Pancreas Lipotoxicity in T2D: Edinburgh Diabetes Remission Study (EDRS)

NCT07364045 | Recruiting

• 1 other identifier: AC23027
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to investigate how fat accumulation in the pancreas contributes to the development of type 2 diabetes (T2D), and how weight loss may reverse this process. Previous research has shown that reducing body weight can lead to diabetes remission, and this was accompanied by lowering intrapancreatic fat and restoration of insulin secretion, but the mechanisms behind this are not fully understood. In particular, the study aims to unravel the role of hepatic de novo lipogenesis (DNL) and lipoprotein metabolism on pancreas lipotoxicity and beta cell recovery after weight loss. Four groups of participants will be recruited (n=26 per group): non-diabetic, pre-diabetic, short-duration T2D (\<6 years), and long-duration T2D (\>10 years). Participants will be aged between 45 and 79 years and have a BMI between 30 and 45 kg/m². All participants will follow a structured weight loss programme using an 800 kcal/day Total Diet Replacement (TDR) for 8-12 weeks, followed by dietary support to maintain weight loss. The study is sponsored by NHS-Lothian and the University of Edinburgh and will be carried out at the Clinical Research Facility, Royal infirmary of Edinburgh by a specialist team (Senior Diabetes Research Nurse, Clinical Fellow, and Research Dietitian). The primary endpoint of this study is to achieve a 10-15% reduction in body weight (\~10 kg) through a low-calorie diet (800 kcal/day) to induce T2D remission and maintain this weight loss with structured dietary support for up to 6-12 months. The primary aim is to compare hepatic de novo lipogenesis-the conversion of sugar into fat by the liver-and lipoprotein export among the groups, and to examine how these parameters change in response to weight loss, improvement in metabolic status, and restoration of normal pancreatic function. Secondary endpoints include changes in weight, HbA1c, intraorgan fat (liver/pancreas), pancreas volume and tissue characteristics, beta cell mass and function (MRI/mixed meal test), circulating blood markers (i.e. lipids, exosomes, adipokines, and inflammatory markers), and the change in adipose tissue biology (fat biopsies). Ultimately, this study aims to understand the mechanisms of T2D remission. It will help clarify the sequence of metabolic events leading to reversible pancreatic lipotoxicity and may inform the development of new, targeted therapies for T2D.

Conditions

Type 2 Diabetes

Keywords

Type 2 Diabetes; Obesity; Remission; Weight loss

Outcome Measures

Primary Outcomes (2)

• Change in body weight from baseline to 6-12 months post-intervention

  The primary endpoint is achieving a 10-15% reduction in body weight (\~10 kg) through a low-calorie diet (800 kcal/day) to induce T2D remission and maintain this weight loss with structured dietary support for up to 6-12 months. The study will also compare four participant groups (non-diabetic, pre-diabetic, short-duration T2D, long-duration T2D) in terms of hepatic de novo lipogenesis and lipoprotein export, and examine changes in these parameters in response to weight loss and improved metabolic status.

  Baseline, 6 months, and 12 months post-intervention

• Change in hepatic de novo lipogenesis measured using stable isotope tracers

  Hepatic de novo lipogenesis will be quantified using stable isotope tracer methodology (deuterated water) at baseline and after intervention.

  Baseline, 6 months, and 12 months

Secondary Outcomes (8)

• Change in liver and pancreas fat measured by MRI

  Baseline, 6 months, and 12 months

• Change in beta-cell function assessed by C-peptide response during mixed meal test

  Baseline, 6 months, and 12 months

• Change in circulating lipoproteins and lipids

  Baseline, 6 months, and 12 months

• Change in pancreas morphology and tissue inflammation

  Baseline, 6 months, and 12 months

• Change in adipose tissue biology

  Baseline and 6 months post-intervention

Study Arms (4)

Non-Diabetic Group

EXPERIMENTAL

Participants without diabetes who are overweight or obese (BMI 30-45 kg/m²) will undergo an 8-12-week Total Diet Replacement (TDR) intervention (\~800 kcal/day) followed by food reintroduction and weight maintenance. Includes metabolic testing, MRI scans, and blood sampling at baseline and follow-up.

Behavioral: Total Diet Replacement (TDR) Program

Pre-Diabetic Group

EXPERIMENTAL

Participants with pre-diabetes who are overweight or obese (BMI 30-45 kg/m²) will receive the same TDR intervention and follow-up schedule as the Non-Diabetic Group, with additional oral glucose tolerance testing during screening.

