Glucagon-like peptide-2 and glucagon in patients with acromegaly and Cushing’s disease: secretion features and influence on glucose metabolism

Aim. To analyze secretion of GLP-2 and glucagon in patients with Cushing’s disease (CD) and acromegaly in response to glucose load.

Material and methods. The study included 42 patients with Cushing’s disease and acromegaly; the mean patient age was 37.5 years. All patients were newly diagnosed with Cushing’s disease and acromegaly: none of them had a history of previous drug therapy, radiotherapy, or pituitary surgery. All patients underwent the oral glucose tolerance test with measurements of glucose, glucagon, and GLP-2 levels at 0, 30, and 120 min, respectively.

Results. A significantly higher glucagon level was observed in CD patients at all cut-off points (р=0.001); in acromegaly patients, the glucagon level did not significantly differ from that in controls (р=0.12). The GLP-2 concentration in CD patients was also significantly higher compared to that in controls (р<0.001). There were no significant differences between acromegaly patients and controls. We also found a strong correlation between GLP-2 and glucagon levels at 0 and 30 min in CD patients. In acromegaly patients, a correlation between GLP-2 and glucagon levels was observed only at 0 min. Different GLP-2 and glucagon secretion patterns in patients with CD and acromegaly suggest a direct influence of glucocorticoids on glucagon secretion and no influence in the case of IGF-1.

Conclusion. The found correlation between GLP-2 and glucagon levels might help specify the role of GLP-2 in carbohydrate metabolism regulation. Interactions of cortisol, IGF-1, and GLP-2 look promising for a better understanding of secondary hyperglycemia pathogenesis.

GLP-2, glucagon, acromegaly, Cushing’s disease, diabetes mellitus

1. Biller BM, Colao A, Petersenn S, et al. Prolactinomas, Cushing’s disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas. BMC Endocr Disord. 2010;10:10. doi: 10.1186/1472-6823-10-10

2. Шестакова Е.А., Ильин А.В., Шестакова М.В., Дедов И.И. Секреция гормонов инкретинового ряда у лиц с факторами риска развития сахарного диабета 2-го типа // Терапевтический архив. — 2014. — Т. 86. — №10. — С. 10—14. [Shestakova EA, Il’in AV, Shestakova MV, Dedov II. Secretion of incretin hormones in people having risk factors for type 2 diabetes mellitus. Ter arkh. 2014;86(10):10-14. (In Russ.)].

3. van Raalte DH, van Genugten RE, Linssen MM, et al. Glucagon-like peptide-1 receptor agonist treatment prevents glucocorticoid-induced glucose intolerance and islet-cell dysfunction in humans. Diabetes Care. 2011;34(2):412-417. doi: 10.2337/dc10-1677

4. Мачехина Л.В., Шестакова Е.А., Белая Ж.Е., и др. Особенности углеводного обмена и секреции гормонов инкретинового ряда у пациентов с болезнью Иценко—Кушинга и акромегалией. Сахарный диабет (в печати). [Machekhina LV, Shestakova EA, Belaya ZE, et al. Features of carbohydrate metabolism and incretin secretion in patients with Cushing disease and acromegaly. Diabetes Mellitus. in press (In Russ.)]. doi: 10.14341/dm8672

5. Yusta B, Huang L, Munroe D, et al. Enteroendocrine localization of GLP-2 receptor expression in humans and rodents. Gastroenterology. 2000;119(3):744-755.

6. Vrang N, Hansen M, Larsen PJ, Tang-Christensen M. Characterization of brainstem preproglucagon projections to the paraventricular and dorsomedial hypothalamic nuclei. Brain Res. 2007;1149:118-126. doi: 10.1016/j.brainres.2007.02.043

7. Ugleholdt R, Zhu X, Deacon CF, et al. Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1. Endocrinology. 2004;145(3):1349-1355. doi: 10.1210/en.2003-0801

8. Cani PD, Possemiers S, Van de Wiele T, et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009;58(8):1091-1103. doi: 10.1136/gut.2008.165886

9. Baldassano S, Amato A, Rappa F, et al. Influence of endogenous glucagon-like peptide-2 on lipid disorders in mice fed a high-fat diet. Endocr Res. 2016;41(4):317-324. doi: 10.3109/07435800.2016.1141950

10. Lovshin J, Estall J, Yusta B, et al. Glucagon-like peptide (GLP)-2 action in the murine central nervous system is enhanced by elimination of GLP-1 receptor signaling. J Biol Chem. 2001;276(24):21489-21499. doi: 10.1074/jbc.M009382200

11. Guan X. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis. Am J Physiol Regul Integr Comp Physiol. 2014;307(6):R585-R596. doi: 10.1152/ajpregu.00096.2014

12. Tang-Christensen M, Larsen PJ, Thulesen J, et al. The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake. Nat Med. 2000;6(7):802-807. doi: 10.1038/77535

13. Bahrami J, Longuet C, Baggio LL, et al. Glucagon-like peptide-2 receptor modulates islet adaptation to metabolic stress in the ob/ob mouse. Gastroenterology. 2010;139(3):857-868. doi: 10.1053/j.gastro.2010.05.006

14. Sorensen LB, Flint A, Raben A, et al. No effect of physiological concentrations of glucagon-like peptide-2 on appetite and energy intake in normal weight subjects. Int J Obes Relat Metab Disord. 2003;27(4):450-456. doi: 10.1038/sj.ijo.0802247

