Metabolic Signalling in Muscle- and Adipose-tissue Following Insulin Withdrawal and Growth Hormone Injection.

NCT02077348 | Completed

• 1 other identifier: 1-10-72-247-13
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Diabetes mellitus type I (DM I) is characterized by lack of endogenous insulin and these patients are 100% dependent on insulin substitution to survive. Insulin is a potent anabolic hormone with its primary targets in the liver, the skeletal muscle-tissue and - adipose-tissue. Severe lack of insulin leads to elevated blood glucose levels, dehydration, electrolyte derangement, ketosis and thus eventually ketoacidosis. Insulin signalling pathways are well-known. Growth hormone (GH) is also a potent anabolic hormone, responsible for human growth and preservation of protein during fasting. GH (in concert with lack of insulin) induces lipolysis during fasting. It is not known how GH exerts its lipolytic actions. The aim is to define insulin and growth hormone (GH) signalling pathways in 3 different states in patients with DM I. And to test whether ATGL-related lipolysis in adipose tissue contributes to the development of ketosis.

1. 1.Good glycemic control
2. 2.Lack of insulin (ketosis/ketoacidosis)
3. 3.Good glycemic control and GH injection

Conditions

Diabetes Mellitus Type I; Ketoacidosis

Keywords

Diabetes Mellitus type I; Ketoacidosis; Insulin withdrawal; Growth hormone injection; Lipolysis and ATGL

Outcome Measures

Primary Outcomes (1)

• Insulin and growth hormone signalling, expressed as 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 mRNA (messenger RNA) expression of target genes assessed with western blotting technique.

  Muscle and fat biopsies obtained on each study day (arm): t1= 7.00 (0 min) am t2=11.30 (270min) am t3= 13.00 pm (360min)

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= 7.00 (0 min) am t2=11.30 (270min) am t3= 13.00 pm (360min)

• Metabolism

  Change in glucose, fat and protein metabolism between study days.

• Ghrelin

  Plasma samples obtained at t=0, t=15, t=30, t=45, t=60, t=75, t=90, t=105, t=120, t=150, t=180, t=210, t=240, t=270, t=300

Study Arms (3)

Insulin

NO INTERVENTION

good glycemic control: 50 % of the subject's basal insulin dosage will be given as a continuous IV administration of insuman rapid overnight (hospitalized and fasting from 10 p.m.) and on the study-day. Basal period from 7.00 am to 12.00pm. The subject will undergo a hyperinsulinemic euglycemic clamp from 12.00 pm to 2.30 pm. Three muscle- and three fat-biopsies will be obtained. A palmitic-acid tracer, a glucose tracer, urea tracer, tyrosine- and phenylalanine- tracers will be given.

Insulin withdrawal

EXPERIMENTAL

10 % of the individual subject's regular insulin dosage will be given as a continuous IV administration of insuman rapid overnight (hospitalized and fasting from 10 p.m.) Basal period from 7.00 am to 12.00 pm (without insulin). The subject will undergo a hyperinsulinemic euglycemic clamp from 12.00 pm to 2.30 pm. Three muscle- and three fat-biopsies will be obtained. A palmitic-acid tracer, a glucose tracer, urea tracer, tyrosine- and phenylalanine- tracers will be given.

Drug: Insulin withdrawal

Norditropin (Growth Hormone)

EXPERIMENTAL

Same amount of insulin administered on the control day (good glycemic control) overnight and on the study day (hospitalized and fasting from 10 p.m.). On the study day, a bolus injection of 0,4 mg of growth hormone (Norditropin) will be administered at 7.05 am. Basal period from 7.00 am to 12.00 pm (good glycemic control).The subject will undergo a hyperinsulinemic euglycemic clamp from 12.00 pm to 2.30 pm. Three muscle- and three fat-biopsies will be obtained. A palmitic-acid tracer, a glucose tracer, urea tracer, tyrosine- and phenylalanine- tracers will be given.

