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.

Association between single nucleotide polymorphisms, TGF-β1 promoter methylation, and polycystic ovary syndrome

“…LAMTOR1, a late endosomal/lysosomal connector, which acts as a MAPK and MTOR activator 1, plays important roles in energy and glucose metabolism. Huang et al [ 52 ] found that mouse models with β-cell LAMTOR1 gene-specific defects have higher glucose tolerance and glucose-stimulated insulin secretion during hyperglycaemic clamp and islet perfusion than control models. LAMTOR1 loss increases the amplification pathway induced by glutamic acid and acetyl-CoA carboxylase 1, ultimately leading to increased insulin secretion.…”

Macrophage LAMTOR1 Deficiency Prevents Dietary Obesity and Insulin Resistance Through Inflammation-Induced Energy Expenditure

“…In previous studies based on LAMTOR1 conditional knockout models, the role of LAMTOR1 in metabolism was rarely explored. Only one recent study reported that the β-cell-specific knockout of LAMTOR1 resulted in improved glucose tolerance and increased glucose-stimulated insulin secretion ( Huang et al, 2020 ). For the first time, this study explored the role of macrophage LAMTOR1 in metabolism.…”

Antipsychotics inhibit the mitochondrial bioenergetics of pancreatic beta cells isolated from CD1 mice

“…71156, Affymetrix). The primer sequences (Table 1) and thermocycling conditions were previously reported in García‐Ruiz et al 35 and Huang et al, 36 respectively. Reactions were performed using the CFX96 Real‑time System (Bio‑Rad Laboratories, Inc).…”