title: An early response transcription factor, Egr-1, enhances insulin resistance in type 2 diabetes with chronic hyperinsulinism.
abstract: One of the most important characteristics of type 2 diabetes is insulin resistance, during which the patients normally experienced hyperinsulinism stress that would alter insulin signal transduction in insulin target tissues. We have previously found that early growth responsive gene-1 (Egr-1), a zinc finger transcription factor, is highly expressed in db/db mice and in the fat tissue of individuals with type 2 diabetes. In this report, we found that chronic exposure to hyperinsulinism caused persistent Erk/MAPK activity in adipocytes and enhanced insulin resistance in an Egr-1-dependent manner. An elevation in Egr-1 augmented Erk1/2 activation via geranylgeranyl diphosphate synthase (GGPPS). Egr-1-promoted GGPPS transcription increased Ras prenylation and caused Erk1/2 activation. The sustained activation of Erk1/2 resulted in the phosphorylation of insulin receptor substrate-1 at Serine 612. Phosphorylation at this site impaired insulin signaling in adipocytes and reduced glucose uptake. The loss of Egr-1 function, knockdown of GGPPS, or inhibition of Erk1/2 activity in insulin-resistant adipocytes restored insulin receptor substrate-1 tyrosine phosphorylation and increased insulin sensitivity. Our results suggest a new mechanism by which the Egr-1/GGPPS/Erk1/2 pathway is responsible for insulin resistance during hyperinsulinism. This pathway provides a new therapeutic target for increasing insulin sensitivity: inhibiting the function of Egr-1.
authors.affiliation: Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the Medical School of Nanjing University, Nanjing 210061, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Shen
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Pan
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004122:Dimethylallyltranstransferase / Q000737:chemistry; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000737:chemistry; D051228:Geranyltranstransferase / Q000737:chemistry; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D010766:Phosphorylation; D014158:Transcription, Genetic
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D007328:Insulin; D004122:Dimethylallyltranstransferase; D051228:Geranyltranstransferase; D051231:Farnesyltranstransferase; C495427:GGPS1 protein, human