Drug: Norditropin

Interventions

Insulin withdrawal DRUG

Withdrawal of usual (evening) insulin, replaced by Insuman Rapid (10% of the amount of usual evening insulin) as a continuous IV- administration overnight until 8 o'clock on the study day.

Also known as: Insuman Rapid

Insulin withdrawal

Norditropin DRUG

0,4 mg of GH administered at 7.05 A.M. on the study day.

Also known as: Growth Hormone

Norditropin (Growth Hormone)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of Diabetes Mellitus Type I, C-peptide negative, 19 \< BMI \< 26, Written consent -

You may not qualify if:

• Ischemic heart disease, Cardiac arrythmia, Epilepsy, Other medical illness

Sponsors & Collaborators

• University of Aarhus: lead

Study Sites (1)

Institute of Clinical Medicine

Aarhus, Aarhus C, 8000, Denmark

Location

Related Publications (15)

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  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

• Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Ryden M, Arner E, Sicard A, Jenkins CM, Viguerie N, van Harmelen V, Gross RW, Holm C, Arner P. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005 Nov;54(11):3190-7. doi: 10.2337/diabetes.54.11.3190.

  PMID: 16249444 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

• 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

• 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

• Teunissen BE, Smeets PJ, Willemsen PH, De Windt LJ, Van der Vusse GJ, Van Bilsen M. Activation of PPARdelta inhibits cardiac fibroblast proliferation and the transdifferentiation into myofibroblasts. Cardiovasc Res. 2007 Aug 1;75(3):519-29. doi: 10.1016/j.cardiores.2007.04.026. Epub 2007 May 3.

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• Birzniece V, Sata A, Ho KK. Growth hormone receptor modulators. Rev Endocr Metab Disord. 2009 Jun;10(2):145-56. doi: 10.1007/s11154-008-9089-x.

  PMID: 18622706 BACKGROUND

• Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24.

  PMID: 19240267 BACKGROUND

• Silva CM, Kloth MT, Whatmore AJ, Freeth JS, Anderson N, Laughlin KK, Huynh T, Woodall AJ, Clayton PE. GH and epidermal growth factor signaling in normal and Laron syndrome fibroblasts. Endocrinology. 2002 Jul;143(7):2610-7. doi: 10.1210/endo.143.7.8909.

  PMID: 12072393 BACKGROUND

• Beauville M, Harant I, Crampes F, Riviere D, Tauber MT, Tauber JP, Garrigues M. Effect of long-term rhGH administration in GH-deficient adults on fat cell epinephrine response. Am J Physiol. 1992 Sep;263(3 Pt 1):E467-72. doi: 10.1152/ajpendo.1992.263.3.E467.

  PMID: 1415526 BACKGROUND

• Fisker FA, Voss TS, Svart MV, Kampmann U, Vendelbo MH, Bengtsen MB, Lauritzen ES, Moller N, Jessen N. Insulin Signaling Is Preserved in Skeletal Muscle During Early Diabetic Ketoacidosis. J Clin Endocrinol Metab. 2023 Dec 21;109(1):e155-e162. doi: 10.1210/clinem/dgad464.

  PMID: 37554078 DERIVED

• 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

• Voss TS, Vendelbo MH, Kampmann U, Pedersen SB, Nielsen TS, Johannsen M, Svart MV, Jessen N, Moller N. Substrate metabolism, hormone and cytokine levels and adipose tissue signalling in individuals with type 1 diabetes after insulin withdrawal and subsequent insulin therapy to model the initiating steps of ketoacidosis. Diabetologia. 2019 Mar;62(3):494-503. doi: 10.1007/s00125-018-4785-x. Epub 2018 Dec 1.

  PMID: 30506451 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Ketosis

Interventions

Human Growth Hormone; Growth Hormone

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Pituitary Hormones, Anterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Niels Møller, MD

  Aarhus University / Aarhus University Hospital

  STUDY CHAIR

• Thomas Voss, MD

  Aarhus University / Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: February 20, 2014
• First Posted: March 4, 2014
• Study Start: May 1, 2014
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: February 24, 2016

Record last verified: 2016-02

Locations

DK (1)