Pancreatic beta cells turnover: effects of endogenous hyperinsulinemia and amyloid deposits

OBJECTIVES: The research activity focused on two research projects. In the first project, we investigated the effects of high local insulin levels on beta cell turnover in a model of endogenous hyperinsulinism. In the second project, we investigated the presence and quantity of amyloid deposits and their role on beta cell death in type 2 diabetes and diabetes secondary to pancreatic diseases. BACKGROUND: Insulin therapy has been suggested to preserve beta-cell mass in patients with diabetes through the mechanisms of beta-cell rest as well as direct effects on beta-cell proliferation. However, data about the effects of hyperinsulinism on beta-cell mass and turnover in humans are sparse. Amyloid aggregates have been suggested to be involved in the pathogenesis of type 2 diabetes, causing beta cell death. Data present in literature make IAPP role in type 2 diabetes controversial. PATIENTS AND METHODS: First research project: pancreatic tissue specimens from 5 patients with pancreatic insulinomas and 10 non diabetic control subjects were examined. Pancreatic sections were stained for insulin, Ki67 (replication) and TUNEL (apoptosis), and quantitative morphometric analyses were performed. Second research project: pancreatic tissues from 7 patients with type 2 diabetes, 10 patients with diabetes secondary to chronic pancreatitis or pancreatic carcinoma and 11 non diabetic control subjects were examined. Pancreatic sections were stained for insulin, TUNEL (apoptosis) and Thioflavin S (amyloid) and morphometric analysis were performed. RESULTS: First research project: fractional beta-cell area was 1.11%±0.67% in the tumor-free pancreatic tissue of the insulinoma patients and 0.78%±0.26% in the control group (p=0.19). There also were no differences in islet size (p=0.62) or beta-cell nuclear diameter (p=0.20). Beta-cell replication and apoptosis were infrequently detected, without any measurable differences between the groups. There were also no differences in percentage of duct cells expressing insulin (p=0.47), a surrogate marker for islet neogenesis. Second research project: fractional beta cell area was 0.33% ± 0.07% in the pancreatic tissue of patients with diabetes secondary to pancreatic diseases, 0.57% ± 0.09% in patients with type 2 diabetes and 0.76% ± 0.13% in the control group (p=0.021). There were no differences in beta cell apoptosis (p=0.10) and extent of islet amyloid (p=0.13) or islet amyloid area (p=0.24) CONCLUSIONS: Beta-cell area and turnover are not significantly altered in the proximity of intra-pancreatic insulinomas. Future in vivo studies, ideally employing larger animal models, are warranted to further evaluate the impact of exogenous insulin on beta-cell turnover. A significant difference in beta cell area but no differences in beta cell apoptosis and amyloid deposition were found between type 2 diabetic patients, patients with diabetes secondary to chronic pancreatitis or pancreatic carcinoma and control subjects. Amyloid deposition is not a cause of beta cell death in type 2 diabetes. Future larger studies, involving also appropriate animal models and sophisticated techniques, could be useful to better understand the aggregation mechanisms of IAPP and its role in beta cell death.