UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

The central focus of our laboratory is beta-cell genesis, differentiation, and gene expression. Translational interests of our group are directed towards understanding where these processes break down in type 2 diabetes, and how to translate our knowledge of beta-cell genesis into novel strategies for curing diabetes (type 1 and 2). The general strategy is to identify the transcription factors that regulate gene expression in progenitors and mature beta-cells. These factors and their genes are then used as tools to understand the process of beta-cell development by studying both how they regulate gene expression and development and how they are regulated themselves, both in mouse models and in vitro . Several lines of investigation are being pursued.

Beta-cell determination and differentiation: Early in pancreatic development, many of the pancreatic and islet transcription factors are uniformly expressed in the pancreatic epithelium, demonstrating that these early cells have multiple potential fates. The mechanisms by which the expression of these factors and the potential to become beta-cells becomes restricted control the differentiation of the beta-cells from their neighbors. Using transgenic and gene knockout mice and in vitro differentiation assays, my lab is beginning to outline the hierarchy of these factors during beta-cell development and to identify their individual roles in beta-cell formation and differentiation.

Beta-cell gene expression: A long-term interest of our lab has been the mechanism by which the transcription of certain genes (most notably the insulin gene) is restricted to the beta-cells and how that expression is regulated by nutrient cues, such as glucose concentration. Unlike differentiation, which involves a cascade of gene expression events, the differentiated state is maintained by a network of interacting factors. Ongoing studies are examining the interactions of transcription factors involved in beta-cell differentiation and maintenance and the transcriptional response to glucose.

Beta-cell replacement: We have begun applying the accumulating knowledge of beta-cell genesis to the development of novel strategies for curing diabetes. Ultimately, a cure for people with type 1 diabetes, as well as many people with type 2 diabetes, requires the replacement of the beta-cell. The genes that control beta-cell development can drive the formation of beta-cells from undifferentiated progenitor cells or stem cells. We are generating methods using these genes to produce new beta-cells both in vitro and in vivo.

Type 2 diabetes: Type 2 diabetes results from increased insulin demand due to insulin resistance in a setting of limited insulin supply caused by beta-cell dysfunction. With age, increasing adiposity and a sedentary lifestyle together contribute to insulin resistance, while at the same time beta-cell function progressively declines. We have been exploring the role of genes controlling beta-cell growth and replacement in determining the risk of developing type 2 diabetes. To date, most of the genes linked to type 2 diabetes in humans regulate beta-cell development or function, including several genes encoding beta-cell transcription factors.

Website: http://germanlab.ucsf.edu/

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