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Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice.

Thorel F, Damond N, Chera S, Wiederkehr A, Thorens B, Meda P, Wollheim CB, Herrera PL - Diabetes (2011)

Bottom Line: We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable.Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration.We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

ABSTRACT

Objective: To evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic α-cells and how this sudden massive depletion affects β-cell function and blood glucose homeostasis.

Research design and methods: We generated a new transgenic model allowing near-total α-cell removal specifically in adult mice. Massive α-cell ablation was triggered in normally grown and healthy adult animals upon diphtheria toxin (DT) administration. The metabolic status of these mice was assessed in 1) physiologic conditions, 2) a situation requiring glucagon action, and 3) after β-cell loss.

Results: Adult transgenic mice enduring extreme (98%) α-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable. Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration. Near-total α-cell ablation did not prevent hyperglycemia in mice having also undergone massive β-cell loss, indicating that a minimal amount of α-cells can still guarantee normal glucagon signaling in diabetic conditions.

Conclusions: An extremely low amount of α-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.

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α-Cell ablation does not prevent streptozotocin (STZ)-induced diabetes. A: Experimental design. One high dose of STZ (200 μg/g of mouse weight) was administered to Glucagon-DTR mice to ablate β-cells 1 week after massive DT-mediated α-cell removal. Animals were killed 2 weeks after STZ. B–G: Confocal images of pancreatic sections show DT-mediated α-cell ablation and STZ-mediated β-cell removal. White arrowheads show remaining α-cells after DT. Scale bars = 20 μm. H: Follow up of glycemia. All STZ-treated mice become hyperglycemic irrespective of DT administration. By contrast, animals that did not receive STZ remain normoglycemic (red ♦: Glucagon-DTR mice treated with both DT and STZ, n = 6; black ▼: Glucagon-DTR mice treated only with STZ, n = 6; black ■: untreated Glucagon-DTR mice, n = 3; red ▲: Glucagon-DTR mice treated only with DT). I: Body weight 15 days after STZ. All mice treated with STZ lose weight and develop typical diabetes symptoms. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 6: α-Cell ablation does not prevent streptozotocin (STZ)-induced diabetes. A: Experimental design. One high dose of STZ (200 μg/g of mouse weight) was administered to Glucagon-DTR mice to ablate β-cells 1 week after massive DT-mediated α-cell removal. Animals were killed 2 weeks after STZ. B–G: Confocal images of pancreatic sections show DT-mediated α-cell ablation and STZ-mediated β-cell removal. White arrowheads show remaining α-cells after DT. Scale bars = 20 μm. H: Follow up of glycemia. All STZ-treated mice become hyperglycemic irrespective of DT administration. By contrast, animals that did not receive STZ remain normoglycemic (red ♦: Glucagon-DTR mice treated with both DT and STZ, n = 6; black ▼: Glucagon-DTR mice treated only with STZ, n = 6; black ■: untreated Glucagon-DTR mice, n = 3; red ▲: Glucagon-DTR mice treated only with DT). I: Body weight 15 days after STZ. All mice treated with STZ lose weight and develop typical diabetes symptoms. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: Inhibition of glucagon signaling (GcgR−/− mice) was recently shown to prevent STZ-induced diabetes (6). We thus assessed whether near-total α-cell ablation in Glucagon-DTR mice affects or prevents hyperglycemia. For this purpose, Glucagon-DTR mice were treated 1 week after DT with a high dose of STZ (200 μg/g) to induce ∼90% β-cell removal (Fig. 6A–G). Interestingly, mice that had only residual α-cells (arrowheads in Fig. 6D and G) became overtly hyperglycemic and lost weight after β-cell destruction, like diabetic mice with normal α-cell mass (Fig. 6H and I). Similarly, the simultaneous coablation of β- and α-cells (in Glucagon-DTR, RIP-DTR double transgenic mice) (13) also induced hyperglycemia and cachexia (Supplementary Fig. 7). These results show that near-total α-cell ablation does not prevent diabetes, contrary to what happens in GcgR−/− mice (6). This was consistent with the unaltered glucagon secretion and counter-regulatory response after removal of 98% of α-cells under physiologic conditions.


Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice.

