Fare Modelinde İnsülin Kaynaklı Hipoglisemi: Karaciğer ve Böbrek Hasarı ile İnflamatuvar Belirteçler Arasındaki İlişki

Öz

Bu çalışmanın amacı, akut insülin kaynaklı hipogliseminin karaciğer ve böbrek dokularında erken histopatolojik ve inflamatuvar etkilerini değerlendirmektir. Akut hipoglisemi, yoğun insülin uygulaması ile deneysel olarak oluşturulmuş ve karaciğer ile böbrek dokuları histolojik olarak incelenmiştir. TNF-α, IL-6 ve NF-κB protein ekspresyonları immünohistokimya ile, TNF-α ve IL-6 gen ekspresyonları ise RT-qPCR yöntemi ile analiz edilmiştir. Akut hipoglisemi her iki organda da erken yapısal değişikliklere yol açmış, böbrekte tübüler ve glomerüler hasar dahil olmak üzere daha belirgin histopatolojik bulgular gözlenirken karaciğer değişiklikleri daha hafif düzeyde kalmıştır. TNF-α, IL-6 ve NF-κB protein düzeylerinde anlamlı bir değişiklik saptanmamıştır. Buna karşılık, böbrek dokusunda TNF-α ve IL-6 mRNA düzeylerinde geçici değişiklikler gözlenmiştir. Bu bulgular, akut insülin kaynaklı hipogliseminin erken dönemde organ hasarına yol açabileceğini ve bu etkinin özellikle böbrek dokusunda daha belirgin olduğunu göstermektedir. Elde edilen sonuçlar, hipoglisemiye bağlı doku hasarının belirgin inflamatuvar protein aktivasyonundan ziyade, metabolik stres mekanizmaları ile ilişkili olabileceğini düşündürmektedir.

Anahtar Kelimeler

• Hipoglisemi
• Karaciğer
• İnflamasyon
• İnsülin
• Böbrek

Insulin-induced Hypoglycemia in a Mouse Model: Association of Inflammatory Markers with Liver and Kidney Injury

Öz

The aim of this study was to evaluate the early histopathological and inflammatory effects of acute insulin-induced hypoglycemia in liver and kidney tissues. Acute hypoglycemia was experimentally induced by insulin administration, and liver and kidney samples were analyzed histologically. Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB) protein expression were assessed by immunohistochemistry, while TNF-α and IL-6 gene expression were evaluated using reverse transcription quantitative polymerase chain reaction. Acute hypoglycemia induced early structural alterations in both organs, with more pronounced and progressive changes observed in the kidney. Renal injury included tubular epithelial degeneration, tubular dilatation, and glomerular alterations, whereas hepatic changes were milder and mainly characterized by sinusoidal dilatation and hyperemia. No significant differences were observed in TNF-α, IL-6, or NF-κB protein expression. However, renal TNF-α and IL-6 messenger RNA levels showed transient alterations over time. In conclusion, acute insulin-induced hypoglycemia leads to early structural injury in liver and kidney tissues, with greater susceptibility observed in the kidney. These changes occur in the absence of significant inflammatory protein activation, suggesting that early tissue injury is primarily driven by metabolic stress rather than overt inflammatory signaling, although transient transcriptional responses may precede detectable protein-level changes.

Anahtar Kelimeler

• Hypoglycemia
• Insulin
• Inflammation
• Kidney
• Liver

Etik Beyan

Approving Committee: Erciyes University Animal Experiments Local Ethics Committee Approval Date: 03.12.2025 Decision No: 25/273

