Colonic L-cell impairment in aged subjects with type 2 diabetes leads to diminished GLP-1 production

Diabetes Metab Syndr. 2023 Dec;17(12):102907. doi: 10.1016/j.dsx.2023.102907. Epub 2023 Nov 11.

Abstract

Aims: Glucagon-like peptide 1 (GLP-1) is produced by the L subtype of enteroendocrine cells (EECs). Patients with type 2 diabetes (T2D) exhibit reduced incretin effect, but the pathophysiology and functional change of the L-cells remain unclear. Deciphering the mechanisms of the biological changes in L-cells under T2D conditions may assist in the research of gut-based strategies for T2D therapy.

Methods: We investigated the fasting serum GLP-1 levels and the distribution of colonic L-cells in young and aged participants with and without T2D. Additionally, we established an aged male T2D Wistar rat model subjected to a long-term high-fat and high-fructose (HFHF) diet. Histological investigations and single-cell RNA sequencing (scRNA-seq) analyses were performed to explore the mechanisms underlying functional changes in the colonic EECs.

Results: We observed a decline in circulating GLP-1 levels and a reduced number of colonic L-cells in elderly patients with T2D. The mechanisms underlying impaired L-cell formation and disturbed GLP-1 production were revealed using aged T2D rats induced by a long-term HFHF diet. The scRNA-seq results showed that the transcription factors that regulate L-cell commitment, such as Foxa1, were downregulated, and the expression of genes that participate in encoding GLP-1, GLP-1 posttranslational processing, hormone secretion, and nutrient sensing was disturbed.

Conclusions: Taken together, the reduced L-cell lineage commitment and disturbed L-cell functions might be the major cause of the reduced GLP-1 production in aged populations with T2D. Our study provides new insights for identifying novel targets in colonic L-cells for improving endogenous GLP-1 production.

Keywords: Aging; Colon; Enteroendocrine cell; Glucagon like peptide 1; High-fat and high-fructose diet.

MeSH terms

  • Aged
  • Animals
  • Diabetes Mellitus, Type 2*
  • Enteroendocrine Cells / metabolism
  • Glucagon-Like Peptide 1*
  • Hepatocyte Nuclear Factor 3-alpha / metabolism
  • Hepatocyte Nuclear Factor 3-alpha / pharmacology
  • Humans
  • L Cells
  • Male
  • Mice
  • Rats
  • Rats, Wistar

Substances

  • Glucagon-Like Peptide 1
  • Foxa1 protein, rat
  • Hepatocyte Nuclear Factor 3-alpha