Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04300049 |
| Other study ID # |
HSC20170682H |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
February 5, 2018 |
| Est. completion date |
August 25, 2026 |
Study information
| Verified date |
September 2023 |
| Source |
The University of Texas Health Science Center at San Antonio |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Purpose/Objectives: To investigate the effect of hyperglucagonemia on insulin action,
particularly on adipose tissue.
Research Design/Plan: Normal glucose tolerant subjects will be studied. Study subjects will
receive a continuous glucagon infusion for 12 hours. Following glucagon infusion, subjects
will receive prime-continuous tracer infusions for additional 4 hours to measure adipocyte
metabolism. Within 6-8 weeks, subjects will return for a repeat study with normal saline as a
control group.
Methods: All subjects will have an oral glucose tolerance test prior to participation to
confirm they are normal glucose tolerant. Subjects will be admitted to the CRC at 4 PM and
will receive a continuous glucagon for 12 hours. At 6 AM on the following morning, subjects
will receive prime-continuous tracer infusions of the following for 4 hours (14C-glycerol,
3-3H glucose, and D2O). At 10 AM continuous indirect calorimetry will be performed to
determine rates of energy expenditure and glucose/lipid oxidation for 40 minutes. At 6 AM a
surgical biopsy of abdominal adipose tissue will be performed for measurement of adipocyte
metabolism. At 8 AM, the study team will infuse insulin/glucose to test for insulin
sensitivity.
Clinical Relevance: The results of this study will help the study team to further understand
the pathophysiology of metabolic disturbances that is induced by hyperglucagonemia in type 2
diabetes patients.
Description:
Visit 1 Screening: All subjects will be performed indirect calorimetry to determine rates of
energy expenditure and glucose/lipid oxidation for 40 minutes prior to all other procedures
to obtain a fasting calorimetry. Subjects then will have a 75 gram oral glucose tolerance
test to document the presence of normal glucose tolerance. Blood will be drawn at -30, -15, 0
and at 15, 30, 45, 60, 90 and 120 minutes thereafter for the determination of plasma glucose,
insulin, C-peptide, glucagon, FFA, glycerol, GLP-1 and GIP concentrations. The total amount
of blood to be taken during the OGTT is 148 ml or about 10 tablespoons. Participants will
also undergo a total body fat (DXA) and hepatic fat content (MRS). Subjects will also have a
routine physical exam, an ECG, weight, height, vitals and collection of prior medical
history. The study team will also check blood glucose (sugar) and blood lipid (fat) levels.
The total amount of blood that we will take for the screening blood tests, HbA1c, lipid, and
other blood tests is 34 ml or about 2 1/3 tablespoons.
Visit 2 Adipose Tissue Metabolism Measurement: Subjects (n=12) will be admitted to the CRC at
4 PM on the day prior to study and received a standardized, weight maintaining diet
containing 50% CHO: 30% fat: 20% protein. At 6 PM subjects will receive a continuous glucagon
(3 ng/kg.min, N=6) or glucagon (6 ng/kg.min, N=6) for 12 hours. Subjects will remain fasting
after 10 PM. Samples for glucagon, FFA, insulin and C-peptide will be collected at 1700,
1730, 1800, 1900, 2100, 2300, 0100, 0300, and 0500 hours.
At 6 AM on the following morning subjects will receive prime-continuous tracer infusions of
the following for 4 hours (see figure 1):
(i) 14-C-glycerol (prime = 30 µCi; continuous infusion = 0.3 µCi/min) for determination of
total body rate of lipolysis.
(ii) 3-3H-glucose (prime = 40 µCi; continuous infusion = 0.4 µCi/min) for determination of
rates of total body glucose appearance and disappearance.
(iii) D2O (5 g/kg fat free mass at 9 PM orally) to determine the rate of de novo lipogenesis.
At 6 AM a surgical biopsy of subcutaneous abdominal adipose tissue will be performed for
measurement of hormone sensitive (HSL) lipase activity, AMPK activity, and serine
phosphorylation of HSL (see Figure 2), FGF-21, FAP, Beta-klotho. Insulin signaling (IR/IRS-1
tyrosine phosphorylation, PI-3 kinase activity, Akt) molecules, GLUT4, markers of
inflammation (IkB, NF-kB, T4R4TLR4, JNK, p38 MAPK, M2/M1 macrophages, IL-1, IL-6, TNF alpha,
MCP-1) also will be measured on the fat biopsy. Lipidomic analysis to quantitate the amount
of and type of fat in the adipose tissue biopsy also will be performed. After surgical biopsy
of adipose tissue, starting the tracer equilibration (6AM) blood will be drawn every 15-30
minutes for 4 hours (6-10 AM) for substrate (glucose, FFA, glycerol, triglycerides), hormone
(glucagon, insulin, C-peptide, GLP-1, GIP, adiponectin, leptin, FGF21 [active and total], FAP
[degrading enzyme]), radioisotope (14-C-glycerol and 3-3H glucose) specific activity.
Participants will place their hand in a transparent plastic thermo-regulated box heated to
50-60°C (122-140°F) to ensure good blood flow to the hand. Pasma samples for radioisotope
activity (background) will be obtained at 6 AM. At 9 AM continuous indirect calorimetry will
be performed to determine rates of energy expenditure and glucose/lipid oxidation for 40
minutes.
The glucagon infusion will be continued through the 4-hour tracer infusion (i.e. 6AM-10AM).
At the end of the glucagon infusion (~10 AM) a repeat measurement of hepatic fat content will
be obtained. A total of 366 ml of blood will be drawn.
At 8 AM the insulin sensitivity test will be done during the last two hours of the tracer
infusion. During the 2 hours of the insulin sensitivity test, the insulin (60 mU/m2 ⋅ min)
and glucose will be given through the catheter in the vein in the subject's arm to determine
rates of whole-body insulin sensitivity. There are no expect adverse reactions to be
experienced by the subjects during both infusions.
