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 the gastrointestinal tract
GLP-1 exerts a number of actions in the gastrointestinal tract, including regulation/inhibition of gut motility, and in preclinical studies, expansion of the epithelial mucosa in the rodent small bowel Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats Am J Physiol Gastrointest Liver Physiol. 2007 Jul;293(1):G288-95. Kunkel and colleagues administered exenatide, 5 ug twice daily to five patients with short bowel syndrome and less than 90 cm of residual small bowel. In this retrospecive analysis, exenatide reduced diarrhea, normalized small bowel motility as assessed by manometry, and 3 patients were able to discontinue their requirements for TPN. Remarkably, the patients discontinued TPN on the same day they started exenatide. The authors attributed the therapeutic effects of GLP-1 therapy to the anti-motility effects of exenatide. Little information was provided about quantitative energy balance prior to or during exenatide use in this report See Efficacy of the glucagon-like peptide-1 agonist exenatide in the treatment of short bowel syndrome Neurogastroenterol Motil. 2011 May 10. doi: 10.1111/j.1365-2982.2011.01723.x.
GLP-1 and human mesenchymal stem cells
The GLP-1 receptor was detected by RT-PCR in mesenchymal stem cells isolated from "normal" human bone marrow. Short term 24h administration of GLP-1 did not affect gene expression of stem cell markers. GLP-1 added to hMSCs during the differentiation process reduced the expression of C/EBPb, LPL, and PPARg; GLP-1 also exerted detectable effects on cell proliferation of undifferentiated cells and reduced apoptosis in serum-starved cells in this culture system SIGNALLING AND BIOLOGICAL EFFECTS OF GLUCAGON-LIKE PEPTIDE 1 (GLP-1) ON THE DIFFERENTIATION OF MESENCHYMAL STEM CELLS FROM HUMAN BONE MARROW. Am J Physiol Endocrinol Metab. 2009 Dec 29. [Epub ahead of print]
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-1R agonists and DPP-4 inhibitors also reduce postprandial lipoprotein levels in hamsters mice and humans, independent of changes in body weight, predominantly through inhibition of intestinal chylomicron synthesis. These actions of GLP-1 are mediated through the known GLP-1 receptor, and are direct actions on the gut. Furthermore, transient blockade of GLP-1R signaling with exendin(9-39), or genetic elimination of GLP-1R signaling in Glp1r-/- mice, results in enhanced appearance of postprandial triglyceride rich lipoproteins. Hence, basal GLP-1R signaling is essential for intestinal control of chylomicron synthesis in vivo. See The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia. 2009 Dec 3. [Epub ahead of print] These findings are also consistent with analysis of postprandial lipoproteins in human diabetic subjects treated with vildagliptin Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes Diabetologia. 2006 Sep;49(9):2049-57. Similar findings were obtained by Tremblay and colleagues who studied 36 subjects with T2DM randomized to treatment with sitagliptin or placebo for 6 weeks, following which an oral lipid tolerance test was performed. Sitagliptin treatment reduced HbA1c from 6.9-6.6%, decreased postprandial levels of ApoB, apoB-48, TGs, VLDL cholesterol, FFAs and glucose, in association with increased levels of active GLP-1 and GIP and reduced levels of glucagon but did not change levels of insulin or C-peptide Effect of sitagliptin therapy on postprandial lipoprotein levels in patients with type 2 diabetes Diabetes Obes Metab. 2011 Jan 12. doi: 10.1111/j.1463-1326.2011.01362.
