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

Not Applicable

Completed

• Conditions: NAFLD - Non-Alcoholic Fatty Liver Disease; Type 2 Diabetes
• Interventions: Other: Hyperinsulinemic euglycaemic clamp

• Registration Number: NCT04698486
• Lead Sponsor: University of Aarhus

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2020-07-03
• Status Verified: 2020-12
• Study First Submitted: 2020-12-15
• Study First Submitted QC: 2021-01-04
• Study First Posted: 2021-01-07
• Primary Completion: 2021-12-01
• Study Completion: 2021-12-01
• Last Update Submitted: 2022-05-23
• Last Update Posted: 2022-05-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 17

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Type 2 Diabetes with NAFLD	Hyperinsulinemic euglycaemic clamp	Patients with Type 2 Diabetes with NAFLD MR spectroscopy verified no steatosis
Type 2 Diabetes without NAFLD	Hyperinsulinemic euglycaemic clamp	Patients with Type 2 Diabetes without NAFLD MR spectroscopy verified steatosis

Primary Outcome Measures

Name	Time	Method
Fatty acid oxidation in Heart (µmol/min)	1 day	Infusion of \[11-C\] palmitate and measured by PET/CT scan.
Fatty acid uptake in Heart (mg/kg/min)	1 day	Infusion of \[11-C\] palmitate and measured by PET/CT scan.

Secondary Outcome Measures

Name	Time	Method
VLDL-triglyceride secretion (µmol/min)	1 day	Ex vivo labeled VLDL \[14C\]-triolein tracer technique.
VLDL-triglyceride oxidation (µmol/min)	1 day	Oxidation is measured by specific activity in exhaled air.
Fatty acid uptake in liver (mg/kg/min)	1 day	Infusion of \[11-C\] palmitate and measured by PET/CT scan.
Fatty acid oxidation in liver (µmol/min)	1 day	Infusion of \[11-C\] palmitate and measured by PET/CT scan.
VLDL-triglyceride uptake in muscle (percent)	1 day	Measurement of fatty acid concentration and specific activity in muscle biopsies
VLDL-triglyceride uptake in adipose tissue (percent)	1 day	Measurement of fatty acid concentration and specific activity in adipose tissue biopsies

Trial Locations

Locations (1)

Department of Endocrinology and Internal Medicine; 🇩🇰 Aarhus N, Denmark