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Insulin resistance (IR) is a metabolic condition in which the body's cells become less responsive to insulin, leading to elevated glucose and insulin levels in the blood. This condition is a precursor to type 2 diabetes (T2DM) and is linked to increased risks of cardiovascular diseases. The Lipoprotein Insulin Resistance Index (LP-IR) is a metric used to assess insulin resistance; it analyzes lipoprotein particle sizes and concentrations, which are metabolic health indicators.
An increased LP-IR score is associated with a higher risk of metabolic syndrome, T2DM, and cardiovascular complications, making early detection and lifestyle interventions crucial for managing and potentially reversing insulin resistance. The LP-IR may provide early detection of IR in apparently low-risk individuals. A low LP-IR generally indicates a low risk of insulin resistance.
Standard Range: LP-IR Below 45
The ODX Range: LP-IR Below 27
Low LP-IR is primarily associated with a decreased risk of insulin resistance. A low LP-IR may be associated with increased mortality in heart failure (Turecamo 2024) and may occur in African Americans at a high risk of IR but who maintain low triglyceride-rich lipoproteins (Sharma 2021).
High LP-IR is associated with insulin resistance, type 2 diabetes (Shalaurova 2014, Mackey 2015), and non-diabetic NAFLD (Vittal 2020).
Overview
Insulin resistance (IR) occurs when liver and peripheral cells become resistant to insulin, causing blood glucose and insulin levels to rise, creating metabolic dysfunction associated with type 2 diabetes (T2DM) and cardiovascular disease. Homeostasis model assessment of insulin resistance (HOMA-IR) calculations, based on fasting glucose and fasting insulin or C-peptide, primarily reflect hepatic IR, while glucose disposal rate (GDR) reflects peripheral IR (i.e., muscle and adipose tissue). Insulin resistance often precedes a diagnosis of T2DM and can be measured and addressed prophylactically. The Lipoprotein Insulin Resistance Index (LP-IR) is strongly associated with HOMA-IR and GDR and can be used to evaluate insulin resistance. The LP-IR algorithm is based on six NMR lipoprotein classes associated with IR: VLDL size, large VLDL particles, HDL size, large HDL particles, small LDL particles, and LDL size, in order of relevance. Alteration in the size and concentration of lipoprotein particles is associated with insulin resistance and T2DM (Shalaurova 2014). An LP-IR score of zero indicates the greatest insulin sensitivity, while a score of 100 reflects the most insulin resistance (Fosam 2022).
Research suggests LP-IR may predict future T2DM by identifying insulin resistance in low-risk subjects years before clinical dysglycemia is detected. Three studies identified this trend: the MESA cohort study, the JUPITER study, and the Women’s Health Study (Flores-Guerrero 2019).
Data from the MESA and MUSC studies were evaluated, and higher LP-IR scores were highly correlated with higher triglycerides, fasting insulin, and lower HDL-C. A linear relationship was observed between LP-IR and HOMA-IR and LP-IR and GDR. The LP-IR also detected insulin resistance even in normal-weight subjects and those with glucose parameters within the normal range (Shalaurova 2014).
A data review from the MESA prospective cohort study confirmed that type 2 diabetes incidence was significantly associated with higher LP-IR, large VLDL-P, small LDL-P, smaller HDL and LDL size, and larger VLDL size. Mean LP-IR was 54.3 and 40.7 in those diagnosed with and without T2DM, respectively. Researchers note that lower HDL-C and higher triglyceride levels and triglyceride:HDL-C ratios were also robustly associated with incident T2DM (Mackey 2015).
Diabetes risk in the Women’s Health Study was lowest with an LP-IR below 30 and highest above 67. Those with an LP-IR below 30 also had a mean baseline triglyceride level of 74 mg/dL (0.84 mmol/L), total cholesterol 202 mg/dL (5.23 mmol/L), LDL-C 113 mg/dL (1.69 mmol/L), HDL-C 65.1 mg/dL (1.69 mmol/L), Apolipoprotein B 86.3 mg/dL (0.86 g/L), Apolipoprotein A-1 of 161 mg/dL (1.61 g/L), and hs-CRP of 1 mg/L, and hemoglobin A1C 4.9% (Harada 2017).
Secondary analysis of data from 9,180 subjects taking part in the JUPITER statin study found that LP-IR predicted T2DM risk in the placebo group and those taking statins. Taking statins is considered a risk factor for T2DM. Diabetes incidence was lowest, with an LP-IR of 40 or below (Dugani 2016).
LP-IR was assessed in a cross-sectional study of 55 South Asian volunteers, a group at increased risk of insulin resistance and type 2 diabetes. Researchers suggest an optimal LP-IR cut-off above 48 for identifying insulin resistance (Fosam 2022). This cut-off is also considered strongly predictive of IR in individuals of European ancestry. However, LP-IR scores may not detect IR in African Americans despite a mean LP-IR of 28.9, as demonstrated in a cohort study of 518 subjects. This population can be at increased cardiometabolic risk with obesity, abnormal glucose tolerance, and higher small LDL particles but have low triglyceride-rich lipoprotein particle levels and decreasing LP-IR scores. Men had significantly higher LP-IR scores than women, i.e., 34 versus 23. Further screening for cardiometabolic risk should be carried out in this population (Sharma 2021).
