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

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified January 2010 by European Foundation for the Study of Diabetes.
Recruitment status was:  Enrolling by invitation
Sponsor:
ClinicalTrials.gov Identifier:
NCT01159847
First Posted: July 12, 2010
Last Update Posted: July 12, 2010
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Chinese Medical Association
Eli Lilly and Company
Information provided by:
European Foundation for the Study of Diabetes
  Purpose
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.

Condition Intervention Phase
Type 1 Diabetes Drug: sitagliptin Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Protective Effects of Sitagliptin on β Cell Function in Patients With Adult-onset Latent Autoimmune Diabetes(LADA)

Resource links provided by NLM:


Further study details as provided by European Foundation for the Study of Diabetes:

Primary Outcome Measures:
  • The effects of sitagliptin on β cell function and insulin sensitivity of LADA patients [ Time Frame: 2 years ]
    1. The assessment of the change of β cell function in patients with LADA treated with sitagliptin or placebo plus insulin by the standardized mixed meal stimulation test and insulin sensitivity by HOMA-IR.
    2. The assessment of the change of insulin sensitivity in LADA patients by sequential insulin infusion with the euglycemic glucose clamp technique and β cell function (first-phase insulin release, FPIR) will be assessed using intravenous glucose tolerance test (IVGTT).


Secondary Outcome Measures:
  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ]
    The change of the frequency of pathogenic Teff (CD4+Th1, Th2, Th17 and CD8+) cells and CD4+CD25+Foxp3+Tregs before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ]
    Effect of sitagliptin on cytokine production of Teff and Tregs before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ]
    Effect of sitagliptin on Foxp3 mRNA expression of Tregs and RORγT mRNA expression of Th17 cells before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ]
    The comparison of GAD65 reactive IFN-γ-Th1, IL-4-Th2, IL-17-Th17 and IL-10-Treg cells detected by ELISPOT before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ]
    The change of the adiponectin, IL-6, IL-17 and CRP etc. before and after the sitagliptin treatment in LADA patients.


Estimated Enrollment: 60
Study Start Date: January 2010
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sitagliptin
sitagliptin combined with insulin therapy
Drug: sitagliptin
sitagliptin tablet,100 mg p.o. qd,2 year
Other Name: Januvia
Active Comparator: insulin Drug: sitagliptin
sitagliptin tablet,100 mg p.o. qd,2 year
Other Name: Januvia

Detailed Description:
Adult-onset latent autoimmune diabetes (LADA), etiologically belongs to type 1 diabetes (T1D), is characterized by the presence of islet autoantibodies, such as islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA), and prones to develop β-cell failure. The goals of treatment for LADA are suppression of autoimmune β cell destruction, preservation of islet function and prevention of diabetic complications. Recently two classes of compounds have been approved by the FDA as T2D therapeutics: the glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic) exenatide (Byetta) and the dipeptidyl peptidase IV (DPP-IV) inhibitor sitagliptin (Januvia) and vildagliptin (Galvus). They have been shown to reduce HbA1c, fasting glucose and to improve β cell function in T2D patients, as a mono-therapy or in combination with metformin or thizolidinediones. Besides, in vitro studies showed incretin-based therapy can stimulate β-cell proliferation and survival, increase β cell insulin content and inhibit apoptosis. Moreover, several short-term pilot studies suggest GLP-1 may also have the potential for treating T1D. Several findings suggest that Ex-4 may also act as a regulator of the immune response in addition to its potential effects on β cell proliferation. Therefore, we hypothesized DPP-IV inhibitors might provide therapeutic advantages in T1D though no study has been reported. Besides the β cell function, another important target is insulin sensitivity. As for DPP-IV inhibitor, clinical trials demonstrated their beneficial effects on insulin sensitivity in subjects with T2D and IFG and indiabetic rat model. We'd like to further explore the possible effect of sitagliptin on insulin sensitivity in LADA patients by HOMA-IR index and euglycemic clamp technique. In addition, the systemic inflammation associated with a wide array of plasma proteins and pro-inflammatory cytokines(i.e., CRP, TNF-α, IL-6) play an additional role in the pathogenesis of insulin resistance in diabetes. It will be of interest to investigate the adipokines and proinflammmatory cytokines after the sitagliptin therapy in the study. Hence, we aim to explore the effects of sitagliptin plus insulin on β cell function, insulin sensitivity, pro-inflammatory cytokines and immune regulation including Teff and Treg frequency, and function in patients with LADA.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   25 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diabetes diagnosed according to the report of WHO in 1999.
  2. Age at onset between 25~70 years.
  3. Disease duration of less than 3 year.
  4. No ketoacidosis within the first 6 months after diagnosis of diabetes.
  5. GADA positive twice within one month.
  6. FCP level of 0.2 nmol/L or more.

Exclusion Criteria:

  1. Insulin requirements more than 0.8 units/kg/day.
  2. Evidence of chronic infection or acute infection affected blood glucose control within 4 weeks prior to visit 1.
  3. History of any malignancy.
  4. Pregnancy, breastfeeding or planned pregnancy within two years.
  5. Secondary diabetes.
  6. Congestive heart failure requiring pharmacologic treatment.
  7. Renal disease or renal dysfunction or diabetic nephropathy suggested by serum creatinine levels≥1.5 mg/dL (132μmol/L) for males and ≥1.4mg/dL (123μmol/L) for females or abnormal creatinine clearance at Visit 1.
  8. Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01159847


Locations
China, Hunan
Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University
Changsha, Hunan, China, 410011
Sponsors and Collaborators
European Foundation for the Study of Diabetes
Chinese Medical Association
Eli Lilly and Company
Investigators
Principal Investigator: Zhiguang Zhou, M.D., Ph.D. Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, China
  More Information

Publications:
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.
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. Review. Erratum in: Regul Pept. 2006 Mar 15;134(1):67-8.
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.
Behme MT, Dupré J, McDonald TJ. Glucagon-like peptide 1 improved glycemic control in type 1 diabetes. BMC Endocr Disord. 2003 Apr 10;3(1):3.
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.
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):1900-9. Epub 2007 Jul 14.
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.
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.
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.
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.
Reinhold D, Bank U, Bühling 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.
Kähne 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.
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. Epub 2006 Sep 26.
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.
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. Epub 2007 Oct 1.
Ahrén 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.
Orskov L, Holst JJ, Møller J, Orskov C, Møller N, Alberti KG, Schmitz O. GLP-1 does not not acutely affect insulin sensitivity in healthy man. Diabetologia. 1996 Oct;39(10):1227-32.
Ahrén 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.
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.
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.
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. Epub 2007 Feb 23. Review.
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.
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.
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.
Korom S, De Meester I, Stadlbauer TH, Chandraker A, Schaub M, Sayegh MH, Belyaev A, Haemers A, Scharpé 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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Zhiguang Zhou/Director, Department of Endocrinology, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Head, Diabetes Center, Central South University, Department of Endocrinology, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Diabetes Center, Central South University
ClinicalTrials.gov Identifier: NCT01159847     History of Changes
Other Study ID Numbers: EFSD DPP-Ⅳ LADA
First Submitted: May 5, 2010
First Posted: July 12, 2010
Last Update Posted: July 12, 2010
Last Verified: January 2010

Keywords provided by European Foundation for the Study of Diabetes:
sitagliptin
LADA
C-Peptide
Flow Cytometry
ELISPOT

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action


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