title: Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice.
abstract: Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on β-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucose±glucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucose±GLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased β-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of β-cell function during development of type 2 diabetes.
authors.affiliation: Department of Clinical SciencesBiomedical Center, Lund University, SE 22184 Lund, SwedenZealand Pharma A/SResearch and Development, DK-2600 Glostrup, Denmark linda.ahlkvist@med.lu.se.
authors.forename: Linda
authors.initials: L
authors.lastname: Ahlkvist
authors.affiliation: Department of Clinical SciencesBiomedical Center, Lund University, SE 22184 Lund, SwedenZealand Pharma A/SResearch and Development, DK-2600 Glostrup, Denmark.
authors.forename: Bilal
authors.initials: B
authors.lastname: Omar
authors.affiliation: Department of Clinical SciencesBiomedical Center, Lund University, SE 22184 Lund, SwedenZealand Pharma A/SResearch and Development, DK-2600 Glostrup, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Valeur
authors.affiliation: Department of Clinical SciencesBiomedical Center, Lund University, SE 22184 Lund, SwedenZealand Pharma A/SResearch and Development, DK-2600 Glostrup, Denmark.
authors.forename: Keld
authors.initials: K
authors.lastname: Fosgerau
authors.affiliation: Department of Clinical SciencesBiomedical Center, Lund University, SE 22184 Lund, SwedenZealand Pharma A/SResearch and Development, DK-2600 Glostrup, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D059305:Diet, High-Fat; D005260:Female; D005934:Glucagon / Q000008:administration & dosage / Q000031:analogs & derivatives; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage; D005947:Glucose / Q000008:administration & dosage; D018149:Glucose Intolerance / Q000209:etiology / Q000503:physiopathology*; D005951:Glucose Tolerance Test / Q000379:methods; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018027:Receptors, Glucagon / Q000187:drug effects / Q000502:physiology*
chemical_list: D007328:Insulin; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose
keywords: chronic glucagon receptor activation; glucose intolerance; insulin; β-cell function