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

Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P - Diabetes (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria. kathrin.eller@medunigraz.at

ABSTRACT

Objective: 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.

Research design and methods: 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.

Results: 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.

Conclusions: 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.

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Obese patients with insulin resistance display significantly decreased Helios but increased FOXP3 mRNA expression in their hVAT. A: hVAT of lean control subjects (white bar, n = 14), obese patients with normal insulin sensitivity (HOMA <2.5, gray bar, n = 39), and obese patients with impaired insulin sensitivity (HOMA >5, black bar, n = 39) was analyzed for Helios and FOXP3 mRNA expression. P < 0.025 was considered significant; n.s., not significant. Correlation of the Helios-to-FOXP3 mRNA ratio in hVAT (n = 92) with BMI (P = 0.121) (B), HOMA-IR (P = 0.003) (C), and fasting blood glucose levels (P = 0.045) (D) was analyzed using Spearman ρ. P < 0.05 was considered significant.
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Figure 1: Obese patients with insulin resistance display significantly decreased Helios but increased FOXP3 mRNA expression in their hVAT. A: hVAT of lean control subjects (white bar, n = 14), obese patients with normal insulin sensitivity (HOMA <2.5, gray bar, n = 39), and obese patients with impaired insulin sensitivity (HOMA >5, black bar, n = 39) was analyzed for Helios and FOXP3 mRNA expression. P < 0.025 was considered significant; n.s., not significant. Correlation of the Helios-to-FOXP3 mRNA ratio in hVAT (n = 92) with BMI (P = 0.121) (B), HOMA-IR (P = 0.003) (C), and fasting blood glucose levels (P = 0.045) (D) was analyzed using Spearman ρ. P < 0.05 was considered significant.

Mentions: To test whether Tregs accumulate in visceral obesity, we analyzed hVAT from 14 lean control subjects, 39 obese patients without insulin resistance (HOMA-IR <2.5), and 39 obese patients with insulin resistance (HOMA-IR >5). We evaluated the mRNA expression of the thymic Treg marker Helios as well as of the master regulator of Tregs FOXP3 in hVAT. We found the mRNA expression of Helios to be downregulated in both obese patient groups, whereas FOXP3 was significantly downregulated only in obese patients without insulin resistance. In obese patients with insulin resistance, mRNA expression of FOXP3 was similar to lean control subjects (Fig. 1A). The Helios-to-FOXP3 ratio correlated inversely with BMI (Fig. 1B), HOMA-IR (Fig. 1C), and fasting glucose levels (Fig. 1D). Significance was reached in the correlation with fasting blood glucose level and HOMA-IR.


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

Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P - Diabetes (2011)

Obese patients with insulin resistance display significantly decreased Helios but increased FOXP3 mRNA expression in their hVAT. A: hVAT of lean control subjects (white bar, n = 14), obese patients with normal insulin sensitivity (HOMA <2.5, gray bar, n = 39), and obese patients with impaired insulin sensitivity (HOMA >5, black bar, n = 39) was analyzed for Helios and FOXP3 mRNA expression. P < 0.025 was considered significant; n.s., not significant. Correlation of the Helios-to-FOXP3 mRNA ratio in hVAT (n = 92) with BMI (P = 0.121) (B), HOMA-IR (P = 0.003) (C), and fasting blood glucose levels (P = 0.045) (D) was analyzed using Spearman ρ. P < 0.05 was considered significant.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3198056&req=5

Figure 1: Obese patients with insulin resistance display significantly decreased Helios but increased FOXP3 mRNA expression in their hVAT. A: hVAT of lean control subjects (white bar, n = 14), obese patients with normal insulin sensitivity (HOMA <2.5, gray bar, n = 39), and obese patients with impaired insulin sensitivity (HOMA >5, black bar, n = 39) was analyzed for Helios and FOXP3 mRNA expression. P < 0.025 was considered significant; n.s., not significant. Correlation of the Helios-to-FOXP3 mRNA ratio in hVAT (n = 92) with BMI (P = 0.121) (B), HOMA-IR (P = 0.003) (C), and fasting blood glucose levels (P = 0.045) (D) was analyzed using Spearman ρ. P < 0.05 was considered significant.
Mentions: To test whether Tregs accumulate in visceral obesity, we analyzed hVAT from 14 lean control subjects, 39 obese patients without insulin resistance (HOMA-IR <2.5), and 39 obese patients with insulin resistance (HOMA-IR >5). We evaluated the mRNA expression of the thymic Treg marker Helios as well as of the master regulator of Tregs FOXP3 in hVAT. We found the mRNA expression of Helios to be downregulated in both obese patient groups, whereas FOXP3 was significantly downregulated only in obese patients without insulin resistance. In obese patients with insulin resistance, mRNA expression of FOXP3 was similar to lean control subjects (Fig. 1A). The Helios-to-FOXP3 ratio correlated inversely with BMI (Fig. 1B), HOMA-IR (Fig. 1C), and fasting glucose levels (Fig. 1D). Significance was reached in the correlation with fasting blood glucose level and HOMA-IR.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria. kathrin.eller@medunigraz.at

ABSTRACT

Objective: 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.

Research design and methods: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus