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

β-Cell function is unaltered after α-cell ablation. A: Pancreatic insulin content measured 1 week after DT. Consistent with the specificity of α-cell ablation, pancreatic insulin content was unaffected after DT (control: 131.1 ± 5.8, n = 6; DT: 134.0 ± 11.0 ng/mg of pancreas, n = 7). B: Glucose tolerance test. DT-treated Glucagon-DTR mice (red ▲) were not intolerant to glucose 1 week after massive α-cell ablation (n = 6 for each group; control, black ♦). C: Insulin secretion measured from perfused pancreas after glucose stimulation. No significant change in insulin secretion was observed 1 week after α-cell ablation (n = 4 for each group).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: β-Cell function is unaltered after α-cell ablation. A: Pancreatic insulin content measured 1 week after DT. Consistent with the specificity of α-cell ablation, pancreatic insulin content was unaffected after DT (control: 131.1 ± 5.8, n = 6; DT: 134.0 ± 11.0 ng/mg of pancreas, n = 7). B: Glucose tolerance test. DT-treated Glucagon-DTR mice (red ▲) were not intolerant to glucose 1 week after massive α-cell ablation (n = 6 for each group; control, black ♦). C: Insulin secretion measured from perfused pancreas after glucose stimulation. No significant change in insulin secretion was observed 1 week after α-cell ablation (n = 4 for each group).

Mentions: α-Cells interact with β-cells, most likely by local intraislet interactions, and α- and β-cells express insulin and glucagon receptors, respectively (3,4,16–18). We thus assessed whether α-cells are important for adequate β-cell function. Pancreatic insulin content was unchanged after DT, indicating that near-total α-cell ablation has no effect on global insulin production (Fig. 3A). Glucagon-DTR mice were also able to recover normoglycemia after glucose challenge (glucose tolerance test), either 1 week or 6 months after DT (Fig. 3B and Supplementary Fig. 4) and did not exhibit any defects in basal or glucose-stimulated insulin secretion, as shown by pancreas perfusion experiments (Fig. 3C). These results, together with the long-term follow-up of glycemia in α-cell–depleted Glucagon-DTR mice, reveal that massive loss of α-cells does not affect blood glucose homeostasis or β-cell function.


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)

β-Cell function is unaltered after α-cell ablation. A: Pancreatic insulin content measured 1 week after DT. Consistent with the specificity of α-cell ablation, pancreatic insulin content was unaffected after DT (control: 131.1 ± 5.8, n = 6; DT: 134.0 ± 11.0 ng/mg of pancreas, n = 7). B: Glucose tolerance test. DT-treated Glucagon-DTR mice (red ▲) were not intolerant to glucose 1 week after massive α-cell ablation (n = 6 for each group; control, black ♦). C: Insulin secretion measured from perfused pancreas after glucose stimulation. No significant change in insulin secretion was observed 1 week after α-cell ablation (n = 4 for each group).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 3: β-Cell function is unaltered after α-cell ablation. A: Pancreatic insulin content measured 1 week after DT. Consistent with the specificity of α-cell ablation, pancreatic insulin content was unaffected after DT (control: 131.1 ± 5.8, n = 6; DT: 134.0 ± 11.0 ng/mg of pancreas, n = 7). B: Glucose tolerance test. DT-treated Glucagon-DTR mice (red ▲) were not intolerant to glucose 1 week after massive α-cell ablation (n = 6 for each group; control, black ♦). C: Insulin secretion measured from perfused pancreas after glucose stimulation. No significant change in insulin secretion was observed 1 week after α-cell ablation (n = 4 for each group).
Mentions: α-Cells interact with β-cells, most likely by local intraislet interactions, and α- and β-cells express insulin and glucagon receptors, respectively (3,4,16–18). We thus assessed whether α-cells are important for adequate β-cell function. Pancreatic insulin content was unchanged after DT, indicating that near-total α-cell ablation has no effect on global insulin production (Fig. 3A). Glucagon-DTR mice were also able to recover normoglycemia after glucose challenge (glucose tolerance test), either 1 week or 6 months after DT (Fig. 3B and Supplementary Fig. 4) and did not exhibit any defects in basal or glucose-stimulated insulin secretion, as shown by pancreas perfusion experiments (Fig. 3C). These results, together with the long-term follow-up of glycemia in α-cell–depleted Glucagon-DTR mice, reveal that massive loss of α-cells does not affect blood glucose homeostasis or β-cell function.

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