Clinical trial NCT04527965: Liver Fat as a Dietary Target for Treating Cardiometabolic Disorders in Prediabetes and Type 2 Diabetes
Official title: Liver Fat as a Dietary Target for Treating Cardiometabolic Disorders in Prediabetes and Type 2 Diabetes: a Randomized Study (NAFLDiet)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: NAFLD
Diabetes Mellitus, Type 2
PreDiabetes
Keywords: NAFLD
Diabetes Mellitus, Type 2
Prediabetes
Fatty acids
Diet
Lipogenesis
Cardiometabolic risk
Lead sponsor: Uppsala University
Sponsor class: OTHER
First posted: 2020-08-27
Enrollment: 150
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel Assignment
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Between-group changes in liver fat content between baseline and month 12
timeFrame: 12 months
Secondary outcomes:
measure: Between-group changes in visceral adipose tissue mass between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in lean tissue mass between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in total body fat mass between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in body weight between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in glycated hemoglobin (HbA1c) between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in fasting plasma glucose between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in fasting serum insulin between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in systolic blood pressure between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in diastolic blood pressure between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in plasma lipids (total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol, apoB and apoA1) between baseline and month 12
timeFrame: 12 months
measure: 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
timeFrame: 12 months
measure: Between-group changes in pancreatic fat between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in flow-mediated dilation (FMD) between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in pulse-wave velocity (PWV) between baseline and month 12
timeFrame: 12 months
measure: Between-group values in FMD at month 12
timeFrame: 12 months
measure: Between-group values in PWV at month 12
timeFrame: 12 months
measure: 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
timeFrame: 12 months
measure: 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
timeFrame: 12 months
measure: 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
timeFrame: 12 months
measure: Between-group changes in FIB-4 between baseline and month 12
timeFrame: 12 months
Other outcomes:
measure: Between-group changes in plasma-derived fatty acids and fatty acid ratios in the lipogenic pathway between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in imaging-derived fatty acids and fatty acid ratios in the lipogenic pathway between baseline and month 12
timeFrame: 12 months
measure: Between-group changes in plasma lipids (ceramides) using a targeted lipidomic approach between baseline and month 12
timeFrame: 12 months
Locations:
city: Uppsala
country: Sweden
facility: Uppsala univeristy hospital
Study officials:
affiliation: Uppsala University
name: Ulf Risérus, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Uppsala University
name: Lars Lind, MD
role: STUDY_DIRECTOR
References: