Liver Fat as a Dietary Target for Treating Cardiometabolic Disorders in Prediabetes and Type 2 Diabetes (NAFLDiet)

Liver Fat as a Dietary Target for Treating Cardiometabolic Disorders in Prediabetes and Type 2 Diabetes: a Randomized Study (NAFLDiet)

The overall aim of this study is to investigate the long-term impact of a customized diet aimed at reducing liver fat specifically and a healthy Nordic diet on ectopic fat (liver, pancreatic and visceral) and cardiometabolic risk in individuals with prediabetes and type 2 diabetes (T2D).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; PreDiabetes; NAFLD
• Intervention / Treatment: Other: Customized diet to reduce liver fat; Other: Healthy Nordic diet; Other: Control

Detailed Description

Randomized controlled studies investigating the impact of replacing dietary carbohydrates with polyunsaturated fat (PUFA) on liver fat content and cardiometabolic risk in individuals with prediabetes and T2D are lacking. Also, the effects of a Healthy Nordic Diet on liver fat content and glycemic control have not be investigated. This study therefore aims to:

• Investigate the effects of the diets on liver fat content (primary aim)
• Investigate the effects of the diets on pancreatic fat, visceral fat, lean tissue, glycemic and lipid control
• Investigate the effects of the diets on plasma markers of de novo lipogenesis (DNL) and desaturation (i.e. stearoyl-Coenzyme desaturase 1, SCD-1) as well as on hepatic DNL using MRI spectroscopy
• Investigate gene-diet interactions, especially if common gene variants (e.g. in PNPLA3) known to increase liver fat and dyslipidemia, may modify the dietary effects.
• Perform lipidomic analyses to identify potential mechanistic pathways that may associate with diet-induced changes in liver fat, pancreatic fat, visceral fat, insulin sensitivity, dyslipidemia or DNL

Our hypothesis is that a customized diet will effectively reduce liver fat through suppression of hepatic DNL and SCD-1 activity, and thereby improve atherogenic dyslipidemia, insulin resistance and hyperglycemia in individuals with prediabetes and T2D.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Sweden
  • Uppsala, Sweden, 75185
    • Uppsala Univeristy Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men and women
• 30-75 years
• BMI 25-40
• T2D (duration ≤10 years, no insulin treatment) or prediabetes (ADA definition 2019) without diagnosed cardiovascular disease (CVD) during the last 2 years (e.g. myocardial infarction, stroke or angina pectoris)

Exclusion Criteria:

• BMI >40
• Alcohol intake >20 g/day
• Unwillingness to follow a new prescribed diet for 1 year
• Diet-induced weight loss (≥10%) the preceding 3 months of screening
• Malignant disease
• Severe kidney and liver disease
• Heart failure or other severe CVD
• claustrophobia or metal parts in the body (MRI)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Customized diet to reduce liver fat; Ad libitum diet high in plant-derived PUFA and lower in carbohydrates	Other: Customized diet to reduce liver fat; Ad libitum diet high in plant-derived PUFA and lower in carbohydrates Carbohydrates: 30 E% Fat: 50 E% (PUFA 10-15 E%) Protein: 20 E% Key foods are provided
Experimental: Healthy Nordic diet; Ad libitum diet, based on Nordic foods, higher in carbohydrates (high fiber/low GI) and lower in fat but rich in monounsaturated fatty acids (MUFA) and PUFA	Other: Healthy Nordic diet; Ad libitum diet, based on Nordic foods, high in carbohydrates (high fiber/low GI) and lower in fat Carbohydrates: 50-55 E% Fat: 25-30 E% (PUFA 5-7.5 E%) Protein: 20 E% Key foods are provided
Active Comparator: Control; Ad libitum diet in accordance with the Nordic Nutrition Recommendations	Other: Control; Ad libitum diet in accordance with the Nordic Nutrition Recommendations Key foods are provided