Eliasson and colleagues examined the effects of placebo (24), alogliptin 25 mg alone (25), or alogliptin plus pioglitazone (22)in patients with type 2 diabetes treated with the different agents for 16 weeks. Reductions in A1c were greater with combination of pioglitazone/alogliptin (0.95% reduction) then with alogliptin alone (0.39%). Alogliptin alone reduced fasting triglyceride levels by 0.56 mM, whereas the Alo/pio combination reduced triglycerides by 0.81 mM. Fasting total and LDL cholesterol did not change significantly in any of the groups. Both alogliptin alone and alogliptin/pioglitaone produced significant reductions in postprandial triglycerides, chylomicrons, and VLDL triglycerides, detectable within 4 weeks of therapy. Postprandial ApoB48 levels and VLDL1 ApoB48 and apoB-100 were reduced to a greater extent by alogliptin alone. Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study Diabetologia. 2012 Jan 12. [Epub ahead of print
Acute administration of a single 10 ug dose of exenatide to subjects with IGT or recently diagnosed T2DM produced highly significant reductions in postprandial triglycerides, apoB48 and CIII, and RLP-cholesterol and triglyceride. The mechanisms mediating this effect in humans require further study Improvement of postprandial endothelial function after a single dose of exenatide in individuals with impaired glucose tolerance and recent-onset type 2 diabetes. Atherosclerosis. 2010 May 25. [Epub ahead of print] and are discussed in an accompanying Editorial Newly appreciated therapeutic effect of GLP-1 receptor agonists: Reduction in postprandial lipemia Atherosclerosis. 2010 Jun 25.
GLP-1 and bone
Several gut peptides, including GIP, PYY, and GLP-2, regulate bone resorption and/or bone formation, primarily in rodents. 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.
Intriguingly, many of these hormones, specifically GLP-1, GIP, PYY, and GLP-2, are all DPP-4 substrates, hence changes, specifically reduction of DPP-4 activity, may result in potential perturbation in bone biology perhaps through indirect modulation of active peptide hormone activity. As patients with type 2 diabetes exhibit increased fracture rates due to a reduction in bone quality, Kyle and colleagues examined multiple parameters of bone strength and bone quality in Dpp4+/+ vs Dpp4-/- mice, with or without estrogen deficiency induced by ovariectomy (OVX). Kyle also studied the same parameters in wildtype mice placed on a high fat diet, with or without OVX, and treated with the DPP-4 inhibitor sitagliptin, or the thiazolidinedione, pioglitazone. The degree of glucose control achieved with the two different anti-diabetic agents was comparable for sitagliptin vs. pioglitazone, as assessed by glucose tolerance and HbA1c, however pioglitazone-treated mice exhibited enhanced insulin sensitivity, significant weight gain and fat accumulation. Consistent with previous reports, the TZD pioglitazone reduced bone mineral density, and bone mineral volume, and decreased bone quality as demonstrated by significant adverse changes in vertebral compression parameters. Pioglitazone also reduced the mineral apposition rate and increased bone marrow adiposity. In contrast, sitagliptin treatment of WT mice was largely neutral on multiple parameters of bone mineral density and bone quality, however modest increases in bone mineral density, trabecular bone mineralization profiles and trabecular architecture were observed with sitagliptin. Similarly, Dpp4-/- mice exhibited very little perturbation in bone mineral density or quality, however both sitagliptin-treated or Dpp4-/- mice did experience further reductions in BMD and bone quality following OVX. See Kyle, K.A., Willett, T.L., Baggio, L.L., Drucker, D. J., Grynpas, M. Differential Effects of PPAR-g Activation vs. Chemical or Genetic reduction of DPP-4 Activity on Bone Quality in Mice Endocrinology 2011 Feb;152(2):457-67
The effects of short term administration of native GLP-1 administered by continuous subcutaenous infusion were examined in male Wistar rats after administration of STZ (type 1 DM model) or fructose feeding to induce insulin resistance (T2DM). GLP-1 produced modest increases in levels of osteocalcin and osteoprotegerin RNAs in tibial RNA from normal and diabetic rats, small increases in bone mineral density, and modest but significant changes in some parameters of trabecular bone structure. The mechanism that mediates these effects was not explored. See Effect of GLP-1 Treatment on Bone Turnover in Normal, Type 2 Diabetic, and Insulin-Resistant States Calcif Tissue Int. 2009 Jun;84(6):453-61
GLP-1 action in the exocrine pancreas, and biliary tree
The putative mechanism through which GLP-1R agonists may act on the exocrine pancreas remains uncertain, and pancreatitis has not been described in the majority of large preclinical studies of GLP-1R agonists. Infusion of GLP-1 inhibits pancreatic exocrine secretions in short term studies of normal human subjects Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993 Apr;38(4):665-73. These effects are likely indirect, due to the effecst of GLP-1 on reduction of gastric emptying, and hence reduced transit of food into the small bowel.
