Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

Pugazhenthi, Umarani; Velmurugan, Kalpana; Tran, Anna H.; Mahaffey, Gregory; Pugazhenthi, Subbiah

doi:10.1007/s00125-010-1849-y

Cited by 54 publications

(38 citation statements)

References 51 publications

(62 reference statements)

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“…Additionally, liraglutide reduced TNFα-induced MCP-1 (also known as CCL2), VCAM1, ICAM1 and E-selectin mRNA expression [44] . Exendin-4 also decreased IFN-γ-induced gene encoding chemokine CXCL10 [(C-X-C motif) ligand (CXCL)10] expression in human islets and in MIN6 cells (a mouse beta cell line) [68] .…”

Section: Glp-1ras and Chemokinesmentioning

confidence: 99%

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Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

Wang¹

2014

WJG

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Glucagon-like peptide1 (GLP-1) is secreted from Langerhans cells in response to oral nutrient intake. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a new class of incretin-based anti-diabetic drugs. They function to stimulate insulin secretion while suppressing glucagon secretion. GLP-1-based therapies are now well established in the management of type 2 diabetes mellitus (T2DM), and recent literature has suggested potential applications of these drugs in the treatment of obesity and for protection against cardiovascular and neurological diseases. As we know, along with change in lifestyles, the prevalence of non-alcoholic fatty liver disease (NAFLD) in China is rising more than that of viral hepatitis and alcoholic fatty liver disease, and NAFLD has become the most common chronic liver disease in recent years. Recent studies further suggest that GLP1RAs can reduce transaminase levels to improve NAFLD by improving blood lipid levels, cutting down the fat REVIEW 14821October 28, 2014|Volume 20|Issue 40| WJG|www.wjgnet.com content to promote fat redistribution, directly decreasing fatty degeneration of the liver, reducing the degree of liver fibrosis and improving inflammation. This review shows the NAFLD-associated effects of GLP-1RAs in animal models and in patients with T2DM or obesity who are participants in clinical trials.

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Section: Glp-1ras and Chemokinesmentioning

confidence: 99%

“…Stimulation with exendin-4 increases the expression of Wnt-4 in β-cells [79] . In addition, the mechanism of the anti-inflammatory action of exendin-4 involved a decrease in signal transducer and activator of transcription-1 levels [68] .…”

Section: Glp-1ras and Other Aspects Of Inflammationmentioning

confidence: 99%

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

Wang¹

2014

WJG

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“…Similar findings were obtained in Min-6 insulinoma cells in a PKA-independent manner independent of H-89. 29 One of the first clues to the pleiotropic beneficial effects of GLP-1 on islet β-cells was the finding that GLP-1 enhanced the number of glucose-responsive islet cells in vitro. 30 This effect of GLP-1 appears to extend to diabetic islets.…”

Section: Research and Reports In Endocrine Disordersmentioning

confidence: 99%

Predicting response to incretin-based therapy

Kalra¹,

Kalra²,

Sahay³

et al. 2011

RRED

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There are two important incretin hormones, glucose-dependent insulin tropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. GLP-1 appears to have a number of additional effects in the gastrointestinal tract and central nervous system. Incretin based therapy includes GLP-1 receptor agonists like human GLP-1 analogs (liraglutide) and exendin-4 based molecules (exenatide), as well as DPP-4 inhibitors like sitagliptin, vildagliptin and saxagliptin. Most of the published studies showed a significant reduction in HbA 1c using these drugs. A critical analysis of reported data shows that the response rate in terms of target achievers of these drugs is average. One of the first actions identified for GLP-1 was the glucose-dependent stimulation of insulin secretion from islet cell lines. Following the detection of GLP-1 receptors on islet beta cells, a large body of evidence has accumulated illustrating that GLP-1 exerts multiple actions on various signaling pathways and gene products in the β cell. GLP-1 controls glucose homeostasis through well-defined actions on the islet β cell via stimulation of insulin secretion and preservation and expansion of β cell mass. In summary, there are several factors determining the response rate to incretin therapy. Currently minimal clinical data is available to make a conclusion. Key factors appear to be duration of diabetes, obesity, presence of autonomic neuropathy, resting energy expenditure, plasma glucagon levels and plasma free fatty acid levels. More clinical evidence is required to identify the factors affecting response rate to incretin therapy.

