Secreted Frizzled-Related Protein 4 Reduces Insulin Secretion and Is Overexpressed in Type 2 Diabetes

• Published in: Cell metabolism Vol. 16; no. 5; pp. 625 - 633
• Main Authors: Mahdi, Taman, Hänzelmann, Sonja, Salehi, Albert, Muhammed, Sarheed J., Reinbothe, Thomas M., Tang, Yunzhao, Axelsson, Annika S., Zhou, Yuedan, Jing, Xingjun, Almgren, Peter, Krus, Ulrika, Taneera, Jalal, Blom, Anna M., Lyssenko, Valeriya, Esguerra, Jonathan Lou S., Hansson, Ola, Eliasson, Lena, Derry, Jonathan, Zhang, Enming, Wollheim, Claes B., Groop, Leif, Renström, Erik, Rosengren, Anders H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.11.2012
• Subjects: Animals; Basic Medicine; Calcium - metabolism; Calcium Channels - metabolism; Cell and Molecular Biology; Cell- och molekylärbiologi; Cells, Cultured; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Exocytosis; Gene Expression; Glucose - pharmacology; Glycated Hemoglobin A - metabolism; Humans; Insulin - metabolism; Insulin Secretion; Interleukin-1beta - metabolism; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction; Wnt Proteins - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.10.009

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 Ca2+ 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. [Display omitted] ▸ SFRP4 is a hub gene in a T2D-associated gene coexpression module in human islets ▸ SFRP4 reduces glucose-induced insulin secretion through decreased β cell exocytosis ▸ Expression and release of SFRP4 from islets is enhanced by interleukin-1β ▸ SFRP4 is elevated in serum several years before clinical diagnosis of T2D