| First Author | Thorel F | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 11 | Pages | 2872-82 |
| PubMed ID | 21926270 | Mgi Jnum | J:189486 |
| Mgi Id | MGI:5445866 | Doi | 10.2337/db11-0876 |
| Citation | Thorel F, et al. (2011) Normal glucagon signaling and beta-cell function after near-total alpha-cell ablation in adult mice. Diabetes 60(11):2872-82 |
| abstractText | OBJECTIVE: To evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic alpha-cells and how this sudden massive depletion affects beta-cell function and blood glucose homeostasis. RESEARCH DESIGN AND METHODS: We generated a new transgenic model allowing near-total alpha-cell removal specifically in adult mice. Massive alpha-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 beta-cell loss. RESULTS: Adult transgenic mice enduring extreme (98%) alpha-cell removal remained healthy and did not display major defects in insulin counter-regulatory response. We observed that 2% of the normal alpha-cell mass produced enough glucagon to ensure near-normal glucagonemia. beta-Cell function and blood glucose homeostasis remained unaltered after alpha-cell loss, indicating that direct local intraislet signaling between alpha- and beta-cells is dispensable. Escaping alpha-cells increased their glucagon content during subsequent months, but there was no significant alpha-cell regeneration. Near-total alpha-cell ablation did not prevent hyperglycemia in mice having also undergone massive beta-cell loss, indicating that a minimal amount of alpha-cells can still guarantee normal glucagon signaling in diabetic conditions. CONCLUSIONS: An extremely low amount of alpha-cells is sufficient to prevent a major counter-regulatory deregulation, both under physiologic and diabetic conditions. We previously reported that alpha-cells reprogram to insulin production after extreme beta-cell loss and now conjecture that the low alpha-cell requirement could be exploited in future diabetic therapies aimed at regenerating beta-cells by reprogramming adult alpha-cells. |
