Endocrinopathy in Pancreatic Cancer Is Characterized by Reduced Islet Size and Density with Preserved Endocrine Composition as Compared to Type 2 Diabetes: Presidential Poster Award: 45

Introduction: Long standing (LS) type 2 diabetes mellitus (T2DM) increases the risk of pancreatic cancer (PC). However, PC induces paraneoplastic NOD and patients with new-onset DM (NOD) are at a 5-8 times higher risk of developing PC within 3 years. Endocrine pathology has been well described in T2DM (reduced insulin, increased glucagon and amyloid). However, there are scant studies identifying the changes in the endocrine pancreas in PC. We aimed to determine if patients with PC have distinctive islet morphometric characteristics as compared to T2DM and controls. Methods: A total of 41,767 islets from 138 patients were studied (43 patients had PC (9 LSDM, 8 NOD and 26 without DM), 50 had T2DM (42 LSDM, 8 NOD) and 45 were controls. Pancreata were obtained from surgically resected PC or autopsy specimens (controls and T2DM). NOD was defined as DM < 3 years from the date of autopsy/PC surgery. Autolysis and/or extensive cancer involvement was ruled out by a pancreas pathologist. Islets in the cancer affected parenchyma were excluded from analyses. Immunohistochemistry was performed for insulin and glucagon and percentage positive area was measured for each. Islet size and density were measured manually on whole sections. Intraislet composition (insulin: glucagon) was assessed by immunofluorescence on a subset of 46 patients (16 with PC, 15 with T2DM and 15 controls). Congo red staining was performed for amyloid. Results: There were no significant differences in the age, BMI and gender distribution of the three groups (n=138) (Table 1). Patients with PC had a significantly lower (˜ 27%) mean islet size as compared to those with T2DM and healthy controls (p=0.006). Patients with PC also had significantly lower (˜45%) islet density (number/mm2) (p<0.0001). % area positive for insulin was significantly lower (p=0.005) while that for glucagon was significantly higher (p <0.001) in patients with T2DM as compared to controls and PC (Figure 1). Despite smaller islet size, patients with PC had preserved insulin: glucagon (I: G) ratio as compared to patients with T2DM who had lower I:G ratio (p=0.03) (Figure 2). Islet amyloid was present in a greater proportion of subjects with T2DM (40%) versus PC-DM (23.5%) than controls (6.7%); p<0.0001* (Figure 2)45_A Figure 1. Demographic and Islet morphometric characteristics of patients with PC and DM as compared to controls.45_B Figure 2. Comparison of islet size and density in patients with Controls, T2DM and PC Top panel (immunohistochemistry) shows representative control, T2DM and PC islets. Bottom Panel: Comparison of islet size and density. Patients with PC have significant reduction in islet size and density.Conclusion: Patients with PC have a marked decrease in islet size and density but preserved I:G ratio. Pathogenesis of DM in PC needs further study as it could lead to identification of biomarkers for be screening for PC in subjects with NOD.45_C Figure 3. Islet Composition in controls, T2DM and PC. Top panel (immunofluorescence) shows representative control, T2DM and PC islets. Insulin is represented in green and glucagon in red. Patients with DM have increased glucagon and reduced insulin leading to reduced insulin: glucagon ratio (Bottom left). Higher proportion of patients with T2DM had amyloid (Bottom right)