Chronic Exposure to Palmitate Impairs Insulin Signaling in an Intestinal L-cell Line: A Possible Shift from GLP-1 to Glucagon Production

Abstract

Obesity and type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and impaired glucagon-like peptide-1 (GLP-1) secretion/function. Lipotoxicity, a chronic elevation of free fatty acids in the blood, could affect insulin-signaling in many peripheral tissues. To date, the effects of lipotoxicity on the insulin receptor and insulin resistance in the intestinal L-cells need to be elucidated. Moreover, recent observations indicate that L-cells may be able to process not only GLP-1 but also glucagon from proglucagon. The aim of this study was to investigate the effects of chronic palmitate exposure on insulin pathways, GLP-1 secretion and glucagon synthesis in the GLUTag L-cell line. Cells were cultured in the presence/absence of palmitate (0.5 mM) for 24 h to mimic lipotoxicity. Palmitate treatment affected insulin-stimulated GLP-1 secretion, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. In our model lipotoxicity induced extracellular signal-regulated kinase (ERK 44/42) activation both in insulin stimulated and basal conditions and also up-regulated paired box 6 (PAX6) and proglucagon expression (Gcg). Interestingly, palmitate treatment caused an increased glucagon secretion through the up-regulation of prohormone convertase 2. These results indicate that a state of insulin resistance could be responsible for secretory alterations in L-cells through the impairment of insulin-signaling pathways. Our data support the hypothesis that lipotoxicity might contribute to L-cell deregulation.

Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity, and impaired glucose tolerance

“…Previous studies have shown a stimulatory effect of fatty acids on glucagon secretion from rodent islets and cell lines and mechanisms involved are signaling through fatty acid G‐protein coupled receptors beta‐oxidation of fatty acids and activation of L‐type Ca 2+ channels . Interestingly, fatty acid palmitate was recently shown to induce a switch to a glucagon secreting phenotype in an intestinal GLP‐1 secreting cell, raising the possibility of fatty acids to induce extrapancreatic glucagon . In the in vivo data, there was a positive relationship between fasting insulin and fasting glucagon concentrations and this was found in the obesity group as well as in the lean group of children and adolescents.…”

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

“…Consistent with our model, Martchenko and colleagues [46] have recently reported fatty acid-induced lowering of circadian release of GLP-1 from L-cells as a result of decreased Bmal1 expression. Similarly, Filipello et al [47] reported decreased insulin-dependent GLP-1 secretion from L-cell-derived GLUTag cells, and increased glucagon release, upon fatty acid treatment. Similar findings on GLP-1 secretion were reported by others [48,49], whist long chain saturated (palmitate) but not unsaturated (oleate) fatty acids lead to L-cell apoptosis [50].…”

Serum coding and non‐coding RNAs as biomarkers of NAFLD and fibrosis severity

“…Human hepatoblastoma cell line HepG2 was cultured as previously reported . To obtain in vitro models of NAFL or NASH, HepG2 at 75% confluence were exposed to a mixture of oleate/palmitate or only palmitate at a final fatty acid concentration of 0.5 mM for 48 h respectively …”