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.
Highlights
Glucagon-like peptide-1 (GLP-1) is a peptide hormone, secreted by intestinal epithelial L-cells in response to hormonal, neural and nutrient stimuli
Since it has been reported that the insulin receptor (IR)-A isoform could up-regulate p-ERK 44/42 protein expression [39], to better investigate basal ERK 44/42 phosphorylation induced by chronic palmitate exposure we analyzed the mRNA expression levels of isoform A (IR-A) and isoform B (IR-B) by reverse transcription polymerase chain reaction (RT-PCR) and, as shown in Figure 5, we found that the IR-A to IR-B mRNA ratio was significantly higher in cells cultured with palmitate compared with control cells
In this work we studied the effect of a chronic exposure to high palmitate levels on insulin-induced GLP-1 secretion, insulin signal pathways and glucagon release in intestinal L-cells
Summary
Glucagon-like peptide-1 (GLP-1) is a peptide hormone, secreted by intestinal epithelial L-cells in response to hormonal, neural and nutrient stimuli. It has been reported that insulin stimulates GLP-1 secretion through the activation of the phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT) and mitogen activated kinase (MAPK)-ERK1/2 pathways in murine and human L-cells [8]. In these cells the insulin receptor (IR) exists in two isoforms, isoform A (IR-A) and isoform B (IR-B) [8], which could be activated by insulin, insulin-like growth factors or other mediators [18]; to date, the role of the IR and its isoforms on L-cell function is largely unknown
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