Analysis of the biological activity of exendin-4 in guinea pig pancreatic exocrine slices revealed that exendin-4 stimulates cyclic AMP release through incompletely characterized mechanisms as outlined in Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992 Apr 15;267(11):7402-5. Susequent experiments revelaed that although exendin-4 alone did not stimulate amylase release, exendin-4 potentiated amylase release induced by CCK, carbamylcholine, bombesin or a calcium ionophore, A23187 Exendin-4, a new peptide from Heloderma suspectum venom, potentiates cholecystokinin-induced amylase release from rat pancreatic acini. Regul Pept. 1992 Sep 22;41(2):149-56. These interactions of exendin-4 with pancreatic acinar cells are also seen with native GLP-1, which also increased cyclic AMP release in comparable studies, actions which were blocked by the GLP-1R antagonist exendin(9-39); similarly, binding sites for both exendin-4 and GLP-1 were detected in experiments using radiolabelled peptides and guinea pig pancreatic acinar cells Truncated glucagon-like peptide-1 interacts with exendin receptors on dispersed acini from guinea pig pancreas. Identification of a mammalian analogue of the reptilian peptide exendin-4. J Biol Chem. 1992 Oct 25;267(30):21432-7. and Use of 125I-[Y39]exendin-4 to characterize exendin receptors on dispersed pancreatic acini and gastric chief cells from guinea pig. Regul Pept. 1994 Aug 31;53(1):47-59
There is very little information available about the possible effects of GLP-1/exendin-4 on the gall bladder or biliary tract. Preclinical studies in rats demonstrate that GLP-1/exendin-4 stimulates cholangiocyte growth, and that proliferating cholangiocytes may be capable of actually synthesizing GLP-1 Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis. Gastroenterology. 2007 Jul;133(1):244-55. Subsequent studies demonstrated that exendin-4 is also capable of exerting anti-apoptotic effects on rat cholangiocytes cultured in vitro, and in a bile duct ligation/toxin (Ccl4)-induced model of cholangiocyte apoptosis in vivo Exendin-4, a Glucagon-Like Peptide 1 receptor agonist, protects cholangiocytes from apoptosis. Gut. 2008 Oct 1. [Epub ahead of print] For an overview of reports linking Glp1r activation to pancreatitis, see GLP-1 SAFETY
GLP-1 action in the liver
Studies of GLP-1 action in the liver continue to generate uncertainty in regard to whether the classical GLP-1 receptor is actually expressed in hepatocytes.
