Postprandial VLDL-triglyceride Metabolism in Type 2 Diabetes Patients With and Without NAFLD

Postprandial Hepatic Fatty Acid Metabolism During Oral High-fat Mixed-meal Challenge Test in Patients With Type 2 Diabetes With and Without NAFLD

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum from simple reversible hepatic steatosis to inflammation and fibrosis termed steatohepatitis (NASH). The mechanisms behind why some subjects progress from NAFLD to NASH are not clear and the responsible mechanism for storage of excess amounts of liver fat in patients with NAFLD are poorly understood.

Patients with type 2 diabetes mellitus (T2D) and abdominally obese subjects very often have accumulation of liver fat (NAFLD).

T2D is also associated with abnormal lipid metabolism (dyslipidemia), including free fatty acids (FFA), hypertriglyceridemia and excessive postprandial hyperlipidemia which increases the risk of ischemic cardiovascular disease (CVD) and heart failure.

In healthy, insulin sensitive subjects the postprandial increase in triglycerides (TG) is primarily caused by meal derived chylomicrons, whereas endogenously produced TG (VLDL-TG) and decreased peripheral TG clearance only becomes quantitatively important in insulin resistant subjects .Thus, postprandial lipidemia in T2D results from both chylomicronemia as well as a reduction in both insulin mediated suppression of VLDL-TG secretion and lipoprotein lipase (LPL) mediated peripheral clearance. A recent study demonstrated that the ability of insulin to suppress hepatic VLDL-TG after a fat-enriched meal and the duration of the postprandial hyperlipidemia was similar in patients with T2D compared with age- and BMI matched individuals without T2D, indicating that the degree of insulin mediated VLDL-TG secretion and hyperlipidemia primarily depends on insulin sensitivity and not the presence of T2D diabetes per se.

In these studies, the investigators want to examine the effect of a fat enriched mixed-meal on hepatic VLDL-TG handling and adipose storage capacity in patients with T2D with and without NAFLD. Investigators will address these questions using carboxyl-14C triolein labeled VLDL-TG, magnetic resonance (MR) spectroscopy of liver, 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 patients with T2D with and without NAFLD in terms of hepatic lipid metabolism.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; NAFLD
• Intervention / Treatment: Dietary supplement: High-fat mixed-meal tolerance test (HF-MMTT)

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

Contacts and Locations

• Study Contact: Name: Indumathi Kumarathas, MD; Phone Number: +4530299715; Email: indumathi@clin.au.dk

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: No

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 must be paused 2 weeks before the examination date and other antidiabetic medication on examination 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 steatosis	Dietary supplement: High-fat mixed-meal tolerance test (HF-MMTT); The test meal consists of a standardized HF-MMTT (791 cal) with 197 g cream (38 % fat), 18 g sugar and 1 g vanilla sugar for taste (75 g fat, 25 g carbohydrate and 4 g protein)
Active Comparator: Type 2 Diabetes without NAFLD; Patients with Type 2 Diabetes without NAFLD MR spectroscopy verified no steatosis	Dietary supplement: High-fat mixed-meal tolerance test (HF-MMTT); The test meal consists of a standardized HF-MMTT (791 cal) with 197 g cream (38 % fat), 18 g sugar and 1 g vanilla sugar for taste (75 g fat, 25 g carbohydrate and 4 g protein)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VLDL-triglyceride secretion - Ex vivo labeled VLDL - [14C]-triolein tracer technique.	(μmol/min)	1 day
VLDL-triglyceride uptake in muscle - Measurement of fatty acid concentration and specific activity in muscle biopsies	(percent)	1 day
VLDL-triglyceride uptake in adipose tissue - Measurement of fatty acid concentration and specific activity in adipose tissue biopsies	(percent)	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VLDL-triglyceride oxidation - Oxidation is measured by specific activity in exhaled air.	(μmol/min)	1 day
Adipose cell size measurement	(μl)	1 day
Insulin sensitivity	(mg/kg/min)	1 day

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2021
• Primary Completion (Actual): February 23, 2023
• Study Completion (Actual): April 23, 2023

Study Registration Dates

• First Submitted: September 4, 2021
• First Submitted That Met QC Criteria: September 4, 2021
• First Posted (Actual): September 14, 2021

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 20, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Liver Diseases; Fatty Liver; Diabetes Mellitus; Diabetes Mellitus, Type 2; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 01072021

Drug and device information, study documents

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