Prediyabet Modelinde ANGPTL4 Düzeylerinin Artışı ve Metabolik Parametrelerle İlişkisi

Yıl 2025, Cilt: 51 Sayı: 3, 387 - 393, 08.12.2025

Pınar Ellergezen , Yusuf Berkcan Yanar , Gülce Sevdar Çeçen , Sinan Çavun

https://doi.org/10.32708/uutfd.1666630

Öz

Prediyabet, diyabet öncesi dönemde ortaya çıkan; insülin direnci, bozulmuş glukoz toleransı ve metabolik dengesizliklerle karakterize bir durumdur. Bu süreçte lipid metabolizması ve enerji dengesinin düzenlenmesinde önemli rol oynayan angiopoietin-like protein 4 (ANGPTL4), enerji dengesi ve lipid metabolizmasını etkileyerek prediyabetin ilerleyişinde önemli bir biyobelirteç olarak öne çıkmaktadır. Ancak prediyabetik bireylerde ANGPTL4 düzeylerinin nasıl değiştiği ve metabolik parametrelerle ilişkisi hakkında yeterli veri bulunmamaktadır. Bu çalışmada, prediabetik rat modelinde ANGPTL4 düzeyleri sağlıklı grupla karşılaştırılmış ve metabolik parametrelerle ilişkisi değerlendirilmiştir. Çalışmada 6-8 haftalık erkek Wistar ratlar, prediabetik (n=24) ve sağlıklı kontrol (n=22) olmak üzere randomize olarak iki gruba ayrılmıştır. Prediyabet modeli oluşturmak için hayvanlar 12 hafta yüksek yağlı diyetle beslenmiş, kontrol grubuna ise standart diyet uygulanmıştır. Kan örneklerinden ELISA yöntemiyle ANGPTL4 düzeyleri ölçülmüş; glukoz, insülin, HbA1c, lipid profili, HOMA-IR ve HOMA-β gibi parametreler değerlendirilmiştir. Prediabet grubunun ANGPTL4 seviyeleri kontrol grubuna göre anlamlı derecede yüksek bulunmuştur (p<0,05). Glukoz, insülin, HOMA-IR ve HOMA-β değerleri de prediabet grubunda kontrol grubuna kıyasla anlamlı derecede yüksektir. ANGPTL4 ile HDL ve total kolesterol düzeyleri arasında pozitif korelasyon saptanmış, ancak ANGPTL4 ile insülin direnciyle ilişkili belirteçler (glukoz, insülin, HOMA-IR, HOMA-β) arasında istatistiksel olarak anlamlı bir ilişki bulunmamıştır. Bu farklılık, ANGPTL4 artışının prediyabetik durumda insülin direnci belirteçleriyle doğrudan lineer bir ilişki göstermeksizin eşlik edebileceğini ve dolaylı ya da daha karmaşık biyolojik mekanizmaları yansıtıyor olabileceğini düşündürmektedir. Bulgular, ANGPTL4’ün prediyabetten diyabete geçişte önemli bir biyobelirteç olabileceğini göstermekte; bu proteinin patogenezdeki rolünü daha iyi anlamak için ileri çalışmalara ihtiyaç duyulmaktadır.

Anahtar Kelimeler

ANGPTL4 , biyobelirteç , insülin direnci , prediyabet

Proje Numarası

TGA-2023-1455

Increase in ANGPTL4 Levels and Its Relationship with Metabolic Parameters in Prediabetes Model

Öz

Prediabetes is a condition characterized by insulin resistance, impaired glucose tolerance, and metabolic imbalance, occurring before the onset of diabetes. Angiopoietin-like protein 4 (ANGPTL4), known for its role in lipid metabolism and energy regulation, has been proposed as a potential biomarker in the progression of prediabetes due to its regulatory role in lipid metabolism and systemic metabolic homeostasis. However, data on ANGPTL4 levels in prediabetic individuals and their association with metabolic parameters remain limited. This study aimed to investigate ANGPTL4 levels in a rat model of prediabetes and assess its relationship with key metabolic indicators. Male Wistar rats (6–8 weeks old) were randomly assigned to two groups: prediabetic (n=24) and healthy controls (n=22). The prediabetic group was fed a high-fat diet for 12 weeks, while the control group received a standard diet. Blood samples were collected, and ANGPTL4 levels were measured using the ELISA method. Metabolic parameters were also evaluated, including glucose, insulin, HbA1c, lipid profile (total cholesterol, LDL, HDL, triglycerides), HOMA-IR, and HOMA-β. ANGPTL4 levels were significantly elevated in the prediabetic group compared to controls (p<0.05). A significant positive correlation was found between ANGPTL4 and HDL as well as total cholesterol, suggesting its involvement in lipid regulation. Fasting glucose, insulin, HOMA-IR, and HOMA-ß were also significantly elevated in the prediabetic group compared to controls. However, no statistically significant correlations were observed between ANGPLT4 and these insulin resistance-related markers. This divergence suggests that ANGPLT4 elevation may accompany the prediabetic state without a direct linear relationship to insulin resistance marker, possibly reflecting indirect or complex pathways. ANGPTL4 may serve as a valuable early biomarker in transitioning from prediabetes to diabetes, highlighting the need for further research on its clinical relevance and mechanistic role.