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“…Exendin-4 was shown to decrease TNF␣ expression in ␤-cells (20). To investigate whether Wnt-4 is involved in mediating this effect, we tested its effect on TNF␣ expression in ␤-cells.…”

Section: No Effect Of Insulin Tolbutamide Rosiglitazone Metforminmentioning

confidence: 99%

Exendin-4 upregulates the expression of Wnt-4, a novel regulator of pancreatic β-cell proliferation

Heller

Kühn

Mülders-Opgenoorth

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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It is not known how the expression of endogenous Wnt-signaling molecules is regulated in ␤-cells. Therefore, we investigated the effect of antidiabetic drugs and glucose on the expression of Wnt-signaling molecules in ␤-cells. Primary islets were isolated and cultured. The expression of Wnt-signaling molecules (Wnt-4, Wnt-10b, Frizzled-4, LRP5, TCF7L2) and TNF␣ was analyzed by semiquantitative PCR and Western blotting. Transient transfections were carried out and proliferation assays of INS-1 ␤-cells performed using [3 H]thymidine uptake and BrdU ELISA. Insulin secretion was quantified. A knockdown (siRNA) of Wnt-4 in ␤-cells was carried out. Exendin-4 significantly increased the expression of Wnt-4 in ␤-cells on the mRNA level (2.8-fold) and the protein level (3-fold) (P Ͻ 0.001). The effect was dose dependent, with strongest stimulation at 10 nM, and it was maintained after long-term stimulation over 4 wk. Addition of exd-(9 -39), a GLP-1 receptor antagonist, abolished the effect of exendin-4. Treatment with glucose, insulin, or other antidiabetic drugs had no effect on the expression of any of the examined Wnt-signaling molecules. Functionally, Wnt-4 antagonized the activation of canonical Wnt-signaling in ␤-cells. Wnt-4 had no effect on glucosestimulated insulin secretion or insulin gene expression. Knocking down Wnt-4 decreased ␤-cell proliferation to 45% of controls (P Ͻ 0.05). In addition, Wnt-4 and exendin-4 treatment decreased the expression of TNFa␣ mRNA in primary ␤-cells. These data demonstrate that stimulation with exendin-4 increases the expression of Wnt-4 in ␤-cells. Wnt-4 modulates canonical Wnt signaling and acts as regulator of ␤-cell proliferation and inflammatory cytokine release. This suggests a novel mechanism through which GLP-1 can regulate ␤-cell proliferation.glucagon-like peptide-1; diabetes RECENT RESULTS FROM INDEPENDENT GROUPS identified the Wntsignaling pathway as a regulator of ␤-cell proliferation and insulin secretion (3,22,27,28). Interestingly, the Wnt-signaling pathway and the incretin system interact at different stages. On one hand, glucagon-like peptide-1 (GLP-1) receptor agonists activate the canonical Wnt-signaling pathway in ␤-cells and increase ␤-cell proliferation, at least partly, through canonical Wnt-signaling (12). On the other hand, canonical Wnt signaling regulates the expression of GLP-1 in intestinal L cells (16,30).The canonical Wnt-signaling pathway consists of extracellular ligands (Wnts), cell membrane receptors [Frizzled and LDL receptor-related protein (LRP)5/6], and intracellular signaling molecules. In the inactivated state, ␤-catenin is constitutively phosphorylated by GSK-3␤, which leads to the ubiquitin-mediated degradation of ␤-catenin in the cytoplasm. Ligand binding leads to the inhibition of GSK-3␤ and stabilization of ␤-catenin. ␤-Catenin is the central player in the canonical Wnt-signaling pathway; as a transcriptional coactivator it translocates to the nucleus and binds to transcription factors of the T cell-specific transcription factor (TC...

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Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

Cited by 54 publications

References 51 publications

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

Predicting response to incretin-based therapy

Exendin-4 upregulates the expression of Wnt-4, a novel regulator of pancreatic β-cell proliferation

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