Insulin Resistance and Insulin Resistance-Associated Metabolic Disorders in Dairy Cows

Öz

Insulin plays a central role in glucose and lipid metabolism. Insulin resistance, characterized by a diminished biological response to normal circulating insulin levels in target tissues, is a key contributor to various metabolic disorders in ruminants—particularly during the transition period in dairy cows. It has been strongly associated with conditions such as ovarian cysts, fatty liver syndrome, hypocalcemia, and ketosis. During periods of negative energy balance, enhanced lipolysis leads to increased circulating non-esterified fatty acids (NEFAs) and ketone bodies, promoting hepatic lipid accumulation and the development of fatty liver syndrome. These metabolic changes disrupt insulin signaling pathways, thereby exacerbating insulin resistance. Ketosis may act both as a consequence of and a contributing factor to insulin resistance; increased ketone body concentrations can impair pancreatic β-cell function, further disrupting glucose homeostasis. Insulin resistance also negatively impacts reproductive performance by disturbing follicular development and increasing susceptibility to ovarian cysts. Additionally, a bidirectional relationship exists between insulin resistance and hypocalcemia: low calcium levels can suppress insulin secretion, while insulin resistance can hinder calcium mobilization, elevating the risk of hypocalcemia. Assessing the presence and severity of insulin resistance can be achieved through diagnostic methods such as the hyperinsulinemic-euglycemic clamp and the intravenous glucose tolerance test (IVGTT). A comprehensive understanding of these complex interrelationships is crucial for the early detection, prevention, and effective management of metabolic disorders in high-producing dairy cows.

Anahtar Kelimeler

• insulin
• insulin resistance
• dairy cow
• reproduction

Süt İneklerinde İnsülin Direnci ve İnsülin Direncine Bağlı Metabolik Hastalıklar

Öz

İnsülin, glukoz ve lipid metabolizmasında anahtar rol oynayan bir hormondur. İnsülin direnci, hedef dokuların insülin düzeyine yetersiz yanıt vermesiyle ortaya çıkar ve ruminantlarda geçiş dönemiyle ilişkili birçok metabolik hastalığın patogenezinde önemli bir rol oynar. Bu durum özellikle süt ineklerinde ovaryum kistleri, hipokalsemi, yağlı karaciğer sendromu ve ketozis gibi hastalıklarla yakın ilişkilidir. Negatif enerji dengesi döneminde artan lipoliz sonucu dolaşımdaki serbest yağ asitleri (NEFA) ve keton cisimcikleri, karaciğerde yağ birikimini arttırarak yağlı karaciğer sendromuna yol açabilir. Aynı zamanda, bu metabolitler insülin sinyal yollarını bozarak insülin direncini de tetikler. Ketozis insülin direncinin hem bir sonucu hem de nedeni olarak karşımıza çıkar; artan keton cisimleri pankreatik β-hücre fonksiyonunu baskılayarak glukoz metabolizmasını bozar. İnsülin direnci, reprodüktif fonksiyonları etkileyerek foliküler gelişiminde bozukluklara ve ovaryum kistlerinin oluşumuna neden olur. Ayrıca hipokalsemi ile insülin direnci arasında çift yönlü bir ilişki mevcuttur. Düşük kalsiyum düzeyleri insülin salımını baskılar, insülin direnci kalsiyum mobilizasyonunu azaltarak hipokalsemi riskini artırır. İnsülin direncinin varlığı ve şiddeti, hiperinsülinemik öglisemik klemp ve IVGTT gibi testlerle ölçülebilir. Bu ilişkilerin daha iyi anlaşılması, metabolik hastalıkların erken tanı ve yönetimi açısından kritik öneme sahiptir.

