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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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NAFLD, Diabetes Mellitus, Type 2, PreDiabetes

Intervention / Treatment
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* Other: Customized diet to reduce liver fat
* Other: Healthy Nordic diet
* Other: Control


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Customized diet to reduce liver fat<br>Ad libitum diet high in plant-derived PUFA and lower in carbohydrates | Other: Customized diet to reduce liver fat<br>* 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<br>|
| Experimental: Healthy Nordic diet<br>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<br>* 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<br>|
| Active Comparator: Control<br>Ad libitum diet in accordance with the Nordic Nutrition Recommendations | Other: Control<br>* Ad libitum diet in accordance with the Nordic Nutrition Recommendations Key foods are provided<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, Diabetes Mellitus, Type 2, Prediabetes, Fatty acids, Diet, Lipogenesis, Cardiometabolic risk