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

NCT04698486 | Completed

• 1 other identifier: 74772
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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.

Conditions

NAFLD - Non-Alcoholic Fatty Liver Disease; Type 2 Diabetes

Outcome Measures

Primary Outcomes (2)

• Fatty acid uptake in Heart (mg/kg/min)

  Infusion of \[11-C\] palmitate and measured by PET/CT scan.

  1 day

• Fatty acid oxidation in Heart (µmol/min)

  Infusion of \[11-C\] palmitate and measured by PET/CT scan.

  1 day

Secondary Outcomes (6)

• VLDL-triglyceride secretion (µmol/min)

  1 day

• VLDL-triglyceride oxidation (µmol/min)

  1 day

• Fatty acid uptake in liver (mg/kg/min)

  1 day

• Fatty acid oxidation in liver (µmol/min)

  1 day

• VLDL-triglyceride uptake in muscle (percent)

  1 day

Study Arms (2)

Type 2 Diabetes with NAFLD

ACTIVE COMPARATOR

Patients with Type 2 Diabetes with NAFLD MR spectroscopy verified no steatosis

Other: Hyperinsulinemic euglycaemic clamp

Type 2 Diabetes without NAFLD

ACTIVE COMPARATOR

Patients with Type 2 Diabetes without NAFLD MR spectroscopy verified steatosis

Other: Hyperinsulinemic euglycaemic clamp

Interventions

Hyperinsulinemic euglycaemic clamp OTHER

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.

Type 2 Diabetes with NAFLD; Type 2 Diabetes without NAFLD

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Aarhus: lead
• Danish Diabetes Academy: collaborator

Study Sites (1)

Department of Endocrinology and Internal Medicine

Aarhus N, 8200, Denmark

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2020
• First Posted: January 7, 2021
• Study Start: July 3, 2020
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: May 27, 2022

Record last verified: 2020-12

Locations

DK (1)