GLP-1 has been used in short term studies to treat subjects with type 1 diabetes, and preclinical studies have examined the efficacy of GLP-1R agonists in models of T1DM such as the NOD mouse. Intriguingly, the results of some of these studies suggest that GLP-1 therapy may have immunomodulatory actions. Initiation of exendin-4 treatment alone after the development of diabetes had little therapeutic benefit in NOD mice. In contrast, exendin-4 together with lysophiline for 28 days, markedly improved glucose control in NOD mice, even 6-14 weeks after cessation of therapy. Furthermore, the combination therapy preserved the number of intact islets, and appeared to reduce the extent of inflammatory cell infiltration in the remaining islets. See Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes. Biochem Biophys Res Commun. 2006 Jun 9;344(3):1017-22. Similarly, continuous administration of native GLP-1 to 8 week old female NOD mice for 4 or 8 weeks lowered blood glucose, increased formation of new b-cells, suppressed b-cell apoptosis and delayed the onset of diabetes as described in Continuous stimulation of human glucagon-like peptide-1 (7-36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes. Diabetologia. 2007 Jul 14; [Epub ahead of print]. In contrast, twice daily administration of exendin-4 at two different doses, 100 ng, and 2 ug twice daily, prior to the development of clinical diabetes in NOD mice, produced only modest effects on the numbers of disease-free mice, with detectable but small increased in beta cell mass and reductions in insulitis. Intriguingly, GLP-1receptor expression was also detected in different immune cell compartments as outlined in Exendin-4 modulates diabetes onset in non obese diabetic mice Endocrinology. 2008 Mar;149(3):1338-49.
Hadjiyanni and colleagues subsequently detected widespread expression of mRNA transcripts encoding a full length GLP-1R in immune cells from bone marow, spleen, thymus and peripheral lymph nodes. Immune GLP-1R expression appeared to be relatively higher in cells from NOD mice compared to cells ontained from C57BL/6 mice. GLP-1R activation increased cyclic AMP formation in immune populations but failed to affect lymphocyte survival, proliferation, or migration. Although no major changes in cell numbers or immune cell function were observed in Glp1r-/- lymphocytes, Glp1r-/- thymocytes exhibited a hypoproliferative response, whilst peripheral Glp1r-/- lymphocytes were hyperproliferative in response to mitogenic stimulation. As these studies were carried out in "normal mice", and in non-diabetic NOD mice, further analysis of the role of the GLP-1R in the context of immune dysfunction, such as T1DM, or other inflammatory or immunological disorders appears warranted. Glucagon-like peptide-1 receptor (GLP-1R) signaling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T-cells Diabetologia 2010 Apr;53(4):730-40.
Iwai et al demonstrated GLP-1 binding to rat brain glial cells and detected GLP-1 receptor expression in cultured astrocytes, microglia, and neurons by RT-PCR. GLP-1 suppressed the induction of IL-1b, IL-6 and iNOS RNA by LPS and decreased IL-1b secretion into culture medium. The effects of GLP-1 to suppress IL-1b expression were blocked by the adenylate cyclase inhibitor SQ22536 Glucagon-like peptide-1 inhibits LPS-induced IL-1beta production in cultured rat astrocytes Neurosci Res. 2006 Aug;55(4):352-60
The GLP-1R agonist exendin-4 also exerted anti-inflammatory actions in 3T3-L1 adipocytes. Incubation of differentiated adipocytes with exendin-4 for 8 hrs increased adiponectin expression and produced a modest increase in adiponectin secretion, effects blocked by exendin(9-39). Exendin-4 reduced the levels of intracellular cAMP and both forskolin and IBMX, and paradoxically, the PKA inhibitor H-89 all blocked the induction of adiponectin expression by exendin-4. Exendin-4 also reduced the expression of IL-6 and MCP1 Exendin-4, a GLP-1 receptor agonist, directly induces adiponectin expression through protein kinase A pathway and prevents inflammatory adipokine expression Biochem Biophys Res Commun. 2009 Dec 18;390(3):613-8
Marx and colleagues examined the actions of GLP-1(1-37), a non-classical weak agonist at the GLP-1 receptor, and exendin-4, a potent GLP-1 receptor agonist, on human CD4+ lymphocyte migration ex vivo. GLP-1(1-37) reduced SDF-1-stimulated lymphocyte migration in a dose-dependent manner, effects not seen with a scrambled GLP-1(1-37) peptide. The modest induction of PI3-kinase activity induced by SDF-1, and the phosphorylation of cofilin and myosin light chain(MLC) was also attenuate by the classical GLP-1 receptor agonist GLP-1(7-37). Similarly, GLP-1(1-37) attenuated the extent of SDF-1-induced F-actin formation in CD4+ lymphocytes. An immunoreactive GLP-1R protein was detected using GLP-1R antisera (Upstate) in human CD4+ lymphocytes and endothelial cells and a functional role for the GLP-1R was invoked by demonstrating that exendin-4 also modestly reduced SDF-1-enhanced lymphocyte migration. Knock down of GLP-1R expresion abrogated the effect of GLP-1(1-37) to reduce ICAM-3 expression, an indirect readout for lymphocyte cell migration. The effects of exendin-4 were not reported in the same GLP-1R knockdown experiments. See Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes Cell Mol Life Sci. 2010 Oct;67(20):3549-55
