title: Administration of heme arginate ameliorates murine type 2 diabetes independently of heme oxygenase activity.
abstract: Amelioration of rodent type 2 diabetes by hemin has been linked to increased heme oxygenase (HO) activity, however alternative mechanisms have recently been proposed for its anti-diabetic effect. We sought to determine the anti-diabetic efficacy of heme arginate (HA), a clinically licensed preparation of heme, and whether its predominant mode of action is via increased HO activity. Intravenous administration of HA reduced hyperglycemia in diabetic (db/db) mice. Co-administration of the HO inhibitor stannous (IV) mesoporphyrin IX dichloride (SM) resulted unexpectedly in a further improvement in glycaemic control despite restoring HO activity to baseline levels. The anti-diabetic effects of HA±SM were associated with increased adiposity, increased serum adiponectin levels, reduced adipose tissue and islet inflammation and preservation of islet β-cell function. HO activity independent effects of HA on adipogenesis and β-cell inflammation were further confirmed in cell culture models using the 3T3-L1 pre-adipocyte and MIN6 β-cell lines, respectively. In conclusion, our work demonstrates that the heme component of HA ameliorates experimental type 2 diabetes by promoting metabolically favourable adipogenesis and preserving islet β-cell function, but this is not mediated via increased HO activity.
authors.affiliation: Medical Research Council Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Abhijeet K
authors.initials: AK
authors.lastname: Choudhary
authors.forename: Jillian
authors.initials: J
authors.lastname: Rennie
authors.forename: Carolynn
authors.initials: C
authors.lastname: Cairns
authors.forename: Gary
authors.initials: G
authors.lastname: Borthwick
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.forename: David
authors.initials: D
authors.lastname: Kluth
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Conway
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D052242:Adiponectin / Q000097:blood / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001120:Arginine / Q000008:administration & dosage*; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006418:Heme / Q000008:administration & dosage*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008665:Metalloporphyrins / Q000008:administration & dosage; D051379:Mice; D010865:Pilot Projects
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D008665:Metalloporphyrins; C518404:stannous mesoporphyrin; D006418:Heme; D001120:Arginine; D006419:Heme Oxygenase (Decyclizing); C048849:heme arginate