Anahtar Kelimeler

• insülin
• insülin direnci
• süt ineği
• reprodüksiyon

Kaynakça

1. Abuelo, A., Hernandez, J., Benedito, J.L., Castillo, C., (2016). Association of oxidative status and insulin sensitivity in periparturient dairy cattle: an observational study. Journal of Animal Physiology and Animal Nutrition, 100, 279–286. https://doi.org/10.1111/jpn.12365.
2. Adamiak, S.J., Mackie, K., Watt, R.G., Webb, R., Sinclair, K.D. (2005). Impact of nutrition on oocyte quality: cumulative effects of body composition and diet leading to hyperinsulinemia in cattle. Biology Reproduction, 73: 918–26. https://doi.org/10.1095/biolreprod.105.041483.
3. Alberti, K.G., Zimmet, P., Shaw, J. (2006). Metabolic syndrome,A new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabetic Medicine, 23, 469–480. https://doi.org/10.1111/j.1464-5491.2006.01858.x.
4. Andersson, L. (1988). Subclinical ketosis in dairy cows. Metabolic diseases of ruminant livestock. Veterinary Clinical North American Food Animal Practice, 4, 233–251. https://doi.org/10.1016/S0749-0720(15)31046-X
5. Baruselli, P. S., Vieira, L. M., Sá Filho, M. F. D., Mingoti, R. D., Ferreira, R. M., Chiaratti, M. R., Sartori, R. (2016). Associations of insulin resistance later in lactation on fertility of dairy cows. Theriogenology, 86(1), 263-269. https://doi.org/10.1016/j.theriogenology.2016.04.039
6. Blum, J.W., Wilson, R.B., Kronfeld, D.S. (1973). Plasma insulin concentrations in parturient cows. Journal of dairy science, 56(4), 459-464. https://doi.org/10.3168/jds.S0022-0302(73)85200-2.
7. Bobe, G., Young, J.W., Beitz, D.C. (2004). Invited review: Pathology, etiology, prevention and treatment of fatty liver in dairy cows. Journal of Dairy Science, 87, 3105-3 124. https://doi.org/10.3168/jds.S0022-0302(04)73446-3.
8. Chagas, L.M., Lucy, M.C., Back, P.J., Blache, D., Lee, J.M., Gore, P.J.S., Roche, J. R. (2009). Insulin resistance in divergent strains of Holstein-Friesian dairy cows offered fresh pasture and increasing amounts of concentrate in early lactation. Journal of dairy science,92(1), 216-222. doi:10.3168/jds.2008-1329. https://doi.org/10.3168/jds.2008-1329.

