Глюкагон и альфа-клетки - новая терапевтическая мишень в лечении сахарного диабета

Десятки исследований последних лет посвящены глюкагону, его физиологическому действию в поддержании нормального уровня глюкозы и роли в патогенезе диабета. В настоящем обзоре представлены данные, раскрывающие основные этапы образования и дифференцировки эндокринных клеток поджелудочной железы. Основное внимание уделено альфа-клеткам и основным механизмам действия глюкагона. Представлены новые направления и перспективы коррекции углеводного обмена у больных сахарным диабетом, основанные на коррекции секреции глюкагона.

1. Lefebvre PJ. Early milestones in glucagon research. Diabetes Obes Metab. 2011;13 Suppl 1:1-4. DOI: http://dx.doi.org/10.1111/j.1463-1326.2011.01437.x

2. Bramswig NC, Kaestner KH. Transcriptional regulation of alpha-cell differentiation. Diabetes Obes Metab. 2011;13 Suppl 1:13-20. DOI: http://dx.doi.org/10.1111/j.1463-1326.2011.01440.x

3. Cnop M, Hughes SJ, Igoillo-Esteve M, Hoppa MB, Sayyed F, van de Laar L, et al. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia. 2010;53(2):321-330. DOI: http://dx.doi.org/10.1007/s00125-009-1562-x [PubMed]

4. Li HJ, Ray SK, Singh NK, Johnston B, Leiter AB. Basic helix-loop-helix transcription factors and enteroendocrine cell differentiation. Diabetes Obes Metab. 2011;13 Suppl 1:5-12. DOI: http://dx.doi.org/10.1111/j.1463-1326.2011.01438.x

5. Collombat P, Hecksher-Sorensen J, Krull J, Berger J, Riedel D, Herrera PL, et al. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. Journal of Clinical Investigation. 2007;117(4):961-970. DOI: http://dx.doi.org/10.1172/JCI29115

6. Collombat P, Mansouri A, Hecksher-Sorensen J, Serup P, Krull J, Gradwohl G, et al. Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes and Development. 2003;17(20):2591-2603. DOI: http://dx.doi.org/10.1101/gad.269003

7. Gosmain Y, Cheyssac C, Masson MH, Guerardel A, Poisson C, Philippe J. Pax6 is a key component of regulated glucagon secretion. Endocrinology. 2012;153(9):4204-4215. DOI: http://dx.doi.org/10.1210/en.2012-1425

8. Gosmain Y, Marthinet E, Cheyssac C, Guerardel A, Mamin A, Katz LS, et al. Pax6 controls the expression of critical genes involved in pancreatic {alpha} cell differentiation and function. Journal of Biological Chemistry. 2010;285(43):33381-33393. DOI: http://dx.doi.org/10.1074/jbc.M110.147215

9. Hayashi Y, Yamamoto M, Mizoguchi H, Watanabe C, Ito R, Yamamoto S, et al. Mice deficient for glucagon gene-derived peptides display normoglycemia and hyperplasia of islet {alpha}-cells but not of intestinal L-cells. Molecular Endocrinology. 2009;23(12):1990-1999. DOI: http://dx.doi.org/10.1210/me.2009-0296

10. Irwin DM. Molecular evolution of mammalian incretin hormone genes. Regulatory Peptides. 2009;155(1-3):121-130. DOI: http://dx.doi.org/10.1016/j.regpep.2009.04.009

11. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Molecular and Cellular Endocrinology. 2009;297(1-2):127-136. DOI: http://dx.doi.org/10.1016/j.mce.2008.08.012

12. Kawamori D, Kurpad AJ, Hu J, Liew CW, Shih JL, Ford EL, et al. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metabolism. 2009;9(4):350-361. DOI: http://dx.doi.org/10.1016/j.cmet.2009.02.007

13. Holst JJ, Christensen M, Lund A, de Heer J, Svendsen B, Kielgast U, et al. Regulation of glucagon secretion by incretins. Diabetes Obes Metab. 2011;13 Suppl 1:89-94. DOI: http://dx.doi.org/10.1111/j.1463-1326.2011.01452.x

14. Balas B, Baig MR, Watson C, Dunning BE, Ligueros-Saylan M, Wang Y, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. Journal of Clinical Endocrinology and Metabolism. 2007;92(4):1249-1255. DOI: http://dx.doi.org/10.1210/jc.2006-1882

15. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocrine Reviews. 1999;20(6):876-913. DOI: http://dx.doi.org/10.1210/er.20.6.876

16. Kielgast U, Holst JJ, Madsbad S. Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual ß-cell function. Diabetes. 2011;60(5):1599-1607. DOI: http://dx.doi.org/10.2337/db10-1790

17. Ahren B. Autonomic regulation of islet hormone secretion--implications for health and disease. Diabetologia. 2000;43(4):393-410. DOI: http://dx.doi.org/10.1007/s001250051322