Potential Role of Regulatory T Cells in Reversing Obesity-Linked Insulin Resistance and Diabetic Nephropathy

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 11; pp. 2954 - 2962
• Main Authors: Eller, Kathrin, Kirsch, Alexander, Wolf, Anna M., Sopper, Sieghart, Tagwerker, Andrea, Stanzl, Ursula, Wolf, Dominik, Patsch, Wolfgang, Rosenkranz, Alexander R., Eller, Philipp
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.11.2011
• Subjects: Analysis; Animals; Body fat; Cytokines - genetics; Cytokines - metabolism; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - immunology; Diabetes Mellitus, Type 2 - metabolism; Diabetic nephropathies; Diabetic Nephropathies - immunology; Diabetic Nephropathies - physiopathology; Diabetic Nephropathies - prevention & control; Diabetic Nephropathies - therapy; Diabetic nephropathy; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene expression; Gene Expression Regulation; Genetic aspects; Glucose; Humans; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - metabolism; Inflammation; Insulin Resistance; Intra-Abdominal Fat - metabolism; Intra-Abdominal Fat - pathology; Kidney - metabolism; Kidney - pathology; Kidney - surgery; Lymphocyte Depletion - adverse effects; Lymphocyte Transfusion; Lymphocytes; Male; Messenger RNA; Metabolism; Mice; Mice, Obese; Monoclonal antibodies; Obesity; Obesity - immunology; Obesity - metabolism; Obesity - pathology; Pathogenesis; Pathophysiology; Physiological aspects; Receptors, Leptin - genetics; Research design; RNA, Messenger - metabolism; Specific Pathogen-Free Organisms; T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Tumor necrosis factor-TNF; Austria
• DOI: 10.2337/db11-0358
• ISSN: 0012-1797; 1939-327X

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.