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KetoacidosisNCT02157155

A Study of Intracellular Signaling in Muscle and Fat Cells During Ketosis

A study testing LPS in people with Ketoacidosis and Diabetes Mellitus Type 1, run by University of Aarhus at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Hypothesis 1. To define whether stimulation of ATGL and suppression of G0/G1 switch gene occur in the initial phases of diabetic ketoacidosis and thus can be identified as the primary mechanisms behind this life threatening condition. 2. Make a human model for studying ketoacidosis. Read more about this study

Who is it for?
Ages 18 to 45 years, men only
Conditions the study is for
Ketoacidosis, Diabetes Mellitus Type 1
What is being tested?
LPS
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
1 siteDenmark
Study dates
Jun 2014to Sep 2015
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 45 years
  • Men only
  • No healthy volunteers
  • Adult

Who may be able to join

  • Diabetes type 1
  • 19 < BMI < 26
  • minimal or negative C-peptide
  • written consent

Who cannot join

  • Severe comorbidity
  • regular medication apart from insulin

Trial locations and contacts

1 site in 1 country.

Denmark1 site

  • Aarhus University Hospital

    Aarhus, 8000

Other trials in Denmark

About this study

Official title: The Role of ATGL and G0/G1 Switch Gene Complex in Lipopolysaccaride (LPS) Induced Ketosis - a Controlled, Randomised, Clinical Experimental Study

Hypothesis

  1. To define whether stimulation of ATGL and suppression of G0/G1 switch gene occur in the initial phases of diabetic ketoacidosis and thus can be identified as the primary mechanisms behind this life threatening condition.
  2. Make a human model for studying ketoacidosis.

The investigators plan to reduce in their regular insulin over night. In the morning we administer endotoxin, which together with a relative lack of insulin will initiate ketogenesis - a state of ketoacidosis. On another occasion strict glycemic control is imposed by means of intravenous insulin. The testing is done two separate days with at least 3 weeks in between and patients are admitted to hospital the evening before the day of testing. The investigators use isotopic tracers to determine metabolic fluxes and analyse fat (ATGL, G0/G1 switch gene) and muscle biopsies.

Being tested
LPS
Medical subject headings
Ketosis, Diabetes Mellitus, Type 1

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LPSBiological

    LPS is endotoxin from gram negative bacteria. It is used scientifically to mimic infection lasting 4-8 hours.

Study groups in NCT02157155
Study groupRoleWhat they receive
InterventionExperimentalInsulin reduction and mimic infection with LPS
Receives: Biological: LPS
ControlNo interventionNormal insulin and no LPS

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Insulin signaling expressed as a CHANGE in phosphorylation of intracellular target proteins and CHANGE in mRNA expression of target genes in muscle- and fat-tissue.

    Change in phosphorylation of target proteins and messenger RNA (mRNA) expression of target genes assessed with western blotting technique.

    Measured: Muscle and fat biopsies obtained on each study day (arm): t1= 6.45 (-75min) am t2=11.15 (195min) am t3= 12.30 pm (270min)

Secondary outcomes (3)

  1. Change in Intracellular markers of lipid metabolism in muscle- and fat tissue biopsies

    Muscle and fat at t1 and t2. Muscle biopsy at t3. Intracellular markers are assessed by western blotting.

    Measured: Muscle and fat biopsies obtained on each study day (arm): t1= 6.45 am (-75min) t2=11.15 (195min) am t3= 12.30 pm (270min)

  2. Metabolism

    Change in glucose, fat and protein metabolism assessed by tracer kinetics on every study day (specific times below) and by indirect calorimetry. [3H 3]Glucose tracer from t=0 - 360min. Palmitic acid tracer from t=165min - 360min. Urea tracer from 0min - 240min. amino acid tracer from 60 min - 360 min.

    Measured: Change in glucose, fat and protein metabolism between study days and during each study day

  3. Cytokines and stress hormones

    Measurement of immune response to endotoxin and hypoinsulinaemia. Estimating the whole body stress during ketoacidosis and pre ketoacidosis.

    Measured: In basal period t=0-240 minutes and in clamp period t=240-390 minutes

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jun 2014 (estimated)
  2. Study startJun 2014
  3. Primary completionMar 2015
  4. Study completionSep 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Crossover
Masking
Single blind
Who is masked
Participant
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02157155
Sponsor's protocol ID
1-10-72-98-14
Status last verified
Jun 2014
First submitted
23 May 2014
Last updated
2 Dec 2015
Results posted
No
Data monitoring committee
No

Publications

  • Andreasen AS, Krabbe KS, Krogh-Madsen R, Taudorf S, Pedersen BK, Moller K. Human endotoxemia as a model of systemic inflammation. Curr Med Chem. 2008;15(17):1697-705. doi: 10.2174/092986708784872393.

