Loss of LAMTOR1 in pancreatic β-cells increases glucose-stimulated insulin secretion in mice

Abstract

Insulin secretion from pancreatic β-cells regulates glucose metabolism and is related to various diseases including diabetes. The late endosomal/lysosomal adaptor MAPK and mTOR activator 1 (LAMTOR1) is one of the subunits of the Ragulator complex and plays an important role in energy metabolism including glucose metabolism. The present study was designed to explore the role of LAMTOR1 in murine pancreatic β-cell function. A murine model with β cell-specific deficiency (βLamtor1-KO) was generated to assess β-cell function (insulin sensitivity paired with β-cell responses) by hyperglycemic clamp in vivo. Islet perfusion and mitochondrial functional analyses were performed to investigate the individual steps in the insulin secretion pathway. Results showed that glucose tolerance in vivo as well as glucose-stimulated insulin secretion in the hyperglycemic clamp and islet perfusion were higher in βLamtor1-KO mice compared to the control models. Although mitochondrial dysfunction was present, the deletion of Lamtor1 increased glutamate content in the mouse insulin granules as well as acetyl-CoA carboxylase 1 (ACC1) activity thus enhancing insulin secretion. Together, our data indicate that LAMTOR1 is important for maintaining mitochondrial function in mouse pancreatic β-cells, however deletion of Lamtor1 increases the amplification pathway induced by glutamate and ACC1, ultimately leading to increased insulin secretion. These findings suggest that knockout of Lamtor1 is a potential technique for improving pancreatic β-cell function and treating diabetes.