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

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ClinicalTrials.gov Identifier: NCT02077348
Recruitment Status : Completed
First Posted : March 4, 2014
Last Update Posted : February 24, 2016
Sponsor:
Information provided by (Responsible Party):
Thomas Schmidt Voss, University of Aarhus

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

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Type I Ketoacidosis Drug: Insulin withdrawal Drug: Norditropin Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Metabolic Signalling in Muscle- and Adipose Tissue Following Insulin Withdrawal and Growth Hormone Injection in Type I Diabetes Mellitus, a Clinical Experimental Study.
Study Start Date : May 2014
Actual Primary Completion Date : September 2015
Actual Study Completion Date : September 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

Arm Intervention/treatment
No Intervention: Insulin

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.

Experimental: Insulin withdrawal

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
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.
Other Name: Insuman Rapid

Experimental: Norditropin (Growth Hormone)

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
0,4 mg of GH administered at 7.05 A.M. on the study day.
Other Name: Growth Hormone




Primary Outcome Measures :
  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. [ Time Frame: 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) ]
    Change in phosphorylation of target proteins and mRNA (messenger RNA) expression of target genes assessed with western blotting technique.


Secondary Outcome Measures :
  1. Change in Intracellular markers of lipid metabolism in muscle- and fat tissue biopsies. [ Time Frame: 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) ]
    Assessed by Western blotting.

  2. Metabolism [ Time Frame: Change in glucose, fat and protein metabolism between study days. ]

    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=80min - 260min. [9,10-3H]Palmitic acid tracer from t=200min - 260min. [13C] Urea tracer from 20min - 260min.

    15N-phenylalanine tracer and 2H4-tyrosine tracer from 80 min - 260 min.


  3. Ghrelin [ Time Frame: 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 ]
    Change in circulating plasma acyl- and desacyl ghrelin levels between study days.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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

-


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02077348


Locations
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Denmark
Institute of Clinical Medicine
Aarhus, Aarhus C, Denmark, 8000
Sponsors and Collaborators
University of Aarhus
Investigators
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Study Chair: Niels Møller, MD Aarhus University / Aarhus University Hospital
Principal Investigator: Thomas Voss, MD Aarhus University / Aarhus University Hospital
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Thomas Schmidt Voss, MD, University of Aarhus
ClinicalTrials.gov Identifier: NCT02077348    
Other Study ID Numbers: 1-10-72-247-13
1-10-72-247-13 ( Other Identifier: Danish Ethics Committee )
First Posted: March 4, 2014    Key Record Dates
Last Update Posted: February 24, 2016
Last Verified: February 2016
Keywords provided by Thomas Schmidt Voss, University of Aarhus:
Diabetes Mellitus type I
Ketoacidosis
Insulin withdrawal
Growth hormone injection
Lipolysis and ATGL
Additional relevant MeSH terms:
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Diabetes Mellitus
Ketosis
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Acidosis
Acid-Base Imbalance
Autoimmune Diseases
Immune System Diseases
Hormones
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists