title: Angiotensin II induces interleukin-1β-mediated islet inflammation and β-cell dysfunction independently of vasoconstrictive effects.
abstract: Pathological activation of the renin-angiotensin system (RAS) is associated with the metabolic syndrome, and the new onset of type 2 diabetes can be delayed by RAS inhibition. In animal models of type 2 diabetes, inhibition of the RAS improves insulin secretion. However, the direct effects of angiotensin II on islet function and underlying mechanisms independent of changes in blood pressure remain unclear. Here we show that exposure of human and mouse islets to angiotensin II induces interleukin (IL)-1-dependent expression of IL-6 and MCP-1, enhances β-cell apoptosis, and impairs mitochondrial function and insulin secretion. In vivo, mice fed a high-fat diet and treated with angiotensin II and the vasodilator hydralazine to prevent hypertension showed defective glucose-stimulated insulin secretion and deteriorated glucose tolerance. Application of an anti-IL-1β antibody reduced the deleterious effects of angiotensin II on islet inflammation, restored insulin secretion, and improved glycemia. We conclude that angiotensin II leads to islet dysfunction via induction of inflammation and independent of vasoconstriction. Our findings reveal a novel role for the RAS and an additional rationale for the treatment of type 2 diabetic patients with an IL-1β antagonist.
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Nadine S
authors.initials: NS
authors.lastname: Sauter
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Constanze
authors.initials: C
authors.lastname: Thienel
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Plutino
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Kapil
authors.initials: K
authors.lastname: Kampe
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Erez
authors.initials: E
authors.lastname: Dror
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Traub
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Timper
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, Geneva, Switzerland University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Benoit
authors.initials: B
authors.lastname: Bédat
authors.affiliation: University Lille Nord de France, Lille, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
authors.affiliation: University Lille Nord de France, Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Jehle
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Böni-Schnetzler
authors.affiliation: Clinic of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland Department of Biomedicine, University of Basel, Basel, Switzerland marc.donath@usb.ch.
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D018932:Chemokine CCL2; D007328:Insulin; D053583:Interleukin-1beta; D000804:Angiotensin II