9. Chilliard, Y., Ferlay, A., Faulconnier, Y. (2000). Adipose tissue metabolism and its role in adaptations to undernutrition in ruminants. Proceedings of the Nutrition Society, 59(1):127–34. https://doi.org/10.1017/S002966510000015X.
10. Cronjé, P.B. (2000). Nutrient-gene interactions: Future potential and adaptations. Pages 409–422 in Ruminant Physiology: Digestion, Metabolism, Growth and Reproduction. P. B. Cronjé ed., CAB International, Wallingford, UK. https://doi.org/10.1079/9780851994635.0409.
11. Cummings, D.E. ve Schwartz, M.W. (2003). Genetics and pathophysiology of human obesity. Annual Review of Medicine, 54:453–71. https://doi.org/10.1146/annurev.med.54.101601.152403.
12. Daghlas, S.A., Mohiuddin, S.S. (2023). StatPearls Publishing; Treasure Island (FL): Biochemistry, Glycogen.
13. Daradics, Z., Crecan, C. M., Rus, M. A., Morar, I. A., Mircean, M. V., Cătoi, A. F., Cătoi, C. (2021). Obesity-related metabolic dysfunction in dairy cows and horses: Comparison to human metabolic syndrome. Life, 11(12), 1406. https://doi.org/10.3390/life11121406.
14. De Koster, J. D., & Opsomer, G. (2013). Insulin resistance in dairy cows. The Veterinary clinics of North America. Food animal practice, 29(2), 299–322. https://doi.org/10.1016/j.cvfa.2013.04.002
15. De Meyts, P. (2008). The insulin receptor: a prototype for dimeric, allosteric membrane receptors? Trends Biochemical Science, 33: 376 –384, 2008. https://doi.org/10.1016/j.tibs.2008.06.003.
16. Diskin, M.G., Mackey, D.R., Roche, J.F., Sreenan, J.M. (2003). Effects of nutrition and metabolic status on circulating hormones and ovarian follicle development in cattle. Animal Reproduction Science. 78, 345- 370. https://doi.org/10.1016/S0378-4320(03)00099-X.
17. Dong, X., Park, S., Lin, X., Copps, K., Yi, X., White, M.F. (2006). Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. Journal of Clinical Investigation,116: 101–114. https://doi.org/10.1172/JCI25735.
18. Grummer, R.R., Mashek, D.G., Hayırlı, A. (2004). Dry matter intake and energy balance in the transition period, Veterinary Clinics of North America: Food Animal Practice, 20, 447-470. https://doi.org/10.1016/j.cvfa.2004.06.013.
19. Grundy, S.M. (2004). Obesity, metabolic syndrome, and cardiovascular disease. The Journal of Clinical Endocrinology and Metabolism, 89, 2595–2600. https://doi.org/10.1210/jc.2004-0372.
20. Haeusler, R.A., McGraw, T.E., Accili, D. (2018). Biochemical and cellular properties of insulin receptor signalling. Nature Reviews Molecular Cell Biology, 19: 31– 44, 2018. https://doi.org/10.1038/nrm.2017.89.
21. Herdt, T. H. (2000). Variability characteristics and test selection in herdlevel nutritional and metabolic profile testing: Metabolic disorders of ruminants. Veterinary Clinics of North America: Food Animal Practice, 16, 2, 387–403. https://doi.org/10.1016/S0749-0720(15)30111-0.
22. Holtenius, K., Agenäs, S., Delavaud, C., Chilliard, Y. (2003). Effects of feeding intensity during the dry period. 2. Metabolic and hormonal responses. Journal of Dairy Science, 86: 883-891. https://doi.org/10.3168/jds.S0022-0302(03)73671-6.
23. Holtenius, P. ve Holtenius, K. (1996). New aspects of ketone bodies in energy metabolism of dairy cows: a review. Transboundary and Emerging Diseases, 43, 579–587. https://doi.org/10.1111/j.1439-0442.1996.tb00491.x.
24. Jaakson, H., Ling, K., Samarütel, J., Ilves, A., Kaart, T., Kärt, O., Ots, M. (2013). Blood glucose and insulin responses during the glucose tolerance test in relation to dairy cow body condition and milk yield. Veterinarija ir Zootechnika, 62, 28–35.
25. Kahn, S.E. (2003). The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia, 46(1):3–19. https://doi.org/10.1007/s00125-002-1009-0.
26. Kawashima, C., Fukihara, S., Maeda, M., Kaneko, E., Montoya, C.A., Matsui, M. (2007). Relationship between metabolic hormones and ovulation of dominant follicle during the first follicular wave post-partum in high-producing dairy cows. reproduction 133:155–63. https://doi.org/10.1530/REP-06-0046.
27. Leiva, T., Cooke, R.F., Brandão, A.P., Aboin, A.C., Ranches, J., Vasconcelos, J.L.M. (2015). Effects of excessive energy intake and supplementation with chromium propionate on insulin resistance parameters, milk production, and reproductive outcomes of lactating dairy cows. Livestock Science, 180:121–8. https://doi.org/10.1016/j.livsci.2015.08.007.
28. Ma, B., Lawson, A., Liese, A., Bell, R., MayerDavis, E. (2006). Dairy, Magnesium, and Calcium Intake in Relation to Insulin Sensitivity: Approaches to Modeling a Dose-dependent Association. American Journal of Epidemiology, 164(5):449-458. https://doi.org/10.1093/aje/kwj246.
29. Masoero Moschini F.M., Moschini, M., Pulimeno A.M. (2003). Serum calcium and magnesium level in dairy cows at calving. Journal Animal Science, 2 (1): 172- 174. https://doi.org/10.4081/ijas.2003.11675951.
