THE INFLUENCE OF THERAPY WITH INCRETINOMETICS AND GLYFLOSINS ON THE FUNCTION OF ALPHA AND BETA CELLS OF THE PANCREAS IN PATIENTS WITH TYPE 2 DM
Abstract
Defect in the function of pancreatic cells is one of the key pathophysiological factors in type 2 diabetes, in particular, an imbalance between the secretion of insulin and glucagon, as well as a decrease in the efficiency of converting proinsulin into insulin, often observed. The aim of the work was to compare the characteristics of the secretory function of pancreatic alpha and beta cells in 43 patients with decompensated type 2 diabetes mellitus when using new classes of anti-diabetic drugs: glucagon-like peptide receptors agonists (GLP1ra) and inhibitors of the sodium-glucose transporter-2 (SGLT2i). Long-term treatment with these drugs (for 12 months) contributed to the normalization of the HbA1c level and a decrease in the % of visceral fat, as well as a decrease in the glucagon level compared to the baseline level. In both groups of patients, subgroups with high and low proinsulin levels have been identified. Under the influence of GLP1ra therapy, in patients of the low proinsulin subgroup, serum concentration of proinsulin and C-peptide significantly decreased, indicating a decrease in insulin secretion and a possible reduce in adaptive release of proinsulin as a result of glycemia decrease. Among patients treated with SGLT-2i, high pre-treatment proinsulin levels associated with higher glucagon and C-peptide concentrations comparing the low proinsulin subgroup. After 12 months of treatment, no significant changes in the concentration of glucagon, C-peptide and proinsulin were observed in both subgroups of patients treated with SGLT2i.
References
Alarcon, C., Boland B., Uchizono Y., Moore, P., Peterson, B., Rajan, S., Rhodes O., Noske, A., Haataja, L., Arvan, P., Marsh, B., Austin, J. & Rhodes, C. (2016). Pancreatic β-Cell Adaptive Plasticity in Obesity Increases Insulin Production but Adversely Affects Secretory Function. Diabetes, 65(2), 438-450. doi: 10.2337/db15-0792.
Al-Rasheed, N., Willars, G. & Brunskill, N. (2006). C-peptide signals via Galpha i to protect against TNFalpha-mediated apoptosis of opossum kidney proximal tubular cells. J. Am. Soc. Nephrol., 17, (4), 986-995. doi: 10.1681/asn.2005080797.
Anderson, S. & Trujillo, J. (2016). Basal Insulin Use With GLP-1 Receptor Agonists. Diabetes Spectr., 29 (3): 152-160. //doi.org/10.2337/diaspect.29.3.152.
Bonner, C., Kerr-Conte, J., Gmyr, V. & Queniat, G. (2015). Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med, 21 (5): 512-517. doi: 10.1038/nm.3828.
Bright, D., Dunseath, G., Peter, R. & Luzio, S. (2018). Stability of proinsulin in whole blood. Clin. Biochem. 52: 153-155. doi: 10.1016/j.clinbiochem.2017.10.005.
Brunskill, N. (2017) C-peptide and diabetic kidney disease. J. Intern. Med. 281 (1): 41-51.
Chakravarthy, H., Gu, X., Enge, M., Dai, X., Wang, Y., Damond, N., Downie, C., Liu, K., Wang, J., Xing, Y., Chera, S., Thorel, F., Quake, S., Oberholzer, J., MacDonald, P., Herrera, P. & Kim S. K. Converting adult pancreatic islet alpha cells into beta cells by targeting both Dnmt1 and Arx. Cell Metab, 25 (3): 622- 634. doi: 10.1016/j.cmet.2017.01.009.
Chen, C., Cohrs, C., Stertmann, J., Bozsak. R. & Speier S. (2017). Human beta cell mass and function in diabetes: Recent advances in knowledge and technologies to understand disease pathogenesis. Mol. Metab. 6 (9): 943-957. doi: 10.1016/j.molmet.06.019.
Clar, C., Gill, J., Court,R. & Waugh, N. (2012). Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open, 2 (5), pii: e001007. http://creativecommons.org/licenses/by-nc/2.0/
Daniele, G., Solis-Herrera, C., Dardano, A., Mari, A., Tura, A., Giusti, L., Kurumthodathu, J. J., Campi, B., Saba, A., Bianchi, A. M., Tregnaghi, C., Egidi, M. F., Abdul-Ghani, M., DeFronzo, R., & Del Prato, S. (2020). Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy. Diabetologia, 63(11), 2423-2433. https://doi.org/10.1007/s00125-020-05254-w.
