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PMID: 21911743 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy.

Diabetes ·Vol. 60 ·No. 11 ·2011-11-00 ·Pages 2954-62

Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P

Abstract

To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans. To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated. Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals. Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

MeSH Terms
Animals Cytokines/genetics,metabolism Diabetes Mellitus, Type 2/complications,immunology,metabolism Diabetic Nephropathies/immunology,physiopathology,prevention & control,therapy Forkhead Transcription Factors/genetics,metabolism Gene Expression Regulation Humans Ikaros Transcription Factor/genetics,metabolism Insulin Resistance Intra-Abdominal Fat/metabolism,pathology Kidney/metabolism,pathology,surgery Lymphocyte Depletion/adverse effects Lymphocyte Transfusion Male Mice Mice, Obese Obesity/immunology,metabolism,pathology RNA, Messenger/metabolism Receptors, Leptin/genetics Specific Pathogen-Free Organisms T-Lymphocytes, Regulatory/immunology,metabolism,pathology
Chemicals
Cytokines FOXP3 protein, human Forkhead Transcription Factors Foxp3 protein, mouse IKZF2 protein, human RNA, Messenger Receptors, Leptin leptin receptor, mouse Ikaros Transcription Factor
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Eller Kathrin
Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria. kathrin.eller@medunigraz.at
Kirsch Alexander
Wolf Anna M
Sopper Sieghart
Tagwerker Andrea
Stanzl Ursula
Wolf Dominik
Patsch Wolfgang
Rosenkranz Alexander R
Eller Philipp
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Article Info
Journal
Diabetes
Abbr.
Diabetes
ISSN
1939-327X
DOI
10.2337/db11-0358
Email
kathrin.eller@medunigraz.at
Published
2011-11-00
Epub
2011-00-12
Pages
2954-62
Language
English
Region
United States
NLM ID
0372763
PMCID
PMC3198056
Subset
IM
Grants
Austrian Science Fund FWF · P 21402 · Austria
External Links
PubMed source DOI: 10.2337/db11-0358 PMC Full Text View journal details
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