Type 2 Diabetes Mellitus (T2DM) pathogenesis increasingly involves "diabetic duodenopathy," characterized by proximal intestinal immune and epithelial dysregulation. This study investigates the endoscopic delivery of adipose-derived mesenchymal stem cells (ADMSCs) into the duodenum and proximal jejunum as a disease-modifying therapy. By leveraging the paracrine immunomodulatory and regenerative effects of ADMSCs in close proximity to the pancreatico-enteroendocrine system, this targeted approach aims to restore insulin sensitivity and $\beta$-cell function while minimizing systemic exposure. The clinical safety and feasibility of this novel delivery route remain to be established.

Inclusion Criteria:

• • Adults aged between 25-70 years

  • Diagnosis of T2DM from at least 1 years
  • HbA1c between 7.5% and 10%
  • BMI between 25 and 35 kg/m²
  • Fasting C-peptide ≥1 ng/ml
  • Stable antidiabetic regimen for ≥3 months (including insulin s.c.)
  • Insulin resistance (HOMA-IR > 5)
  • Healthy volunteers: BMI < 25, age between 18-75 and no diagnosis of T2DM or insulin resistance (HOMA-IR<2.5), with no significant acute or chronic medical conditions and not taking medications that could interfere with the esophagogastroduodenoscopy + biopsies

Exclusion Criteria:

• Type 1 DM or secondary diabetes
• Celiac disease
• History of pancreatitis or GI surgery
• Active infection or malignancies ongoing
• Active gastro-duodenal ulcers
• Duodenum not accessible endoscopically for previous surgery or other conditions
• History of autoimmune disease
• Active malignancy or recent cancer treatment
• Use of certain medications (e.g., immunosuppressants, systemic corticosteroids)
• Active Smoking (>5 sigarettes/die)
• Anticoagulant treatment not suspendable
• Myocardial infarction during the past 6 months or/and heart failure class III or IV according to the New York Heart association's classification.
• Drug or alcohol abuse
• Continuous glucocorticoid or anti-inflammatory treatment
• Uncontrolled thyroid disease.
• Pregnancy, breastfeeding
• Psychiatric or cooperative problems or low compliance that is a contraindication from participating in the study.
• Liver cirrhosis of any Child-Phugh stage or MELD> 15
• Chronic Severe Renal Insufficiency (eGFR < 30 ml/min/1.73 m2 based on CKD-EPI equation)
• Currently participating in other study, or previously participated in an experimental drugs trial within 30 days before or 5 half-life of the drug administered
• Any health issue that might put the patient at risk if the treatment is performed, judged by the investigator.