Administration of heme arginate ameliorates murine type 2 diabetes independently of heme oxygenase activity

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 preparati...

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Bibliographic Details
Published in:PloS one 2013-10, Vol.8 (10), p.e78209-e78209
Main Authors: Choudhary, Abhijeet K, Rennie, Jillian, Cairns, Carolynn, Borthwick, Gary, Hughes, Jeremy, Morton, Nicholas M, Kluth, David, Conway, Bryan R
Format: Article
Language:English
Subjects:
3T3 Cells
Adipocytes - drug effects
Adipocytes - metabolism
Adipogenesis
Adipogenesis - drug effects
Adiponectin
Adiponectin - blood
Adiponectin - metabolism
Adipose tissue
Adipose Tissue - drug effects
Adipose Tissue - metabolism
Adiposity - drug effects
Animal models
Animals
Arginine - administration & dosage
Blood Glucose - drug effects
Cell culture
Cell Line
Cell lines
Diabetes mellitus
Diabetes Mellitus, Experimental - blood
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Glucose
Heme
Heme - administration & dosage
Heme Oxygenase (Decyclizing) - metabolism
Hemin
Hyperglycemia
Hyperglycemia - blood
Hyperglycemia - drug therapy
Hyperglycemia - metabolism
Inflammation - blood
Inflammation - drug therapy
Inflammation - metabolism
Insulin resistance
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - metabolism
Intravenous administration
Kinases
Metalloporphyrins - administration & dosage
Mice
Mode of action
Nitric oxide
Oxygenase
Pilot Projects
Preservation
Rodents
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0078209