title: Acute disruption of glucagon secretion or action does not improve glucose tolerance in an insulin-deficient mouse model of diabetes.
abstract: OBJECTIVE
  Normal glucose metabolism depends on pancreatic secretion of insulin and glucagon. The bihormonal hypothesis states that while lack of insulin leads to glucose underutilisation, glucagon excess is the principal factor in diabetic glucose overproduction. A recent study reported that streptozotocin-treated glucagon receptor knockout mice have normal glucose tolerance. We investigated the impact of acute disruption of glucagon secretin or action in a mouse model of severe diabetes by three different approaches: (1) alpha cell elimination; (2) glucagon immunoneutralisation; and (3) glucagon receptor antagonism, in order to evaluate the effect of these on glucose tolerance.
  
  
  METHODS
  Severe diabetes was induced in transgenic and wild-type mice by streptozotocin. Glucose metabolism was investigated using OGTT in transgenic mice with the human diphtheria toxin receptor expressed in proglucagon producing cells allowing for diphtheria toxin (DT)-induced alpha cell ablation and in mice treated with either a specific high affinity glucagon antibody or a specific glucagon receptor antagonist.
  
  
  RESULTS
  Near-total alpha cell elimination was induced in transgenic mice upon DT administration and resulted in a massive decrease in pancreatic glucagon content. Oral glucose tolerance in diabetic mice was neither affected by glucagon immunoneutralisation, glucagon receptor antagonism, nor alpha cell removal, but did not deteriorate further compared with mice with intact alpha cell mass.
  
  
  CONCLUSIONS
  Disruption of glucagon action/secretion did not improve glucose tolerance in diabetic mice. Near-total alpha cell elimination may have prevented further deterioration. Our findings support insulin lack as the major factor underlying hyperglycaemia in beta cell-deficient diabetes.
authors.affiliation: Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, building 12.2, DK-2200, Copenhagen, Denmark.
authors.forename: Vivi R
authors.initials: VR
authors.lastname: Steenberg
authors.affiliation: Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, building 12.2, DK-2200, Copenhagen, Denmark.
authors.forename: Signe M
authors.initials: SM
authors.lastname: Jensen
authors.affiliation: Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, building 12.2, DK-2200, Copenhagen, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Pedersen
authors.affiliation: Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Madsen
authors.affiliation: Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, building 12.2, DK-2200, Copenhagen, Denmark.
authors.forename: Johanne A
authors.initials: JA
authors.lastname: Windeløv
authors.affiliation: Section for Metabolic Receptology, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.affiliation: Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, building 12.2, DK-2200, Copenhagen, Denmark.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Quistorff
authors.affiliation: Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, building 12.2, DK-2200, Copenhagen, Denmark.
authors.forename: Steen S
authors.initials: SS
authors.lastname: Poulsen
authors.affiliation: Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, building 12.2, DK-2200, Copenhagen, Denmark. jjholst@sund.ku.dk.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004167:Diphtheria Toxin; D005934:Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000473:pathology; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005951:Glucose Tolerance Test; D007328:Insulin / Q000172:deficiency* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics; D013311:Streptozocin
chemical_list: D001786:Blood Glucose; D004167:Diphtheria Toxin; D007328:Insulin; D018027:Receptors, Glucagon; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon
keywords: Endocrine pancreas; Glucagon; Glucose homeostasis; Streptozotocin; Type 1 diabetes