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

• DOI: 10.1016/j.cmet.2012.10.009
• Publication Date: 2012-11-06T16:03:37Z
• Authors: Taman Mahdi; Sonja Hänzelmann; Albert Salehi; Sarheed J. Muhammed; Thomas M. Reinbothe; Yunzhao Tang; Annika S. Axelsson; Yuedan Zhou; Xingjun Jing; Peter Almgren; Ulrika Krus; Jalal Taneera; Anna M. Blom; Valeriya Lyssenko; Jonathan Lou S. E...; Ola Hansson; Lena Eliasson; Jonathan Derry; Enming Zhang; Claes B. Wollheim; Leif Groop; Erik Renström; Anders H. Rosengren
• Keywords: 0301 basic medicine; Calcium/metabolism; Calcium Channels/metabolism; Physiology; Interleukin-1beta; Gene Expression; RNA, Small Interfering/metabolism; Exocytosis; Hemoglobin A, Glycosylated/metabolism; Islets of Langerhans; Mice; 03 medical and health sciences; Wnt Proteins/metabolism; Proto-Oncogene Proteins; Insulin Secretion; Animals; Humans; Insulin; info:eu-repo/classification/ddc/612; RNA, Small Interfering; ddc:612; Molecular Biology; Cells, Cultured; Islets of Langerhans/cytology/metabolism; Glycated Hemoglobin; Proto-Oncogene Proteins/antagonists & inhibitors/genetics/metabolism; Cell Biology; Glucose/pharmacology; Wnt Proteins; Glucose; Insulin/metabolism/secretion; Diabetes Mellitus, Type 2; Interleukin-1beta/metabolism; Calcium; RNA Interference; Calcium Channels; Diabetes Mellitus, Type 2/metabolism/pathology; Cell and Molecular Biology; Signal Transduction

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.