NCT02748369

Brief Summary

This is a pilot study to establish an arterial venous methodology to measure the activity of the TCA cycle or flux directly in tissues of human beings. It will also perform correlative studies to study the proteome, metabolome, oxygen consumption, carbon dioxide production and exosomes derived from the arterial venous supply of tissues with correlation to the TCA cycle activity.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
17

participants targeted

Target at below P25 for phase_1

Timeline
Completed

Started Jul 2016

Shorter than P25 for phase_1

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

April 12, 2016

Completed
10 days until next milestone

First Posted

Study publicly available on registry

April 22, 2016

Completed
2 months until next milestone

Study Start

First participant enrolled

July 1, 2016

Completed
8 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 2, 2017

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

March 2, 2017

Completed
Last Updated

August 3, 2022

Status Verified

August 1, 2022

Enrollment Period

8 months

First QC Date

April 12, 2016

Last Update Submit

August 2, 2022

Conditions

Normal Cellular Metabolism

Keywords

TCA cycle fluxin vivo measurementsStable isotopesArteriovenous balanceMetabolomeProteomeExosomes

Outcome Measures

Primary Outcomes (1)

  • In Vivo TCA cycle flux in skeletal muscle and splanchnic tissue

    Normal healthy study participants will receive an initial priming dose followed by a continuous infusion of 2-13C-Acetate, 2-15N-Glutamine and D5-Phenylalanine in order to achieve steady state enrichment of 13C and 15N in their system. Serial arteriovenous blood samples will be obtained from the femoral artery, femoral vein and hepatic vein and serial skeletal muscle tissue biopsies will be obtained from the vastus lateralis. These samples will be analyzed by GC-MS and NMR spectroscopy to quantify the isotopomer intermediates of the TCA cycle and measure the corresponding TCA cycle flux. The flux estimations from the arteriovenous blood samples will be compared to that obtained directly from the skeletal muscle tissue. This methodology will be validated in the setting of low insulin levels alone or in combination with high glucagon concentrations.

    12 hours

Secondary Outcomes (6)

  • Changes in the protein and metabolite contents within circulating exosomes derived from the arterial-venous blood supply of the skeletal muscle and splanchnic tissue

    12 hours

  • Changes in the metabolome derived from the arterial-venous blood supply of the skeletal muscle and splanchnic tissue

    12 hours

  • Changes in the proteome derived from the arterial-venous blood supply of the skeletal muscle and splanchnic tissue in response to hormonal manipulation.

    12 hours

  • Oxygen consumption in skeletal muscle and splanchnic tissue in response to hormonal manipulation

    12 hours

  • Mitochondrial respiration in skeletal muscle tissue

    12 hours

  • +1 more secondary outcomes

Study Arms (2)

Control Group

NO INTERVENTION

No somatostatin and glucagon infusions

Intervention Group

ACTIVE COMPARATOR

Somatostatin and glucagon infusions

Drug: SomatostatinDrug: Glucagon

Interventions

SomatostatinDRUG

Somatostatin infusion to create a low insulin state.

Also known as: growth hormone-inhibiting hormone
Intervention Group
GlucagonDRUG

Glucagon infusion in the setting of ongoing somatostatin.

Also known as: Glucagen
Intervention Group

Eligibility Criteria

Age18 Years - 45 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64)

You may qualify if:

  • Ages 18-45
  • Able to provide written consent

You may not qualify if:

  • Diabetes mellitus or impaired fasting glucose levels (fasting blood glucose \>110mg/dl).
  • Renal Failure
  • Pregnancy
  • Steroid use
  • Muscle Disease
  • Liver Disease
  • Major Depression
  • Anemia
  • H/O alcohol use
  • Medications other than OCPs
  • BMI of 30 or greater

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Related Publications (6)

  • Akram M. Citric acid cycle and role of its intermediates in metabolism. Cell Biochem Biophys. 2014 Apr;68(3):475-8. doi: 10.1007/s12013-013-9750-1.

    PMID: 24068518BACKGROUND

  • Befroy DE, Perry RJ, Jain N, Dufour S, Cline GW, Trimmer JK, Brosnan J, Rothman DL, Petersen KF, Shulman GI. Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nat Med. 2014 Jan;20(1):98-102. doi: 10.1038/nm.3415. Epub 2013 Dec 8.

    PMID: 24317120BACKGROUND

  • Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 2011 Dec 7;14(6):804-10. doi: 10.1016/j.cmet.2011.11.004.

    PMID: 22152305BACKGROUND

  • Schumann WC, Magnusson I, Chandramouli V, Kumaran K, Wahren J, Landau BR. Metabolism of [2-14C]acetate and its use in assessing hepatic Krebs cycle activity and gluconeogenesis. J Biol Chem. 1991 Apr 15;266(11):6985-90.

    PMID: 2016310BACKGROUND

  • Alves TC, Pongratz RL, Zhao X, Yarborough O, Sereda S, Shirihai O, Cline GW, Mason G, Kibbey RG. Integrated, Step-Wise, Mass-Isotopomeric Flux Analysis of the TCA Cycle. Cell Metab. 2015 Nov 3;22(5):936-47. doi: 10.1016/j.cmet.2015.08.021. Epub 2015 Sep 24.

    PMID: 26411341BACKGROUND

  • Jones JG, Solomon MA, Cole SM, Sherry AD, Malloy CR. An integrated (2)H and (13)C NMR study of gluconeogenesis and TCA cycle flux in humans. Am J Physiol Endocrinol Metab. 2001 Oct;281(4):E848-56. doi: 10.1152/ajpendo.2001.281.4.E848.

    PMID: 11551863BACKGROUND

Related Links

MeSH Terms

Interventions

SomatostatinSomatostatin-28GlucagonGlucagon-Like Peptide 1

Intervention Hierarchy (Ancestors)

Pituitary Hormone Release Inhibiting HormonesHypothalamic HormonesPeptide HormonesHormonesHormones, Hormone Substitutes, and Hormone AntagonistsPancreatic HormonesNeuropeptidesPeptidesAmino Acids, Peptides, and ProteinsNerve Tissue ProteinsProteinsProglucagonGlucagon-Like PeptidesGastrointestinal Hormones

Study Officials

  • K Sreekumaran Nair

    Mayo Clinic

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
NONE
Purpose
BASIC SCIENCE
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
M.D., P.h.D. ; Professor of Medicine

Study Record Dates

First Submitted

April 12, 2016

First Posted

April 22, 2016

Study Start

July 1, 2016

Primary Completion

March 2, 2017

Study Completion

March 2, 2017

Last Updated

August 3, 2022

Record last verified: 2022-08

Data Sharing

IPD Sharing
Will not share

Locations

US(1)