The aim of this study was examine how the diameters of three fractions of lipoprotein co-varied, and to create a phenotype that, for the first time, reflects the pattern of lipoprotein diameters across VLDL, LDL and HDL particles. By examining the co-variation of this phenotype with the individual components of the MetS, we report that the MetS occurs alongside a reduction in LDL and HDL particle diameters. However, although VLDL diameter alone does not associate with MetS features, some of the most extreme IR features (the highest glucose, diabetes prevalence, TG, and WC) occur alongside smaller LDL and HDL particles, simultaneously with larger VLDL particles. As increased fasting glucose and TGs and increased WC are important indicators of CVD risk, the pattern of VLDL-LDL (or VLDL-HDL) diameters may have implications for starting identifying the highest risk groups for progression of IR into type II diabetes and cardiovascular disease.
Although previous studies into the role of LDL particle size in the MetS have largely used an increase in the concentration of the small LDL subfraction(s) as a marker of the MetS, previous analyses using particle diameters have been shown to be analogous to results using the concentration of particle subfractions . Using diameters as trait components, instead of subfraction concentrations, has two potential advantages:  there is no clear agreement on the number of subfractions within each fraction. Diameters are measured in nm and are a standardized unit. Using a standardized measurement (such NMR-based nm scale) over subfractions based on centrifugation and related techniques, makes replication in independent samples more straightforward, and may ease the use of information in clinical settings. The average diameter may reflect the distribution across NMR-based subfractions more than a single subfraction concentration alone. That is, an increase in a particular subfraction concentrations does not give information about whether this reflects an overall increase across all the subfractions. Overall shift in average particle diameter reflects subfraction distribution.
Our descriptive analysis reports that the MetS, and its individual features were characterized by small LDL and HDL particles. Previous research suggests that an increased concentration of small LDL particles is considered a marker of raised TG [5, 8], raised fasting glucose [4, 9], lowered HDL-C , increased WC  and hypertension . Much of the research supports a shift to smaller HDL in IR [3, 4, 12–14]. The groups created during the LCA showed significant differences in all components of the MetS, and so our study unifies previous information, and supports the association of small LDL  and HDL particles with the components of the MetS.
To extend our understanding of how lipoprotein diameters may be a marker of IR features, LCA analysis grouped individuals by their similarities for each of the three fractions of lipoprotein. Thus, the groups reflected relationships between the diameters of the various fractions of lipoprotein within a unified trait. As LDL particle diameter increased across the groups, so did HDL particle diameter. VLDL diameter was not correlated with LDL diameter, which is important as it indicates at least partially separable genetic and/or environmental influences to LDL and VLDL particle diameter formation.
The groups containing individuals with small LDL and HDL diameters are highly enriched for the presence of the MetS, a risk factor for incident diabetes and cardiometabolic disease [1, 2]. The inclusion of VLDL diameter into the particle diameter pattern stratified those with the MetS into two further groups, one of which (group 2) has more extreme IR features i.e., increased WC, glucose, TG and diabetes prevalence, although there was not a significant difference in the average number of MetS components between the groups. Thus, when LDL diameter is known, the inclusion of HDL diameter in a trait is minimally informative. But knowledge of the VLDL diameter increased trait sensitivity as to the degree of abnormality across several of the individual components of the MetS. Given the relationship of IR to and cardiovascular events , this trait may provide, or contribute to, a useful tool, available from a quick serum test, for identifying those at the highest risk of incident diabetes or cardiometabolic disease from those who meet MetS criteria.
To confirm that the associations between the groups and components of the MetS were not confounded by an association between particle diameter and overall particle numbers, we additionally controlled for lipoprotein concentrations. In these models, WC, fasting TG, systolic BP and HDL-C did differ significantly between the groups (P < 0.0001), but fasting glucose and diastolic BP showed only a trend towards an association (P = 0.05). Thus, the association between the mean value for components of the MetS and a trait created from fasting particle diameter pattern is not attributable to any shared association with overall lipoprotein concentrations.
Although the clustering of individuals by VLDL, LDL and HDL particle diameter may provide an important trait for future risk stratification, our study should be viewed in light of some limitations. Firstly, differences by race both in lipoprotein patterns, and in the association of lipoprotein pattern with MetS features needs examination, which was not possible within the current sample. Secondly, and crucially, the use of cross-sectional data precluded any causal inferences regarding predictive value of particle diameter clustering to the MetS, or regarding the association between particle diameter clustering and incident diabetes/cardiometabolic disorder. This is an important future direction for this work.
Overall, while LDL particle diameter correlated with HDL particle diameter (in a fasted state), VLDL diameter varied independently of LDL, and the inclusion of information on diameter from three fractions of lipoprotein was more informative about MetS features than that of a single fraction. The MetS was marked by small LDL and HDL diameters, but, together, large VLDL and small LDL and HDL diameters marked those with the highest glucose, diabetes prevalence, TG, and WC. Thus, together, a combination of LDL and VLDL diameter may provide the best tool for identifying those at increased risk for type II diabetes or CVD. It is of great interest to see, in longitudinal studies, if changes in lipoprotein diameter pattern occur before the presence of the MetS, or simply alongside, and to establish whether this pattern of small LDL and large VLDL particles can be shown to convey increased risk for incident diabetes and cardiovascular events.