Incretin mimetics are widely used pharmacological treatments for weight loss, known for their high efficacy and favorable safety profile. As the most commonly prescribed drug in this class, semaglutide is effective in both diabetic and non-diabetic individuals. However, treatment responses vary significantly, with non-diabetic individuals typically experiencing better weight loss outcomes. Despite this, up to 10% of non-diabetic individuals show little or no response to treatment, and the reasons for this variability remain unclear.
The TRIM-IR study aims to investigate the role of insulin resistance (IR) in weight loss outcomes among non-diabetic obese individuals receiving semaglutide. This single-center, observational study will assess the impact of IR on weight loss, body composition, and adipose tissue function during the first 16 weeks of semaglutide therapy. The study will also explore molecular markers of adipose tissue dysfunction, focusing on the transition from dysfunctional to healthy adipose tissue.
The investigators hypothesize, that individuals with lower IR will experience greater weight loss than those with higher IR, and that the glucose infusion rate (GIR) during hyperinsulinemic euglycemic clamp testing will correlate with weight loss variability. Secondary objectives include comparing changes in fat and lean mass, reductions in visceral fat, and improvements in adipose tissue function before and after 16 weeks of treatment. Exploratory analyses will assess adipocyte subpopulations and their response to insulin sensitivity changes.
A total of 40 participants, equally distributed by gender, will be enrolled to ensure statistical power for detecting clinically relevant differences. The study aims to optimize semaglutide use for personalized obesity treatment and provide insights into the relationship between obesity, insulin resistance, and adipose tissue plasticity, with implications for improving obesity management and cardiovascular health outcomes.
Age between 18 and 60 years
BMI 30 - 40 kg/m2
Planned therapy with semaglutide as a weight loss intervention
No known presence of a diabetic state
Pregnancy or active breast feeding
Therapy with semaglutide is not approved for use during pregnancy or while breastfeeding, as its safety and efficacy in these conditions have not been established.
Pregnancy is an exclusion criterion for the planned investigations to avoid placing pregnant individuals under unnecessary physical or psychological stress that could pose risks to both the individual and the fetus.
Medication and/or pathologies that prevent the safe execution of the fat tissue biopsies (e.g. allergy towards local anesthetics, disorders of coagulation, treatment with anticoagulants)
The investigators plan to include a total of 40 non-diabetic, obese individuals that will undergo treatment with semaglutide as a weight-loss intervention independent of our observational study. To avoid a highly heterogeneous participant group, inclusion in the study will be limited to individuals with a BMI between 30 and 40 kg/m². Patients with a prediabetic state will not be excluded.
Case-only
Prospective
Not listed
Change in body weight (%)
Change in fat mass (%)
measured by DEXA (dual energy x-ray absorptiometry)
Change in lean mass (%)
measured by DEXA
Change in abdominal visceral fat area (in cm2)
measured by DEXA
Change in cell size of adipose tissue after 16 weeks of semaglutide treatment
The size of adipocytes is a direct measure of adipose tissue quality and function. It will be evaluated through histological examinations.
Changes in cell distribution of adipose tissue after 16 weeks of semaglutide treatment
Changes in the distribution of adipocytes and other components of adipose tissue (e.g. macrophages, progenitors) serve as a direct measure of adipose tissue quality and function. It will be evaluated through histological examinations.
Changes in signs of fibrosis in adipose tissue after 16 weeks of semaglutide treatment
Signs of fibrosis are a direct measure of adipose tissue quality and function. They will be evaluated through histopathological analysis.
Changes in inflammatory activity of adipose tissue after 16 weeks of semaglutide treatment
Inflammatory activity, measured by the number and type of white blood cells infiltrating adipose tissue, is a direct way to assess adipose tissue quality and function. It will be evaluated by quantifying inflammatory cells within the tissue.
