Obesity is one of the greatest risk factors towards the development of type 2 diabetes (T2DM). The rapidly increasing rates of obesity among children and adults in the United States presents a need for understanding the mechanisms of susceptibility to T2DM. Rare obesity disorders, such as the obesity ciliopathies Alstrm Syndrome and Bardet-Biedl Syndrome (BBS), are a valuable tool for investigating these mechanisms. Both Alstrm and BBS are characterized by high prevalence of obesity; however, they have strikingly different rates of T2DM. The rate of T2DM is 70% by age 20 among Alstrm patients, and as low as 2-6% among BBS patients. Whole transcriptome sequencing has identified several exocrine pancreas enzymes including chymotrypsin-like elastase, trypsin, and chymotrypsin, which are differentially expressed between models of these disorders, potentially impacting endocrine pancreas function and development of T2DM. These enzymes were significantly downregulated in models of Alstrm and significantly upregulated in models of BBS. Based on these observations, we hypothesize that depleted ?-cell capacity in alms1- deficient animals is due to the loss of pancreatic proteases, and is not seen in BBS-gene depleted animals because of increased expression of the genes encoding these enzymes. We will test this hypothesis through the following specific aims: (1) Determine the role of ciliopathy proteins in protease production/secretion. (2) Determine a role for pancreatic proteases in ?-cell production. The objective of this study is to define the role that the exocrine pancreas plays in the development of T2DM in Alstrm and BBS, and to determine the mechanism through which this effect is carried out. This study will investigate a novel mechanism of susceptibility to the development of T2DM, loss of pancreatic proteases, and a potential novel interaction between the exocrine and endocrine pancreas.
More than 29 million people in the United States are living with diabetes, and obesity is one of the greatest risk factors towards the development of type 2 diabetes (T2DM). The goal of this project is to elucidate these mechanisms by comparing mechanisms of T2DM in two rare obesity disorders with significantly different rates of T2DM. The proposed work focuses on understanding the discrepant production of pancreatic ?-cells between Bardet-Biedl Syndrome and Alstrm Syndrome by exploring a potential role for exocrine pancreatic enzymes.
