This study aims to identify the inhibitory role of the spinal glucagon like peptide-1 receptor (GLP-1R) signaling in pain hypersensitivity and its mechanism of action in rats and mice. First, GLP-1Rs were identified to be specifically expressed on microglial cells in the spinal dorsal horn, and profoundly upregulated after peripheral nerve injury. In addition, intrathecal GLP-1R agonists GLP-1(7-36) and exenatide potently alleviated formalin-, peripheral nerve injury-, bone cancer-, and diabetes-induced hypersensitivity states by 60 -90%, without affecting acute nociceptive responses. The antihypersensitive effects of exenatide and GLP-1 were completely prevented by GLP-1R antagonism and GLP-1R gene knockdown. Furthermore, exenatide evoked ␤-endorphin release from both the spinal cord and cultured microglia. Exenatide antiallodynia was completely prevented by the microglial inhibitor minocycline, ␤-endorphin antiserum, and opioid receptor antagonist naloxone. Our results illustrate a novel spinal dorsal horn microglial GLP-1R/␤-endorphin inhibitory pathway in a variety of pain hypersensitivity states.

Objective: To investigate the effects of exenatide on blood glucose, body weight and hepatic enzymes in patients with type 2 diabetes mellitus (T2DM) and concomitant non-alcoholic fatty liver disease (NAFLD). Subjects and methods: One hundred and seventeen patients with T2DM and NAFLD were randomly divided into exenatide group and metformin group. Patients were treated with exenatide and metformin, respectively, for 12 weeks. Results: After 12 weeks of treatment, body weight, body mass index (BMI), waist-to-hip ratio, HbA1c, FPG, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were significantly reduced, and the AST/ALT ratio and adiponectin were markedly increased in both groups. BMI, waist-to-hip ratio, 2-h PPG, ALT, AST, γ-GT, and hs-CRP were markedly lower, and AST/ ALT ratio and adiponectin in the exenatide group were dramatically higher than in the metformin group. Conclusion: Compared with metformin, exenatide is better to control blood glucose, reduces body weight and improves hepatic enzymes, attenuating NAFLD in patients with T2DM concomitant with NAFLD. Arq Bras Endocrinol Metab. 2013;57(9):702-8 Keywords Exenatide; metformin; non-alcoholic fatty liver disease; type 2 diabetes mellitus RESUMO Objetivo: Investigar os efeitos do exenatide sobre a glicose sérica, peso corporal e enzimas hepá-ticas em pacientes com diabetes melito tipo 2 (T2DM) e doença hepática gordurosa não alcoólica (DHGNA). Sujeitos e métodos: Um total de 117 pacientes com T2DM e DHGNA foi aleatoriamente separado em dois grupos, um tratado com exenatide e um tratado com metformina. Os pacientes foram tratados por 12 semanas. Resultados: Após 12 semanas de tratamento, o peso corporal, índice de massa corporal (IMC), relação cintura-quadril, HbA1c, FPG, glicose pós-prandial, ALT, AST, γ-GT e proteína C-reativa foram significativamente reduzidos, e a relação AST/ALT e a adiponectina aumentaram marcadamente nos dois grupos. O IMC, relação cintura-quadril, glicose pós-prandial, ALT, AST, γ-GT e proteína C-reativa foram marcadamente menores, e a relação AST/ALT e a adiponectina foram dramaticamente mais altas no grupo tratado com exenatide do que no grupo tratado com metformina. Conclusão: Comparado com a metformina, o exenatide controla melhor a glicose sérica, reduz o peso corporal e melhora as enzimas hepáticas, atenuando a DHGNA em pacientes com T2DM de ocorrência concomitante com a DHGNA. Arq Bras Endocrinol Metab. 2013;57(9):702-8 Descritores Exenatide; metformina; doença hepática gordurosa não alcoólica; diabetes melito tipo 2

