Poster Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Deletion of the pro-apoptotic BH3-only protein Bim results in increased islet size in a mouse model of type 2 diabetes (#243)

Jingjing Ge 1 2 , Jibran A Wali 1 2 , Helen Thomas 1 2 , Ellen Mathieson 1 , Ross Laybutt 3 , Ian Smyth 4 , Esteban Gurzov 1 2
  1. St Vincent's Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Medicine, St Vincent's Hospital, The University of Melbourne, Melbourne
  3. Diabetes and Obesity Division, Garvan Institute, Sydney
  4. Developmental Diseases, Monash University, Melbourne

Type 2 Diabetes is an enormous health burden affecting 350 million people worldwide. Loss of b cell mass is a feature of the disease, and evidence suggests that this is the result of apoptosis. We were the first to identify that the pro-apoptotic Bcl-2 homology domain 3 (BH3)-only molecules Bim is required for glucose-induced apoptosis of islet cells. High concentrations of glucose induce ER and oxidative stress, which result in islet cell death mediated by Bim. Islets isolated from organ donors with type 2 diabetes had increased expression of Bim compared with non-diabetic donors, suggesting Bim is also important in loss of b cells in humans. To determine whether Bim deficiency protects b cells from apoptosis in type 2 diabetes, we crossed Bim-deficient mice with leptin receptor mutant Leprdb/dbmice. These mice were significantly protected from development of hyperglycaemia. We also observed a striking increase in islet size in Bim-deficient Leprdb/dbmice. To quantify this increase in islet mass, we performed optical projection tomography, 3-dimensional imaging of whole pancreas stained with anti-insulin antibodies. Data analysis revealed 2-fold increased islet volume in Bim-deficient compared with wild-type Leprdb/dbmice. There was no difference in islet cell proliferation between wild type and Bim-deficient mice, measured by BrdU uptake. Further studies will determine whether apoptosis is reduced in Bim-deficient islets. Bim is ubiquitously expressed and may be important in many cell types involved in type 2 diabetes pathogenesis, including b cells, the immune system and insulin-sensitive peripheral tissues. Our data suggest that Bim has a direct role in the loss of islet mass in type 2 diabetes. Future studies will determine whether specific deletion of Bim in b cells only also produces the same phenotype.