Tomas and colleagues provide evidence that a carboxyterminal nonapeptide derived from GLP-1 via NEP24.11 cleavage, GLP-1(28-36) amide, is biologically active in hepatocytes where it suppresses hepatic glucose production. Fluorescent-label (FAM was added to the N-terminus) GLP-1(28-36)amide entered mouse hepatocytes where it appeared to localize to mitochondria, whereas 3 control peptides did not exhibit the same pattern of localization. The stimulation of gluconeogenesis with cAMP, dexamethasone and lactate was inhibited in a dose-dependent manner by GLP-1(28-36)amide at concentrations o 0.1-10 mM through mechanisms not blocked by exendin(9-39) although Ex(9-39) also weakly inhibited gluconeogenesis. Induction of oxidative stress in mouse hepatocytes or H4IIE cells with tBHP or hydrogen peroxide produced a fall in ATP that was prevented by GLP-1(28-36). Similarly, tBHP increased levels of ROS that were decreased by GLP-1(28-36). See GLP-1-Derived Nonapeptide GLP-1(28-36)amide Targets To Mitochondria and Suppresses Glucose Production and Oxidative Stress in Isolated Mouse Hepatocytes Regul Pept. 2011 Apr 11;167(2-3):177-84
Evidence for a structurally and functionally distinct GLP-1 receptor also derives from studies of GLP-1 action in the liver. Several studies have shown that GLP-1 binds to liver membranes, and is displaced by GLP-1(1-36)amide Glucagon-like peptide-1 binding to rat hepatic membranes. J Endocrinol. 1995 Jul;146(1):183-9. Experiments using human hepatoma cells have shown that GLP-1 modulates the cell content of radiolabelled glycosylphosphatidylinositols (GPIs), Inositolphosphoglycans are possible mediators of the glucagon-like peptide 1 (7-36)amide action in the liver. J Endocrinol Invest. 1996 Feb;19(2):114-8. Incubation of rat hepatocytes with GLP-1 resulted in inhibition of glucagon-stimulated glycogenolysis, an effect additive with insulin. The authors postulated that this effect is through a distinct receptor, as GLP-1 did not displace glucagon binding from liver membranes. See Glucagon-like peptide-1 inhibits glucagon-induced glycogenolysis in perivenous hepatocytes specifically. Regul Pept. 2003 Mar 28;111(1-3):207-10.
Similarly, GLP-1activated PI3K/PKB, p70s6k, p44 and p42 MAP-kinase in rat liver cells and the activation of PI3K/PKB, PKC and PP-1, but not PP-2A, appeared to mediate the GLP-1 stimulatory action on glycogen synthase a in rat hepatocytes, while MAPKs and p70s6k were postulated to participate in other GLP-1effects. Whether these cells expressed the known GLP-1 receptor remains unclear. See Cell signalling of the GLP-1 action in rat liver. Mol Cell Endocrinol. 2003 Jun 30;204(1-2):43-50.
Exendin-4 has also been shown to promote transdifferentiation of liver cells in the context of ectopic pdx-1 expression. Although expression of the known GLP-1R was not identified in liver cells, either prior to or following the transdifferentiation process, Ex-4 increased levels of cAMP in human liver cells, and increased levels of phosphoCREB, Akt, PKC, and ERK1/2. Following Pdx-1 transduction, Ex-4 increased insulin promoter activity and insulin gene expression in transduced liver cells. Similarly, Ex-4 induced expression of a broad number of transcription factors and proteins associated with specialized beta cell function. Ex-4 was also found to increase liver cell proliferation and likely increases the proportion of cells susceptible to transduction by Pdx-1 Exendin-4 promotes liver cell proliferation and enhances PDX-1-induced liver to pancreas transdifferentiation J Biol Chem. 2009 Sep 15. [Epub ahead of print]
Raab and colleagues assessed the actions of exendin-4 after treatment of neonatal rats with intrauterine growth retardation. Exendin-4 reduced basal hepatic glucose output and increased liver insulin sensitivity. Remarkably, the direct effects of exendin-4 on neonatal rat hepatocytes, namely reduce PEPCK expression and improved insulin signaling, were observed in the absence of detectable expression of the known GLP-1R-See Neonatal Exendin-4 Treatment Reduces Oxidative Stress and Prevents Hepatic Insulin Resistance in Intrauterine Growth Retarded Rats Am J Physiol Regul Integr Comp Physiol. 2009 Oct 21. [Epub ahead of print]
In contrast, Svegliati-Baroni and co-authors report detection of PCR products (142 bp) corresponding to human Glp1r in RNA from normal liver, and Glp1r expression levels were reduced in livers from subjects with Nash. A GLP-1R-immunoreactive protein was easily detected using whole extracts from human pancreas, human HepG2 cells, and human liver using an antibody from Alpha Diagnostics. A 453 b.p Glp1r PCR product was also detected in RNA from rat liver and the abundance of the transcripts and immunoreactive protein was reduced after several months of high fat feeding. The immunoreactive GLP-1R protein was also detected in isolated rat hepatocytes frm rats with NASH and a 24h incubation with exenatide induced the expression of Pparg, Ppara, Cpt1a and Acox1. Exenatide also increased the activity of pAKT, PKA and AMPK in rat hepatocytes. The induction of pAKT was sensitive to inhibitors of cAMP and PI3K. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis Liver Int. 2011 Feb 15. doi: 10.1111/j.1478-3231.2011.02462.x.