Anahtar Kelimeler

ANGPTL4 , biomarker , insulin resistance , prediabetes

Proje Numarası

TGA-2023-1455

Kaynakça

• 1. Daisy D, Andre PK, Justin BET. Screening for Diabetes and Prediabetes and their Prediction. Endocrinol Metab Clin North Am. 2021; 50(3):369–385.
• 2. Magge SN, Silverstein J, Elder D, Nadeau K, Hannon TS. Evaluation and Treatment of Prediabetes in Youth. J Pediatr. 2020; 219:11-22.
• 3. Lam K, Lee SJ. Prediabetes A Risk Factor Twice Removed. JAMA Intern Med. 2021; 181(4):520-521.
• 4. Echouffo-Tcheugui JB, Selvin E. Prediabetes and What It Means: The Epidemiological Evidence. Annu Rev Public Health. 2021; 42:59-77.
• 5. Escalada San Martín J. Prediabetes: what are we talking about? Adv Lab Med. 2021; 2(3):305-312.
• 6. Stefan N, Roden M. Diabetes and Fatty Liver. Exp Clin Endocrinol Diabetes. 2024; 132(3):136-141.
• 7. Yousef H, Khandoker AH, Feng SF, Helf C, Jelinek HF. Inflammation, oxidative stress, and mitochondrial dysfunction in the progression of type II diabetes mellitus with coexisting hypertension. Front Endocrinol (Lausanne). 2023; 14:1173402.
• 8. Zhang R, Zhang K. A unified model for regulating lipoprotein lipase activity. Trends Endocrinol Metab. 2024; 35(6):490-504.
• 9. Zhao Z, Lian H, Liu Y, Sun L, Zhang Y. Application of systemic inflammation indices and lipid metabolism-related factors in coronary artery disease. Coron Artery Dis. 2023; 34(5):306-313.
• 10. Bini S, D'Erasmo L, Di Costanzo A, Minicocci I, Pecce V, Arca M. The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases. Int J Mol Sci. 2021; 22(2):742.
• 11. Hezarkhani S, Hajighaderi A, Hosseinzadeh S et al. The serum levels of angiopoietin-like protein 3 and 4 in type 2 diabetic patients with and without metabolic syndrome compared to the control group. Endocrinol Diabetes Metab. 2024; 7(1):e466.
• 12. Xu F, Shen L, Yang Y et al. Association Between Plasma Levels of ANGPTL3, 4, 8 and the Most Common Additional Cardiovascular Risk Factors in Patients with Hypertension. Diabetes Metab Syndr Obes. 2023; 7:16:1647-1655.
• 13. Sylvers-Davie KL, Davies BSJ. Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8. Am J Physiol Endocrinol Metab. 2021; 321(4):E493-E508.
• 14. Ruppert PMM, Michielsen CCJR, Hazebroek EJ et al. Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue. Mol Metab. 2020; 40:101033.
• 15. Tjeerdema N, Georgiadi A, Jonker JT et al. Inflammation increases plasma angiopoietin-like protein 4 in patients with metabolic syndrome and type 2 diabetes. BMJ Open Diabetes Res Care. 2014; 2(1):e000034.
• 16. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-9
• 17. Lafferty MJ, Bradford KC, Erie DA, Neher SB. Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase. J Biol Chem. 2013; 288(40):28524–28534.
• 18. Dijk W, Beigneux AP, Larsson M et al. Angiopoietin-like 4 promotes intracellular degradation of lipoprotein lipase in adipocytes. JLR. 2016; 57(9):1670-1683.
• 19. Lichtenstein L, Berbée JFP, van Dijk SJ et al. Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL-Dependent Hepatic Cholesterol Uptake. ATVB. 2007; 27(11):2420-2427.
• 20. Nahon, KJ. Combatting metabolic disease: ethnic aspects, mechanisms, and novel treatment strategies. 2018; https://hdl.handle.net/1887/66800
• 21.Yang LY, Yu CG, Wang XH et al. Angiopoietin-Like Protein 4Is a High-Density Lipoprotein (HDL) Component for HDLMetabolism and Function in Nondiabetic Participants andType-2 Diabetic Patients. J Am Heart Assoc. 2017; 6(6):e005973.
• 22.Sylvers-Davie KL, Davies BSJ. Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8. Am JPhysiol Endocrinol Metab. 2021; 321: E493–E508.
• 23.Sander Kersten. Role and mechanism of the action of angiopoietin-like protein ANGPTL4 in plasma lipidmetabolism. J Lipid Res. 2021; 62:100150.
• 24.Samar A. Antara, Nada A. Ashourc, Marwa Sharakyd et al.Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of neweffective treatments. Biomed Pharmacother. 2023; 168:115734
• 25.Fernandez-Hernando C, Suárez Y. ANGPTL4, AMultıfunctıonal Proteın Involved In Metabolısm And Vascular Homeostasıs. Curr Opin Hematol. 2020; 27(3):206–213.
• 26.Dludla PV, Mabhida SE, Ziqubu K et al. Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammationand oxidative stress. World J Diabetes. 2023; 14(3):130–146.
• 27.Singh AK, Chaube B, Zhang X et al. Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetesand mitigates atherosclerosis in mice. J Clin Invest. 2021;131(17):e140989.