title: Nogo-A downregulation improves insulin secretion in mice.
abstract: Type 2 diabetes (T2D) is characterized by β-cell dysfunction and the subsequent depletion of insulin production, usually in a context of increased peripheral insulin resistance. T2D patients are routinely treated with oral antidiabetic agents such as sulfonylureas or dipeptidyl peptidase-4 antagonists, which promote glucose- and incretin-dependent insulin secretion, respectively. Interestingly, insulin secretion may also be induced by neural stimulation. Here we report the expression of Nogo-A in β-cells. Nogo-A is a membrane protein that inhibits neurite outgrowth and cell migration in the central nervous system. We observed that Nogo-A-deficient mice display improved insulin secretion and glucose clearance. This was associated with a stronger parasympathetic input and higher sensitivity of β-cells to the cholinergic analog carbachol. Insulin secretion was also improved in diabetic db/db mice treated with neutralizing antibody against Nogo-A. Together, these findings suggest that promoting the vagal stimulation of insulin secretion through the selective inhibition of Nogo-A could be a novel therapeutic approach in T2D.
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Claire B
authors.initials: CB
authors.lastname: Bonal
authors.forename: Delphine E
authors.initials: DE
authors.lastname: Baronnier
authors.forename: Caroline
authors.initials: C
authors.lastname: Pot
authors.forename: Mahdia
authors.initials: M
authors.lastname: Benkhoucha
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
authors.forename: Patrice H
authors.initials: PH
authors.lastname: Lalive
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000009:adverse effects / Q000627:therapeutic use; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D006943:Hyperglycemia / Q000517:prevention & control; D007003:Hypoglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D009185:Myelin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000070798:Nogo Proteins; D010275:Parasympathetic Nervous System / Q000187:drug effects; D046509:Tissue Culture Techniques; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D018679:Cholinergic Agonists; D007004:Hypoglycemic Agents; D007328:Insulin; D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse; D002217:Carbachol