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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
104
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.
Clinical Research Facility, Royal Infirmary of Edinburgh
Edinburgh, United Kingdom
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.
Time frame: 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.
Time frame: Baseline, 6 months, and 12 months
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline, 6 months, and 12 months
Change in blood pressure
Blood pressure will be measured at baseline and after intervention to assess cardiometabolic improvement.
Time frame: Baseline, 6 months, and 12 months
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