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BACKGROUND AND PURPOSETwo peptide agonists of the glucagon-like peptide-1 (GLP-1) receptor, exenatide and GLP-1 itself, exert anti-hypersensitive effects in neuropathic, cancer and diabetic pain. In this study, we have assessed the anti-allodynic and anti-hyperalgesic effects of the non-peptide agonist WB4-24 in inflammatory nociception and the possible involvement of microglial β-endorphin and pro-inflammatory cytokines. EXPERIMENTAL APPROACHWe used rat models of inflammatory nociception induced by formalin, carrageenan or complete Freund's adjuvant (CFA), to test mechanical allodynia and thermal hyperalgesia. Expression of β-endorphin and pro-inflammatory cytokines was measured using real-time quantitative PCR and fluorescent immunoassays. KEY RESULTSWB4-24 displaced the specific binding of exendin (9-39) in microglia. Single intrathecal injection of WB4-24 (0.3, 1, 3, 10, 30 and 100 μg) exerted dose-dependent, specific, anti-hypersensitive effects in acute and chronic inflammatory nociception induced by formalin, carrageenan and CFA, with a maximal inhibition of 60-80%. Spinal WB4-24 was not effective in altering nociceptive pain. Subcutaneous injection of WB4-24 was also antinociceptive in CFA-treated rats. WB4-24 evoked β-endorphin release but did not inhibit expression of pro-inflammatory cytokines in either the spinal cord of CFA-treated rats or cultured microglia stimulated by LPS. WB4-24 anti-allodynia was prevented by a microglial inhibitor, β-endorphin antiserum and a μ-opioid receptor antagonist. CONCLUSIONS AND IMPLICATIONSOur results suggest that WB4-24 inhibits inflammatory nociception by releasing analgesic β-endorphin rather than inhibiting the expression of proalgesic pro-inflammatory cytokines in spinal microglia, and that the spinal GLP-1 receptor is a potential target molecule for the treatment of pain hypersensitivity including inflammatory nociception.

ObjectiveHypothyroidism (HO) can induce significant metabolic dysfunction and increase cardiovascular disease risk. In the present study, we investigated the relationship between homocysteine (Hcy) and insulin resistance (IR) in patients with HO or subclinical hypothyroidism (SHO).MethodsA total of 270 subjects were enrolled. All subjects were divided into the following three groups: HO, SHO and control. Plasma levels of Hcy were measured, and each patient’s homeostatic index of insulin resistance (HOMA-IR) was calculated. Statistical analyses were carried out to evaluate the correlations among groups and to determine the predictors of IR in patients with HO or SHO.ResultsThe HOMA-IR value was significantly higher in the HO group than in the SHO and control groups. Plasma levels of Hcy were markedly increased in the HO group compared with those of the SHO group and controls. In addition, plasma levels of Hcy were positively correlated with the HOMA-IR values in both the HO and SHO groups. Multiple linear regression models showed that plasma levels of Hcy and free thyroxine (FT4) were the only predictors of HOMA-IR in patients with HO or SHO.ConclusionsPlasma levels of Hcy and HOMA-IR were increased in patients with HO or SHO. Our results suggest that HO and SHO may increase the risk for atherogenesis and cardiovascular disease by increased IR. The increased IR induced by hyperhomocysteinemia in patients with HO or SHO may partially explain this adverse effect.

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Semicarbazide-sensitive amine oxidase (SSAO) resides on the vascular endothelium and smooth muscle cell surface and is capable of deaminating short chain aliphatic amines and producing toxic aldehydes and hydrogen peroxide. The enzyme, also known as a vascular adhesion protein-1, is involved in the inflammation process. This intriguing protein with dual functions is increased in the serum of diabetic and heart failure patients. In the present study we assessed the involvement of SSAO in a lipopolysaccharide-induced pulmonary inflammation model using transgenic mice that overexpress human vascular adhesion protein-1. Overexpression of SSAO activity increased the formation of protein-formaldehyde deposits in tissues. Lysine residues of proteins were the primary targets for cross-linkage with formaldehyde derived from deamination of methylamine. Lipo-polysaccharide-induced increases in inflammatory cells in the bronchoalveolar lavage (BAL) fluid were significantly higher in the transgenic than in the nontransgenic mice. BAL cell counts were also higher in the untreated transgenic than in nontransgenic mice. Blocking SSAO activity with a selective inhibitor significantly reduced the number of neutrophils as well as levels of macrophage inflammatory protein-1alpha, granulocyte colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-6 in the BAL fluid. Inhalation of methylamine also increased BAL neutrophil counts. Together, these results suggest a role for SSAO-mediated deamination in pulmonary inflammation.