Evidence for paracrine/autocrine regulation of GLP-1-producing cells

Abstract

Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9-39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP-1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion.

Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt–Sfrp2 pathways

“…Tatarkiewicz et al [47] suggested the existence of an additional novel receptor signaling pathway complementing the actions of Ex-4. Kappe et al [48] found the cross talk between tyrosine kinase receptors (e.g., the insulin receptor) and GLP-1R and that Ex-4 may exert an effect on tyrosine kinase receptors, which transmit signals to activate downstream pathways of GLP-1R. However, the exact mechanism of how Ex-4 enters into ADMSCs and subsequently activates signal pathways needs more research.…”

The regulation of function, growth and survival of GLP-1-producing L-cells

“…the insulin-producing β-cells [120]. Such autocrine feedback may be operative also in GLP-1-secreting cells, where GLP-1R expression on L-cells and its involvement in GLP-1 secretion has previously been suggested by data from in vivo and in vitro studies [77,121]. Although a recent study indicated that GLP-1 and its degradation products do not modulate L-cell basal secretion of GLP-1(7-36) amide, any potential feedback mechanisms acting on post prandial responses were not investigated [122].…”

“…Whether intestinal L-cells express the GLP-1R, which would facilitate autocrine signalling by the peptide, is still debated. Some studies indicate the presence of the GLP-1R in GLP-1 producing cells [77,121], where the GLP-1R has been demonstrated with immunocytochemistry, and GLP-1R mRNA expression has been reported in GLP-1-producing GLUTag cells [121]. However, other studies have failed to detect any GLP-1R expression in GLP-1-producing cells [50].…”

“…Few studies have been designed to investigate effects of this on L-cells and whether lipotoxicity occurs also in these cells. In a series of recent studies, cells of the GLUTag cell line were exposed to simulated hyperlipidaemia using the saturated fatty acid palmitate, the most abundant saturated fatty acid in serum [121,184,185]. This resulted in increased DNA fragmentation and caspase-3 activity in conjunction with reduced viability of GLP-1-producing cells [121,184,185].…”

“…In a series of recent studies, cells of the GLUTag cell line were exposed to simulated hyperlipidaemia using the saturated fatty acid palmitate, the most abundant saturated fatty acid in serum [121,184,185]. This resulted in increased DNA fragmentation and caspase-3 activity in conjunction with reduced viability of GLP-1-producing cells [121,184,185]. In resemblance with the β-cells, and in accordance with what has previously been found, there was a positive secretory response to acute exposure to the fatty acid, whereas impaired function was observed following long-term exposure.…”