Although the principal focus of GLP-1 research has been on pleiotropic actions that ultimately converge on regulation of nutrient intake and disposal through effects on CNS satiety centers, gastrointestinal motility, islet function and β cell growth, the GLP-1 receptor is widely expressed in several tissues not considered classic metabolic regulators of energy homeostasis, such as the heart, kidney, and lungs. Our understanding of GLP-1 actions in these tissues is incomplete, but likely to grow over the next few years.
GLP-1 and bone
Several gut peptides, including GIP, PYY, and GLP-2, regulate bone resorption and/or bone formation. Although GLP-1 is not known to directly regulate skeletal homeostasis, Chizumi Yamada and colleagues have shown that the Glp1r-/- mouse exhibits a number of defects in bone density, including cortical osteopenia and enhanced bone fragility, likely attributable to increased bone resorption. Moreover, the actions of GLP-1R agonists appear to be indirect, possibly associated with reduced GLP-1R-dependent calcitonin production by thyroid C cells. Whether treatment with GLP-1R agonists will modify bone density or strength has not been determined. See The Murine Glp1r is essential for control of bone resorption Endocrinology 2008 Feb;149(2):574-9.
GLP-1 and taste receptors
Taste receptors have been shown to be expressed on gut GLP-1-producing L cells and these receptors modulate GLP-1 secretion in mice. Moreover, GLP-1, may also be produced in subsets of murine taste cells, together with its receptor expressed on adjacent nerve endings, where it appears to contribute to gustatory discrimination. Moreover, Glp1r-/- mice exhibit reduced taste responses to sweeteners, implicating a functional role for the GLP-1 system in murine taste discrimination. See Modulation of taste sensitivity by GLP-1 signaling J Neurochem. 2008 Apr 5; [Epub ahead of print] and Expression of glucagon-like peptide-1 in the taste buds of rat circumvallate papillae Acta Histochem. 2008;110(2):151-4. Epub 2007 Dec 3
GLP-1 and hypothalamic-pituitary function
Although much recent attention has focused on the role of hypothalamic GLP-1 in the control of food intake, GLP-1 may also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin and vasopressin secretion. To review the data generated using cell lines and rodents, see Glucagon-like peptide-1 (GLP-1) releases thyrotropin (TSH): characterization of binding sites for GLP-1 on alpha-TSH cells. Endocrinology. 1996 Oct;137(10):4130-8.and Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line. J Clin Invest. 1998 Mar 15;101(6):1334-41 and Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology. 1997 Oct;138(10):4445-55
These GLP-1 actions do not appear to be essential for HPA function, as GLP-1R-/- mice cycle normally, are fertile, and exhibit normal basal levels of plasma osmolarity, corticosterone, thyroid hormones, estradiol, and testosterone Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling. Endocrinology. 2000 Feb;141(2):752-62. Conversely, transgenic mice with sustained elevations in circulating exendin-4 are fertile and do not exhibit significant disturbances in eating or drinking behavior Sustained expression of exendin-4 does not perturb glucose homeostasis, beta-cell mass, or food intake in metallothionein-preproexendin transgenic mice. J Biol Chem. 2000 Nov 3;275(44):34471-7
GLP-1 and the lung
GLP-1 receptor mRNA transcripts have been localized to the lung in rodents and humans, and several studies have confirmed the presence of GLP-1 binding sites using rat lung membrane preparations. Nevertheless, the precise pulmonary cell types that express the GLP-1R remain incompletely identified. Several reports have suggested that GLP-1 may exert actions both on airways (tracheal rings) and on pulmonary vasculature. Addition of GLP-1 to lung preparations increased macromolecule secretion and relaxed preconstricted pulmonary arteries. See GLP-1 stimulates secretion of macromolecules from airways and relaxes pulmonary artery. Am J Physiol. 1993 Oct;265(4 Pt 1):L374-81. Subsequent studies demonstrated that GLP-1 increases pulmonary surfactant production from isolated rat pneumocytes Glucagon-like peptide-1-(7-36)amide increases pulmonary surfactant secretion through a cyclic adenosine 3',5'- monophosphate- dependent protein kinase mechanism in rat type II pneumocytes. Endocrinology. 1998 May;139(5):2363-8 and similar studies have also been carried out using human lung cells Glucagon-like Peptide-1(7-36) Amide Stimulates Surfactant Secretion in Human Type II Pneumocytes. Am J Respir Crit Care Med. 2001 Mar 15;163(4):840-846.