Behavioral: Total Diet Replacement (TDR) Program

Short-Duration Type 2 Diabetes Group

EXPERIMENTAL

Participants with type 2 diabetes diagnosed \<6 years who are overweight or obese (BMI 30-45 kg/m²) will undergo the TDR intervention and extended follow-up (up to 12-24 months) with additional metabolic visits and blood sampling.

Behavioral: Total Diet Replacement (TDR) Program

Long-Duration Type 2 Diabetes Group

EXPERIMENTAL

Participants with type 2 diabetes diagnosed \>10 years who are overweight or obese (BMI 30-45 kg/m²) will receive the same TDR intervention and standard follow-up schedule as other arms.

Behavioral: Total Diet Replacement (TDR) Program

Interventions

Total Diet Replacement (TDR) Program BEHAVIORAL

Participants will follow a structured Total Diet Replacement (TDR) program consisting of approximately 800 kcal/day using commercially available soups and shakes for 8-12 weeks. This is followed by a 2-week food reintroduction phase and a weight maintenance phase up to 6 months, supervised by a research dietitian. The intervention aims to induce rapid weight loss and assess its impact on intrapancreatic fat, insulin secretion, and type 2 diabetes remission. All participants receive dietary counseling and monitoring throughout the study.

Also known as: Low-Calorie Diet, Meal Replacement Program

Long-Duration Type 2 Diabetes Group; Non-Diabetic Group; Pre-Diabetic Group; Short-Duration Type 2 Diabetes Group

Eligibility Criteria

• Age: 45 Years - 79 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Overweight/obese (BMI: 30-45 kg/m²) who have had T2D for less than 6 years or longer than 10 years, and are on treatment with diet alone or diet plus oral medication.
• Overweight/obese (BMI: 30-45 kg/m²) who are at pre-diabetes stage, defined as fasting blood glucose 5.6-6.9 mmol/L.
• Overweight/obese (BMI: 30-45 kg/m²) who are non-diabetic (control group).
• Age between 45 and 79 years inclusive.
• Post-menopausal women only (to exclude sex hormone effects on lipid metabolism).
• Good communication in English (able to give informed consent and follow dietary advice).
• Willing and able to adhere to the study protocol, including dietary intervention and scheduled follow-up visits.

You may not qualify if:

• Insulin therapy
• HbA1c \>12% (108 mmol/mol)
• Weight loss \>5 kg in last 6 months
• Recent MI (within 6 months)
• Known cancer in last 5 years
• First-degree relatives of people with T2D (control group)
• History of gestational diabetes
• MRI contraindications (metal implants, claustrophobia)
• Alcohol \>14 units/week
• Advanced kidney or liver disease
• Use of steroids or antipsychotics
• Participation in another clinical trial
• Life expectancy \<1 year
• Allergy to local anaesthetic (for biopsy subgroup)
• Any disorder that may jeopardise safety or compliance

Sponsors & Collaborators

• University of Edinburgh: lead
• NHS Lothian: collaborator

Study Sites (1)

Clinical Research Facility, Royal Infirmary of Edinburgh

Edinburgh, EH16 4SA, United Kingdom

RECRUITING

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity; Weight Loss

Interventions

Thymidine; Caloric Restriction

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Body Weight Changes

Intervention Hierarchy (Ancestors)

Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Diet Therapy; Nutrition Therapy; Therapeutics; Energy Intake; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Study Officials

• Ahmad Al-Mrabeh, PhD

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Study Team

CONTACT

+44(0)131 242 6717; edrs@ed.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants are assigned to one of four parallel groups based on baseline glycemic status: non-diabetic, pre-diabetic, short-duration type 2 diabetes (\<6 years), and long-duration type 2 diabetes (\>10 years). All groups receive the same dietary intervention (8-12-week Total Diet Replacement followed by food reintroduction and weight maintenance), but remain in their respective groups for analysis. No crossover or sequential assignment occurs.

Study Record Dates

• First Submitted: January 8, 2026
• First Posted: January 23, 2026
• Study Start: January 30, 2026
• Primary Completion (Estimated): March 30, 2029
• Study Completion (Estimated): December 31, 2029
• Last Updated: March 4, 2026

Record last verified: 2026-03

Locations

GB (1)