Investigating the Role of Twist1 in Diabetes Pathogenesis
Abstract
Diabetes mellitus is a devastating metabolic disease characterized by hyperglycemia that can occur through distinct mechanisms, such as islet b-cell destruction, b-cell failure, and insulin resistance in peripheral tissues. The increasing prevalence of diabetes also affects the military personnel. Several genes associated with diabetes have been identified in genome wide association studies, but their genetic validation as causative factors remains largely unexplored. In this grant proposal, we focused on one of these genes, Twist1, whose conditional overexpression in the pancreatic tissue led to severe hyperglycemia and diabetes. We proposed experiments to investigate howTwist1 induces diabetes. The results showed that conditional overexpression of Twist1 in pancreatic progenitor cells in mice resulted in fatty pancreas development, leading to pancreatic insufficiency and diabetes. Mechanistic experiments demonstrate that Twist1 drives fatty pancreas formation by selectively reprogramming acinar cells towards the adipocyte lineage. Besides driving fatty pancreas formation,Twist1 also suppresses expression of Pdx1, the master transcription factor in b-cell, which drives expression of insulin. Loss-of-function genetic experiments demonstrated that Twist1 deletion against fatty pancreas formation driven by obesity, thereby improving glucose tolerance and diabetes. Overall, these findings implicate Twist1 as a possible target for attenuating diabetes associated with obesity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2018
- Accession Number
- AD1054010
Entities
People
- Azeddine Atfi
- Hao Mei
- Parash Parajuli
Organizations
- University of Mississippi