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

July 30, 2018 updated by: Zhiguang Zhou, European Foundation for the Study of Diabetes
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 is prone 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 type 2 diabetes (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 thiazolidinediones. 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 impaired fasting glucose (IFG) and in diabetic rat model. We'd like to further explore the possible effect of sitagliptin on insulin sensitivity in LADA patients by homeostasis model assessment for insulin resistance (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., C reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6) play an additional role in the pathogenesis of insulin resistance in diabetes. It will be of interest to investigate the adipokines and proinflammatory 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.

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Hunan
      • Changsha, Hunan, China, 410011
        • Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

23 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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. Fasting C-peptide (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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sitagliptin
Patients will receive insulin therapy with sitagliptin.
Drug: Insulin
Drug: sitagliptin
sitagliptin tablet,100 mg p.o. qd,2 year
Other Names:
  • Januvia
Active Comparator: Insulin
Patients will receive insulin therapy without sitagliptin.
Drug: Insulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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 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.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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+Treg cells before and after sitagliptin treatment in LADA patients.
2 years
The possible immunomodulatory effects of sitagliptin on LADA patients
Time Frame: 2 years
Effect of sitagliptin on cytokine production of Teff and Treg cells before and after sitagliptin treatment in LADA patients.
2 years
The possible immunomodulatory effects of sitagliptin on LADA patients
Time Frame: 2 years
Effect of sitagliptin on Foxp3 mRNA expression of Treg cells and RORγT mRNA expression of Th17 cells before and after sitagliptin treatment in LADA patients.
2 years
The possible immunomodulatory effects of sitagliptin on LADA patients
Time Frame: 2 years
The comparison of glutamic acid decarboxylase 65 (GAD65) reactive interferon-γ-Th1, IL-4-Th2, IL-17-Th17 and IL-10-Treg cells detected by enzyme-linked immunospot (ELISPOT) before and after sitagliptin treatment in LADA patients.
2 years
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.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

European Foundation for the Study of Diabetes

Collaborators

Eli Lilly and Company
Chinese Medical Association

Investigators

  • Principal Investigator: Zhiguang Zhou, M.D., Ph.D., Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, China

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2010

Primary Completion (Actual)

July 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

May 5, 2010

First Submitted That Met QC Criteria

July 9, 2010

First Posted (Estimate)

July 12, 2010

Study Record Updates

Last Update Posted (Actual)

July 31, 2018

Last Update Submitted That Met QC Criteria

July 30, 2018

Last Verified

July 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EFSD DPP-Ⅳ LADA

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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