Anti-inflammatory actions of exendin-4 were demonstrated in human islet cultures ex vivo. Treatment of islets with interferon-g induced expression of the chemokine CXCL10 and multiple other chemokines. Treatment of islets with exendin-4 and the PDE inhibitor rolipram suppressed the induction of CXCL9, CXCL10, and CXCL10; the effects of exendin-4 in the absence of rolipram were much more modest, wehereas forskolin and dbcAMP robustly inhibited chemokine expression. Exendin-4 and cyclic AMP also reduced the expression of STAT-1, a mediator of CXCL10 expression in human islets and the anti-inflammatory actions of exendin-4 were blocked by the adenylate cyclase inhibitor SQ22536, but not by the PKA inhibitor H89, which paradoxically enhanded the supression of CXCL10 expression by cAMP. Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients Diabetologia. 2010 Nov;53(11):2357-68
Dozier et al demonstrated cytoprotective and anti-inflammatory actions of GLP-1 on mesenteric endothelium. Although GLP-1 had no effect on basal microvascular permeability in non-inflamed vessels, LPS increased and GLP-1 decreased permeability in rat mesenteric post-capillary venules. The effects of GLP-1 to reduce inflammation-related permeability were reduced by co-treatment with exendin(9-39) or with the cAMP synthesis inhibitor ddA, whereas rolipram, an inhibitor of PDE4 and cAMP degradation, potentiated the actions of GLP-1 and the PKA inhibitor H-89 blocked the anti-permeability actions of GLP-1. See Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation Peptides 2009 Sep;30(9):1735-41. In contrast, using a different model of endothelial dysfunction, Nathanson and colleagues failed to find any effect of the degradation-resistant GLP-1R agonist exenatide on rat conduit arteries. Incubation of rat femoral artery rings with intralipid impaired acetylcholine-induced vasorelaxation however exenatide had no effect on intralipid-induced endothelial dysfunction. In contrast, significant vasorelaxation was observed following incubation of femoral rings with GLP-1, GLP-1(9-36), ACh and SNP; 23+/-4%, 38+/-4%, 79+/-3% and 97+/-4% relaxation, respectively. These observations suggest that the effect of GLP-1 on endothelial relaxation may be independent of the classical GLP-1R Endothelial dysfunction induced by triglycerides is not restored by exenatide in rat conduit arteries ex vivo Regul Pept. 2009 Oct 9;157(1-3):8-13
Hattori et al examined the ant-inflammatory actions of liraglutide in Human Umbilical Vein Endothelial Cells. Liraglutide increased NO production in a dose- and time-dependent manner, actions eliminated by the AMPK inhibitor compund C. Consistent with the putative importance of AMPK, liraglutide promoted AMPK phosphorylation and increased eNOS expression and decreased NF-kB activation in HUVECs and SVEC4 cells treated with TNFa. Liraglutide also decreased the expression of cytokines induced by TNFa. A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells Diabetologia. 2010 Oct;53(10):2256-63
Kodera and colleagues observed renoprotective effects and reduced inflammation in rats with STZ-induced diabetes treated with exendin-4, 10 ug/kg/day, for 8 weeks. Ex-4 improved blood glucose and renal histology, decreased glomerulat typ IV collagen and urinary albumin excretion, and reduced the expression of pro-inflammatory genes (Cd14, Icam1, Tgfb1) in the renal cortex. Levels of glomerular and urinary 8-OHdG (a marker of oxidative stress), Nox4 gene expression, and NF-kB activity were also reduced in kidneys from Ex-4-treated animals. Expression of the Glp1r was detected in glomerular endothelial cells by IHC, in human THP-1 cells and human monocytes by RT-PCR. High glucose increased cytokine levels in THP-1 cells that were reduced by Ex-4 in an exendin(9-39)-dependent manner. Ex-4 also reduced ICAM1 expression in human glomerular 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 Apr;54(4):965-78.
Psoriasis
Hogan and colleagues observed improvements in clinical disease activity in 3 patients with psoriasis who were treated with GLP-1R agonosts. The patients had only modest changes in blood glucose but did experience weight loss. These authors found that GLP-1R activation in iNKT cell lines reduced cytokine secretion, providing a mechanistic link for how anti-inflammatory effects of GLP-1 might improve disease activity. See Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis Diabetologia. 2011 Jul 9.
A subsequent report described a single patient with a long standing history of psoriasis and T2DM; within days of starting liraglutide, the patient experienced reduced itching and clearling of the skin, before any significant weight loss had been reported. By week 5, a 2 kg weight loss and 2.5% reduction in HbA1c was observed, with further improvements continuing over the next several months. No immunological investigations were carried out in this patient. Improvement in psoriasis after treatment with the glucagon-like peptide-1 receptor agonist liraglutide Acta Diabetol. 2011 Dec 13. A summary of potential mechanisms that might contribute to the improvement in psoriasis in such patients is provided in Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology Diabetologia. 2011 Nov;54(11):2741-4. .
Chaudhuri assessed parameters of inflammation in human diabetic subjects treated with a single 5 ug dose of exenatide, followed by exenatide 10 ug twice daily or placebo for 12 weeks. Exenatide therapy was associated with reduction in fasting glucose and A1c (8.6 to 7.4%), and increased levels of plasma insulin, and decreased plasma FFAs. ROS generation and NfkB DNA binding activity, and TNFa, IL-1b, JNK-1, TLR-2 and SOCS-3 expression in mononuclear cells was suppressed after acute or chronic exenatide. Plasma levels of MCP-1, SAA, MMP-9 and IL-6 were also reduced after chronic exenatide. Whether these actions are due to GLP-1 receptor activation, or the acute and chronic glucoregulatory or metabolic actions of exenatide, remain uncertain.