Islet-exocrine crosstalk in diabetes: Distinguishing whole-pancreas pathology from causal communication

To critically evaluate how communication between the endocrine and exocrine pancreas contributes to diabetes and to distinguish whole-pancreas involvement from mechanistically demonstrated crosstalk.

We conducted a narrative review of anatomical, imaging, histological, molecular and experimental evidence on endocrine-exocrine communication, prioritising recent primary human and mechanistic studies.

Islets and exocrine tissue communicate through local vascular, neural, stromal and extracellular matrix routes. Diabetes is associated with distinct whole-pancreas phenotypes: type 1 diabetes (T1D) shows reduced pancreatic volume, acinar loss, exocrine immune infiltration and periductal or perivascular fibrosis, whereas type 2 diabetes (T2D) more often shows acinar-to-ductal metaplasia, lobular or parenchymal fibrosis, angiopathy and increased pancreatic fat fraction on imaging, although histological adiposity is inconsistent. The strongest mechanistic evidence supports insulin-mediated acinar protection, acinar protease effects on β-cells and transfer of mutant carboxyl ester lipase in maturity-onset diabetes of the young type 8 (MODY8), while stromal, matrix and immune signals represent important but less fully validated amplifying pathways. In T1D and T2D, crosstalk most plausibly acts as a stage-dependent amplifier rather than a universal initiating event.

Diabetes should be studied as a multicellular pancreatic disorder without interpreting associated pathology as evidence of causation. Longitudinal human studies and multicellular models that allow selective perturbation are required to identify clinically actionable interactions.