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

NCT02157155 | Completed

• 1 other identifier: 1-10-72-98-14
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Hypothesis

1. 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. 2.Make a human model for studying ketoacidosis.

Conditions

Ketoacidosis; Diabetes Mellitus Type 1

Outcome Measures

Primary Outcomes (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.

  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)

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

  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)

• Metabolism

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

• Cytokines and stress hormones

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

Study Arms (2)

Intervention

EXPERIMENTAL

Insulin reduction and mimic infection with LPS

Biological: LPS

Control

NO INTERVENTION

Normal insulin and no LPS

Interventions

LPS BIOLOGICAL

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

Intervention

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• Severe comorbidity
• regular medication apart from insulin

Sponsors & Collaborators

• University of Aarhus: lead

Study Sites (1)

Aarhus University Hospital

Aarhus, 8000, Denmark

Location

Related Publications (14)

• 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.

  PMID: 18673219 BACKGROUND

• 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.

  PMID: 15550674 BACKGROUND

• 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.

  PMID: 19433586 BACKGROUND

• 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.

  PMID: 16675698 BACKGROUND

• 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.

  PMID: 17074755 BACKGROUND

• 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.

  PMID: 20197052 BACKGROUND

• 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.

  PMID: 21613358 BACKGROUND

• 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.

  PMID: 11229425 BACKGROUND

• 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.

  PMID: 8496310 BACKGROUND

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

  PMID: 11891406 BACKGROUND

• 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.

  PMID: 2589967 BACKGROUND

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

  PMID: 16848698 BACKGROUND

• 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.

  PMID: 33074729 DERIVED

• 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.

  PMID: 28389705 DERIVED

MeSH Terms

Conditions

Ketosis; Diabetes Mellitus, Type 1

Condition Hierarchy (Ancestors)

Acidosis; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Glucose Metabolism Disorders; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Mads Svart, MD

  Aarhus University / Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

• Niels Møller, MD

  Aarhus University / Aarhus University Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2014
• First Posted: June 5, 2014
• Study Start: June 1, 2014
• Primary Completion: March 1, 2015
• Study Completion: September 1, 2015
• Last Updated: December 2, 2015

Record last verified: 2014-06

Locations

DK (1)