Eş Zamanlı İnsülin ve Glukagon Konsantrasyon Artışının Karaciğer Glikoz Üretimine Etkisinin Matematik Model Kullanarak Analizi

Yıl 2024, , 268 - 280, 23.08.2024

Perihan Hatice Aydın , Fatih Karaaslan

https://doi.org/10.19113/sdufenbed.1316013

Öz

Sağlıklı kişilerde, kan glikoz değeri dar bir aralıkta sabit olarak tutulur. İnsülin hormonu, kan glikoz konsantrasyonu artışında salgılanır ve dokularda glikoz kullanımını artırarak ve karaciğerde glikoz üretimini azaltarak, glikoz konsantrasyonun normal değerine inmesine yardımcı olur. Glukagon ise, glikoz konsantrasyonu azaldığında salgılanır ve karaciğerden glikoz salınımını artırarak, glikoz konsantrasyonunun artmasına etki eder. İnsülin ve glukagon hormonlarının, karaciğerde glikoz üretimi üzerine olan bu zıt etkileri bilinmesine rağmen, eş zamanlı insülin ve glukagon artışının karaciğerde glikoz üretimine etkisi hakkında yapılmış az sayıda in vivo çalışma vardır. İnsülin ve glukagonun, eş zamanlı artışında, karaciğerden glikoz çıkışını test etmek için bir matematik model geliştirilmiştir. Glikoz, insülin ve glukagon dinamiklerini içeren bu model, öncelikle, sağlıklı insanlar üzerinde yapılmış çeşitli çalışma sonuçları ile test edilmiştir. Modelin, glikoz tolerans testi, insülin infüzyonu, insülin ve glikoz infüzyonu, glukagon infüzyonu çalışmalarına benzer sonuçlar verdiği gözlenmiştir. Daha sonra, modelde, eş zamanlı olarak, insülin ve glukagon infüzyonu ile, kan insülin ve glukagon konsantrasyonları yaklaşık 4 katına çıkarıldığında, karaciğerden glikoz çıkışının azaldığı gözlenmiştir. Bu sonuç, insülin hormonunun karaciğer glikoz üretimini inhibe edici özelliğinin, glukagonun glikoz üretimini uyarıcı etkisinden daha güçlü olduğu hipotezini desteklemektedir.

