Normal Glucagon Signaling and β-Cell Function After Near-Total α-Cell Ablation in Adult Mice

OBJECTIVE-To evaluate whether healthy or diabetic adult mice can tolerate an extreme loss of pancreatic a-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 a-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 a-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. Diabetes 60:2872-2882, 2011