Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes

Cell Metab. 2012 Nov 7;16(5):625-33. doi: 10.1016/j.cmet.2012.10.009.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • 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
  • 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

Substances

  • Calcium Channels
  • Glycated Hemoglobin A
  • Insulin
  • Interleukin-1beta
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • SFRP4 protein, human
  • Wnt Proteins
  • hemoglobin A1c protein, human
  • Glucose
  • Calcium

Associated data

  • GEO/GSE41762