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

Investigation of Hepatic and Cardiac Fatty Acid Metabolism in Patients With Type 2 Diabetes Mellitus With and Without Non-alcoholic Fatty Liver Disease

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; NAFLD - Non-Alcoholic Fatty Liver Disease
• Intervention / Treatment: Other: Hyperinsulinemic euglycaemic clamp

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aarhus N, Denmark, 8200
    • Department of Endocrinology and Internal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Danish Diabetes Academy

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2020
• Primary Completion (Actual): December 1, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: December 15, 2020
• First Submitted That Met QC Criteria: January 4, 2021
• First Posted (Actual): January 7, 2021

Study Record Updates

• Last Update Posted (Actual): May 27, 2022
• Last Update Submitted That Met QC Criteria: May 23, 2022
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Liver Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 74772

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No