1560-P: Inflammation in the Exocrine Pancreas Impairs Insulin Secretion

Introduction: In patients with type 2 diabetes, increasing evidence points to pathological changes not only in the endocrine but also in the exocrine pancreas. In particular, the number of immune cells is increased in both compartments. Furthermore, patients with chronic pancreatitis, a form of exocrine inflammation, have an increased risk to develop diabetes. However, the causal relationship between exocrine pathologies and impaired endocrine insulin secretion is unknown.

Methods: We established a mouse model of chronic pancreatitis using caerulein injections, thereby stimulating digestive enzymes secretion in exocrine cells. Over 3 weeks, wild-type mice underwent treatment combined with a high-fat diet to induce insulin resistance. To avoid body weight differences due to the anorexic effect of caerulein, saline-treated control mice were pair-fed. We evaluated insulin secretion and glucose metabolism by in vivo glucose tolerance testing and assessing ex vivo glucose-stimulated insulin secretion in isolated islets. Pancreata were immunohistochemically evaluated and transcriptional changes in islets were studied using RNA sequencing.

Results: Chronic pancreatitis in caerulein-treated mice was confirmed by elevated immune cells in the exocrine pancreas, whereas no increase in immune cells was observed in islets. Functionally, mice with chronic pancreatitis had severely impaired insulin secretion and resulted in hyperglycemia compared to the saline-treated control mice. Islets isolated from caerulein-treated mice showed reduced glucose-stimulated insulin secretion. Surprisingly, despite exocrine tissue destruction and reduced exocrine tissue mass, β-cell mass was not reduced. Further, differentially expressed genes were not associated with β-cell signatures but with extracellular matrix components.

Conclusion: Impaired insulin secretion in chronic pancreatitis may be due to alterations in the extracellular matrix components of the islets rather than to destruction of β-cells.