Anahtar Kelimeler

Glikoz, İnsülin, Glukagon, Matematik Model

Kaynakça

• [1] Hall, J.E. 2011. Guyton and Hall Textbook of Medical Physiology, 12th ed., Elsevier, USA ,939-954.
• [2] Barrett, K.E., Barman, S.M., Boitano, S., Brooks, H.L., 2010. Ganong's Review of Medical Physiology, 24th ed., McGraw Hill, New York, 315-336
• [3] Henquin, J.C., Dufrane D., Kerr, J., Nenquin, M. 2015. Dynamics of Glucose-Induced Insulin -Secretion in Normal Human Islets. Am J Physiol Endocrinol Metab,309, 640–650.
• [4] Bertin, F.R., Taylor, S.D., Bianco, A.W., Sojka-Kritchevsky, J.E. 2016. The Effect of Fasting Duration on Baseline Blood Glucose Concentration, Blood Insulin Concentration, Glucose/Insulin Ratio, Oral Sugar Test, and Insulin Response Test Results in Horses. Journal of Veterinary Internal Medicine. 30, 1726–1731.
• [5] Bouche, C., Lopez, X., Fleischman, E., Cypess, A., O’Shea, S., Stefanovski, D., Bergman, R., Rogatsky, E., Stein, D., Kahn, C.D., Kulkarni, R., Goldfine, A.B. 2010. Insulin Enhances Glucose-Stimulated Insülin Secretion in Healthy Humans. Proceedings of the National Academy of Sciences of the United States of America, 107(10), 4770–4775.
• [6] Nesher, R., Cerasi, E. 2002. Modeling Phasic Insulin Release. Diabetes, 51, 53–59.
• [7] Muscelli, E., Mari, A., Natali, A., Astiarraga, A., Camastra, S., Frascerra, S., Holst, J.J., Ferrannini. E. 2006. Impact of Incretin Hormones on β Cell Function in Subjects with Normal or Impaired Glucose Tolerance. Am J Physiol Endocrinol Metab, 291, 1144–1150.
• [8] Steiner, K. E., Williams, P. E., Lacy, W. W., Cherrington, A.D. 1990. Effects of Insulin on Glucagon-Stimulated Glucose Production in the Conscious Dog. Metabolism, 39(12), 1325-1333.
• [9] Khoo, M. 2000. Physiological Control Systems, John Wiley& Sons, Inc., New Jersey, 124-128.
• [10] Stolwijk, J.E., Hardy, J.D. 1974. Regulation and Control in Physiology. Medical Physiology, 13th ed., VB. Mountcastle. C.V Mosby, St.Louis, 1343-1358.
• [11] Prato, D., Leonetti S., Simonson, F., Sheehan, P., Matsuda, M., DeFronzo, R.A. 1994. Effect of Sustained Physiologic Hyperinsulinaemia and Hyperglycaemia on Insulin Secretion and Insulin Sensitivity in Man. Diabetologia, 37, 1025-1035.
• [12] O’Connor, MD., Landahl, H. D., Grodsky, G.M. 1977. Role of Rate of Change of Glucose Concentration as a Signal for Insulin Release. Endocrinology, 101(1), 85-8.
• [13] Steil, G.M., Grodsky, G.M. 2013. The Artificial Pancreas: is It Important to Understand How the β Cell Controls Blood Glucose?. J Diabetes Sci Technol., 7(5),1359-1369.
• [14] Steil G.M, Rebrin K, Janowski R, Darwin C, Saad M.F. 2003. Modeling Beta-Cell Insulin Secretion--Implications for Closed-Loop Glucose Homeostasis. Diabetes Technol Ther, 5(6), 953-964.
• [15] Mari, A., Schmitz, O., Gastaldelli, A., Oestergaard, T., Nyholm, B., Ferrannini, E. 2002.Meal and Oral Glucose Tests for Assessment of Beta-Cell Function: Modeling Analysis in Normal Subjects, Am J Physiol Endocrinol Metab, 283(6), 1159-1166.
• [16] Richter, E.A., Galbo, H., Holst, J.J., Sonne, B. 1981. Significance of Glucagon for Insulin Secretion and Hepatic Glycogenolysis During Exercise in Rats. Horm Metab Res., 13(6),323-326.
• [17] Kaneto, A., Kaneko, T., Kajinuma, H., Kosaka, K. 1977. Effect of Vasoactive Intestinal Polypeptide Infused Intrapancreatically on Glucagon and Insulin Secretion, Metabolism, 26(7),781-786.
• [18] Galbo, H., Holst, J.J., Christensen, N.J. 1979. The Effect of different diets and of insulin on the Hormonal Response to Prolonged Exercise. Acta Physiol Scand, 107(1),19-32.
• [19] Raskin, P., Unger, R.H. 1978. Glucagon and Diabetes. Med Clin North Am., 62(4),713-722.
• [20] Felig, P., Wahren, J., Sherwin, R., Hendler, R. 1976. Insulin, Glucagon, and Somatostatin in Normal Physiology and Diabetes Mellitus. Diabetes, 25(12),1091-1099.
• [21] Schade, D.S., Eaton, R.P. 1977. The Effect of Short term Physiological Elevations of Plasma Glucagon Concentration on Plasma Triglyceride Concentration in Normal and Diabetic Man. Horm Metab Res, 9(4),253-257.
• [22] DeFronzo, R. A., Davidson, J. A., Del Prato, S. 2012.The Role of the Kidneys in Glucose Homeostasis: a New Path Towards Normalizing Glycaemia. Diabetes, Obesity and Metabolism, 14(1), 5-14.
• [23] Triplitt, C.L. 2012. Understanding the Kidneys' role in Blood Glucose Regulation. American Journal of Managed Care, 18(1), 11.
• [24] Mather, A., Pollock, C. 2011. Glucose Handling by the Kidney, Kidney International, 79, 1-6.
• [25] De Marco, V. G., Aroor, A. R., Sowers, J. R. 2014. The Pathophysiology of Hypertension in Patients With Obesity. Nature Reviews Endocrinology, 10(6), 364-376.
• [26] Wanner, M. 1986. Handbook of Experimental Pharmacology. ss 1-83. Born, G. V. R., Farah, A., Herken, H., Welch, A. D., eds. 1985. Continuation of Handbuch der experimentellen Pharmakologie, Vol. 78, The Tetracyclines. Editors, Hlavka, J. J., Boothe, J. H. SPB Academic Publishing, Netherlands, 803s.
• [27] Ohneda, A., Aguilar, E., Eisentraut, A. M., Unger, R. H. 1969. Control of Pancreatic Glucagon Secretion by Glucose. Diabetes, 18(1), 1-10.
• [28] Unger, R. H., Aguilar, E., Müller, W. A., Eisentraut, A. M. 1970. Studies of Pancreatic Alpha Cell Function in Normal and Diabetic Subjects. The Journal of Clinical Investigation, 49(4), 837-848.
• [29] Cooperberg, B. A., & Cryer, P. E. 2010. Insulin Reciprocally Regulates Glucagon Secretion in Humans. Diabetes, 59(11), 2936-2940.
• [30] Edgerton, D.S., Kraft, G., Smith, M., Farmer, B., Williams, P.E., Coate, K.C., Printz, R.L., O'Brien, R.M., Cherrington, A.D. 2017. Insulin's Direct Hepatic Effect Explains the Inhibition of Glucose Production Caused by Insulin Secretion. JCI Insight. 2(6),1863.
• [31] Shulman, G.I., Liljenquist, J.E., Williams, P.E., Lacy, W.W., Cherrington, A.D. 1978. Glucose Disposal During Insulinopenia in Somatostatin-Treated Dogs, The Roles of Glucose and Glucagon. J Clin Invest. 62(2),487-491.
• [32] Cherrington, A. D. 2010. Control of Glucose Production in Vivo by Insulin and Glucagon. Comprehensive Physiology, 759-785.
• [33] Perley, M.J., Kipnis, D.M. 1967. Plasma Insulin Responses to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects. J Clin Invest., 46(12),1954-1962.
• [34] Elrick, H., Hlad, J., Arai, Y., Smith A. 1956. The Interaction of Glucagon and Insulin on Blood Glucose. J Clin Invest., 35(7),757-762.
• [35] Sönksen, P.H., Srivastava, M.C., Tompkins, C.V., Nabarro, J.D. 1972. Growth-Hormone and Cortisol Responses to Insulin Infusion in Patients with Diabetes Mellitus. Lancet, 2(7769),155-159.
• [36] Fradkin, J., Shamoon, H., Felig, P., Sherwin, R.S. 1980. Evidence for an Important Role of Changes in Rather Than Absolute Concentrations of Glucagon in the Egulation of Glucose Production in Humans. J Clin Endocrinol Metab, 50(4),698-703.
• [37] Pedersen, C., Bouman, S. D., Porsgaard, T., Rosenkilde, M. M., Roed, N. K. 2018. Dual Treatment with a Fixed Ratio of Glucagon and Insulin Increases the Therapeutic Window of Insulin in Diabetic Rats. Physiological Reports, 6(6), 1-9.