title: Hyperglycemia downregulates Connexin36 in pancreatic islets via the upregulation of ICER-1/ICER-1γ.
abstract: Channels formed by the gap junction protein Connexin36 (CX36) contribute to the proper control of insulin secretion. We previously demonstrated that chronic exposure to glucose decreases Cx36 levels in insulin-secreting cells in vitro. Here, we investigated whether hyperglycemia also regulates Cx36 in vivo. Using a model of continuous glucose infusion in adult rats, we showed that prolonged (24-48 h) hyperglycemia reduced the Cx36 gene Gjd2 mRNA levels in pancreatic islets. Accordingly, prolonged exposure to high glucose concentrations also reduced the expression and function of Cx36 in the rat insulin-producing INS-1E cell line. The glucose effect was blocked after inhibition of the cAMP/PKA pathway and was associated with an overexpression of the inducible cAMP early repressor ICER-1/ICER-1γ, which binds to a functional cAMP-response element in the promoter of the Cx36 gene Gjd2. The involvement of this repressor was further demonstrated using an antisense strategy of ICER-1 inhibition, which prevented glucose-induced downregulation of Cx36. The data indicate that chronic exposure to glucose alters the in vivo expression of Cx36 by the insulin-producing β-cells through ICER-1/ICER-1γ overexpression. This mechanism may contribute to the reduced glucose sensitivity and altered insulin secretion, which contribute to the pathophysiology of diabetes.
authors.affiliation: Service of Internal Medicine, Department of Physiology, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Jacques-Antoine
authors.initials: JA
authors.lastname: Haefliger
authors.forename: Françoise
authors.initials: F
authors.lastname: Rohner-Jeanrenaud
authors.forename: Dorothée
authors.initials: D
authors.lastname: Caille
authors.forename: Anne
authors.initials: A
authors.lastname: Charollais
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.forename: Florent
authors.initials: F
authors.lastname: Allagnat
mesh_terms: D000818:Animals; D001786:Blood Glucose; D045744:Cell Line, Tumor; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051381:Rats; D000097004:Gap Junction delta-2 Protein
chemical_list: D001786:Blood Glucose; D017630:Connexins; D051786:Cyclic AMP Response Element Modulator; D005947:Glucose; D000097004:Gap Junction delta-2 Protein
keywords: ICER-1; connexin36; gap junctions; glucose