Davies, M. J., D'Alessio, D. A., Fradkin, J., Kernan, W. N., Mathieu, C., Mingrone, G., Rossing, P., Tsapas, A., Wexler, D. J., & Buse, J. B. (2018). Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes care, 41(12), 2669–2701. https://doi.org/10.2337/dci18-0033.
DeFronzo, R. A. (2009). From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes, 58, 773–795. https://doi.org/10.2337/db20-0616.
Frías, J. P., Guja, C., Hardy, E., Ahmed, A., Dong, F., Öhman, P., & Jabbour, S. A. (2016). Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. The lancet. Diabetes & endocrinology, 4(12), 1004–1016. https://doi.org/10.1016/S2213-8587(16)30267-4.
Ferrannini, E., Gastaldelli, A., Miyazaki, Y., Matsuda, M., Mari, A., & DeFronzo, R,A. (2005). Вeta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J. Clin. Endocrinol. Metab., 90 (1): 493-500. doi: 10.1210/jc.2004-1133.
Ferrannini, E., Muscelli, E., Frascerra, S., Baldi, S., Mari, A., Heise, T., Broedl, U. C., & Woerle, H. J. (2014). Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. The Journal of clinical investigation, 124(2), 499–508. https://doi.org/10.1172/JCI72227.
Garber, A. J., Abrahamson, M. J., Barzilay, J. I., Blonde, L., Bloomgarden, Z. T., Bush, M. A., Dagogo-Jack, S.,
Davidson, M. B., Einhorn, D., Garber, J. R., Garvey, W. T., Grunberger, G., Handelsman, Y., Hirsch, I. B., Jellinger, P. S., McGill, J. B., Mechanick, J. I., Rosenblit, P. D., Umpierrez, G. E., American Association of Clinical Endocrinologists (AACE), … American College of Endocrinology (ACE) (2015). CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2015 EXECUTIVE SUMMARY. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 21(12), 1403– 1414. https://doi.org/10.4158/EP151063.CS.
Goldenberg, M., Verma, S., Perkins, B. A, Gilbert, J. D. & Zinman, B. (2017). Can the combination of incretin agents and sodium-glucose cotransporter 2 (SGLT2) inhibitors reconcile the yin and yang of glucagon? Can J Diabetes, 41(1): 6-9. doi: 10.1016/j.jcjd.2016.08.001.
Gurgle, H., White, K. & McAdam‐Marx, C. (2016). SGLT2 inhibitors or GLP‐1 receptor agonists as second‐line therapy in type 2 diabetes: patient selection and perspectives. Vasc Health Risk Manag, 12, 239–249. doi: 10.2147/VHRM.S83088.
Hædersdal, S., Lund, А., Knop, F. & Vilsbøll, T. (2018). The role of glucagon in the pathophysiology and treatment of type 2 diabetes Mayo Clinic. Proceedings, 93(2), 217-239. doi: 10.1016/j.mayocp.2017.12.003.
Handelsman, Y., Bloomgarden, Z. T., Grunberger, G., Umpierrez, G., Zimmerman, R. S., Bailey, T. S., Blonde, L., Bray, G. A., Cohen, A. J., Dagogo-Jack, S., Davidson, J. A., Einhorn, D., Ganda, O. P., Garber, A. J., Garvey, W. T., Henry, R. R., Hirsch, I. B., Horton, E. S., Hurley, D. L., Jellinger, P. S., … Zangeneh, F. (2015). American association of clinical endocrinologists and american college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 21 Suppl 1(Suppl 1), 1–87. https://doi.org/10.4158/EP15672.GL.
Hansen, L., Iqbal, N., Ekholm, E., Cook, W. & Hirshberg, B. (2014). Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy. Endocr Pract, 20 (11): 1187-1197. doi: 10.4158/EP14489.OR.
Hou, X., Liu, J., Song, J., Wang, C., Liang, K., Sun, Y., Ma, Z., Yang, W., Li, C., Zhang, X., Lin, P., Gong, L., Wang, M., Liu, F., Li, W., Yan, F., Qin, J., Wang, L., Liu, J., Zhao, R., … Chen, L. (2016). Relationship of Hemoglobin A1c with β Cell Function and Insulin Resistance in Newly Diagnosed and Drug Naive Type 2 Diabetes Patients. Journal of diabetes research, 2016, 8797316. https://doi.org/10.1155/2016/8797316.
Inzucchi, S. E., Bergenstal, R. M., Buse, J. B., Diamant, M., Ferrannini, E., Nauck, M., Peters, A. L., Tsapas, A., Wender, R., & Matthews, D. R. (2015). Management of hyperglycemia in type 2 diabetes, 2015: a patientcentered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care, 38(1), 140–149. https://doi.org/10.2337/dc14-2441.
