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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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Adoptive Treg transfer restores insulin sensitivity in type 2 diabetes. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray cubes and bar, n = 8). Control animals received CD4+FoxP3− cells (black diamonds and bar, n = 8). Body weight (A) and blood glucose levels (B) were measured weekly. On day 56, the insulin-sensitivity testing was performed (C) and the HOMA-IR index was calculated (D). Pooled data of two independent experiments are shown. *P < 0.05.
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Figure 5: Adoptive Treg transfer restores insulin sensitivity in type 2 diabetes. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray cubes and bar, n = 8). Control animals received CD4+FoxP3− cells (black diamonds and bar, n = 8). Body weight (A) and blood glucose levels (B) were measured weekly. On day 56, the insulin-sensitivity testing was performed (C) and the HOMA-IR index was calculated (D). Pooled data of two independent experiments are shown. *P < 0.05.

Mentions: Db/db mice underwent uninephrectomy at the age of 6 weeks. On days 4, 18, 32, and 46 after uninephrectomy, CD4+FoxP3+GFP+ (Tregs) or CD4+FoxP3−GFP− (control) T cells isolated from healthy donor animals were adoptively transferred into db/db mice. No difference in the body weight was observed between the two groups (Fig. 5A). The blood glucose levels were significantly decreased only in the Treg-treated mice on day 28, whereas on the other evaluated time points, no difference between the groups was detectable (Fig. 5B). Moreover, significantly improved insulin sensitivity was observed in db/db mice treated with Tregs compared with db/db mice injected with control T cells (Fig. 5C). A trend toward an improved HOMA-IR in Treg-treated obese animals was detected, but no statistical significance was reached (Fig. 5D). In addition, Treg-treated db/db mice displayed a significantly decreased mVAT cell diameter as compared with controls (Fig. 6A), whereas we could not detect any difference in the mSAT cell diameters (data not shown). Treg transfer increased the expression of the Treg marker FoxP3 and the Th1 cytokine IFN-γ in mVAT, whereas IL-6, TNF-α, Gata-3, and IL-10 mRNA were not differentially regulated (Fig. 6B). It is interesting that the percentage of proinflammatory mVAT-infiltrating CD8+CD69+ effector T cells was significantly decreased in Treg-treated db/db mice (Fig. 6C and D), whereas no difference of these cells could be detected in mSAT (Fig. 6C). Of note, no difference in the mVAT and mSAT infiltration of CD4+CD69+ T cells was observed (Fig. 6C).


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)

Adoptive Treg transfer restores insulin sensitivity in type 2 diabetes. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray cubes and bar, n = 8). Control animals received CD4+FoxP3− cells (black diamonds and bar, n = 8). Body weight (A) and blood glucose levels (B) were measured weekly. On day 56, the insulin-sensitivity testing was performed (C) and the HOMA-IR index was calculated (D). Pooled data of two independent experiments are shown. *P < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 5: Adoptive Treg transfer restores insulin sensitivity in type 2 diabetes. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray cubes and bar, n = 8). Control animals received CD4+FoxP3− cells (black diamonds and bar, n = 8). Body weight (A) and blood glucose levels (B) were measured weekly. On day 56, the insulin-sensitivity testing was performed (C) and the HOMA-IR index was calculated (D). Pooled data of two independent experiments are shown. *P < 0.05.
Mentions: Db/db mice underwent uninephrectomy at the age of 6 weeks. On days 4, 18, 32, and 46 after uninephrectomy, CD4+FoxP3+GFP+ (Tregs) or CD4+FoxP3−GFP− (control) T cells isolated from healthy donor animals were adoptively transferred into db/db mice. No difference in the body weight was observed between the two groups (Fig. 5A). The blood glucose levels were significantly decreased only in the Treg-treated mice on day 28, whereas on the other evaluated time points, no difference between the groups was detectable (Fig. 5B). Moreover, significantly improved insulin sensitivity was observed in db/db mice treated with Tregs compared with db/db mice injected with control T cells (Fig. 5C). A trend toward an improved HOMA-IR in Treg-treated obese animals was detected, but no statistical significance was reached (Fig. 5D). In addition, Treg-treated db/db mice displayed a significantly decreased mVAT cell diameter as compared with controls (Fig. 6A), whereas we could not detect any difference in the mSAT cell diameters (data not shown). Treg transfer increased the expression of the Treg marker FoxP3 and the Th1 cytokine IFN-γ in mVAT, whereas IL-6, TNF-α, Gata-3, and IL-10 mRNA were not differentially regulated (Fig. 6B). It is interesting that the percentage of proinflammatory mVAT-infiltrating CD8+CD69+ effector T cells was significantly decreased in Treg-treated db/db mice (Fig. 6C and D), whereas no difference of these cells could be detected in mSAT (Fig. 6C). Of note, no difference in the mVAT and mSAT infiltration of CD4+CD69+ T cells was observed (Fig. 6C).

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