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group changes in liver fat content between baseline and month 12	Assessed by magnetic resonance imaging (MRI)	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group changes in visceral adipose tissue mass between baseline and month 12	Assessed by magnetic resonance imaging (MRI)	12 months
Between-group changes in lean tissue mass between baseline and month 12	Assessed by magnetic resonance imaging (MRI)	12 months
Between-group changes in total body fat mass between baseline and month 12	Assessed by magnetic resonance imaging (MRI)	12 months
Between-group changes in body weight between baseline and month 12	Assessed by using a Tanita bioelectrical impedance analysis (BIA) scale	12 months
Between-group changes in glycated hemoglobin (HbA1c) between baseline and month 12	Assessed by routine clinical chemistry	12 months
Between-group changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) between baseline and month 12	Assessed by routine clinical chemistry	12 months
Between-group changes in fasting plasma glucose between baseline and month 12	Assessed by routine clinical chemistry	12 months
Between-group changes in fasting serum insulin between baseline and month 12	Assessed by routine clinical chemistry	12 months
Between-group changes in systolic blood pressure between baseline and month 12	Assessed by using an automated blood pressure monitor	12 months
Between-group changes in diastolic blood pressure between baseline and month 12	Assessed by using an automated blood pressure monitor	12 months
Between-group changes in plasma lipids (total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol, apoB and apoA1) between baseline and month 12	Assessed by routine clinical chemistry	12 months
Between-group changes in circulating inflammatory markers (CRP, Tumor Necrosis Factor Alpha-receptor 1 and 2, Interleukin-1 receptor antagonist, Fibroblast growth factor 21) between baseline and month 12	Assessed by routine clinical chemistry and ELISA	12 months
Between-group changes in pancreatic fat between baseline and month 12	Assessed by magnetic resonance imaging (MRI)	12 months
Between-group changes in flow-mediated dilation (FMD) between baseline and month 12	Assessed by ultrasound in approximately half of the study population (n=75)	12 months
Between-group changes in pulse-wave velocity (PWV) between baseline and month 12	Assessed by ultrasound in approximately half of the study population (n=75)	12 months
Between-group values in FMD at month 12	Assessed by ultrasound in the whole population (n=150)	12 months
Between-group values in PWV at month 12	Assessed by ultrasound in the whole population (n=150)	12 months
Between-group changes in liver fat in prespecified subgroups and in individuals with low respectively high dietary compliance based on dietary and lipogenic biomarkers changes between baseline and month 12	Assessed by magnetic resonance imaging (MRI)	12 months
Between-group changes in HbA1c in prespecified subgroups and in individuals with low respectively high dietary compliance based on dietary and lipogenic biomarkers changes between baseline and month 12	Assessed by routine clinical chemistry	12 months
Between-group changes in blood lipids in prespecified subgroups and in individuals with low respectively high dietary compliance based on dietary and lipogenic biomarkers changes between baseline and month 12	Assessed by routine clinical chemistry	12 months
Between-group changes in FIB-4 between baseline and month 12	Assessed by routine clinical chemistry in combination with age	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group changes in plasma-derived fatty acids and fatty acid ratios in the lipogenic pathway between baseline and month 12	Assessed by gas chromatography (GC)	12 months
Between-group changes in imaging-derived fatty acids and fatty acid ratios in the lipogenic pathway between baseline and month 12	Assessed by proton magnetic resonance spectroscopy (1 H-MRS)	12 months
Between-group changes in plasma lipids (ceramides) using a targeted lipidomic approach between baseline and month 12	Lipids are measured using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)	12 months

Collaborators and Investigators

• Sponsor: Uppsala University
• Investigators: Principal Investigator: Ulf Riserus, PhD, Uppsala University; Study Director: Lars Lind, MD, Uppsala University

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2020
• Primary Completion (Actual): December 20, 2022
• Study Completion (Actual): December 20, 2022

Study Registration Dates

• First Submitted: August 5, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 27, 2020

Study Record Updates

• Last Update Posted (Estimate): December 22, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Prediabetes; Diet; NAFLD; Diabetes Mellitus, Type 2; Fatty acids; Cardiometabolic risk; Lipogenesis
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Prediabetic State; Glucose Intolerance
• Other Study ID Numbers: NAFLDiet

Drug and device information, study documents

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