Open this publication in new window or tab >>Univ British Columbia, Life Sci Inst, Ctr Blood Res, Fac Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Pathol & Lab Med, Vancouver, BC, Canada..
Natl Cheng Kung Univ, Int Ctr Wound Repair & Regenerat, Tainan, Taiwan..
Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, Tainan, Taiwan..
SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY USA..
SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY USA.;Vet Affairs Med Ctr, Northport, NY USA..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
Univ Alberta, Alberta Diabet Inst, Dept Physiol, Edmonton, AB, Canada.;Univ Alberta, Grp Mol & Cell Biol Lipids, Edmonton, AB, Canada..
Univ British Columbia, Life Sci Inst, Ctr Blood Res, Fac Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Pathol & Lab Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Ctr Blood Res, 4306-2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada..
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2024 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 99, article id 104906Article in journal (Refereed) Published
Abstract [en]
Background
In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance.
Methods
Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens.
Findings
Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis.
Interpretation
Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance.
Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Adipocyte, Insulin resistance, Glucose, Metabolism, Obesity, CD248, Lipid, Insulin receptor
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-523256 (URN)10.1016/j.ebiom.2023.104906 (DOI)001135042400001 ()38061240 (PubMedID)
Funder
DiabetesfondenErnfors FoundationNovo Nordisk
2024-02-162024-02-162024-02-16Bibliographically approved