Differential molecular and cellular responses of GLP-1 secreting L-cells and pancreatic alpha cells to glucotoxicity and lipotoxicity

Exp Cell Res. 2015 Aug 1;336(1):100-8. doi: 10.1016/j.yexcr.2015.05.022. Epub 2015 May 28.

Abstract

Knowledge of the effects of glucotoxic and lipotoxic environments on proglucagon producing intestinal L cells and pancreatic alpha cells is limited compared with pancreatic beta cells. This study compares the in vitro responses of these cell types to hyperglycaemia and hyperlipidaemia. Glucose (30 mM) and palmitate (0.5mM) reduced GLUTag and MIN6 cell viability while alpha TC1 cells were sensitive only to lipotoxicity. Consistent with this, Cat mRNA expression was substantially higher in GLUTag and alpha TC1 cells compared to MIN6 cells. Glucose and palmitate reduced GLUTag cell secretory function while hypersecretion of glucagon was apparent from alpha TC1 cells. Glucose exposure increased transcription of Cat and Sod2 in MIN6 and GLUTag cells respectively while it decreased transcription of Cat and Gpx1 in alpha TC1 cells. Palmitate increased transcription of Cat and Sod2 in all three cell lines. Upregulation of antioxidant enzyme expression by palmitate was accompanied by an increase in Nfkb1 transcription, indicative of activation of defence pathways. Lipotoxicity activated ER stress response, evident from increased Hspa4 mRNA level in GLUTag and MIN6 cells. Glucose and palmitate-induced DNA damage and apoptosis, with substantially smaller effects in alpha TC1 cells. Thus alpha cells are resistant to gluco- and lipotoxicity, partly reflecting higher expression of genes involved in antioxidant defence. In contrast, intestinal L cells, like beta cells, are prone to gluco- and lipotoxicity, possibly contributing to abnormalities of GLP-1 secretion in type 2 diabetes.

Keywords: Alpha cells; Beta cells; GLP-1; Glucotoxicity; L cells; Lipotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Biomarkers / analysis
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Endoplasmic Reticulum Stress / drug effects*
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Secreting Cells / cytology
  • Glucagon-Secreting Cells / drug effects
  • Glucagon-Secreting Cells / metabolism*
  • Glucose / toxicity*
  • Hyperglycemia / physiopathology
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Palmitates / toxicity*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sweetening Agents / toxicity

Substances

  • Biomarkers
  • Insulin
  • Palmitates
  • RNA, Messenger
  • Sweetening Agents
  • Glucagon-Like Peptide 1
  • Glucose