11-Keto-β-boswellic acid inhibits infiltration of lymphocytes into pancreatic islets in NOD-mice

Introduction: Previously we have shown that 11-Keto-β-boswellic acid (KBA) and O-acetyl-11-Keto-β-boswellic acid (AKBA) prevent hyperglycemia, infiltration of lymphocytes into pancreatic islets and the increase of proinflammatory cytokines in the model of multiple low dose-streptozotocin (MLD-STZ) diabetic mice (Ammon and Shehata, 2011).

Aim of study: It was aimed to study whether or not such an effect could also be observed in NOD-mice which develop a genetically type 1 diabetes similar to human type 1 diabetes.

Methods: Female NOD mice 4 weeks of age (Charles River) were i.p. injected for 3 weeks with 7.5mg/kg KBA – a dose which has turned in our earlier MLD-STZ experiments to be most effective. After 3 weeks of KBA-treatment, animals were killed and blood was collected for determination of glucose and cytokines (IL-1A, IL-1B, IL-2, IL-6, IFN-γ, TNF-α). Pancreases were isolated for histology. Another group of mice was followed up for monitoring of blood glucose and body weight. Cytokines were analyzed using Multi-Analyte ELISArray (™). Lymphocytes infiltration into pancreatic islet cells and apoptosis were detected with anti-CD3 and anti-caspase 3 respectively. Blood glucose was evaluated with test strips (Accu-check aviva glucometer).

Results: In the seventh week of age there was infiltration of lymphocytes and appearance of apoptotic cells in pancreatic islets of all control mice. Cytokines in the blood showed no change at this time, but blood glucose was significantly decreased (106.5±4.6 vs. 77.3±5.4mg/dl).

From 6 animals treated with KBA 4 showed no infiltration of lymphocytes as well as no apoptotic cells in all while blood glucose levels did not change. Furthermore, there was no change of cytokines in comparison to control.

After 12 weeks control group still exhibited decrease of blood glucose (71.7±2.9mg/dl) and body weight was not increased compared to four weeks old animals (16.5±0.4 vs. 15.0±0.8). However, in KBA treated animals body weight increased (17.8±0.4 vs. 23.2±0.6) and blood glucose level was still normal (91.5±3.0 vs. 100.2±4.5mg/dl).

Conclusion: Similar to recent results obtained in mice with MLD-STZ-diabetes, KBA reduced development of insulitis and apoptosis of islet cells of NOD mice. Consequently the hypoglycemia appearing in control NOD mice which may be due to insulin leakage from damaged β-cells could be prevented by KBA treatment. Moreover, KBA treatment of NOD mice allowed normal development of body weight even after stopping KBA treatment.

Since so far KBA was effective in two different animal models of type 1 diabetes, the data are promising for clinical studies in autoimmune diabetes

References: H.P.T. Ammon, A.M. Shehata, Prevention of Multiple Low Dose-Streptozotocin (MLD-STZ)-Induced Diabetes in Mice by Extract from Gum Resin of Boswellia serrata and 11-Keto-β-boswellic acids. Diabetologia (2011) 54:S1; S184