    PubMed 18673219

  • Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004 Nov 19;306(5700):1383-6. doi: 10.1126/science.1100747.

    PubMed 15550674

  • Bezaire V, Mairal A, Ribet C, Lefort C, Girousse A, Jocken J, Laurencikiene J, Anesia R, Rodriguez AM, Ryden M, Stenson BM, Dani C, Ailhaud G, Arner P, Langin D. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J Biol Chem. 2009 Jul 3;284(27):18282-91. doi: 10.1074/jbc.M109.008631. Epub 2009 May 11.

    PubMed 19433586

  • Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006 May 5;312(5774):734-7. doi: 10.1126/science.1123965.

    PubMed 16675698

  • Schweiger M, Schreiber R, Haemmerle G, Lass A, Fledelius C, Jacobsen P, Tornqvist H, Zechner R, Zimmermann R. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem. 2006 Dec 29;281(52):40236-41. doi: 10.1074/jbc.M608048200. Epub 2006 Oct 30.

    PubMed 17074755

  • Yang X, Lu X, Lombes M, Rha GB, Chi YI, Guerin TM, Smart EJ, Liu J. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 2010 Mar 3;11(3):194-205. doi: 10.1016/j.cmet.2010.02.003.

    PubMed 20197052

  • Nielsen TS, Vendelbo MH, Jessen N, Pedersen SB, Jorgensen JO, Lund S, Moller N. Fasting, but not exercise, increases adipose triglyceride lipase (ATGL) protein and reduces G(0)/G(1) switch gene 2 (G0S2) protein and mRNA content in human adipose tissue. J Clin Endocrinol Metab. 2011 Aug;96(8):E1293-7. doi: 10.1210/jc.2011-0149. Epub 2011 May 25.

    PubMed 21613358

  • Burge MR, Garcia N, Qualls CR, Schade DS. Differential effects of fasting and dehydration in the pathogenesis of diabetic ketoacidosis. Metabolism. 2001 Feb;50(2):171-7. doi: 10.1053/meta.2001.20194.

    PubMed 11229425

  • Burge MR, Hardy KJ, Schade DS. Short-term fasting is a mechanism for the development of euglycemic ketoacidosis during periods of insulin deficiency. J Clin Endocrinol Metab. 1993 May;76(5):1192-8. doi: 10.1210/jcem.76.5.8496310.

    PubMed 8496310

  • West MA, Heagy W. Endotoxin tolerance: A review. Crit Care Med. 2002 Jan;30(1 Supp):S64-S73.

    PubMed 11891406

  • Sanchez-Cantu L, Rode HN, Christou NV. Endotoxin tolerance is associated with reduced secretion of tumor necrosis factor. Arch Surg. 1989 Dec;124(12):1432-5; discussion 1435-6. doi: 10.1001/archsurg.1989.01410120082016.

    PubMed 2589967

  • Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1-22. doi: 10.1146/annurev.nutr.26.061505.111258.

    PubMed 16848698

  • Lauritzen ES, Svart MV, Voss T, Moller N, Bjerre M. Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans. Endocr Res. 2021 Feb;46(1):20-27. doi: 10.1080/07435800.2020.1831015. Epub 2020 Oct 19.

    PubMed 33074729

  • Svart MV, Rittig N, Kampmann U, Voss TS, Moller N, Jessen N. Metabolic effects of insulin in a human model of ketoacidosis combining exposure to lipopolysaccharide and insulin deficiency: a randomised, controlled, crossover study in individuals with type 1 diabetes. Diabetologia. 2017 Jul;60(7):1197-1206. doi: 10.1007/s00125-017-4271-x. Epub 2017 Apr 7.

    PubMed 28389705

Questions about this trial

What is this clinical trial studying?

A study testing LPS in people with Ketoacidosis and Diabetes Mellitus Type 1, run by University of Aarhus at 1 site in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Dec 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Insulin signaling expressed as a CHANGE in phosphorylation of intracellular target proteins and CHANGE in mRNA expression of target genes in muscle- and fat-tissue. (time frame: Muscle and fat biopsies obtained on each study day (arm): t1= 6.45 (-75min) am t2=11.15 (195min) am t3= 12.30 pm (270min)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02157155, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2015.

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