Plasma Heme Oxygenase-1 Concentration Is Elevated in Individuals with Type 2 Diabetes Mellitus

Abstract

BackgroundCirculating concentrations of heme oxygenase-1 (HO-1) have been recently reported to be elevated in several chronic disorders. However, no study has ever examined the association between circulating HO-1 concentrations and type 2 diabetes mellitus (T2DM).Methods and Findings581 cases with newly-diagnosed T2DM (New-T2DM) and 611 comparison controls were recruited in this two-phase case-control study, comprising 420 cases and 429 controls collected in the first phase study and 161 cases and 182 controls in the second phase replication study. Analyses, using both separated data and combined data from the two-phase studies, show that plasma HO-1 concentrations were significantly increased in New-T2DM cases compared to controls (P<0.001). Plasma HO-1 concentrations were significantly correlated with plasma glucose concentrations, HOMA-beta and HOMA-IR (P<0.001). After adjustment for age, sex, BMI and family history of diabetes, the ORs for New-T2DM in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 8.23 (95% CI 5.55–12.21; P for trend <0.001). The trend remained significant after additional adjustment for fasting plasma glucose/insulin, HOMA-beta/HOMA-IR, TC/TG, smoking, drinking and history of hypertension, and even in further stratification analysis by age, sex, BMI, smoking, drinking and history of hypertension.ConclusionsElevated plasma HO-1 concentrations are associated with higher ORs for New-T2DM, which add more knowledge regarding the important role of oxidative stress in T2DM. More consequent studies were warranted to confirm the clinical utility of plasma HO-1, especially in diagnosis and prognosis of T2DM and its complications.

Identification and Validation of Novel Adipokines Released from Primary Human Adipocytes

“…Recent studies have shown elevated plasma levels in several chronic disorders, like Parkinson's disease and hemophagocytic syndrome, and in newly diagnosed type 2 diabetics (49-51). Until today, the sources of circulating HO-1 are unknown and it is postulated that plasma HO-1 is due to "leakage" of the enzyme from tissues to the plasma compartment (49,52). Here, we demonstrate that HO-1 is an adipokine expressed and released by human primary adipocytes in a differentiation-dependent manner and that circulating levels of HO-1 are increased in obese men, correlating with the size of subcutaneous adipocytes.…”

Plasma and Urinary Heme Oxygenase-1 in AKI

“…For example, Bao et al 26 found slightly increased plasma HO-1 concentrations in patients with newly diagnosed type II diabetes (2.4 ng/ml), compared with controls (1.1 ng/ml). This was felt to reflect the effects of hyperglycemia, a known pro-oxidant state.…”

Iron and carbon monoxide enhance coagulation and attenuate fibrinolysis by different mechanisms

“…Given that both iron and carbon monoxide are products of HO-1 activity, it is likely that they coexist in various micromolar concentrations in conditions such as cancer [27][28][29][30][31], diabetes mellitus [21], rheumatoid arthritis [22], and mechanical circulatory support [18,26]. Although it is not possible to directly extrapolate our findings as the underpinning of hypercoagulability in these various settings [18,22,[26][27][28][29][30][31], it is possible that exposure of circulating fibrinogen to various combinations of iron and carbon monoxide may be enhancing coagulation in these disease states.…”

“…Catalytically released iron may also contribute to hydroxyl radical modification of fibrinogen [19] or bind directly to fibrinogen [20] as recently demonstrated. HO-1 activity is also increased systemically in inflammatory disorders associated with thrombophilia, such as diabetes mellitus [21] and rheumatoid arthritis [22]. Critically, SEM-based investigations demonstrated that the fibrin matrix formed from blood obtained from individuals with diabetes mellitus [23] or rheumatoid arthritis [24] was very similar to that observed when normal blood was exposed to ferric chloride [2][3][4][5][6][7].…”