Discovering human diabetes-risk gene function with genetics and physiological assays.

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Understanding type 2 diabetes (T2D) genetic risk requires identifying cell-specific gene functions.
• Existing in vivo systems lack efficiency in discovering T2D risk gene functions relevant to human cells.

Purpose of the Study:

• To develop and apply interdisciplinary approaches combining Drosophila genetics and human islet biology.
• To identify T2D risk genes regulating insulin output in Drosophila and human beta cells.

Main Methods:

• Identified Drosophila orthologs of T2D-risk genes regulating insulin output.
• Conducted genetic studies in human islets to identify human T2D-risk genes affecting beta cell function.
• Performed gene expression profiling to understand BCL11A-dependent regulation of insulin exocytosis.

Main Results:

• Identified T2D risk genes in Drosophila that regulate insulin output.
• Identified human BCL11A as a T2D risk gene that regulates human beta cell function.
• Loss of BCL11A in human islet cells enhanced insulin secretion, with BCL11A regulating genes involved in insulin exocytosis.

Conclusions:

• The developed genetic and physiological systems advance the identification of cell-specific T2D risk gene functions.
• This approach bridges Drosophila and human islet biology to uncover mechanisms of T2D.
• BCL11A plays a significant role in regulating human beta cell insulin secretion.