The effects of pioglitazone and exenatide in combination, with or without metformin in human subjects with T2DM and NAFLD were examined in an open label study of pioglitazone alone (30 mg initially, increased to 45 mg for 50 weeks(n=10); or pioglitazone plus exenatide for 50 weeks (n=11). Exenatide therapy abrogated the weight gain experienced by the patients receiving pioglitazone alone (3.7 kg), and the reduction in hepatic fat (61%) was significantly greater in subjects treated with exenatide plus pioglitazone. Fasting plasma FGF-21 levels were also reduced (2.3 to 1.1 ng/ml) in patients treated with both pio plus exenatide. Continuous delivery of exenatide alone via osmotic minipump to high fat fed mice for 4 weeks resulted in very high plasma levels of exenatide (1,734 pM), improved glucose tolerance and a significant reduction in liver weight and hepatic fat (triacylglycerol) content and decreased levels of hepatic and plasma FGF-21. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial Diabetologia. 2011 Sep 29. [Epub ahead of print
Sharma and colleagues assessed the direct effect of exenatide in human hepatocytes exposed to different fatty acids and in high fat fed mice treated with liraglutide. Human hepatocytes loaded with fatty acids exhibited a reduction in fatty acid storage as quantified by Oil Red O staining. Hepatocyte viability, quantified by cleavage of tetrazolium salt XTT, DNA condensation, and levels of cleaved caspase-3 and CHOP, were also improved with 24 hrs of exendin-4 treatment. Exendin-4 treated human hepatocytes and liver from liraglutide-treated high fat fed mice also exhibited changes in markers of autophagy, lysosomal turnover, and increased numbers of autophagic vacuoles. The signal transduction pathways and receptor(s) mediating these observations were not identified in these studies. GLP-1 Analogs Reduce Hepatocyte Steatosis and Improve Survival by Enhancing the Unfolded Protein Response and Promoting Macroautophagy PLoS One. 2011;6(9):e25269. Epub 2011 Sep 21
A follow-up study by the same group examined the consequences of liraglutide therapy, 200 ug/kg daily,for 4 weeks in mice fed a "Western" diet (45% calories from fat; 40% of the fat representing hydrogenated vegetable oil previously shown to produce hepatic injury in C57BL/6 mice. Liraglutide improved hepatic insulin sensitivity, reduced blood pressure, adiposity, and decreased liver weight, with only modest reductions in body weight after 4 weeks. Liraglutide reduced plasma cholesterol and triglycerides and reduced hepatic fat accumulation. Liraglutide therapy was asssociated with a 400-fold increase in mRNA transcripts for LFABP, reduced levels of CPT-1alpha, and preservation of levels of MTTP, and ApoB hepatic mRNA transcripts. GLP-1 analogue, liraglutide ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a western diet Am J Physiol Gastrointest Liver Physiol. 2011 Oct 28
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 Glp1r-/- 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 kidney
The GLP-1 receptor is expressed in the kidney and GLP-1R activation rapidly promotes natriuresis through incompletely understood mechanisms
Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men J Clin Endocrinol Metab. 2004 Jun;89(6):3055-61. The importance of neurotransmission for the effects of GLP-1 on kidney function was demonstrated in studies using denervated kidney preparations, where the natriuretic and diuretic response to rGLP-1 was attenuated in the denervated kidney. The natriuretic effects of GLP-1 appear to be associated with inhibition of Na+ reabsorption in the proximal tubule Renal effects of glucagon-like peptide in rats Eur J Pharmacol. 