High mannose correlates with surrogate indexes of insulin resistance and predicts cardiovascular events independently of glycaemic status and traditional risk factors
Authors: Fortin E , Campi B , Ferrannini E , Mari A , Mellbin L , Norhammar A , Nasman P , Ryden L , Saba A , Ferrannini G 
Published: November 2023

Abstract

Background
Plasma mannose, an emerging marker of insulin resistance (IR), is independently associated with coronary artery disease and cardiovascular (CV) events, not only in patients with altered glycaemic status, but also among those with normal glucose tolerance (NGT) [1, 2]. Whether mannose is a predictor of future CV events is not known.

Purpose
To investigate the association of mannose with surrogate indexes of IR as well as with long-term prognosis in patients with and without dysglycaemia.

Methods
Fasting plasma mannose was measured by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS-MS) in 696 cases with a first myocardial infarction (MI) and 707 controls matched for age, gender and living area from the PAROKRANK study [3]. Subjects free of known diabetes were further categorized as having either NGT (n=1045) or newly detected dysglycaemia (i.e., impaired glucose tolerance or type 2 diabetes; n=358) according to the results of an oral glucose tolerance test (OGTT). Surrogate indexes of IR and insulin secretion were calculated using glucose, insulin and C-peptide levels measured at 0, 30 and 120 minutes during the OGTT. The relationship between plasma mannose and different indexes was explored by fitting univariate and multivariate linear regression models. Kaplan-Meier functions were used to estimate crude survival across mannose quartiles. Unadjusted and adjusted Cox proportional hazards models were used to investigate the prognostic capacity of mannose, categorized as high (top quartile) vs low (lowest three quartiles), in relation to major adverse cardiac events (MACE) defined as CV death, MI and stroke during 10 years of follow-up. Secondary outcomes were single components of MACE and all-cause mortality.

Results
Mannose levels were associated with indexes of IR independently of BMI and other covariates in both the NGT and dysglycaemia subgroups. There was no difference in crude MACE-free survival between subjects with high and low mannose (log-rank p=0.10; Figure 1). However, high mannose remained as the only predictor of MACE in the overall population (Hazard ratio (HR): 1.58 (1.10-2.27); p=0.014) after multiple adjustments (Figure 2). This association was independent of the presence of dysglycaemia (interaction p between mannose category and dysglycaemia group=0.94) and IR expressed as HOMA-IR. High mannose also predicted MI, independently of the presence of a first MI (HR: 1.62 (1.00-2.62); p=0.050), while there was no significant association with the other secondary outcomes.

Conclusions
In a case-control setting of first MI, high mannose was the only significant predictor of future CV events, independently of traditional CV risk factors including a previous MI, glycaemic state and IR. Our findings expand the knowledge indicating that mannose might be used as a clinical tool for CV risk stratification.