Jones, A. G., McDonald, T. J., Shields, B. M., Hill, A. V., Hyde, C. J., Knight, B. A., Hattersley, A. T., & PRIBA Study Group. (2016). Markers of β-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes. Diabetes care, 39(2), 250–257. https://doi.org/10.2337/dc15-0258.
Kalra, S. & Gupta, Y. (2016) The insulin:glucagon ratio and the choice of glucose-lowering drugs. Diabetes Ther, 7 (1): 1-9. doi: 10.1007/s13300-016-0160-4.
Knop, F., Aaboe, K., Vilsbøll, T., Vølund, A., Holst, J., Krarup, T., & Madsbad, S. (2012). Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab, 14 (6): 500-510. doi: 10.1111/j.1463-1326.2011.01549.x.
Leighton E, Sainsbury C, Jones GC. (2017) A Practical Review of C-Peptide Testing in Diabetes Diabetes Ther. Jun; 8(3): 475–487. doi: 10.1007/s13300-017-0265-4
Lewin A, DeFronzo R, Patel S, et al. (2015) Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care, 38 (3): 394-402. https://doi.org/10.2337/dc14-2365
Lund, A., Bagger, J. I., Wewer Albrechtsen, N. J., Christensen, M., Grøndahl, M., Hartmann, B., Mathiesen, E. R., Hansen, C. P., Storkholm, J. H., van Hall, G., Rehfeld, J. F., Hornburg, D., Meissner, F., Mann, M., Larsen, S., Holst, J. J., Vilsbøll, T., & Knop, F. K. (2016). Evidence of Extrapancreatic Glucagon Secretion in Man. Diabetes, 65(3), 585 597. https://doi.org/10.2337/db15-1541.
Lundkvist, P., Sjöström, C. D., Amini, S., Pereira, M. J., Johnsson, E., & Eriksson, J. W. (2017). Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebocontrolled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes, obesity & metabolism, 19(1), 49–60. https://doi.org/10.1111/dom.12779.
Miyagawa, K., Kondo, T., Goto, R., Matsuyama, R., Ono, K., Kitano, S., Kawasaki, S., Igata, M., Kawashima, J., Matsumura, T., Motoshima, H., & Araki, E. (2013). Effects of combination therapy with vildagliptin and valsartan in a mouse model of type 2 diabetes. Cardiovascular diabetology, 12, 160. https://doi.org/10.1186/1475-2840-12160.
Nagai, Y., Akio, O., Yukiyoshi, S., Hiroyuki & Tanaka, Y. (2017). Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes. Expert Opin Pharmacother, 18 (1), 13-17. doi: 10.1080/14656566.2016.1261110.
Nathan, D. M., Buse, J. B., Davidson, M. B., Ferrannini, E., Holman, R. R., Sherwin, R., Zinman, B., American Diabetes Association, & European Association for Study of Diabetes (2009). Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care, 32(1), 193–203. https://doi.org/10.2337/dc08-9025.
Nauck, M. (2016). Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes. Metab., 18 (3): 203-216. doi: 10.1111/dom.12591.
Okuno, Y., Komada, H., Sakaguchi, K., Nakamura, T., Hashimoto, N., Hirota, Y., Ogawa, W., & Seino, S. (2013). Postprandial serum C-peptide to plasma glucose concentration ratio correlates with oral glucose tolerance test- and glucose clamp-based disposition indexes. Metabolism: clinical and experimental, 62(10), 1470–1476. https://doi.org/10.1016/j.metabol.2013.05.022.
Palmer JP, Fleming GA, Greenbaum CJ, et al. (2004) C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes, 53: 250-264. doi: 10.2337/diabetes.53.1.250.
Pfützner, A., Pfützner, A., Kann, P. & Burgard, G. (2017). Clinical and Laboratory Evaluation of a New Specific Point-of-Care Test for Intact Proinsulin. J. Diabetes Sci. Technol., 11 (2): 278-283. doi: 10.1177/1932296816663745.
Polidori D, Mari A, Ferrannini Е. (2014) Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia, 57(5): 891–901. doi: 10.1007/s00125-014-3196-x.
Redford, C. (2015). SGLT2 inhibitors and the risk of diabetic ketoacidosis. Pract Diabetes, 32: 263–264. doi: https://doi.org/10.1016/j.clinthera.2016.11.002.
Rehackova, L., Araújo-Soares, V., Adamson, A., Stevens, S., Taylor, R. & Sniehotta, F. (2017). Acceptability of a very low energy diet in type 2 diabetes: patient experiences and behaviour regulation. Diabetic Med., 34: 1554 1567. doi: 10.1111/dme.13426.