Thorel F, Damond N, Chera S, Wiederkehr A, Thorens B, Meda P, Wollheim CB, Herrera PL - Diabetes (2011)

α-Cell ablation does not prevent streptozotocin (STZ)-induced diabetes. A: Experimental design. One high dose of STZ (200 μg/g of mouse weight) was administered to Glucagon-DTR mice to ablate β-cells 1 week after massive DT-mediated α-cell removal. Animals were killed 2 weeks after STZ. B–G: Confocal images of pancreatic sections show DT-mediated α-cell ablation and STZ-mediated β-cell removal. White arrowheads show remaining α-cells after DT. Scale bars = 20 μm. H: Follow up of glycemia. All STZ-treated mice become hyperglycemic irrespective of DT administration. By contrast, animals that did not receive STZ remain normoglycemic (red ♦: Glucagon-DTR mice treated with both DT and STZ, n = 6; black ▼: Glucagon-DTR mice treated only with STZ, n = 6; black ■: untreated Glucagon-DTR mice, n = 3; red ▲: Glucagon-DTR mice treated only with DT). I: Body weight 15 days after STZ. All mice treated with STZ lose weight and develop typical diabetes symptoms. (A high-quality digital representation of this figure is available in the online issue.)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198058&req=5

Figure 6: α-Cell ablation does not prevent streptozotocin (STZ)-induced diabetes. A: Experimental design. One high dose of STZ (200 μg/g of mouse weight) was administered to Glucagon-DTR mice to ablate β-cells 1 week after massive DT-mediated α-cell removal. Animals were killed 2 weeks after STZ. B–G: Confocal images of pancreatic sections show DT-mediated α-cell ablation and STZ-mediated β-cell removal. White arrowheads show remaining α-cells after DT. Scale bars = 20 μm. H: Follow up of glycemia. All STZ-treated mice become hyperglycemic irrespective of DT administration. By contrast, animals that did not receive STZ remain normoglycemic (red ♦: Glucagon-DTR mice treated with both DT and STZ, n = 6; black ▼: Glucagon-DTR mice treated only with STZ, n = 6; black ■: untreated Glucagon-DTR mice, n = 3; red ▲: Glucagon-DTR mice treated only with DT). I: Body weight 15 days after STZ. All mice treated with STZ lose weight and develop typical diabetes symptoms. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: Inhibition of glucagon signaling (GcgR−/− mice) was recently shown to prevent STZ-induced diabetes (6). We thus assessed whether near-total α-cell ablation in Glucagon-DTR mice affects or prevents hyperglycemia. For this purpose, Glucagon-DTR mice were treated 1 week after DT with a high dose of STZ (200 μg/g) to induce ∼90% β-cell removal (Fig. 6A–G). Interestingly, mice that had only residual α-cells (arrowheads in Fig. 6D and G) became overtly hyperglycemic and lost weight after β-cell destruction, like diabetic mice with normal α-cell mass (Fig. 6H and I). Similarly, the simultaneous coablation of β- and α-cells (in Glucagon-DTR, RIP-DTR double transgenic mice) (13) also induced hyperglycemia and cachexia (Supplementary Fig. 7). These results show that near-total α-cell ablation does not prevent diabetes, contrary to what happens in GcgR−/− mice (6). This was consistent with the unaltered glucagon secretion and counter-regulatory response after removal of 98% of α-cells under physiologic conditions.

Bottom Line: We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable.Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration.We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

ABSTRACT

Objective: To evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic α-cells and how this sudden massive depletion affects β-cell function and blood glucose homeostasis.

Research design and methods: We generated a new transgenic model allowing near-total α-cell removal specifically in adult mice. Massive α-cell ablation was triggered in normally grown and healthy adult animals upon diphtheria toxin (DT) administration. The metabolic status of these mice was assessed in 1) physiologic conditions, 2) a situation requiring glucagon action, and 3) after β-cell loss.

Results: Adult transgenic mice enduring extreme (98%) α-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal α-cell mass produced enough glucagon to ensure near-normal glucagonemia. β-Cell function and blood glucose homeostasis remained unaltered after α-cell loss, indicating that direct local intraislet signaling between α- and β-cells is dispensable. Escaping α-cells increased their glucagon content during subsequent months, but there was no significant α-cell regeneration. Near-total α-cell ablation did not prevent hyperglycemia in mice having also undergone massive β-cell loss, indicating that a minimal amount of α-cells can still guarantee normal glucagon signaling in diabetic conditions.

Conclusions: An extremely low amount of α-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that α-cells reprogram to insulin production after extreme β-cell loss and now conjecture that the low α-cell requirement could be exploited in future diabetic therapies aimed at regenerating β-cells by reprogramming adult α-cells.

Show MeSH
Related in: MedlinePlus