes. SGK1 is ubiquitously expressed with exquisitely high transcriptional volatility. Stimulators of SGK1 expression include hyperglycemia, cell shrinkage, ischemia, glucocorticoids and mineralocorticoids. SGK1 is activated by insulin and growth factors via PI3K, 3-phosphoinositide dependent kinase PDK1 and mTOR. SGK1 activates ion channels (including ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and CLCKa/Barttin), carriers (including NCC, NKCC, NHE3, SGLT1 and EAAT3), and the Na(+)/K(+)-ATPase. It regulates the activity of several enzymes (e.g., glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2, phosphomannose-mutase-2), and transcription factors (e.g., forkhead-transcription-factor FOXO3a, beta-catenin and NF-kappaB). A common SGK1 gene variant ( approximately 3 - 5% prevalence in Caucasians, approximately 10% in Africans) is associated with increased blood pressure, obesity and type 2 diabetes. In patients suffering from type 2 diabetes, SGK1 presumably contributes to fluid retention and hypertension, enhanced coagulation and increased deposition of matrix proteins leading to tissue fibrosis such as diabetic nephropathy. Accordingly, targeting SGK1 may favourably influence occurrence and course of type 2 diabetes.
Lang
Florian
F
Eberhard-Karls-University of Tuebingen, Department of Physiology, Gmelinstrasse 5, Tuebingen 72076, Germany. florian.lang@uni-tuebingen.de
Görlach
Agnes
A
Vallon
Volker
V
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000099184:Serum-Glucocorticoid Regulated Kinases
D007004:Hypoglycemic Agents; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases