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.

• Authors: Camilla Kappe, Qimin Zhang, Jens J Holst, Thomas Nyström, Ake Sjöholm
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 305 Issue 10 Pg. C1041-9 (Nov 15 2013) ISSN: 1522-1563 [Electronic] United States
• PMID: 23986202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Insulin
• Peptides
• Reactive Oxygen Species
• Receptors, Glucagon
• Venoms
• Glucagon-Like Peptide 1
• Exenatide

Topics

• Animals
• Cell Line
• Cell Proliferation
• Cell Survival
• Enteroendocrine Cells (cytology, drug effects, metabolism)
• Exenatide
• Gene Expression Regulation (physiology)
• Glucagon-Like Peptide 1 (genetics, metabolism)
• Glucagon-Like Peptide-1 Receptor
• Insulin (administration & dosage, pharmacology)
• Mice
• Peptides (administration & dosage, pharmacology)
• Reactive Oxygen Species
• Receptors, Glucagon (genetics, metabolism)
• Time Factors
• Venoms (administration & dosage, pharmacology)