Protective Effects of Sitagliptin on β Cell Function in Patients With Adult-onset Latent Autoimmune Diabetes (LADA)

Summary

The aim of this study is to investigate the protective effects of sitagliptin on β cell function in patients with adult-onset latent autoimmune diabetes (LADA) and its mechanisms.

Timeline

Start

2010-01

Primary completion

2012-07

Completion

2012-12

Publications

• Background Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes. 1993 Feb;42(2):359-62. doi: 10.2337/diab.42.2.359.
• Background Dupre J. Glycaemic effects of incretins in Type 1 diabetes mellitus: a concise review, with emphasis on studies in humans. Regul Pept. 2005 Jun 15;128(2):149-57. doi: 10.1016/j.regpep.2004.06.003.
• Background Dupre J, Behme MT, Hramiak IM, McFarlane P, Williamson MP, Zabel P, McDonald TJ. Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM. Diabetes. 1995 Jun;44(6):626-30. doi: 10.2337/diab.44.6.626.
• Background Behme MT, Dupre J, McDonald TJ. Glucagon-like peptide 1 improved glycemic control in type 1 diabetes. BMC Endocr Disord. 2003 Apr 10;3(1):3. doi: 10.1186/1472-6823-3-3.
• Background Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care. 1996 Jun;19(6):580-6. doi: 10.2337/diacare.19.6.580.
• Background Zhang J, Tokui Y, Yamagata K, Kozawa J, Sayama K, Iwahashi H, Okita K, Miuchi M, Konya H, Hamaguchi T, Namba M, Shimomura I, Miyagawa JI. Continuous stimulation of human glucagon-like peptide-1 (7-36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes. Diabetologia. 2007 Sep;50(9):1900-1909. doi: 10.1007/s00125-007-0737-6. Epub 2007 Jul 14.
• Background Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, Piteau S, Demuth HU, McIntosh CH, Pederson RA. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats. Diabetes. 2003 Mar;52(3):741-50. doi: 10.2337/diabetes.52.3.741.
• Background Pospisilik JA, Ehses JA, Doty T, McIntosh CH, Demuth HU, Pederson RA. Dipeptidyl peptidase IV inhibition in animal models of diabetes. Adv Exp Med Biol. 2003;524:281-91. doi: 10.1007/0-306-47920-6_34. No abstract available.
• Background Kim SJ, Nian C, Doudet DJ, McIntosh CH. Inhibition of dipeptidyl peptidase IV with sitagliptin (MK0431) prolongs islet graft survival in streptozotocin-induced diabetic mice. Diabetes. 2008 May;57(5):1331-9. doi: 10.2337/db07-1639. Epub 2008 Feb 25.
• Background Flentke GR, Munoz E, Huber BT, Plaut AG, Kettner CA, Bachovchin WW. Inhibition of dipeptidyl aminopeptidase IV (DP-IV) by Xaa-boroPro dipeptides and use of these inhibitors to examine the role of DP-IV in T-cell function. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1556-9. doi: 10.1073/pnas.88.4.1556.
• Background Reinhold D, Bank U, Buhling F, Lendeckel U, Faust J, Neubert K, Ansorge S. Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor-beta 1 in PWM-stimulated PBMC and T cells. Immunology. 1997 Jul;91(3):354-60. doi: 10.1046/j.1365-2567.1997.d01-2258.x.
• Background Kahne T, Neubert K, Faust J, Ansorge S. Early phosphorylation events induced by DPIV/CD26-specific inhibitors. Cell Immunol. 1998 Oct 10;189(1):60-6. doi: 10.1006/cimm.1998.1355.
• Background Yang Z, Zhou Z, Huang G, Ling H, Yan X, Peng J, Li X. The CD4(+) regulatory T-cells is decreased in adults with latent autoimmune diabetes. Diabetes Res Clin Pract. 2007 Apr;76(1):126-31. doi: 10.1016/j.diabres.2006.08.013. Epub 2006 Sep 26.
