title: Normal glucagon signaling and β-cell function after near-total α-cell ablation in adult mice.
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.
  
  
  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.
authors.affiliation: Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Damond
authors.forename: Simona
authors.initials: S
authors.lastname: Chera
authors.forename: Andreas
authors.initials: A
authors.lastname: Wiederkehr
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004167:Diphtheria Toxin / Q000633:toxicity; D005934:Glucagon / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D007003:Hypoglycemia / Q000517:prevention & control; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D018027:Receptors, Glucagon / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction; D013311:Streptozocin / Q000633:toxicity; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004167:Diphtheria Toxin; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D018027:Receptors, Glucagon; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D013311:Streptozocin; D005934:Glucagon