Effects of Exercise and Inhibition of Dipeptidyl Peptidase-4 on Insulin Secretion in Subjects With Type 1 Diabetes (EXTYPE-1)

Increasing evidence suggests pancreatic islet beta-cell regeneration occurs throughout the course of the disease in patients with type 1 diabetes. Therefore, decreased beta-cell mass in type 1 diabetes may be improved through inhibition of beta-cell destruction and stimulation of proliferation, even after prolonged duration of disease.

Physical activity improves insulin secretion via unknown underlying mechanisms. We recently observed that Interleukin-6 induces glucagon like Peptide (GLP)-1 production and release from the islet alpha-cell and the intestinal L-cell. Furthermore, exercise induces release of Interleukin-6 from skeletal muscle resulting in elevated circulating Interleukin-6 levels. Therefore we hypothesize that exercise-induced Interleukin-6 promotes glucagon like peptide-1 secretion from the islet α-cell and the intestinal L-cell, thereby providing a mechanism how physical activity can help maintain and improve beta-cell function in patients with type 1 diabetes. This mechanism can be enhanced by concomitant dipeptidyl peptidase-IV inhibition.

Physical activity is also known to enhance insulin sensitivity and to attenuate the immune system activity.

Therefore by combining physical activity and dipeptidyl peptidase-IV inhibition we aim to allow for beta-cell regeneration in a interventional randomized open-label study.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus Type 1
• Intervention / Treatment: Drug: Sitagliptin; Drug: Exercise

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Type 1 diabetes (American Diabetes Association criteria) of > 2 year duration that is judged to be stable by the investigator
2. No clinically significant change in treatment regimen for type 1 diabetes (defined as a 20% change) during the 3 months prior to Screening
3. Positive glutamic acid decarboxylase 65 and/or Islet Antigen (IA)-2 auto-antibodies
4. Age ≥ 18 years and ≤ 55 years
5. HbA1c < 7.5% for the previous two measurements including the measurement taken at Screening (both measurements must occur within 6 months prior to enrollment)
6. Body-mass index (BMI) > 18 and < 28 kg/m2
7. Willingness to maintain current doses/regimens of vitamins and dietary supplements through the end of the study
8. For subjects with reproductive potential, a willingness to use contraceptive measures adequate to prevent the subject or the subject's partner from becoming pregnant during the study. Adequate contraceptive measures include hormonal methods used for two or more cycles prior to Screening (e.g., oral contraceptive pills, contraceptive patch, or contraceptive vaginal ring), double barrier methods (e.g., contraceptive sponge, diaphragm used in conjunction with contraceptive foam or jelly, and condom used in conjunction with contraceptive foam or jelly), intrauterine methods (IUD), sterilization (e.g., tubal ligation or a monogamous relationship with a vasectomized partner), and abstinence.

Exclusion Criteria:

1. Regular training of more than 90 minutes / week
2. History or signs of cardiovascular disease, proliferative retinopathy, nephropathy or neuropathy
3. Signs of current infection
4. Neutropenia
5. Anemia
6. Clinically significant kidney or liver disease
7. Current immunosuppressive treatment or documented immunodeficiency

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin; Patients receive Sitagliptin (100mg/d) without further intervention	Drug: Sitagliptin
Experimental: Sitagliptin and exercise; Patients receive sitagliptin (100mg/d) and follow a physical training intervention program	Drug: Sitagliptin; Drug: Exercise

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in beta-cell function as derived from change in C-peptide and glucose levels during the mixed meal test	Day 90 compared to baseline (Day 1 pre-dose)

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in insulin sensitivity as derived from change in C-peptide and glucose levels during the mixed meal test	Day 90 compared to baseline (Day 1 pre-dose)
Change in insulin requirements: 3-day average daily insulin dose	baseline (Day -3 through Day -1) compared to Day 90 (Day 87 through Day 89)
Change in HbA1c levels	baseline (Day 1 pre-dose) at Day 90
Change in fasting glucose	baseline (Day 1 pre-dose) at Day 90
Change in fasting glucagon and cortisol	baseline (Day 1 pre-dose) at Day 90
Change in total number of hypoglycemic events compared to treatment groups	baseline (Day 1 pre-dose) to Day 90
Change in markers of systemic inflammation	from baseline (Day 1 pre-dose) at Day 90
Change in composition of immune cells	from baseline at Day 90
Change in meal-stimulated GLP-1 and gastric inhibitory peptide	Day 90 compared to baseline
Change in lipids profile	baseline at Day 90
Change in fatigue according to the Fatigue Scale for Motor and Cognitive Functions questionnaire	from baseline at Day 90
Change in plasma copeptin and procalcitonin levels	from baseline (Day 1 pre-dose) at Day 90
Change in retinal vascular diameter	Day 90 compared to baseline (Day 1 pre-dose)
Change in arterial stiffness	Day 90 compared to baseline (Day 1 pre-dose)
Change in fractalkine	Day 90 compared to baseline (Day 1 pre-dose)

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Marc Donath, Prof. MD, University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): August 5, 2016

Study Registration Dates

• First Submitted: April 28, 2014
• First Submitted That Met QC Criteria: April 29, 2014
• First Posted (Estimate): April 30, 2014

Study Record Updates

• Last Update Posted (Actual): July 27, 2017
• Last Update Submitted That Met QC Criteria: July 25, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate
• Other Study ID Numbers: EKBB 349/12