title: The Angiotensin-(1-7)/Mas Axis Improves Pancreatic β-Cell Function in Vitro and in Vivo.
abstract: The angiotensin-converting enzyme 2/angiotensin (Ang)-(1-7)/Mas axis of the renin-angiotensin system often opposes the detrimental effects of the angiotensin-converting enzyme/Ang II/Ang II type 1 receptor axis and has been associated with beneficial effects on glucose homeostasis, whereas underlying mechanisms are mostly unknown. Here we investigate the effects of Ang-(1-7) and its receptor Mas on β-cell function. Isolated islets from Mas-deficient and wild-type mice were stimulated with Ang-(1-7) or its antagonists and effects on insulin secretion determined. Islets' cytoplasmic calcium and cAMP concentrations, mRNA amounts of Ins1, Ins2, Pdx1, and Mafa and effects of inhibitors of cAMP downstream signaling were determined. Ang-(1-7) was also applied to mice by osmotic pumps for 14 days and effects on glucose tolerance and insulin secretion were assessed. Ang-(1-7) increased insulin secretion from wild-type islets, whereas antagonists and genetic Mas deficiency led to reduced insulin secretion. The Mas-dependent effects of Ang-(1-7) on insulin secretion did not result from changes in insulin gene expression or changes in the excitation-secretion coupling but from increased intracellular cAMP involving exchange protein activated directly by cAMP. Administration of Ang-(1-7) in vivo had only marginal effects on glucose tolerance in wild-type mice but still resulted in improved insulin secretion from islets isolated of these mice. Interestingly, although less pronounced than in wild types, Ang-(1-7) still affected insulin secretion in Mas-deficient islets. The data indicate a significant function of Ang-(1-7) in the regulation of insulin secretion from mouse islets in vitro and in vivo, mainly, but not exclusively, by Mas-dependent signaling, modulating the accessory pathway of insulin secretion via increase in cAMP.
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Sahr
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Wolke
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Maczewsky
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Krippeit-Drews
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Tetzner
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Gisela
authors.initials: G
authors.lastname: Drews
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Venz
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gürtler
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: van den Brandt
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Berg
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Döring
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology (A.S., C.W., S.V., S.G.M, U.L.), Institute of Pathology (P.D., F.D.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Pharmacology (J.M., P.K.-D., G.D.), Institute of Pharmacy, University of Tübingen, D-72076, Tübingen, Germany; Department of Pharmacology and Therapeutics (A.T., T.W.), University College Cork, Cork, Ireland; Clinic for Pediatric Surgery and Department of Obstetrics (A.T., T.W.), University Medical Centre Leipzig, D-04103 Leipzig, Germany; and Central Core and Research Facility of Laboratory Animals (J.v.d.B., S.B.), University Medicine Greifswald, D-17489 Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Lendeckel
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C514817:Ins1 protein, mouse; C561967:Ins2 protein, mouse; D007328:Insulin; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D000803:Angiotensin I; D000242:Cyclic AMP; C118790:angiotensin I (1-7)