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

Mechanisms Mediating Reversible Lipotoxicity of the Pancreas in Obesity-induced Type 2 Diabetes: Edinburgh Diabetes Remission Study (EDRS)

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.

Study Overview

• Status: Recruiting
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Behavioral: Total Diet Replacement (TDR) Program

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Study Team; Phone Number: +44(0)131 242 6717; Email: edrs@ed.ac.uk

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom, EH16 4SA
    • Recruiting
    • Clinical Research Facility, Royal Infirmary of Edinburgh
    • Contact: Study Team; Phone Number: +44 131 242 6717; Email: edrs@ed.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non-Diabetic Group; 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; 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.; Other Names: Low-Calorie Diet; Meal Replacement Program
Experimental: Pre-Diabetic Group; 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; 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.; Other Names: Low-Calorie Diet; Meal Replacement Program
Experimental: Short-Duration Type 2 Diabetes Group; 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; 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.; Other Names: Low-Calorie Diet; Meal Replacement Program
Experimental: Long-Duration Type 2 Diabetes Group; 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; 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.; Other Names: Low-Calorie Diet; Meal Replacement Program

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in liver and pancreas fat measured by MRI	Hepatic and intrapancreatic fat will be assessed by MRI at baseline and after intervention to evaluate the effect of weight loss on intraorgan fat deposition.	Baseline, 6 months, and 12 months
Change in beta-cell function assessed by C-peptide response during mixed meal test	Beta-cell function will be evaluated using C-peptide modeling during a standardised mixed meal test at baseline and after intervention.	Baseline, 6 months, and 12 months
Change in circulating lipoproteins and lipids	Lipoproteins (i.e. VLDL) and plasma/serum lipids will be measured using ultracentrifugation and mass spectrometry techniques.	Baseline, 6 months, and 12 months
Change in pancreas morphology and tissue inflammation	Pancreas size, shape, and tissue inflammation will be evaluated by assessed by MR methods at baseline and after intervention.	Baseline, 6 months, and 12 months
Change in adipose tissue biology	MRI will be used to assess fat saturation, and fat biopsies will be performed to evaluate molecular changes in adipose tissue biology.	Baseline and 6 months post-intervention
Change in circulating markers	Changes in circulating adipokines, inflammatory markers, and exosomes will be measured using commercial kits to assess systemic metabolic responses to weight loss.	Baseline and 6 months post-intervention
Change in lipid profile	Fasting lipids (TGs, HDL, LD cholesterol) will be measured at baseline and after intervention at NHS- accredited lab to assess cardiometabolic improvement.	Baseline, 6 months, and 12 months
Change in blood pressure	Blood pressure will be measured at baseline and after intervention to assess cardiometabolic improvement.	Baseline, 6 months, and 12 months

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian
• Investigators: Principal Investigator: Ahmad Al-Mrabeh, PhD, University of Edinburgh

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2026
• Primary Completion (Estimated): March 30, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: January 8, 2026
• First Submitted That Met QC Criteria: January 16, 2026
• First Posted (Actual): January 23, 2026

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Obesity; Type 2 Diabetes; Weight loss; Remission
• Additional Relevant MeSH Terms: Endocrine System Diseases; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Body Weight Changes; Glucose Metabolism Disorders; Diabetes Mellitus; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Weight Loss; Diabetes Mellitus, Type 2; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Nucleic Acids, Nucleotides, and Nucleosides; Diet, Food, and Nutrition; Physiological Phenomena; Nutritional Physiological Phenomena; Pyrimidine Nucleosides; Pyrimidines; Diet Therapy; Nutrition Therapy; Diet; Nucleosides; Deoxyribonucleosides; Energy Intake; Caloric Restriction; Thymidine
• Other Study ID Numbers: AC23027

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No