Non-alcoholic Fatty Liver Disease in Low Birth Weight Individuals

Sponsor

Steno Diabetes Center Copenhagen (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05842850

Collaborator

Aarhus University Hospital (Other), Lund University (Other)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The investigators will conduct a proof-of-principle deep phenotyping 4-weeks caloric restriction intervention study in low birth weight (LBW) subjects with NAFLD and normal birth weight (NBW) controls. Furthermore, the investigators will provide extended in-depth mechanistic insight into the role of impaired subcutaneous adipose tissue (SAT) expandability in ectopic fat deposition in LBW subjects in LBW individuals with and without NAFLD.

Condition or Disease	Intervention/Treatment	Phase
NAFLD	Behavioral: Caloric restriction intervention Other: No intervention	N/A

Detailed Description

An adverse fetal environment characterized by low birth weight (LBW) plays a key role in the development of type 2 diabetes (T2D). The investigators recently demonstrated a 3-fold increase in liver fat in 26 early middle-aged LBW compared to 22 normal birth weight (NBW) men, and 20% of the LBW - but none of the normal birth weight (NBW) - men had previously unknown non-alcoholic fatty liver disease (NAFLD). The investigators hypothesize that ectopic fat deposition and NAFLD is among the earliest disease manifestations and on the critical path to the development of more severe cardiometabolic disease in LBW. The investigators furthermore hypothesize, that LBW individuals exhibit ectopic liver fat due to reduced capacity to store fat in the subcutaneous adipose tissue (SAT) depot, and that early detection and subsequent intensive caloric restriction, in middle-aged LBW individuals with overt NAFLD, may represent a targeted and highly efficient way forward to prevent more severe cardiometabolic disease manifestations in LBW subjects. To further explore the recent findings, the investigators aim to perform an extended nested case-control screening study for NAFLD in 250 early middle-aged non-obese LBW men and women, and subsequently to conduct a deep-phenotyping, proof-of-principle 4 week time-restricted eating (TRE) intervention study in 12 LBW subjects with NAFLD including measures of hepatic fat content, glucose, insulin and lipid metabolism, as well as 24h metabolic profiles using respiratory chambers. Finally, the investigators will provide extended in-depth mechanistic insight into transcriptional, epigenetic as well as functional SAT and preadipocyte perturbations underlying impaired SAT expandability in LBW individuals with and without NAFLD and NBW controls studied before and after different dietary interventions including TRE and high carbohydrate overfeeding.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Participants will be recruited from a nested case-control (NAFLD) screening study. Participants will be examined on two separate days at baseline (both groups) and after 4-weeks caloric restriction (LBW with NAFLD only). The caloric restriction intervention will start immediately after completion of baseline examinations. Participants will adhere to a caloric restriction protocol for 4-weeks limiting daily food intake to a window of 8 hours (8am to 4pm) and water-fasting for the remaining hours of the day. Participants will be instructed to eat a balanced diet according to the current dietary guidelines reduced by 20% calories to ensure energy deficit. A weighed food diary and accelerometers will be used for 3-days to estimate baseline dietary intake and physical activity and to monitor intervention adherence after 2 and 4 weeks.Participants will be recruited from a nested case-control (NAFLD) screening study. Participants will be examined on two separate days at baseline (both groups) and after 4-weeks caloric restriction (LBW with NAFLD only). The caloric restriction intervention will start immediately after completion of baseline examinations. Participants will adhere to a caloric restriction protocol for 4-weeks limiting daily food intake to a window of 8 hours (8am to 4pm) and water-fasting for the remaining hours of the day. Participants will be instructed to eat a balanced diet according to the current dietary guidelines reduced by 20% calories to ensure energy deficit. A weighed food diary and accelerometers will be used for 3-days to estimate baseline dietary intake and physical activity and to monitor intervention adherence after 2 and 4 weeks.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Increased Risk of Non-alcoholic Fatty Liver Disease in Low Birth Weight Individuals - Reversibility and Mechanistic Studies.

Anticipated Study Start Date :

Dec 1, 2023

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LBW individuals with NAFLD LBW individuals with NAFLD	Behavioral: Caloric restriction intervention The intervention consist of 4-weeks limiting daily food intake to a window of 8 hours (8am to 4pm) and water-fasting for the remaining hours of the day. Participants (LBW NAFLD individuals only) will be instructed to eat a balanced diet according to the current dietary guidelines reduced by 20% calories to ensure energy deficit. Other Names: No intervention
Placebo Comparator: NBW controls without NAFLD Age-, gender- and body mass index-matched NBW controls without NAFLD	Other: No intervention No intervention

Arm

Intervention/Treatment

Experimental: LBW individuals with NAFLD

LBW individuals with NAFLD

Behavioral: Caloric restriction intervention

The intervention consist of 4-weeks limiting daily food intake to a window of 8 hours (8am to 4pm) and water-fasting for the remaining hours of the day. Participants (LBW NAFLD individuals only) will be instructed to eat a balanced diet according to the current dietary guidelines reduced by 20% calories to ensure energy deficit.

Other Names:

No intervention

Placebo Comparator: NBW controls without NAFLD

Age-, gender- and body mass index-matched NBW controls without NAFLD

Other: No intervention

No intervention

Outcome Measures

Primary Outcome Measures

Liver fat content [Change from baseline in liver fat content at 4 weeks]
Liver elastography (FibroScan)
Liver fat content [Change from baseline in liver fat content at 4 weeks]
Validation by Magnetic resonance spectroscopy (MRS)

Secondary Outcome Measures

Liver fibrosis [Baseline and after 4 weeks]
Liver elastography (FibroScan)
Whole-body insulin sensitivity [Baseline and after 4 weeks]
Stepwise hyperinsulinemic-euglycemic clamp
Beta-cell function [Baseline and after 4 weeks]
Intravenous glucose tolerance test
Glucose turnover rate [Baseline and after 4 weeks]
Stable isotope dilution technique
Fat turnover rate [Baseline and after 4 weeks]
Stable isotope dilution techniques
Urea turnover rate [Baseline and after 4 weeks]
Stable isotope dilution techniques
24-hour energy metabolism [Baseline and after 4 weeks]
Indirect calorimetry in respiratory chamber
Body composition [Baseline and after 4 weeks]
DEXA scan

Other Outcome Measures

Adipocyte size [Baseline and after 4 weeks]
Adipose tissue immunohistochemistry
Collagen content [Baseline and after 4 weeks]
Adipose tissue immunohistochemistry
Transcriptomics [Baseline and after 4 weeks]
RNAseq of bulk subcutaneous adipose tissue
Transcriptomics [Baseline and after 4 weeks]
RNAseq of ex vivo cultured preadipocytes
Epigenetics [Baseline and after 4 weeks]
Genome-wide DNA methylation of subcutaneous adipose tissue
Epigenetics [Baseline and after 4 weeks]
Genome-wide DNA methylation of ex vivo cultured preadipocytes
Metabolism of ex vivo differentiated preadipocytes [Baseline and after 4 weeks]
Functional characterization of lipid metabolism
Metabolism of ex vivo differentiated preadipocytes [Baseline and after 4 weeks]
Functional characterization of glucose metabolism

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

LBW subjects with NAFLD (liver fat content ≥5% liver fat content verified on MRS)
Gender- and body mass index-matched NBW controls without NAFLD
Born at term (weeks 39-41)