The main findings of the present investigation are that: (1) mannose levels gradually increase with worsening glucose perturbations; (2) mannose is independently associated with a first MI; and (3) this association persists in subjects with NGT, but not in those with glucose perturbations.
Our results support previous works reporting higher mannose levels in individuals with glucose perturbations than in those without [20, 21], further extending them by documenting significantly higher levels in patients with previously known DM compared to those with newly detected T2DM. Even though there is no reference range for mannose concentrations, mainly because of different assay methods, our findings in patients with known DM, 98.0 (79.4−120.7) μmol/L, are comparable to the concentrations measured by assays based on mass spectrometry [18, 20]. Consistent with previous observations [9, 12, 20, 21], we noted a positive linear correlation between mannose and glucose concentrations in the total population. Taken together, this strongly supports the hypothesis that mannose is a strong marker of insulin resistance [11, 12, 22]. Even though insulin resistance was not directly assessed in the current study, it is likely that subjects with increasing levels of glucose intolerance are more insulin resistant than those with NGT and, accordingly, have increasing concentrations of plasma mannose. As recently reported in a cell-specific integrated network analysis , the pathophysiological explanation is that, in insulin-resistant patients, dysregulations of enzymes involved in sugar metabolism led to an increase in hepatic glucose utilisation while decreasing mannose phosphorylation. Consequently, mannose accumulates in the cytoplasm and may regurgitate into the blood stream, thus explaining high circulating mannose levels in such patients. This association gains crucial importance when considering that insulin resistance promotes atherogenesis and significantly increases the risk of CVD regardless of the presence of glucose perturbations [13, 23].
The potential role of mannose as a biomarker of CVD has recently gained interest, although it has been investigated only in a few studies so far. A large prospective cohort study reported an association between mannose levels and incident T2DM and CV outcomes including CHD and MI . A validation study, including patients with varying CV risk whose CAD was quantitated by coronary computed angiography, invasive coronary angiography and optical coherence tomography, found an association between plasma mannose and CAD with a vulnerable plaque phenotype, which was independent of traditional CV risk factors . In the effort to minimize the effect of additional confounders the present study selected patients with a first MI, i.e. with a rather benign CV risk profile compared with matched controls. Our results support the hypothesis that mannose is a novel marker of clinically manifest coronary atherosclerosis, on the basis of pathophysiological mechanisms that do not depend on acute settings. In this regard, in the present population hs-CRP, which is a marker of acute inflammation, was not significantly correlated with a first MI.
Interestingly, the association between mannose levels and a first MI was no longer significant in the subgroup of subjects with altered glycaemic state, although its magnitude was similar to that found in patients with NGT (OR 1.8 vs 2.0). A reasonable pathophysiological interpretation of these findings may be that, in subjects with glucose perturbations, the association of mannose with CAD is, at least partially, trumped by the presence of severe insulin resistance, which is its main regulator . The absence of this association in the group with glucose perturbations could also be explained by the fact that mannose might mediate the CV risk in these patients. It should be acknowledged that the number of patients in each group with glucose perturbations is smaller than in the NGT group, introducing the possibility of an excessive sample size imbalance; however, this is unlikely, since the association remains non-significant even when grouping all patients with glucose perturbations together. Further, one could speculate whether the association is attenuated also by grouping patients with newly detected glucose perturbations with those with known diabetes, as the latter might be treated with drugs affecting mannose levels and/or insulin sensitivity. Thus, from a clinical point of view, the assay of mannose among subjects without apparent glucose perturbations may represent a valuable tool for the early detection of patients at high risk for coronary events and possibly encourage more aggressive prevention strategies towards selected groups of patients.
Strengths and limitations
To the best of our knowledge, this is the only investigation addressing the association between plasma mannose levels in a large group of subjects with different and well-characterized degrees of glucose tolerance. The major strength of the present investigation is its large, well phenotyped, and homogeneous population . The glycaemic state of all participants without established DM was carefully investigated by the means of a standard OGTT, which allowed us to detect a significant proportion of subjects with previously undetected glucose perturbations (i.e., new IGT or new T2DM) among both patients and controls. IGT is a state of intermediate glucose intolerance that can only be diagnosed with an OGTT and that has a high prognostic value for future CV events in patients with CAD [6, 24,25,26,27,28,29]. The use of HPLC–MS-MS for the assay of plasma mannose not only eliminates the interference of blood glucose, which is present at much higher concentrations, but thanks to its adequate selectivity, reproducibility (relative SD < 10%), accuracy (96–104%), and limited cost, represents a suitable tool for mannose quantification in clinical settings [12, 18].
Some limitations should be considered. First, the proportion of subjects with glucose perturbations is somewhat lower compared with previous works, reporting approximately two thirds of coronary patients being affected by either IGT or T2DM [30, 31]. This discrepancy is likely explained by the selection of a healthier and younger population in the present study, which also contributes to the imbalance in size between the subgroups of subjects with and without glucose perturbations . The large sample size and the consistency of results when grouping all patients with glucose perturbations together do, however, suggest that the investigation is adequately powered. Moreover, there is a lack of information on the impact that may be exerted by pharmacological treatments, such as glucose-lowering drugs prescribed in patients with known DM, on plasma mannose concentrations. However, the proportion of patients with known DM is low and comparable between patients and controls (10.1% vs. 8.2%).
Finally, because of the observational design of the PAROKRANK study , the current investigation cannot demonstrate the presence of a causal relationship between high mannose and MI. Hence, further studies are needed to confirm the importance of measuring mannose in a clinical setting, for instance by evaluating its impact on future CV events and mortality in subjects with different glycaemic states.