Kaynakça

1. 1. Kalra S, Mukherjee JJ, Venkataraman S, et al. Hypoglycemia: The neglected complication. Indian J Endocrinol Metab. 2013;17(5):819-834. doi:10.4103/2230-8210.117219
2. 2. Nakhleh A, Shehadeh N. Hypoglycemia in diabetes: An update on pathophysiology, treatment, and prevention. World J Diabetes. 2021;12(12):2036-2049. doi:10.4239/wjd.v12.i12.2036
3. 3. Mathew TK, Zubair M, Tadi P. Blood Glucose Monitoring. In: StatPearls. StatPearls Publishing; 2025. Accessed April 1, 2025. http://www.ncbi.nlm.nih.gov/books/NBK555976/
4. 4. Kahal H, Halama A, Aburima A, et al. Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects. Sci Rep. 2020;10(1):4750. doi:10.1038/s41598-020-61531-z
5. 5. Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 2017;13(10):572-587. doi:10.1038/nrendo.2017.80
6. 6. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, Diabetes, and Cardiovascular Events. Diabetes Care. 2010;33(6):1389-1394. doi:10.2337/dc09-2082
7. 7. Hoffmann A, Cheng G, Baltimore D. NF-κB: master regulator of cellular responses in health and disease. Immun Inflamm. 2025;1(1):2. doi:10.1007/s44466-025-00014-0
8. 8. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2(1):17023. doi:10.1038/sigtrans.2017.23