15. Meier JJ, Nauck MA, Pott A, et al. Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology. 2006;130(1):44-54. doi: 10.1053/j.gastro.2005.10.004

16. Biller BM, Colao A, Petersenn S, et al. Prolactinomas, Cushing’s disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas. BMC Endocr Disord. 2010;10:10. doi: 10.1186/1472-6823-10-10

17. Drozdowski L, Thomson AB. Intestinal hormones and growth factors: Effects on the small intestine. World J Gastroenterol. 2009;15(4):385-406. doi: 10.3748/wjg.15.385

18. Дедов И.И., Шестакова М.В., Майоров А.Ю., и др. Алгоритмы специализированной медицинской помощи больным сахарным диабетом / Под ред. И.И. Дедова, М.В. Шестаковой, А.Ю. Майорова. – 8-й выпуск // Сахарный диабет. — 2017. — Т. 20. — №1S. — C. 1—121. [Dedov II, Shestakova MV, Mayorov AY, Vikulova OK, Galstyan GR, Kuraeva TL, et al. Standards of specialized diabetes care. Edited by Dedov II, Shestakova MV, Mayorov AY. 8th edition. Diabetes mellitus. 2017;20(1S):1-121. (In Russ.)]. doi: 10.14341/DM20171S8

19. Bortvedt SF, Lund PK. Insulin-like growth factor 1: common mediator of multiple enterotrophic hormones and growth factors. Curr Opin Gastroenterol. 2012;28(2):89-98. doi: 10.1097/MOG.0b013e32835004c6

20. Белая Ж.Е., Ильин А.В., Мельниченко Г.А., и др. Автоматизированный электрохемилюминесцентный метод определения кортизола в слюне для диагностики эндогенного гиперкортицизма среди пациентов с ожирением // Ожирение и метаболизм. — 2011. — Т. 8. — №2. — С. 56—63. [Belaya ZE, Il’in AV, Mel’nichenko GA, et al. Avtomatizirovannyy elektrokhemilyuminestsentnyy metod opredeleniya kortizola v slyune dlya diagnostiki endogennogo giperkortitsizma sredi patsientov s ozhireniem. Obesity and metabolism. 2011;8(2):56-63. (In Russ.)]. doi: 10.14341/2071-8713-4954

21. Мельниченко Г.А., Дедов И.И., Белая Ж.Е., и др. Болезнь Иценко—Кушинга: клиника, диагностика, дифференциальная диагностика, методы лечения // Проблемы Эндокринологии. — 2015. — Т. 61. — №2. — C. 55—77. [Melnichenko GA, Dedov II, Belaya ZE, et al. Cushing’s disease: the clinical features, diagnostics, differential diagnostics, and methods of treatment. Problems of Endocrinology. 2015;61(2):55-77. (In Russ.)]. doi: 10.14341/probl201561255-77

22. Дедов И.И., Молитвословова Н.Н., Рожинская Л.Я., Мельниченко Г.А. Федеральные клинические рекомендации по клинике, диагностике, дифференциальной диагностике и методам лечения акромегалии // Проблемы Эндокринологии. — 2013. — Т. 59. — №6. — C. 4—18. [Dedov II, Molitvoslovova NN, Rozhinskaia LYa, Mel’nichenko GA. Russian association of endocrinologists national practice guidelines (clinical signs, diagnosis, differential diagnosis, treatment). Acromegaly. Problems of Endocrinology. 2013;59(6):4-18. (In Russ.)]. doi: 10.14341/probl20135964-18

23. Meier JJ, Nauck MA, Pott A, et al. Glucagon-like peptide 2 stimulates glucagon secretion, enhances lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology. 2006;130(1):44-54. doi: 10.1053/j.gastro.2005.10.004

24. Шестакова Е.А., Ильин А.В., Деев А.Д., и др. Регуляция секреции глюкагона гормонами инкретинового ряда у лиц с факторами риска сахарного диабета 2-го типа // Проблемы Эндокринологии. — 2014. — Т. 60. — №1. — C. 32—35. [Shestakova EA, Ilyin AV, Deev AD, et al. Regulation of glucagon secretion by incretin-like hormone family in the patients at risk of developing type 2 diabetes mellitus.Problems of Endocrinology. 2014;60(1):32-35. (In Russ.)]. doi: 10.14341/probl201460132-35

25. Арапова С.Д., Завадский П.С., Марова Е.И. Динамика содержания глюкагона и C-пептида у больных с болезнью Иценко—Кушинга // Советская медицина. — 1980. — №2. — С. 42—46. [Arapova SD, Zavadskij PS, Marova EI. Dinamika soderzhanija gljukagona i C-peptida u bol’nyh s bolezn’ju Icenko-Kushinga. Sovetskaja medicina. 1980;(2):42-46. (In Russ.)].

26. Dedov II, Marova EI, Abrosimov AI, и др. Экспрессия рецепторов соматостатина и дофамина в АКТГ-продуцирующих опухолях // Проблемы Эндокринологии. — 2010. — Т. 56. — №1. — C. 14—18. [Dedov II, Marova EI, Abrosimov AI, et al. Expression of somatostatin and dopamine receptors in ACTH-producing tumours. Problems of Endocrinology. 2010;56(1):14-18. (In Russ.)]. doi: 10.14341/probl201056114-18