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Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice.
OBJECTIVEEvaluate 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 METHODSWe 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.RESULTSAdult 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.CONCLUSIONSAn 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.
Animals, Apoptosis/drug effects, Cell Count, Diabetes Mellitus, Experimental/blood, Diabetes Mellitus, Experimental/chemically induced, Diphtheria Toxin/toxicity, Glucagon/blood, Glucagon/genetics, Glucagon-Secreting Cells/drug effects, Glucagon-Secreting Cells/metabolism, Hyperglycemia/chemically induced, Hyperglycemia/prevention & control, Hypoglycemia/prevention & control, Insulin/blood, Insulin/metabolism, Insulin-Secreting Cells/drug effects, Insulin-Secreting Cells/metabolism, Intercellular Signaling Peptides and Proteins/genetics, Intercellular Signaling Peptides and Proteins/metabolism, Male, Mice, Mice, Transgenic, Pancreas/drug effects, Pancreas/metabolism, Promoter Regions, Genetic, Receptors, Glucagon/metabolism, Selective Estrogen Receptor Modulators/pharmacology, Signal Transduction, Streptozocin/toxicity, Tamoxifen/pharmacology
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