9. 9. Dong Y, Liu Y, Kou X, et al. The protective or damaging effect of Tumor necrosis factor-α in acute liver injury is concentration-dependent. Cell Biosci. 2016;6:8. doi:10.1186/s13578-016-0074-x
10. 10. Tiegs G, Horst AK. TNF in the liver: targeting a central player in inflammation. Semin Immunopathol. 2022;44(4):445-459. doi:10.1007/s00281-022-00910-2
11. 11. Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol. 2016;64(6):1403-1415. doi:10.1016/j.jhep.2016.02.004
12. 12. Navarro-González JF, Mora-Fernández C. The Role of Inflammatory Cytokines in Diabetic Nephropathy. J Am Soc Nephrol. 2008;19(3):433. doi:10.1681/ASN.2007091048
13. 13. Taheri S, Karaca Z, Rassoulzadegan M, et al. The Characterization of Sex Differences in Hypoglycemia-Induced Activation of HPA Axis on the Transcriptomic Level. Cell Mol Neurobiol. 2022;42(5):1523-1542. doi:10.1007/s10571-021-01043-0
14. 14. Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res. 2018;25(21):20968-20984. doi:10.1007/s11356-018-2242-5
15. 15. Okan A, Doğanyiğit Z, Yilmaz S, Uçar S, Arikan Söylemez ES, Attar R. Evaluation of the protective role of resveratrol against sepsis caused by LPS via TLR4/NF-κB/TNF-α signaling pathways: Experimental study. Cell Biochem Funct. 2023;41(4):423-433. doi:10.1002/cbf.3790
16. 16. Silici S, Demiray S, Okan A, Ertuğrul S, Alizada S, Doğanyiğit Z. Effects of short‐ and long‐term use of propolis extracts on liver and kidney in rats. Food Sci Nutr. 2024;12(8):5538-5547. doi:10.1002/fsn3.4199
17. 17. Godfrey TE, Kim SH, Chavira M, et al. Quantitative mRNA Expression Analysis from Formalin-Fixed, Paraffin-Embedded Tissues Using 5′ Nuclease Quantitative Reverse Transcription-Polymerase Chain Reaction. J Mol Diagn. 2000;2(2):84-91. doi:10.1016/S1525-1578(10)60621-6
18. 18. Duman EM, Uz A, Sancak S, Abusalim MRS, Çınar V, Taheri S. Transcriptional and Proliferative Heterogeneity Among Leukemia Cell Lines: A Baseline Characterization of Epigenetic and DNA-Repair Pathways. Erciyes Biog. 2025;(1):11-21.
19. 19. Livak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods. 2001;25(4):402-408. doi:10.1006/meth.2001.1262
20. 20. Drummond JB, Barbosa IG, Dantzer R, Teixeira AL. The effect of insulin-induced hypoglycemia on inflammatory markers: A systematic review. Brain Behav Immun. 2018;73:41-50. doi:10.1016/j.bbi.2018.05.003
21. 21. Iqbal A, Prince LR, Novodvorsky P, et al. Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans. J Clin Endocrinol Metab. 2019;104(4):1187-1199. doi:10.1210/jc.2018-01168
22. 22. Wright RJ, Newby DE, Stirling D, Ludlam CA, Macdonald IA, Frier BM. Effects of Acute Insulin-Induced Hypoglycemia on Indices of Inflammation. Diabetes Care. 2010;33(7):1591-1597. doi:10.2337/dc10-0013
23. 23. Petersen MC, Vatner DF, Shulman GI. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol. 2017;13(10):572-587. doi:10.1038/nrendo.2017.80
24. 24. Shen L xiao, Wu Y gui, Ke M dan, Shen L xiao, Wu Y gui, Ke M dan. The Liver Disease-Related Hypoglycemia: An Overview of the Impact, Management Approaches, and Underlying Mechanisms. Br J Hosp Med. 2025;86(6):1-18. doi:10.12968/hmed.2025.0028
25. 25. Alsahli M, Gerich JE. Renal glucose metabolism in normal physiological conditions and in diabetes. Diabetes Res Clin Pract. 2017;133:1-9. doi:10.1016/j.diabres.2017.07.033
26. 26. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-142. doi:10.1111/j.1464-5491.2009.02894.x
27. 27. Bhardwaj SK, Sharma ML, Gulati G, et al. Effect of starvation and insulin-induced hypoglycemia on oxidative stress scavenger system and electron transport chain complexes from rat brain, liver, and kidney. Mol Chem Neuropathol. 1998;34(2):157-168. doi:10.1007/BF02815077
28. 28. Drummond JB, Barbosa IG, Dantzer R, Teixeira AL. The effect of insulin-induced hypoglycemia on inflammatory markers: A systematic review. Brain Behav Immun. 2018;73:41-50. doi:10.1016/j.bbi.2018.05.003
29. 29. Cardoso Santos G, Alves de Jesus A, Passaglia P, et al. Central angiotensin-(1–7) attenuates hypoglycemia in sepsis-like conditions via reducing systemic and hepatic inflammation. Cytokine. 2024;179:156637. doi:10.1016/j.cyto.2024.156637
30. 30. Kahal H, Halama A, Aburima A, et al. Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects. Sci Rep. 2020;10(1):4750. doi:10.1038/s41598-020-61531-z
31. 31. Atkin AS, Moin ASM, Nandakumar M, et al. Impact of severe hypoglycemia on the heat shock and related protein response. Sci Rep. 2021;11(1):17057. doi:10.1038/s41598-021-96642-8
32. 32. González-Lafuente L, Mercado-García E, Vázquez-Sánchez S, et al. Interleukin-6 as a prognostic marker in acute kidney injury and its klotho-dependent regulation. Nefrol Engl Ed. 2024;44(6):818-829. doi:10.1016/j.nefroe.2024.11.010
33. 33. Li L, Li X, Zhang F. The pivotal role of cytokines in liver disease pathogenesis and therapeutic potential. Front Immunol. 2025;16. doi:10.3389/fimmu.2025.1694582
34. 34. Oriquat G, Mohammed MH, Badraldin SQ, et al. Inflammatory biomarkers in chronic kidney disease. Clin Chim Acta. Published online June 2, 2026:121139. doi:10.1016/j.cca.2026.121139
35. 35. Emanuele MA, Emanuele NV, Gamelli RL, Kovacs EJ, LaPaglia N. Effects of Insulin on Hepatic Inflammation Induced by Ethanol and Burn Injury in a Murine Model of Critical Illness. J Burn Care Res. 2007;28(3):490-499. doi:10.1097/BCR.0B013E318053DAED
36. 36. Jeschke MG, Klein D, Herndon DN. Insulin Treatment Improves the Systemic Inflammatory Reaction to Severe Trauma. Ann Surg. 2004;239(4):553. doi:10.1097/01.sla.0000118569.10289.ad
37. 37. Stein V, Geserick P, Friedrich K, et al. Pro-inflammatory cytokines as regulators of protein tyrosine phosphatases and insulin signaling in murine skeletal muscle cells. Cell Signal. 2025;135:112037. doi:10.1016/j.cellsig.2025.112037