Limits...
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.

Show MeSH

Related in: MedlinePlus

α-Cell ablation in Glucagon-DTR mice. A: DT injection triggers α-cell ablation in Glucagon-DTR transgenic mice but not in wild-type mice. Two days after DT injection, dying cells are detected by TUNEL, mainly at islet periphery in Glucagon-DTR animals (middle). At 1 week after DT injection, islets in transgenic mice are devoid of glucagon-expressing cells (right). The dashed lines delineate islets. Scale bars = 20 μm. B: At 1 week after DT treatment, 97.9% of glucagon-expressing cells were destroyed (*P = 0.05, one-tailed Mann-Whitney U test; values in Table 1). C: At 1 week after DT, pancreatic glucagon content was reduced to 0.86% of control (***P = 0.0001, one-tailed Mann-Whitney U test; values in Table 1). (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3198058&req=5

Figure 1: α-Cell ablation in Glucagon-DTR mice. A: DT injection triggers α-cell ablation in Glucagon-DTR transgenic mice but not in wild-type mice. Two days after DT injection, dying cells are detected by TUNEL, mainly at islet periphery in Glucagon-DTR animals (middle). At 1 week after DT injection, islets in transgenic mice are devoid of glucagon-expressing cells (right). The dashed lines delineate islets. Scale bars = 20 μm. B: At 1 week after DT treatment, 97.9% of glucagon-expressing cells were destroyed (*P = 0.05, one-tailed Mann-Whitney U test; values in Table 1). C: At 1 week after DT, pancreatic glucagon content was reduced to 0.86% of control (***P = 0.0001, one-tailed Mann-Whitney U test; values in Table 1). (A high-quality digital representation of this figure is available in the online issue.)

Mentions: We previously generated the Glucagon-DTR mouse line in which the administration of diphtheria toxin (DT) induces selective and massive ablation of adult α-cells (13). This is achieved through the transgenic expression of human DT receptor (DTR) on the α-cell surface, driven by a 1.6-kb proximal fragment of the rat glucagon promoter (Fig. 1A).


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 in Glucagon-DTR mice. A: DT injection triggers α-cell ablation in Glucagon-DTR transgenic mice but not in wild-type mice. Two days after DT injection, dying cells are detected by TUNEL, mainly at islet periphery in Glucagon-DTR animals (middle). At 1 week after DT injection, islets in transgenic mice are devoid of glucagon-expressing cells (right). The dashed lines delineate islets. Scale bars = 20 μm. B: At 1 week after DT treatment, 97.9% of glucagon-expressing cells were destroyed (*P = 0.05, one-tailed Mann-Whitney U test; values in Table 1). C: At 1 week after DT, pancreatic glucagon content was reduced to 0.86% of control (***P = 0.0001, one-tailed Mann-Whitney U test; values in Table 1). (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198058&req=5

Figure 1: α-Cell ablation in Glucagon-DTR mice. A: DT injection triggers α-cell ablation in Glucagon-DTR transgenic mice but not in wild-type mice. Two days after DT injection, dying cells are detected by TUNEL, mainly at islet periphery in Glucagon-DTR animals (middle). At 1 week after DT injection, islets in transgenic mice are devoid of glucagon-expressing cells (right). The dashed lines delineate islets. Scale bars = 20 μm. B: At 1 week after DT treatment, 97.9% of glucagon-expressing cells were destroyed (*P = 0.05, one-tailed Mann-Whitney U test; values in Table 1). C: At 1 week after DT, pancreatic glucagon content was reduced to 0.86% of control (***P = 0.0001, one-tailed Mann-Whitney U test; values in Table 1). (A high-quality digital representation of this figure is available in the online issue.)
Mentions: We previously generated the Glucagon-DTR mouse line in which the administration of diphtheria toxin (DT) induces selective and massive ablation of adult α-cells (13). This is achieved through the transgenic expression of human DT receptor (DTR) on the α-cell surface, driven by a 1.6-kb proximal fragment of the rat glucagon promoter (Fig. 1A).

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