2002 Jan 11;434(3):163-7. Consistent with these findings, GLP-1R mRNA transcripts were detected im primary cultures of porcine kidney epithelial cells and GLP-1 directly inhibited Na+ but not glucose reabsorption Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells Regul Pept. 2007 Jun 7;141(1-3):120-8. Infusion of native GLP-1 into salt-senstive Dahl rats for 14 days reduced the development of hypertension and proteinuria, improved Na+ excretion and was associated with decreased histological evidence for cardiac and renal damage Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats J Hypertens. 2003 Jun;21(6):1125-35. Similar findings were then obtained in studies using GLP-1 or an exendin-4 analogue infused, with or without captopril, for 4 weeks in Dahl rats, with histological evidence for attenuation of renal damage The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats Cardiovasc Diabetol. 2010 Aug 3;9:3. These data are also consistent with findings reported in in salt-sensitive obese db/db mice and angiotensin II (angII)-infused C57BLK6/J mice, where exendin-4 treatment attenuated the development of hypertension and enhanced sodium excretion Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model Biochem Biophys Res Commun. 2009 Feb 27;380(1):44-9
Treatment of diabetic db/db mice with exendin-4 reduced blood glucose, decreased urine albumin excretion and reduced histological parameters of glomerular injury, TGF-beta1 expression, and type IV collagen accumulation with fewer infiltrating inflammatory cells and apoptotic cells in the glomeruli Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice J Am Soc Nephrol. 2007 Apr;18(4):1227-38. Similarly, treatment of rats with STZ-induced diabetes with exendin-4, 10mg/kg once daily for 8 weeks had no significant effect on body weight or HbA1c, but reduced albumin excretion, decreased glomerular hypertrophy, and reduced markers of inflammation, fibrosis, and oxidative stress in the kidney. GLP-1 receptor mRNA was detected in rat glomeruli, glomerular endothelial cells, human monocytes, and THP-1 macrophages and exendin-4 directly attenuated the expression of high glucose-stimulated TNFa and IL-1b in THP-1 cells and in human glomerular microvascular endothelial cells Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes Diabetologia. 2011 Jan 21
A direct role for exendin-4 in modulation of Na+ exchange was also suggested in experiments using renal proximal tubular LLC-PK(1) cells. Treatment with exendin-4 modulated the activity of the activity of Na(+)/H(+) exchanger NHE3 in part via cAMP-dependent mechanisms associated with NHE3 phsophorylation. The porcine GLP-1 receptor was detected by RT-PCR in LLC-PK(1) cells and in cells isolated from the porcine kidney cortex, but not the medulla and exendin-4 increased cAMP accumulation in LLC-PK(1) cells, effects that were blocked by the antagonist exendin(9-39) Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells Am J Physiol Renal Physiol. 2009 Dec;297(6):F1647-55.
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. Surprisingly, the GLP-1R antagonist 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
The relationship between GLP-1 and visfatin, a polyfunctional adipokine with enzymatic activity have been described in studies in normal human subjects. Both normal weight and obese subjects exhibited a decrease in serum visfatin levels following oral glucose administration. Insulin and GLP-1 significantly reduced visfatin secretion in 3T3L1 cells in vitro. GLP-1 also produced a modest decrease on levels of phospho ERK1/2 in 3T3 L1 cells. Whether GLP-1 significantly contributes to control of visfatin secretion in vivo remains unclear. In Vivo Suppression of Visfatin by Oral Glucose Uptake: Evidence for a Novel Incretin-Like Effect by Glucagon-Like Peptide-1 (GLP-1). J Clin Endocrinol Metab. 2011 Jun 15.
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 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