Sarwar, N., Sattar, N., Gudnason, Y. & Danesh, J. (2007). Circulating concentrations of insulin markers and coronary heart disease: a quantitative review of 19 Western prospective studies. Eur Heart J, 28, 2491-2497. DOI: 10.1093/eurheartj/ehm115.
Schernthaner, G., Gross, J. L., Rosenstock, J., Guarisco, M., Fu, M., Yee, J., Kawaguchi, M., Canovatchel, W., & Meininger, G. (2013). Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes care, 36(9), 2508–2515. https://doi.org/10.2337/dc12-2491.
Sims, E. K., Chaudhry, Z., Watkins, R., Syed, F., Blum, J., Ouyang, F., Perkins, S. M., Mirmira, R. G., Sosenko, J., DiMeglio, L. A., & Evans-Molina, C. (2016). Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes care, 39(9), 1519–1526. https://doi.org/10.2337/dc15-2849.
Stenlöf, K., Cefalu, W., Kim, K., Alba, M., Usiskin, K., Tong, C., Canovatchel, W. & Meininger, G. (2013). Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes. Metab., 15 (4): 372-82. doi: 10.1111/dom.12054.
Sun, X. F., Wang, Y., Zhao, W. J., Wang, L., Bao, D. Q., Qu, G. R., Yao, M. X., Luan, J., Wang, Y. G., & Yan, S. L (2019). Zhonghua nei ke za zhi, 58(1), 33–38. https://doi.org/10.3760/cma.j.issn.0578-1426.2019.01.006.
Takabe, M., Matsuda, T., Hirota, Y., Hashimoto, N., Nakamura, T., Sakaguchi, K., Ogawa, W., & Seino, S. (2012). C-peptide response to glucagon challenge is correlated with improvement of early insulin secretion by liraglutide treatment. Diabetes research and clinical practice, 98(3), e32–e35. https://doi.org/10.1016/j.diabres.2012.09.036.
Thong, K. Y., McDonald, T. J., Hattersley, A. T., Blann, A. D., Ramtoola, S., Duncan, C., Carr, S., Adamson, K., Nayak, A. U., Khurana, R., Hunter, S. J., Ali, A., Au, S., & Ryder, R. E. (2014). The association between postprandial urinary C-peptide creatinine ratio and the treatment response to liraglutide: a multi-centre observational study. Diabetic medicine: a journal of the British Diabetic Association, 31(4), 403–411. https://doi.org/10.1111/dme.12367.
Tomkin, G. H. (2014). Treatment of type 2 diabetes, lifestyle, GLP1 agonists and DPP4 inhibitors. World J Diabetes, 5(5): 636–650. doi: 10.4239/wjd.v5.i5.636.
Vangipurapu, J., Stančáková, A., Kuulasmaa, T., Kuusisto, J. & Laakso, M. (2015). Both fasting and glucose-stimulated proinsulin levels predict hyperglycemia and incident type 2 diabetes: a population-based study of 9,396 Finnish men. PLoS One, 10(4): e0124028. doi: 10.1371/journal.pone.0124028.
Wahren, J. & Larsson, C. (2015). C-peptide: new findings and therapeutic possibilities. Diabetes Res. Clin. Pract, 107(3): 309-319. doi: 10.1016/j.diabres. 2015.01.016.
Wang, X., Yang, J., Chang, B., Shan, C., Xu, Y., Zheng, M., Wang, Y., Ren, H., & Chen, L. (2016). Glucagon secretion is increased in patients with Type 2 diabetic nephropathy. Journal of diabetes and its complications, 30(3), 488–493. https://doi.org/10.1016/j.jdiacomp.2015.12.020.
Wilding, J. P., Charpentier, G., Hollander, P., González-Gálvez, G., Mathieu, C., Vercruysse, F., Usiskin, K., Law, G., Black, S., Canovatchel, W., & Meininger, G. (2013). Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. International journal of clinical practice, 67(12), 1267–1282. https://doi.org/10.1111/ijcp.12322.
Yosten, G., Maric-Bilkan, C., Luppi, P. & Wahren, J. (2014). Physiological effects and therapeutic potential of proinsulin C-peptide. Am J Physiol Endocrinol Metab, 307, E955–E968. doi: 10.1152/ajpendo.00130.2014.
Views:
320
Downloads:
0
Downloads:
175
Copyright (c) 2021 Кушнарёва Н. Н., Зиныч Л. В., Ковальчук А. В., Прибила О. В., Шишкань-Шишова Е. А.
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