GLP-1 action in fat and muscle cells
GLP-1 has been shown to exert modest effects on fat and muscle cells in vitro, however convincing evidence for a major physiologically relevant action of GLP-1 on lipolysis has not been forthcoming. GLP-1 binding sites have been identified in human adipose tissue however the molecular identity of the adipose tissue GLP-1R remains unclear Presence of glucagon and glucagon-like peptide-1-(7-36)amide receptors in solubilized membranes of human adipose tissue. J Clin Endocrinol Metab. 1993 Dec;77(6):1654-7.. Studies using rat explants studying the incorporation of [14C]acetate into saponifiable fat demonstrated that both GIP and GLP-1(7-36) stimulated fatty acid synthesis within the physiological range of the circulating hormones. At lower concentrations of the hormones, GLP-1(7-36) amide was a more potent stimulator of fatty acid synthesis than GIP in omental adipose tissue culture. See Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue. J Endocrinol. 1991 Aug; 130 (2):267-72
Bertin and colleagues have studied the effects of GLP-1 infusion on lipolysis and local blood flow in nine healthy human volunteers infused with either epinephrine, glucagon, GLP-1, or saline. These investigators analyzed dialysate glycerol content, ethanol ratio, and blood flow in sc abdominal adipose tissue and the gastrocnemius skeletal muscle. Neither glucagon or GLP-1 affected the rate of lipolysis in fat or muscle. See Action of Glucagon and Glucagon-Like Peptide-1-(7-36) Amide on Lipolysis in Human Subcutaneous Adipose Tissue and Skeletal Muscle in Vivo. J Clin Endocrinol Metab. 2001 Mar 1;86(3):1229-1234.
The actions of exendin-4, GLP-1, and exendin(9-39) have been studied in human adipocytes in vitro. GLP-1, Ex-4 and insulin, but not Ex-9, increased glucose uptake in adipocytes isolated from "normal subjects", actions that were blocked by inhibitors of PI3K and MAPKs blocked the stimulatory action of GLP-1, Ex-4 and insulin. Exendin(9-39) enhanced PI3K and stimulated p42 MAPK. The actions of GLP-1 and exendin-4 were impaired in adipocytes from obese subjects. The receptor delineating these actions was not delineated. See The action of GLP-1 and exendins upon glucose transport in normal human adipocytes, and on kinase activity as compared to morbidly obese patients. Int J Mol Med. 2007 Jun;19(6):961-6
Nevertheless, there continue to be reports describing actions of GLP-1 on muscle, including studies with human muscle cells and strips, suggesting actions of glucagon-like peptide agonists and antagonists. In muscle strips, GLP-1 stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity. In cultured myotubes, GLP-1 at very low doses of 0.1-1 pM stimulated glucose incorporation into glycogen. Curiously, exendin-4 and its truncated form 9-39 amide (Ex-9) both exert the same types of effects on glycogen synthesis and synthase a activity without stimulating an increase in cAMP accumulation. The identity of the receptor that transduces these intriguing effects remains unknown. See Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. J Endocrinol. 2002 Jun; 173( 3): 465-73
GLP-1, plasma lipids, and lipid absorption
Very little is currently known about the effects of GLP-1 on levels of circulating lipids, lipid biosynthesis, or lipid clearance. Qin and colleagues examined the effects of intravenous GLP-1 on lipid metabolism in rats following intraduodenal lipid infusion. GLP-1 reduced lymph flow, inhibited intestinal triolein absorption, and reduced lymphatic apolipoprotein output. See GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol. 2005 May;288(5):G943-9.
GLP-1 action in the liver and biliary tree
Cholangiocytes have been shown to express the GLP-1 receptor, and GLP-1R expression is upregulated following development of cholestasis. Both GLP-1 and exendin-4 increased cholangiocyte growth in vitro and in vivo and proliferating cholangiocytes synthesized GLP-1 whereas GLP-1R antagonists blunt the cholangiocyte response to cholestasis-see Glucagon-like Peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis. Gastroenterology. 2007 Jul;133(1):244-55.