• Background Xue S, Wasserfall CH, Parker M, Brusko TM, McGrail S, McGrail K, Moore M, Campbell-Thompson M, Schatz DA, Atkinson MA, Haller MJ. Exendin-4 therapy in NOD mice with new-onset diabetes increases regulatory T cell frequency. Ann N Y Acad Sci. 2008 Dec;1150:152-6. doi: 10.1196/annals.1447.049.
• Background Utzschneider KM, Tong J, Montgomery B, Udayasankar J, Gerchman F, Marcovina SM, Watson CE, Ligueros-Saylan MA, Foley JE, Holst JJ, Deacon CF, Kahn SE. The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose. Diabetes Care. 2008 Jan;31(1):108-13. doi: 10.2337/dc07-1441. Epub 2007 Oct 1.
• Background Ahren B, Pacini G, Foley JE, Schweizer A. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care. 2005 Aug;28(8):1936-40. doi: 10.2337/diacare.28.8.1936.
• Background Orskov L, Holst JJ, Moller J, Orskov C, Moller N, Alberti KG, Schmitz O. GLP-1 does not not acutely affect insulin sensitivity in healthy man. Diabetologia. 1996 Oct;39(10):1227-32. doi: 10.1007/BF02658511.
• Background Ahren B, Larsson H, Holst JJ. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1997 Feb;82(2):473-8. doi: 10.1210/jcem.82.2.3728.
• Background Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002 Mar 9;359(9309):824-30. doi: 10.1016/S0140-6736(02)07952-7.
• Background Pospisilik JA, Stafford SG, Demuth HU, McIntosh CH, Pederson RA. Long-term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study. Diabetes. 2002 Sep;51(9):2677-83. doi: 10.2337/diabetes.51.9.2677.
• Background Pietropaolo M, Barinas-Mitchell E, Kuller LH. The heterogeneity of diabetes: unraveling a dispute: is systemic inflammation related to islet autoimmunity? Diabetes. 2007 May;56(5):1189-97. doi: 10.2337/db06-0880. Epub 2007 Feb 23.
• Background Viswanathan P, Chaudhuri A, Bhatia R, Al-Atrash F, Mohanty P, Dandona P. Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin. Endocr Pract. 2007 Sep;13(5):444-50. doi: 10.4158/EP.13.5.444.
• Background Duttaroy A, Voelker F, Merriam LQ, et al. The DPP-4 inhibitor Vildagliptin increases pancreatic β-cell neogenesis and decreases apoptosis. Diabetes, 2005; 54 (Suppl. 1): A141.
• Background Yang ZF, Zhou ZG, Tang WL, Huang G, Peng J, Li X, He L. [Decrease of FOXP3 mRNA in CD4+ T cells in latent autoimmune diabetes in adult]. Zhonghua Yi Xue Za Zhi. 2006 Sep 26;86(36):2533-6. Chinese.
• Background Korom S, De Meester I, Stadlbauer TH, Chandraker A, Schaub M, Sayegh MH, Belyaev A, Haemers A, Scharpe S, Kupiec-Weglinski JW. Inhibition of CD26/dipeptidyl peptidase IV activity in vivo prolongs cardiac allograft survival in rat recipients. Transplantation. 1997 May 27;63(10):1495-500. doi: 10.1097/00007890-199705270-00021.
• Yang L, Liang H, Liu X, Wang X, Cheng Y, Zhao Y, Liu L, Huang G, Wang X, Zhou Z. Islet Function and Insulin Sensitivity in Latent Autoimmune Diabetes in Adults Taking Sitagliptin: A Randomized Trial. J Clin Endocrinol Metab. 2021 Mar 25;106(4):e1529-e1541. doi: 10.1210/clinem/dgab026.
• Wang X, Yang L, Cheng Y, Liang H, Hu J, Zheng P, Huang G, Zhou Z. Downregulation of T-Cell Transcription Factors in Adult Latent Autoimmune Diabetes with High-Titer Glutamic Acid Decaroxylase Antibody. Diabetes Ther. 2019 Jun;10(3):917-927. doi: 10.1007/s13300-019-0594-6. Epub 2019 Mar 20.
• Zhao Y, Yang L, Xiang Y, Liu L, Huang G, Long Z, Li X, Leslie RD, Wang X, Zhou Z. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains beta-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab. 2014 May;99(5):E876-80. doi: 10.1210/jc.2013-3633. Epub 2014 Jan 16.

Drugs

Indications