title: 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.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Unit for Diabetes Research, Södersjukhuset, Stockholm, Sweden;
authors.forename: Camilla
authors.initials: C
authors.lastname: Kappe
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D019858:Enteroendocrine Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D017382:Reactive Oxygen Species; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D017382:Reactive Oxygen Species; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: L cell; exendin-4; glucagon-like peptide-1; insulinotropic; lipotoxicity