LP-IR can be a valuable tool in NAFLD evaluation. Tissue insulin resistance is closely associated with non-alcoholic fatty liver disease (NAFLD), a disorder characterized by an accumulation of triglycerides in the liver and impaired insulin clearance. The LP-IR score may better assess hepatic insulin resistance in NAFLD than IR markers dependent on fasting insulin, which may not accurately reflect hepatic insulin exposure. A retrospective study of 93 NAFLD patients found LP-IR predicted IR and liver fat accumulation in non-diabetic subjects without fibrosis (Vittal 2020).
Lifestyle interventions can have a profound effect on insulin sensitivity. An education and lifestyle intervention based on diet changes, strength and endurance plan, and stress management significantly improved LP-IR in subjects with type 2 diabetes, coronary artery disease, or at a high risk of these disorders. A strict vegetarian (intensive intervention) and a Mediterranean-style diet (moderate intervention) significantly reduced both groups' LP-IR and large VLDL particles. Large VLDL particles are rich in triglycerides and are associated positively with the development of insulin resistance and coronary artery calcification. The more intensive vegetarian diet was more effective for subjects with a severe LP-IR of 75 or above than the moderate Mediterranean intervention (Ellsworth 2016).
Interestingly, a higher LP-IR was associated with lower mortality in a study of 1382 heart failure patients with an ejection fraction below 50%. LP-IR and mean HDL particle size were inversely and significantly associated with mortality in this group. The lowest and highest 5-year survival probabilities were observed with an LP-IR of 0-20 and above 60, respectively. Those with a higher LP-IR tended to have lower NT-proBNP levels but were more likely to smoke and have diabetes. Researchers note that higher total and LDL cholesterol levels are associated with improved survival rates in heart failure and point out that cholesterol-carrying lipoproteins can be protective due to their antioxidant and toxin-binding effects (Turecamo 2024).
Note: The LP-IR Score is inaccurate if the patient is not fasting.
References
Dugani, Sagar B et al. “Association of Lipoproteins, Insulin Resistance, and Rosuvastatin With Incident Type 2 Diabetes Mellitus : Secondary Analysis of a Randomized Clinical Trial.” JAMA cardiology vol. 1,2 (2016): 136-45. doi:10.1001/jamacardio.2016.0096
Ellsworth, D L et al. “Lifestyle modification interventions differing in intensity and dietary stringency improve insulin resistance through changes in lipoprotein profiles.” Obesity science & practice vol. 2,3 (2016): 282-292. doi:10.1002/osp4.54
Flores-Guerrero, Jose L et al. “Lipoprotein insulin resistance index, a high-throughput measure of insulin resistance, is associated with incident type II diabetes mellitus in the Prevention of Renal and Vascular End-Stage Disease study.” Journal of clinical lipidology vol. 13,1 (2019): 129-137.e1. doi:10.1016/j.jacl.2018.11.009
Fosam, Andin et al. “Lipoprotein Insulin Resistance Index: A Simple, Accurate Method for Assessing Insulin Resistance in South Asians.” Journal of the Endocrine Society vol. 7,3 bvac189. 10 Dec. 2022, doi:10.1210/jendso/bvac189
Harada, Paulo H N et al. “Lipoprotein insulin resistance score and risk of incident diabetes during extended follow-up of 20 years: The Women's Health Study.” Journal of clinical lipidology vol. 11,5 (2017): 1257-1267.e2. doi:10.1016/j.jacl.2017.06.008
Mackey, Rachel H et al. “Lipoprotein particles and incident type 2 diabetes in the multi-ethnic study of atherosclerosis.” Diabetes care vol. 38,4 (2015): 628-36. doi:10.2337/dc14-0645
Shalaurova, Irina et al. “Lipoprotein insulin resistance index: a lipoprotein particle-derived measure of insulin resistance.” Metabolic syndrome and related disorders vol. 12,8 (2014): 422-9. doi:10.1089/met.2014.0050
Sharma, Vandhna Rani et al. “Lipoprotein Insulin Resistance Score: Validation and Utility in African Ancestry Populations.” Journal of the Endocrine Society vol. 5,Suppl 1 A291–A292. 3 May. 2021, doi:10.1210/jendso/bvab048.593
Turecamo, Sarah et al. “Lipoprotein Insulin Resistance Score and Mortality Risk Stratification in Heart Failure.” The American journal of medicine vol. 137,7 (2024): 640-648. doi:10.1016/j.amjmed.2024.03.033
Vittal, Anusha et al. “Lipoprotein Insulin Resistance Index Reflects Liver Fat Content in Patients With Nonalcoholic Fatty Liver Disease.” Hepatology communications vol. 5,4 589-597. 29 Dec. 2020, doi:10.1002/hep4.1658
