title: Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes.
abstract: A plethora of candidate genes have been identified for complex polygenic disorders, but the underlying disease mechanisms remain largely unknown. We explored the pathophysiology of type 2 diabetes (T2D) by analyzing global gene expression in human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly overexpressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1β. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca(2+) channels and suppressed insulin exocytosis. SFRP4 thus provides a link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from T2D patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.
authors.affiliation: Lund University Diabetes Centre, Lund University, 20502 Malmö, Sweden.
authors.forename: Taman
authors.initials: T
authors.lastname: Mahdi
authors.forename: Sonja
authors.initials: S
authors.lastname: Hänzelmann
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.forename: Sarheed J
authors.initials: SJ
authors.lastname: Muhammed
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Reinbothe
authors.forename: Yunzhao
authors.initials: Y
authors.lastname: Tang
authors.forename: Annika S
authors.initials: AS
authors.lastname: Axelsson
authors.forename: Yuedan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xingjun
authors.initials: X
authors.lastname: Jing
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Ulrika
authors.initials: U
authors.lastname: Krus
authors.forename: Jalal
authors.initials: J
authors.lastname: Taneera
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Jonathan Lou S
authors.initials: JL
authors.lastname: Esguerra
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Derry
authors.forename: Enming
authors.initials: E
authors.lastname: Zhang
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.forename: Anders H
authors.initials: AH
authors.lastname: Rosengren
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D005089:Exocytosis; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D002118:Calcium; D015220:Calcium Channels; D005947:Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D053583:Interleukin-1beta; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D051153:Wnt Proteins; C118723:SFRP4 protein, human; D000094742:Secreted Frizzled-Related Proteins; C517652:hemoglobin A1c protein, human