title: Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.
abstract: Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism.
authors: Instituto de Investigaciones Sanitarias (IDIS), CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain. Electronic address: eva.tuduri@usc.es.
authors: Eva
authors: E
authors: Tudurí
authors: Instituto de Investigaciones Sanitarias (IDIS), CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
authors: Daniel
authors: D
authors: Beiroa
authors: Department of Nephrology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
authors: Johannes
authors: J
authors: Stegbauer
authors: KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway.
authors: Johan
authors: J
authors: Fernø
authors: Instituto de Investigaciones Sanitarias (IDIS), CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
authors: Miguel
authors: M
authors: López
authors: Instituto de Investigaciones Sanitarias (IDIS), CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
authors: Carlos
authors: C
authors: Diéguez
authors: Instituto de Investigaciones Sanitarias (IDIS), CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain; Department of Physiology, CIMUS, University of Santiago de Compostela, Santiago de Compostela 15782, Spain. Electronic address: ruben.nogueiras@usc.es.
authors: Rubén
authors: R
authors: Nogueiras
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002262:Carboxy-Lyases / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000701:Analgesics, Opioid; D007328:Insulin; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D005934:Glucagon; D005952:Glucose-6-Phosphatase; D002262:Carboxy-Lyases; D005947:Glucose
keywords: DAMGO; DAMGO (PubChem CID: 5462471); Glucose metabolism; Islets; SNC-80 (PubChem CID: 123924); U-50.488 (PubChem CID: 6604724); β-Cells; β-FNA (PubChem CID: 57339687)