TY - JOUR

T1 - GLP-1 receptor localization in monkey and human tissue

T2 - novel distribution revealed with extensively validated monoclonal antibody

AU - Pyke, Charles

AU - Heller, R Scott

AU - Kirk, Rikke K

AU - Ørskov, Cathrine

AU - Reedtz-Runge, Steffen

AU - Kaastrup, Peter

AU - Hvelplund, Anders

AU - Bardram, Linda

AU - Calatayud, Dan

AU - Knudsen, Lotte Bjerre

PY - 2014/4

Y1 - 2014/4

N2 - Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the muscularis externa in the stomach and in myenteric plexus neurons throughout the gut. No GLP-1R was seen in primate liver and thyroid. GLP-1R expression seen with immunohistochemistry was confirmed by functional expression using in situ ligand binding with (125)I-GLP-1. In conclusion, these results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLP-1R.

AB - Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in β-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the muscularis externa in the stomach and in myenteric plexus neurons throughout the gut. No GLP-1R was seen in primate liver and thyroid. GLP-1R expression seen with immunohistochemistry was confirmed by functional expression using in situ ligand binding with (125)I-GLP-1. In conclusion, these results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLP-1R.

KW - Animals

KW - Antibodies, Monoclonal/chemistry

KW - Blood Pressure

KW - Body Weight

KW - Cell Line

KW - Cricetinae

KW - Duodenum/metabolism

KW - Glucagon/secretion

KW - Glucagon-Like Peptide 1/analogs & derivatives

KW - Glucagon-Like Peptide-1 Receptor

KW - Haplorhini

KW - Heart Rate

KW - Humans

KW - Insulin/secretion

KW - Ligands

KW - Liraglutide

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Peptides/chemistry

KW - Protein Binding

KW - Receptors, Glucagon/metabolism

KW - Tissue Distribution

KW - Transfection

KW - Venoms/chemistry

U2 - 10.1210/en.2013-1934

DO - 10.1210/en.2013-1934

M3 - Journal article

C2 - 24467746

VL - 155

SP - 1280

EP - 1290

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0013-7227

IS - 4

ER -