Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02344186 |
| Other study ID # |
21440 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
May 2014 |
| Est. completion date |
December 31, 2023 |
Study information
| Verified date |
July 2022 |
| Source |
Temple University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The main objective of the study will be to test the hypothesis that treatment with
Liraglutide will decrease ER stress and adipose tissue in obese patients with type 2
diabetes. Experimental Approach: The investigators will use a prospective, single blind,
placebo controlled study design to study 12 obese patients with type 2 diabetes mellitus
(T2DM). 6 patients will first receive Liraglutide for 24 weeks followed by placebo for 12
weeks. The other 6 patients will first receive placebo for 12 weeks followed by Liraglutide
for 24 weeks.
Measurements: The investigators will determine glycemic control (with HbA1c), body
composition (bioelectric impedance analysis), insulin sensitivity (with
hyperinsulinemic-euglycemic clamps), insulin secretion (with oral glucose tolerance testing),
energy balance (calories in vs. calories out), plasma lipid levels and obtain subcutaneous
fat biopsies to determine ER stress response markers before and after placebo and before and
after Liraglutide treatment.
Description:
This will be a prospective, single-blind, placebo-controlled study with a crossover design.
Visit Procedures: After a 1 month run-in period during which there will be no changes in
medications, physical activity or diet, patients will be randomly divided into 2 groups of 6
patients each. Subjects have a 50:50 chance of being randomized to either group 1 or group 2.
In Group 1, (n=6), liraglutide will be started first with 0.6 mg/d for 1 week, then increased
to 1.2 mg/d from week 2 to week 12, followed by 1.8 mg/d from week 12 to week 24. Group 1
patients will then be switched from liraglutide to placebo injections for another 12 weeks.
For subjects in Group 1 the placebo period (weeks 24 to 36 will be the washout period.
Group 2 patients (n=6) will be started with placebo for 12 weeks and then switched to
liraglutide for the next 24 weeks (0.6 mg/d for 1 week, 1.2 mg/d for 11 weeks and 1.8 mg/d
for 12 weeks).
Assessment of Efficacy
Outpatient visits:
During the entire study, all patients (Groups 1 and 2) will perform home glucose monitoring 7
times/day (pre and ~ 2 h post breakfast, lunch and dinner and bedtime) and will be seen at
Temple University Hospital as outpatients at 4 week intervals.
One week before the first, second or third and final inpatient visit, patients will undergo a
75, gram 2-hour oral glucose tolerance test.
Inpatient visits:
All patients (Groups 1 and 2) will be studied in our Clinical Research Center (CRC) at Temple
University Hospital in the morning after an overnight fast, at the end of the run-in period
(Week 0 ) and again at Weeks 12, 24 and 36. All study patients will be admitted to the CRC
the evening before their study and discharged in the afternoon of the following day.
During the inpatient visits, the following procedures will be performed.
1. At baseline and again at weeks 12 and 36, subcutaneous fat biopsies will be obtained
from the lateral aspect of one thigh by a surgeon as described (8) for determination of
ER stress markers. In brief, the skin will be cleaned with betadine and anesthetized
with 1% lidocaine without epinephrine in a field block pattern (at 2 X 3 in). (We have
found that injection of lidocaine too close to the biopsy site interfered with the
measurement of acetyl-CoA). After an incision (~ 1 in.) will be made through the skin, ~
300 mg of fat will be mobilized and excised. The fat will be dropped immediately into
isopentane, kept at its freezing point (-160°C) by liquid nitrogen. The frozen fat will
be stored at -70°. To screen for changes in unfolded protein response (UPR) genes, we
will first perform an UPR PCR microarray (SA Biosciences, Frederick, MD) using pooled
fat biopsy extracts. This array profiles expression of 84 key genes recognizing and
responding to misfolded protein accumulation in the ER. Significant changes (> 1.5 fold
comparing post vs. pre drug biopsies) will then be confirmed by real time reverse
transcription (RT)-PCR of the UPR messenger RNAs (mRNAs). Thus, mRNAs of the identified
UPR markers (for instance, GRP78, X-box-binding-protein 1 (XBP-1), activating
transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), protein
disulfide isomerase (PDI), calreticulin, calnexin) will be measured by real time RT-PCR
in triplicate and normalized against 18s and β-actin mRNAs and will be expressed as
arbitrary units. The respective proteins will be analyzed by Western blots.
2. Glycemic control will be assessed by
1. measurement of HbA1c
2. patients home glucose monitoring records
3. Determination of insulin resistance will be determined (with euglycemic-hyperinsulinemic
clamping with use of stable isotopes for determination of peripheral (GRd) and hepatic
(GRa) insulin action as described (18).
4. . Determination of energy balance, which will be calculated as change in fat mass (by
bioelectric impedance analysis) plus total energy expenditure (determined with indirect
calorimetry and the doubly labeled water method) (17).
5. Postabsorptive blood samples will be obtained for determination of plasma lipids (total
cholesterol, LDL, HDL and triglycerides).
6. Assessment of changes in insulin secretion will be determined with Oral Glucose
Tolerance Testing.
