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.

The emerging role of adiponectin in cerebrovascular and neurodegenerative diseases

“…Because adiponectin is a protein, orally administered adiponectin cannot be absorbed [87]. Currently, adiponectin is administered via intravenous or intraperitoneal injection [87,88]. The blood-brain barrier (BBB) is formed by endothelial cells and tight junctions, which form capillary walls.…”

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

“…For example, it is unclear what mechanism(s) underpin any observed changes in body weight. Reduced food intake [218,220] and elevated metabolism, heat production and activity [279] have been proposed although, at least in some instances, these changes appear to occur in the presence of HO-1 inhibition [280,282], arguing against a central role for HO-1 activity in this context. However, perhaps the most thought-provoking and challenging work in this area comes from the recent, elegant and comprehensive report from Pospisilik, Esterbauer and colleagues [204] which continues to put HO-1 centre-stage of obesity and insulin resistance but as a driver rather than a brake of obesity-associated inflammation.…”

“…For example, the beneficial effects of heme arginate in diabetic (db/db) mice were unaffected by co-treatment with a HO-1 inhibitor [282]. Moreover, genetic approaches to increase HO-1 in adipocytes have typically failed to improve metabolic parameters in the context of diet-induced obesity [204,281], including the reduction in circulating adiponectin levels [281].…”

“…Perhaps surprisingly then, the major site(s) of action and molecular details of these effects remain poorly understood as does the precise role of HO-1. Indeed, reports involving genetic or pharmacological approaches to manipulate the 'HO-1 axis' provide results that highlight the complexity of the axis and the need for considered interpretation and subsequent integration of the findings [204,281,282].…”

“…Indeed, strategies to induce HO-1 in humans are under investigation [206,207,263] as this is generally considered an attractive therapeutic strategy in diseases including obesity and type 2 diabetes [195,262,284]. However, some lines of evidence suggest that HO-1 per se may not be involved [282] and may even play a negative role in the aetiology of obesity-associated inflammation and cardiometabolic complications [204].…”