Connection Found Between Angiopoietin-Like Proteins 3 and 4 and Dyslipidemia

A recent case-control study conducted at the Kalinga Institute of Medical Sciences indicated that angiopoietin-like proteins 3 and 4 (ANGPTL 3 and 4) are associated with dyslipidemia in type 2 diabetes mellitus (T2DM).

Dyslipidemia, the leading cause of death in many developing countries and one of the central aspects of T2DM, is defined as an abnormal lipid profile. It is characterized by low high-density lipoprotein cholesterol (HDLc), high low-density lipoprotein cholesterol (LDLc), high total cholesterol (TC), and high triglycerides levels. Poor glycemic control is a critical risk factor for the development of high LDLc, hypercholesterolemia, and hypertriglyceridemia among patients with T2DM.2

ANGPTLs are directly responsible for monitoring and transforming lipids. ANGPTL3 operates primarily in response to feeding by transferring energy to storage or oxidative tissues. ANGPTL4 is increased during fasting and inhibits LPLs by transforming LPL homodimers into inactive monomers. This has led to several treatments focusing on ANGPTL3 and 4 as a way to monitor dyslipidemia in patients with T2DM.1

“Though ANGPTLs are now widely considered as therapy targets, the evidence for their function in lipid metabolism and T2DM pathophysiology remains mixed,” wrote Rik Swarnakar, PhD student at Kalinga Institute of Medical Sciences, and colleagues. “With this backdrop, the purpose of this study was to determine the levels of ANGPTL 3 and 4 in T2DM and better understand their relationship in causing dyslipidemia in T2DM.”1

Investigators collected 61 patients with T2DM between 25-65 years and 27 age-matched control participants. 5 ml of fasting venous blood samples was collected from each patient for glycemic tests (FBS and HbA1c) and analysis of serum cholesterol, triglycerides, c, HDL, ANGPTL-3 and 4, insulin, and free fatty acids (FFA).1

Investigators noted that serum ANGPTL3 (P <.05) and ANGPTL4 (P <.001) were substantially decreased in the T2DM cohort. ANGPTL4 was also negatively correlated to PPBS (.03), HbA1C (P = .05), and IR (P = .04). No correlation was observed with ANGPTL3; however, lipid parameters exhibited a correlation between ANGPTL3 (LDL P = .03, total cholesterol-to-HDL (TC/HDL) P = .02). A significant relationship was also observed between ANGPTL3, 4 and FFA (P = .002 and .03, respectively).1

Upon further analysis, Swarnakar and colleagues discovered that ANGPTL3 and ANGPTL4 levels were both substantially decreased in the T2DM cohort compared to control. Levels also tended to be lower in overweight obese individuals compared to those with healthy BMI. Overall, ANGPTL4 was negatively correlated with FBS and PPBS in T2DM, as well as HbA1C. Notably, however, there was no correlation between HbA1C and ANGPTL3 levels.1

Patients with T2DM also exhibited higher serum cholesterol, LDLc, and a TC/HDL ratio, while HDLc and FFA were significantly lower. There was a negative relationship between ANGPTL3 and LDLc, as well as between it and TC/HDL.1

“The current study adds to the prior findings indicating ANGPTL3 and 4 have a role to play in dyslipidemia in T2DM and requires future investigations to establish their relevance by taking into account various criteria, including individual’s nutritional status, metabolic profile, and methods for testing ANGPTL3, 4, to identify the pathogenic importance and therapeutic potential of these proteins in T2DM patients,” wrote Swarnakar and colleagues.1

References

1. Swarnakar R, Sahu D, Bahinipati J, et al. The significance of ANGPTL3 and ANGPTL4 proteins in the development of dyslipidemia in Type 2 diabetes mellitus. J Family Med Prim Care. 2025;14(3):947-953. doi:10.4103/jfmpc.jfmpc_1256_24

2. Al Quran TM, Bataineh ZA, Al-Mistarehi AH, et al. Prevalence and Pattern of Dyslipidemia and Its Associated Factors Among Patients with Type 2 Diabetes Mellitus in Jordan: A Cross-Sectional Study. Int J Gen Med. 2022;15:7669-7683. Published 2022 Oct 4. doi:10.2147/IJGM.S377463