Glucose Sensing in L Cells: A Primary Cell Study

TLDR

GLP‑1 is an enteric hormone that improves glycaemia in type 2 diabetes, yet strategies to boost its endogenous release from L cells are limited by incomplete knowledge of these cells. The study aims to uncover pathways that regulate GLP‑1 release from L cells to inform future therapeutic strategies. Using L cell‑specific fluorescent protein transgenic mice, the authors performed electrophysiology, calcium imaging, and expression analysis on primary L cells, demonstrating their electrical excitability and glucose responsiveness. They found that GLP‑1 secretion is triggered by glucose via SGLT1 and ATP‑sensitive K⁺ channels, as evidenced by tolbutamide sensitivity and low‑millimolar glucose/α‑methylglucopyranoside responses and corroborated by high transporter and channel expression in purified L cells.

Abstract

Glucagon-like peptide-1 (GLP-1) is an enteric hormone that stimulates insulin secretion and improves glycaemia in type 2 diabetes. Although GLP-1-based treatments are clinically available, alternative strategies to increase endogenous GLP-1 release from L cells are hampered by our limited physiological understanding of this cell type. By generating transgenic mice with L cell-specific expression of a fluorescent protein, we studied the characteristics of primary L cells by electrophysiology, fluorescence calcium imaging, and expression analysis and show that single L cells are electrically excitable and glucose responsive. Sensitivity to tolbutamide and low-millimolar concentrations of glucose and α-methylglucopyranoside, assessed in single L cells and by hormone secretion from primary cultures, suggested that GLP-1 release is regulated by the activity of sodium glucose cotransporter 1 and ATP-sensitive K+ channels, consistent with their high expression levels in purified L cells by quantitative RT-PCR. These and other pathways identified using this approach will provide exciting opportunities for future physiological and therapeutic exploration.