Mechanisms Mediating Reversible Lipotoxicity of the Pancreas in Obesity-induced Type 2 Diabetes: Edinburgh Diabetes Remission Study (EDRS)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 104
- 试验地点
- 1
- 主要终点
- Change in body weight from baseline to 6-12 months post-intervention
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 45 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Total Diet Replacement (TDR) Program (Behavioral)
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.
干预措施: Total Diet Replacement (TDR) Program (Behavioral)
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.
干预措施: Total Diet Replacement (TDR) Program (Behavioral)
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.
干预措施: Total Diet Replacement (TDR) Program (Behavioral)
结局指标
主要结局
Change in body weight from baseline to 6-12 months post-intervention
时间窗: Baseline, 6 months, and 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.
Change in hepatic de novo lipogenesis measured using stable isotope tracers
时间窗: Baseline, 6 months, and 12 months
Hepatic de novo lipogenesis will be quantified using stable isotope tracer methodology (deuterated water) at baseline and after intervention.
次要结局
- 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)
- Change in circulating markers(Baseline and 6 months post-intervention)
- Change in lipid profile(Baseline, 6 months, and 12 months)
- Change in blood pressure(Baseline, 6 months, and 12 months)