A Study of Intracellular Signaling in Muscle and Fat Cells During Ketosis
NCT ID: NCT02157155
Last Updated: 2015-12-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
NA
9 participants
INTERVENTIONAL
2014-06-30
2015-09-30
Brief Summary
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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.
Detailed Description
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Conditions
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Study Design
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RANDOMIZED
CROSSOVER
BASIC_SCIENCE
SINGLE
Study Groups
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Intervention
Insulin reduction and mimic infection with LPS
LPS
LPS is endotoxin from gram negative bacteria. It is used scientifically to mimic infection lasting 4-8 hours.
Control
Normal insulin and no LPS
No interventions assigned to this group
Interventions
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LPS
LPS is endotoxin from gram negative bacteria. It is used scientifically to mimic infection lasting 4-8 hours.
Eligibility Criteria
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Inclusion Criteria
* 19 \< BMI \< 26
* minimal or negative C-peptide
* written consent
Exclusion Criteria
* regular medication apart from insulin
18 Years
45 Years
MALE
No
Sponsors
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University of Aarhus
OTHER
Responsible Party
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Principal Investigators
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Mads Svart, MD
Role: PRINCIPAL_INVESTIGATOR
Aarhus University / Aarhus University Hospital
Niels Møller, MD
Role: STUDY_CHAIR
Aarhus University / Aarhus University Hospital
Locations
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Aarhus University Hospital
Aarhus, , Denmark
Countries
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
West MA, Heagy W. Endotoxin tolerance: A review. Crit Care Med. 2002 Jan;30(1 Supp):S64-S73.
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.
Cahill GF Jr. Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1-22. doi: 10.1146/annurev.nutr.26.061505.111258.
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.
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.
Other Identifiers
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1-10-72-98-14
Identifier Type: -
Identifier Source: org_study_id