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The Novel Adipokine Gremlin 1 Antagonizes Insulin Action and Is Increased in Type 2 Diabetes and NAFLD/NASH

Journal article
Authors Shahram Hedjazifar
Roxana Khatib Shahidi
Ann Hammarstedt
Laurianne Bonnet
C. Church
Jeremie Boucher
M. Bluher
Ulf Smith
Published in Diabetes
Volume 69
Issue 3
Pages 331-341
ISSN 0012-1797
Publication year 2020
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 331-341
Language en
Links dx.doi.org/10.2337/db19-0701
Keywords bmp4 gene-therapy, adipose-tissue, nonalcoholic steatohepatitis, protein, inflammation, sensitivity, obesity, white, differentiation, adipogenesis, Endocrinology & Metabolism
Subject categories Endocrinology and Diabetes

Abstract

The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

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