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Hepatic and Cardiac Metabolic Flexibility in Subjects With T2DM With and Without NAFLD

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ClinicalTrials.gov Identifier: NCT04698486
Recruitment Status : Recruiting
First Posted : January 7, 2021
Last Update Posted : January 7, 2021
Sponsor:
Collaborator:
Danish Diabetes Academy
Information provided by (Responsible Party):
University of Aarhus

Study Description
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Brief Summary:
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum from simple reversible hepatic steatosis to inflammation and fibrosis termed steatohepatitis (NASH) and cirrhosis. Accumulating evidence indicates that NAFLD is associated with development of heart failure, abnormal ventricular glucose and fatty acid (FA) utilisation and cardiac steatosis. The mechanisms behind why some subjects progress from NAFLD to NASH and the link between cardiac involvement and NAFLD are poorly understood, but must include altered cardiac and intrahepatic lipid handling. Investigators plan comprehensive kinetic studies of heart and liver FA uptake and oxidation, ventricular function and substrate utilisation, and hepatic triglyceride (TG) secretion in order to assess mechanisms governing cardiac and hepatic lipid and glucose trafficking in subjects with type 2 diabetes with and without NAFLD and NASH and the relationship with heart function. In addition, the investigators will assess skeletal muscle and adipose tissue enzyme activities, gene expression and protein concentrations in type 2 diabetic subjects to define mechanisms involved in the cross-talk between heart, liver, muscle and adipose tissues. Investigators will address these questions using tracer techniques (11Cpalmitate PET tracers and triglyceride (TG) tracers) to study cardiac and liver substrate trafficking, as well as MR spectroscopy, echocardiography, muscle and fat biopsies in combination with state-of-the art muscle and adipose tissue enzyme kinetics, gene- and protein expression. The overarching goals are to define abnormalities and differences between NAFLD and NASH in hepatic lipid (FA and TG) metabolism.

Condition or disease Intervention/treatment Phase
NAFLD - Non-Alcoholic Fatty Liver Disease Type 2 Diabetes Other: Hyperinsulinemic euglycaemic clamp Not Applicable

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Investigation of Hepatic and Cardiac Fatty Acid Metabolism in Patients With Type 2 Diabetes Mellitus With and Without Non-alcoholic Fatty Liver Disease
Actual Study Start Date : July 3, 2020
Estimated Primary Completion Date : January 1, 2022
Estimated Study Completion Date : January 1, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Type 2 Diabetes with NAFLD

Patients with Type 2 Diabetes with NAFLD

MR spectroscopy verified no steatosis

 Other: Hyperinsulinemic euglycaemic clamp

Infusion of constant intravenous insulin to achieve hyperinsulinemia and concomitant infusion of glucose to maintain euglycemia (plasma glucose at 5 mM).

Infusion of palmitate and VLDL-triglyceride tracer. PET/CT scans of heart and liver, both in basal period and during intervention.
Active Comparator: Type 2 Diabetes without NAFLD

Patients with Type 2 Diabetes without NAFLD

MR spectroscopy verified steatosis

 Other: Hyperinsulinemic euglycaemic clamp

Infusion of constant intravenous insulin to achieve hyperinsulinemia and concomitant infusion of glucose to maintain euglycemia (plasma glucose at 5 mM).

Infusion of palmitate and VLDL-triglyceride tracer. PET/CT scans of heart and liver, both in basal period and during intervention.


Outcome Measures
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Primary Outcome Measures :
  1. Fatty acid uptake in Heart (mg/kg/min) [ Time Frame: 1 day ]
    Infusion of [11-C] palmitate and measured by PET/CT scan.

  2. Fatty acid oxidation in Heart (µmol/min) [ Time Frame: 1 day ]
    Infusion of [11-C] palmitate and measured by PET/CT scan.


Secondary Outcome Measures :
  1. VLDL-triglyceride secretion (µmol/min) [ Time Frame: 1 day ]
    Ex vivo labeled VLDL [14C]-triolein tracer technique.

  2. VLDL-triglyceride oxidation (µmol/min) [ Time Frame: 1 day ]
    Oxidation is measured by specific activity in exhaled air.

  3. Fatty acid uptake in liver (mg/kg/min) [ Time Frame: 1 day ]
    Infusion of [11-C] palmitate and measured by PET/CT scan.

  4. Fatty acid oxidation in liver (µmol/min) [ Time Frame: 1 day ]
    Infusion of [11-C] palmitate and measured by PET/CT scan.

  5. VLDL-triglyceride uptake in muscle (percent) [ Time Frame: 1 day ]
    Measurement of fatty acid concentration and specific activity in muscle biopsies

  6. VLDL-triglyceride uptake in adipose tissue (percent) [ Time Frame: 1 day ]
    Measurement of fatty acid concentration and specific activity in adipose tissue biopsies


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects with Type 2 Diabetes with and without NAFLD (steatosis FF% > 5,6% on MR spectroscopy for NAFLD and NASH groups)

Exclusion Criteria:

  • Active smoking
  • Comorbidity other than hypertension and hyperlipidemia
  • Fixed medical drug consumption (including insulin) except statins and anti-diabetic medications. However, statins and weekly based GLP-1 agonist must be paused 1 week before the examination date and other antidiabetic medication 3 days before the study date.
  • Patients with cancer or former cancer patients
  • Blood donation within the last 3 months prior to the study
  • Participation in experiments involving radioactive isotopes within the last 3 months
  • Alcohol abuse (over 21 items per week for men and over 14 for women)
  • Pregnancy
Contacts and Locations
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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): NCT04698486


Contacts
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Contact: Indumathi Kumarathas, MD +4530299715 indumathi@clin.au.dk

Locations
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Denmark
Department of Diabetes and Hormone diseases in Aarhus University Hospital Recruiting
Aarhus N, Denmark, 8200
Sponsors and Collaborators
University of Aarhus
Danish Diabetes Academy
  Study Documents (Full-Text)

Documents provided by University of Aarhus:
Study Protocol and Statistical Analysis Plan  [PDF] July 3, 2020

More Information
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT04698486    
Other Study ID Numbers: 74772
First Posted: January 7, 2021    Key Record Dates
Last Update Posted: January 7, 2021
Last Verified: December 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Diabetes Mellitus, Type 2
Diabetes Mellitus
 Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Digestive System Diseases