30. Mayasari, N., Nurjanah, L.T., Setyowati, E.Y., Arfiana, A., Sitanggang, F., Salman, L.B. (2019). Assocıatıon Between Plasmatıc Glucose And Urea In Daıry Cows Wıth Subclınıcal Hypocalcemıa. Lucrări Științifice-Universitatea de Științe Agricole şi Medicină Veterinară, Seria Zootehnie, (72), 22-27.
31. Mlinar, B., Marc, J., Janež, A., & Pfeifer, M. (2007). Molecular mechanisms of insulin resistance and associated diseases. Clinica chimica acta, 375(1-2), 20-35. https://doi.org/10.1016/j.cca.2006.07.005.
32. Muniyappa, R., Lee, S., Chen, H. (2008). Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. American Journal of Physiology-Endocrinology and Metabolism, 294(1): E15–26. https://doi.org/10.1152/ajpendo.00645.2007
33. Okur, D.T. ve Polat, B. (2019). İneklerde anöstrus: nedenleri ve sınıflandırılması. Atatürk Üniversitesi Veteriner Bilimleri Dergisi, 14(3), 354-361. https://doi.org/10.17094/ataunivbd.547777.
34. Oliveira, L.H., Nascimento, A.B., Monteiro Jr, P.L.J., Guardieiro, M.M., Wiltbank, M.C., Sartori, R. (2016). Development of insulin resistance in dairy cows by 150 days of lactation does not alter oocyte quality in smaller follicles. Journal of dairy science, 99(11), 9174-9183. https://doi.org/10.3168/jds.2015-10547.
35. Petersen, M. C. ve Shulman, G. I. (2018). Mechanisms of insulin action and insulin resistance. Physiological reviews. https://doi.org/10.1152/physrev.00063.2017.
36. Roche, J.R., Friggens, N.C., Kay, J.K., Fisher, M.W., Stafford, K.J., Berry, D.P. (2009). Invited review: Body condition score and its association with dairy cow productivity, health, and welfare. Journal of dairy science, 92(12), 5769-5801. https://doi.org/10.3168/jds.2009-2431.
37. Rodríguez, E.M., Arís, A., Bach, A. (2017). Associations between subclinical hypocalcemia and postparturient diseases in dairy cows. Journal of dairy science, 100(9), 7427-7434. https://doi.org/10.3168/jds.2016-12210.
38. Rossetti, G. (2021). A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance. Science Advances, 7, eabi7514. https://doi.org/10.1038/541598-023-49496-1.
39. Shukla, A. (2009). Insulin analogues: analysis of proliferative potency and characterization of receptors and signalling pathways activated in human mammary epithelial cells (Doctoral dissertation). https://doi.org/10.11588/heidok.00008991.
40. Sinclair, K.D. (2010). Declining fertility, insulin resistance and fatty acid metabolism in dairy cows: developmental consequences for the oocyte and pre-implantation embryo. Acta Scientiae Veterinariae, 38:545–57.
41. Slater, T., Haywood, N.J., Matthews, C., Cheema, H., Wheatcroft, S.B. (2019). Insulin-like growth factor binding proteins and angiogenesis: from cancer to cardiovascular disease. Cytokine and Growth Factor Reviews, 46:28-35. https://doi.org/10.1016/j.cytogfr.2019.03.005.
42. Sordillo, L. M. ve Raphael, W. (2013). Significance of metabolic stress, lipid mobilization, and inflammation on transition cow disorders. Veterinary Clinics of North America: Food Animal Practice, 29, 267–278. https://doi.org/10.1016/j.cvfa.2013.03.002.
43. Steppan, C.M., Bailey, S.T., Bhat, S. (2001). The hormone resistin links obesity to diabetes. Nature, 409:307–12. https://doi.org/10.1038/35053000.
44. Vargas, E., Joy, N. V., & Carrillo Sepulveda, M. A. (2022). Biochemistry, Insulin Metabolic Effects. StatPearls.
45. Wagner, A., Dallongeville, J., Haas, B., Ruidavets, J.B., Amouyel, P., Ferrieres, J. (2012). Sedentary behaviour, physical activity and dietary patterns are independently associated with the metabolic syndrome. Diabetes Metabolism, 38:428–35. http://doi.org/10.1016/j.diabet.2012.04.005.
46. Wankhade, P.R., Manimaran, A., Kumaresan, A., Jeyakumar, S., Ramesha, K.P., Sejian, V., Rajendran, D. Varghese, M.R. (2017). Metabolic and immunological changes in transition dairy cows: A review. Vet. World, 10, 1367–1377. http://doi.org/10.14202/vetworld.2017.1367-1377.
47. Webber, J. (2003). Energy balance in obesity. Proceedings of the Nutrition Society, 62:539–43. http://doi.org/10.1079/PNS2003256.
48. Xu, C., Shu, S., Xia, C., Wang, B., Zhang, H. Y. (2014). Investigation on the Relationship of Insulin Resistance and Ketosis in Dairy Cows. Journal of Veterinary Science Technology, 5, 162. http://doi.org/10.4172/2157-7579.1000162.
49. Yang, M.Y., Fortune, J.E. (2015). Changes in the transcriptome of bovine ovarian cortex during follicle activation in vitro. Physiology Genomics, 47, 600-612. https://doi.org/10.1152/physiolgenomics.00060.2015.
50. Youssef, M. ve El-Ashker, M. (2017). Significance of insulin resistance and oxidative stress in dairy cattle with subclinical ketosis during the transition period. Tropical animal health and production, 49, 239-244. http://doi.org/10.1007/s11250-016-1211-6.
51. Zhao, L., Wang, L., Zhang, Y., Xiao, S., Bi, F., Zhao, J., Ding, J. (2017). Glucose oxidase-based glucose-sensitive drug delivery for diabetes treatment. Polymers, 9(7), 255. https://doi.org/10.3390/polym9070255.