The ARTI-UP study evaluates whether daily consumption of a supplement made from artichoke by-products, rich in hydroxycinnamic acids (HCAs), in combination with an energy-restricted Mediterranean diet (erMeDiet), can improve glycaemic control, reduce insulin resistance and contribute to weight loss in subjects with overweight or obesity. In addition, it seeks to understand the biological mechanisms involved using omic techniques and to establish predictive biomarkers that will enable progress towards personalised nutrition strategies.

Type 2 diabetes (T2D) and obesity represent major global public health challenges, largely driven by insulin resistance and excess body weight. Lifestyle interventions based on energy-restricted Mediterranean dietary patterns have demonstrated beneficial effects on glycemic control and body weight; however, substantial interindividual variability in response persists. Emerging evidence suggests that specific dietary bioactive compounds, such as hydroxycinnamic acids (HCAs), may play a relevant role in improving insulin sensitivity, yet their contribution within structured dietary interventions remains insufficiently explored.

In this context, the hypothesis of the present study is that daily supplementation with an artichoke by-product powder rich in bioavailable HCAs, administered within an energy-restricted Mediterranean diet (erMeDiet), will lead to greater improvements in insulin resistance and body weight compared with an erMeDiet alone in overweight and obese adults with insulin resistance. Furthermore, interindividual variability in response to HCAs is hypothesized to be partially explained by differences in metabolic, microbiota-related, and epigenetic profiles.

Following recruitment and screening, the study will consist of a 16-week randomized, controlled, double-blind, parallel-group lifestyle intervention. Participants will be randomly assigned (1:1) to one of two intervention arms:

Intervention group: Energy-restricted Mediterranean diet (approximately -500 kcal/day) combined with physical activity counselling and daily supplementation with an artichoke by-product powder providing a minimum of 600 mg/day of bioavailable hydroxycinnamic acids.

Control group: Energy-restricted Mediterranean diet and identical physical activity counselling, supplemented with an isocaloric placebo powder matched for macronutrient composition but devoid of HCAs.

All participants will receive individualized dietary counselling and guidance to achieve at least 150 minutes per week of moderate-intensity physical activity. Clinical visits will be conducted at baseline and throughout the intervention to monitor adherence, collect biological samples, and assess outcomes.

The primary outcomes of the study are changes in insulin resistance, assessed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and changes in body weight after 16 weeks of intervention. Secondary outcomes include changes in anthropometric parameters, glucose metabolism markers, lipid profile, inflammatory and oxidative stress markers, dietary intake, physical activity, and continuous glucose monitoring metrics.

In addition, a comprehensive multi-omics approach will be applied to investigate the biological mechanisms underlying the effects of HCAs. This includes targeted and untargeted metabolomics, gut microbiota metagenomics, and genome-wide DNA methylation analyses. Machine learning methods will be used to integrate clinical and omics data in order to identify biomarkers predictive of individual response to the intervention, contributing to the advancement of precision nutrition strategies for T2D prevention.

This study aims to provide robust clinical and mechanistic evidence supporting the use of sustainable, upcycled plant-based bioactive compounds as complementary dietary tools for improving insulin resistance and preventing type 2 diabetes in high-risk populations.

Inclusion Criteria:

• BMI between 25.0 and 35.0 kg/m²
• HOMA-IR ≥ 2.5.
• Adequate physical examination and vital signs or clinically irrelevant to the intervention (those not related to metabolic health).
• Subjects must be able to understand and be willing to sign the informed consent form, and must comply with all study procedures and requirements.
• Subjects must have a stable means of communication, either by email and/or telephone.

Exclusion Criteria:

• Weight loss of more than 5% in the last 6 months prior to surgery.
• Consumption of antibiotics in the 3 months prior to the intervention.
• Subjects who are undergoing treatment for weight loss/body composition modification, use medication for weight loss or blood glucose control, or have had weight loss surgery.
• Have a medical diagnosis of type 1 or type 2 diabetes.
• History of inflammatory bowel disease and/or resection of the large or small intestine. Subjects with relevant functional or structural abnormalities of the digestive system.
• Inability to follow the recommended diet or physical exercise.
• Unavailability in terms of time or location to attend study visits.
• Failure to sign the informed consent form.
• Inability to communicate with the research team.
• Endocrine-related excess weight (except for treated hypothyroidism, at least 3 months of stable treatment).
• Being pregnant or planning a pregnancy during the intervention period.
• Being breastfeeding.
• Having an allergy to artichokes.
• Severe psychiatric illnesses that have required hospitalisation in the last 6 months.
• Renal failure.
• Having immunodeficiency or being HIV positive.
• Being treated with immunosuppressive drugs or cytotoxic agents.
• High alcohol intake: more than 14 units (women) and 20 units (men) per week.
• Participation in another randomised clinical trial.
• Volunteers undergoing drug treatment for less than 3 months with a stable dose/stable treatment.
• Taking nutritional supplements (supplements: plant derivatives, for weight loss, fibre and probiotics) unless the person is willing to stop taking them for 3 months prior to the start of the trial.
• Taking nutritional supplements (supplements: plant-derived, for weight loss, fibre and probiotics) unless the person is willing to stop taking them for the 16 weeks of the study intervention and a minimum washout period of 14 days prior to baseline measurements is guaranteed.
• Having donated blood in the 14 days prior to the baseline visit.
• Subjects with any type of cancer or undergoing treatment for cancer, or who have not been in remission for at least 5 years.
• Any other condition that may interfere with adherence to the intervention.