The EXPAND study is a prospective observational study designed to investigate the biological mechanisms underlying the heterogeneity of type 2 diabetes and related metabolic disorders.

The study will enroll adults with and without pancreatic disease, including patients undergoing pancreatic surgery, individuals with chronic pancreatitis, subjects at high risk of type 2 diabetes, and patients with newly diagnosed type 2 diabetes. Clinical, metabolic, imaging, genetic, microbiome, and molecular data will be integrated to identify distinct metabolic endotypes and to investigate the interactions between the exocrine pancreas, endocrine pancreas, and adipose tissue. The ultimate goal is to improve the understanding of diabetes pathophysiology and support the development of precision medicine approaches.

Type 2 diabetes mellitus is a heterogeneous disease characterized by substantial variability in pathophysiological mechanisms, disease progression, and clinical outcomes. Current clinical classifications do not fully capture the biological complexity underlying metabolic dysfunction.

The EXPAND (Exocrine-Endocrine Pancreatic Axis in Diabetes) study is a prospective observational study aimed at identifying and characterizing metabolic endotypes through the integration of clinical, metabolic, imaging, genetic, microbiome, and multi-omic data. The study is based on the hypothesis that interactions among the exocrine pancreas, endocrine pancreas, and adipose tissue contribute to beta-cell dysfunction and metabolic heterogeneity.

Approximately 440 participants will be enrolled across five predefined cohorts: patients undergoing pancreatic resection for pancreatic diseases, patients with chronic or previous pancreatitis, individuals at increased risk of type 2 diabetes, and subjects with newly diagnosed type 2 diabetes.

Participants will undergo detailed metabolic phenotyping including oral glucose tolerance tests, hyperglycemic/euglycemic clamp studies, laboratory assessments, magnetic resonance imaging-based body fat quantification, dietary assessment, genetic analyses, microbiome profiling, and biomarker measurements. For surgical cohorts, pancreatic and adipose tissue samples obtained during clinically indicated surgery will also be analyzed.

Unsupervised clustering and archetype analysis approaches will be used to identify metabolic endotypes. Associations between endotypes and clinical, metabolic, imaging, histopathological, genetic, and molecular characteristics will be explored. Longitudinal analyses in surgical cohorts will evaluate metabolic changes following pancreatic resection.

The results are expected to improve the understanding of diabetes pathophysiology and facilitate the development of biomarker-driven precision medicine strategies.

Inclusion Criteria:

• Adults aged 20 to 78 years.
• Ability and willingness to provide written informed consent.
• Eligibility for one of the study cohorts:
• Individuals undergoing pancreatectomy for non-endocrine pancreatic disease.
• Individuals with pancreatic ductal adenocarcinoma undergoing pancreatectomy.
• Individuals with chronic pancreatitis or a previous episode of acute pancreatitis.
• Individuals at increased risk of type 2 diabetes mellitus, including impaired fasting glucose and/or impaired glucose tolerance.
• Individuals with newly diagnosed type 2 diabetes mellitus.
• Ability to undergo study-related metabolic assessments and sample collection procedures.

Exclusion Criteria:

• Age <20 years or >78 years.
• Inability or unwillingness to provide informed consent.
• Pregnancy or breastfeeding.
• Diagnosis of type 1 diabetes mellitus.
• Participation in another interventional clinical trial involving an investigational medicinal product within 30 days before enrollment.
• Clinical conditions that preclude completion of the planned metabolic assessments.
• Inability to comply with study procedures.

Participants will be recruited from patients receiving care at Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy). The study population includes adults with and without pancreatic disease, including individuals undergoing pancreatic resection, patients with chronic or previous pancreatitis, subjects at increased risk of type 2 diabetes mellitus, and individuals with newly diagnosed type 2 diabetes mellitus. Participants will be consecutively enrolled from the Departments of Endocrinology, Diabetology, Gastroenterology, and Pancreatic Surgery according to the predefined eligibility criteria.