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

Official title

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

Overview

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.

Interventions

• 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 couns

Primary outcome measures

• Change in body weight from baseline to 6-12 months post-intervention [Time frame: Baseline, 6 months, and 12 months post-intervention]
• Change in hepatic de novo lipogenesis measured using stable isotope tracers [Time frame: Baseline, 6 months, and 12 months]

Secondary outcome measures (8)

• Change in liver and pancreas fat measured by MRI [Time frame: Baseline, 6 months, and 12 months]
• Change in beta-cell function assessed by C-peptide response during mixed meal test [Time frame: Baseline, 6 months, and 12 months]
• Change in circulating lipoproteins and lipids [Time frame: Baseline, 6 months, and 12 months]
• Change in pancreas morphology and tissue inflammation [Time frame: Baseline, 6 months, and 12 months]
• Change in adipose tissue biology [Time frame: Baseline and 6 months post-intervention]
• Change in circulating markers [Time frame: Baseline and 6 months post-intervention]
• Change in lipid profile [Time frame: Baseline, 6 months, and 12 months]
• Change in blood pressure [Time frame: Baseline, 6 months, and 12 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 1 center

• Clinical Research Facility, Royal Infirmary of Edinburgh — Edinburgh

Identifiers

NCT: NCT07364045 · AC23027

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