Non-alcoholic Fatty Liver Disease in Low Birth Weight Individuals

NAFLD Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05842850
• Other study ID #: NAFLD reversibility
• Status: Not yet recruiting
• Phase: N/A
• Start date: August 2024
• Est. completion date: August 2025

Study information

• Verified date: April 2024
• Source: Steno Diabetes Center Copenhagen
• Contact: Charlotte Brøns, PhD
• Phone: +4526129093
• Email: charlotte.broens.01[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 24
• Est. completion date: August 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 40 Years

Eligibility

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)

Exclusion Criteria:

• BMI<18.5 and BMI>30 kg/m2
• Family history of diabetes (siblings, parent, and grandparents)
• Disease/medication known to affect primary outcome
• Self-reported high physical activity level
• Alcohol intake above general recommendations.
• Metabolic/liver disease
• Weight gain/loss of >3 kg within the past 6 months

Related Conditions & MeSH terms

• Birth Weight
• Fatty Liver
• Liver Diseases
• NAFLD
• Non-alcoholic Fatty Liver Disease

Intervention

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:
• No intervention
No intervention

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Steno Diabetes Center Copenhagen	Aarhus University Hospital, Lund University

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adipocyte size	Adipose tissue immunohistochemistry	Baseline and after 4 weeks
Other	Collagen content	Adipose tissue immunohistochemistry	Baseline and after 4 weeks
Other	Transcriptomics	RNAseq of bulk subcutaneous adipose tissue	Baseline and after 4 weeks
Other	Transcriptomics	RNAseq of ex vivo cultured preadipocytes	Baseline and after 4 weeks
Other	Epigenetics	Genome-wide DNA methylation of subcutaneous adipose tissue	Baseline and after 4 weeks
Other	Epigenetics	Genome-wide DNA methylation of ex vivo cultured preadipocytes	Baseline and after 4 weeks
Other	Metabolism of ex vivo differentiated preadipocytes	Functional characterization of lipid metabolism	Baseline and after 4 weeks
Other	Metabolism of ex vivo differentiated preadipocytes	Functional characterization of glucose metabolism	Baseline and after 4 weeks
Primary	Liver fat content	Liver elastography (FibroScan)	Change from baseline in liver fat content at 4 weeks
Primary	Liver fat content	Validation by Magnetic resonance spectroscopy (MRS)	Change from baseline in liver fat content at 4 weeks
Secondary	Liver fibrosis	Liver elastography (FibroScan)	Baseline and after 4 weeks
Secondary	Whole-body insulin sensitivity	Stepwise hyperinsulinemic-euglycemic clamp	Baseline and after 4 weeks
Secondary	Beta-cell function	Intravenous glucose tolerance test	Baseline and after 4 weeks
Secondary	Glucose turnover rate	Stable isotope dilution technique	Baseline and after 4 weeks
Secondary	Fat turnover rate	Stable isotope dilution techniques	Baseline and after 4 weeks
Secondary	Urea turnover rate	Stable isotope dilution techniques	Baseline and after 4 weeks
Secondary	24-hour energy metabolism	Indirect calorimetry in respiratory chamber	Baseline and after 4 weeks
Secondary	Body composition	DEXA scan	Baseline and after 4 weeks