A more accessible lipid phenotype for predicting type 2 diabetes
Authors: Paola A Ramos, Jeffrey W Meeusen
Journal: The Lancet Healthy Longevity (2022)

Clinical studies using advanced lipoprotein profiling have identified elevated concentrations of larger VLDL particles, and smaller LDL particles are predictive of insulin resistance and type 2 diabetes.1Dugani SB Akinkuolie AO Paynter N Glynn RJ Ridker PM Mora S Association of lipoproteins, insulin resistance, and rosuvastatin with incident type 2 diabetes mellitus: secondary analysis of a randomized clinical trial.JAMA Cardiol. 2016; 1: 136-145Crossref PubMed Scopus (37) Google Scholar However, quantifying lipoprotein particle size and concentration requires specialised equipment not routinely available at most clinical laboratories. Fortunately, the ratio of LDL cholesterol per apolipoprotein B (apoB), which is considered a surrogate for LDL size, has also been associated with type 2 diabetes.2Tani S Yagi T Atsumi W Kawauchi K Matsuo R Hirayama A Relation between low-density lipoprotein cholesterol/apolipoprotein B ratio and triglyceride-rich lipoproteins in patients with coronary artery disease and type 2 diabetes mellitus: a cross-sectional study.Cardiovasc Diabetol. 2017; 16: 123Crossref PubMed Scopus (23) Google Scholar In The Lancet Healthy Longevity, Karol Pencina and colleagues3Pencina KM Pencina MJ Dufresne L Holmes M Thanassoulis G Sniderman AD An adverse lipoprotein phenotype—hypertriglyceridaemic hyperapolipoprotein B—and the long-term risk of type 2 diabetes: a prospective, longitudinal, observational cohort study.Lancet Healthy Longev. 2022; 3: e339-e346Summary Full Text Full Text PDF Scopus (1) Google Scholar present a new lipid phenotype (the hypertriglyceridaemic hyperapoB phenotype), characterised by hypertriglyceridaemia, elevated apoB, low HDL cholesterol, and low LDL cholesterol to apoB ratio. The association between obesity and type 2 diabetes has been recognised for decades and individuals with obesity represent 90% of all cases of diabetes. The hallmark of type 2 diabetes is elevated blood glucose due to insulin resistance or insulin deficiency. Insulin resistance is a reduced ability of tissues to respond to insulin and is often an early metabolic defect preceding the development of type 2 diabetes. Due to its slow progression, it is believed that insulin resistance goes undetected for years as hyperglycaemia develops gradually. In later stages, β-cell failure occurs, leading to insulin deficiency and other complications such as microvascular disease. As the primary defect of type 2 diabetes, insulin resistance represents a target of great interest to identify cases earlier and intervene to prevent type 2 diabetes.4Goldstein BJ Insulin resistance as the core defect in type 2 diabetes mellitus.Am J Cardiol. 2002; 90: 3G-10GSummary Full Text Full Text PDF PubMed Google Scholar Previous consensus on insulin resistance screening focused on glucose metabolism; however, growing evidence supports an association between dysregulation of lipid metabolism and type 2 diabetes.5Mooradian AD Dyslipidemia in type 2 diabetes mellitus.Nat Clin Pract Endocrinol Metab. 2009; 5: 150-159Crossref PubMed Scopus (657) Google Scholar Elevated triglycerides and reduced HDL cholesterol are increasingly accepted as risk factors for type 2 diabetes. Basic science research has found mechanistic links between insulin and apoB dysregulation. The liver secretes and clears apoB-containing lipoprotein particles. Insulin regulates apoB by promoting apoB degradation within the hepatocyte, thereby reducing the rate of apoB-lipoproteins (VLDL) secreted into the blood. Insulin resistance and deficiency cause important changes in lipoprotein kinetics. Increased secretion and decreased clearance of apoB-containing lipoprotein particles are the net result of disrupted insulin signalling. This has been shown in mouse models with liver-specific knock out of the insulin receptor followed by observations of increased secretion of apoB and decreased LDL clearance.6Han S Liang CP Westerterp M et al.Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice.J Clin Invest. 2009; 119: 1029-1041PubMed Google Scholar The association between incident type 2 diabetes and increased apoB was confirmed in Pencina and colleagues’ study3Pencina KM Pencina MJ Dufresne L Holmes M Thanassoulis G Sniderman AD An adverse lipoprotein phenotype—hypertriglyceridaemic hyperapolipoprotein B—and the long-term risk of type 2 diabetes: a prospective, longitudinal, observational cohort study.Lancet Healthy Longev. 2022; 3: e339-e346Summary Full Text Full Text PDF Scopus (1) Google Scholar of the Framingham Offspring cohort. Pencina and colleagues excluded participants with previous diabetes or cardiovascular disease to evaluate lipid markers as predictors of incident type 2 diabetes. Previously reported associations between type 2 diabetes and standard risk factors such as waist circumference, fasting blood glucose, and hypertriglyceridaemia were also confirmed. Patients were followed up for 20 years, and it was found that in addition to elevated apoB, reduced LDL cholesterol to apoB ratio and HDL cholesterol were also predictive of type 2 diabetes. Furthermore, adding LDL cholesterol to apoB ratio and HDL cholesterol to a baseline linear regression model negated the relationship between triglycerides and type 2 diabetes. Pencina and colleagues3Pencina KM Pencina MJ Dufresne L Holmes M Thanassoulis G Sniderman AD An adverse lipoprotein phenotype—hypertriglyceridaemic hyperapolipoprotein B—and the long-term risk of type 2 diabetes: a prospective, longitudinal, observational cohort study.Lancet Healthy Longev. 2022; 3: e339-e346Summary Full Text Full Text PDF Scopus (1) Google Scholar went on to show predictive utility of their lipid phenotypes by comparing participants with the hypertriglyceridaemic hyperapoB phenotype with participants with optimal lipid levels (hazard ratio for risk of type 2 diabetes 4·24 [95% CI 2·64–6·78]). Interestingly, the study found a stronger relationship between lipid phenotype group and type 2 diabetes among male participants. This might be due to the inclusion of HDL cholesterol with a single cutoff at 50 mg/dL. There is well documented evidence of a strong effect of sex on HDL cholesterol, with women known to have substantially higher concentrations. It is possible that addition of sex-specific cutoffs might normalise the sex-specific association of type 2 diabetes with the hypertriglyceridaemic hyperapoB phenotype. Pencina and colleagues’ study adds further evidence in support of lipid assessment for the prediction of incident type 2 diabetes. Moreover, the hypertriglyceridaemic hyperapoB phenotype can be readily assessed using standard methods widely available to most clinical laboratories. The Framingham Heart Study and other studies have previously established the importance of apoB as a potent marker for atherosclerosis and cardiovascular disease. Although further interventional studies are needed to establish a causal role of this phenotype in type 2 diabetes, this study strengthens the argument in favour of apoB as an important lipid biomarker for disease. We declare no competing interests. An adverse lipoprotein phenotype—hypertriglyceridaemic hyperapolipoprotein B—and the long-term risk of type 2 diabetes: a prospective, longitudinal, observational cohort studyOur findings suggest that individuals with hypertriglyceridaemic hyperapoB are at high risk of new-onset diabetes and might benefit from intensive measures to prevent diabetes. The association between this phenotype and incident diabetes is consistent with a pro-diabetic effect due to increased clearance of apoB particles from plasma, which could injure pancreatic islet cells. This mechanism might explain the increased risk of diabetes with statin therapy. Full-Text PDF Open Access