The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits β-cell apoptosis in vitro

Bregenholt, Søren; Møldrup, Annette; Blume, Niels; Karlsen, Allan E.; Friedrichsen, Birgitte Nissen; Tornhave, Ditte; Knudsen, Lotte Bjerre; Petersen, J.

doi:10.1016/j.bbrc.2005.03.013

Cited by 158 publications

(118 citation statements)

References 43 publications

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“…The pharmacological inhibitors of PI3 kinase and cAMP, LY294002 (50 μM) and Rp-cAMP (50 μM) respectively, were found to significantly reduce the effect of GLP-1, whereas the MAPK inhibitor, PD098059 (50 μM) did not do so. Similar results were recently obtained using the long acting GLP-1R agonist liraglutide that has a modification so as to eliminate proteolysis by DPP-IV (Bregenholt et al, 2005). In a later study from the Perfetti group GLP-1 (10 nM) was shown to reduce caspase 3 and increase Bcl-2 expression in human islets cultured over 3-5 days (Farilla et al, 2003).…”

Section: β Cell Toxicity and Death: Protective Effects Of Glp-1r Agonsupporting

confidence: 76%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

574

465

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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Section: β Cell Toxicity and Death: Protective Effects Of Glp-1r Agonsupporting

confidence: 76%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

574

465

View full text Add to dashboard Cite

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“…10,12 The NO synthase blocker NG-methyl-L-arginine (L-NMMA), which fully prevents cytokine-induced NO production in b-cells (data not shown; Cardozo et al 10 ), had no effect on thapsigargin-mediated Mcl-1 decrease, whereas it completely prevented the (Figure 2c). On the other hand, forskolin, an adenylate cyclase activator, which partially protects b-cells against cytokine-and palmitate-induced apoptosis, 14,15 failed to prevent Mcl-1 degradation (Figure 2c). INS-1E cells then were transfected with an siRNA targeting the PKR-like endoplasmic reticulum kinase (PERK), which is activated upon ER stress and phosphorylates the elongation factor eIF2a, resulting in decreased protein synthesis.…”

Section: Pro-inflammatory Cytokines and Palmitate Decreasementioning

confidence: 99%

Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to β-cell apoptosis

et al. 2010

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Pancreatic b-cell apoptosis is a key feature of diabetes mellitus and the mitochondrial pathway of apoptosis is a major mediator of b-cell death. We presently evaluated the role of the myeloid cell leukemia sequence 1 (Mcl-1), an antiapoptotic protein of the Bcl-2 family, in b-cells following exposure to well-defined b-cell death effectors, for example, pro-inflammatory cytokines, palmitate and chemical endoplasmic reticulum (ER) stressors. All cytotoxic stresses rapidly and preferentially decreased Mcl-1 protein expression as compared with the late effect observed on the other antiapoptotic proteins, Bcl-2 and Bcl-xL. This was due to ER stress-mediated inhibition of translation through eIF2a phosphorylation for palmitate and ER stressors and through the combined action of translation inhibition and JNK activation for cytokines. Knocking down Mcl-1 using small interference RNAs increased apoptosis and caspase-3 cleavage induced by cytokines, palmitate or thapsigargin, whereas Mcl-1 overexpression partly prevented Bax translocation to the mitochondria, cytochrome c release, caspase-3 cleavage and apoptosis induced by the b-cell death effectors. Altogether, our data suggest that Mcl-1 downregulation is a crucial event leading to b-cell apoptosis and provide new insights into the mechanisms linking ER stress and the mitochondrial intrinsic pathway of apoptosis. Mcl-1 is therefore an attractive target for the design of new strategies in the treatment of diabetes.

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“…The incretin hormone glucagon-like peptide (GLP)-1 is currently receiving considerable interest because of its ability not only to reduce blood glucose levels but also to potentially regenerate islet BCM [2]. Several in vitro [3,4] and rodent in vivo studies [5][6][7] have demonstrated antiapoptotic and proliferative effects of GLP-1 on pancreatic beta cells. Clearly, restoration of beta cell function will be of a great therapeutic value in the treatment of diabetes.…”

Section: Introductionmentioning

confidence: 99%