Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemoarchitecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (betaAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD.
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PMID:A new Alzheimer's disease interventive strategy: GLP-1. 1527 Feb 3

Glucagon-like peptide-1 (7-36)--amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion, and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, are coupled to the cyclic AMP second messenger pathway, and are expressed throughout the brain of rodents and humans. We previously reported that GLP-1 and exendin-4, a naturally occurring, long-acting analogue of GLP-1 that binds the GLP-1 receptor (GLP-1R), possess neurotrophic properties. GLP-1R agonists protect neurons against amyloid-beta peptide (Abeta) and glutamate-induced apoptosis in cell culture studies and attenuate cholinergic neuron atrophy in the basal forebrain of the rat following an excitotoxic lesion. The biochemical cascades activated by neural GLP-1R stimulation are discussed in comparison to those activated by pancreatic receptors, and, additionally, are compared to signaling pathways associated with the classical neurotrophins. GLP-1R stimulation promotes pathways that favour cell survival over apoptosis. GLP-1 readily enters brain, and its diverse physiological actions, which include insulinotropic, cardiovascular as well as neurotrophic ones, may prove beneficial in a variety of diseases prevalent in aging, including Alzheimer's disease (AD). Its ability to lower brain levels of Abeta in mice would appear to be particularly pertinent in this regard. Furthermore, the ready availability of clinical material and the clinical history of its long term use in subjects with type 2 diabetes would support testing the value of GLP-1R agonists in AD trials.
Curr Alzheimer Res 2005 Jul
PMID:Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease. 1597 3

G protein-coupled receptors (GPCRs) play pivotal roles in regulating the function and plasticity of neuronal circuits in the nervous system. Among the myriad of GPCRs expressed in neural cells, class II GPCRs which couples predominantly to the Gs-adenylate cyclase-cAMP signaling pathway, have recently received considerable attention for their involvement in regulating neuronal survival. Neuropeptides that activate class II GPCRs include secretin, glucagon-like peptides (GLP-1 and GLP-2), growth hormone-releasing hormone (GHRH), pituitary adenylate cyclase activating peptide (PACAP), corticotropin-releasing hormone (CRH), vasoactive intestinal peptide (VIP), parathyroid hormone (PTH), and calcitonin-related peptides. Studies of patients and animal and cell culture models, have revealed possible roles for class II GPCRs signaling in the pathogenesis of several prominent neurodegenerative conditions including stroke, Alzheimer's, Parkinson's, and Huntington's diseases. Many of the peptides that activate class II GPCRs promote neuron survival by increasing the resistance of the cells to oxidative, metabolic, and excitotoxic injury. A better understanding of the cellular and molecular mechanisms by which class II GPCRs signaling modulates neuronal survival and plasticity will likely lead to novel therapeutic interventions for neurodegenerative disorders.
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PMID:Class II G protein-coupled receptors and their ligands in neuronal function and protection. 1605 36

The formation of polypeptide aggregates, including amyloid fibrils and prions, is a biochemical process of considerable interest in the context of its association with ageing and neurodegeneration. Aggregation occurs typically with a lag phase and a growth phase that reflect an underlying nucleation-polymerisation mechanism. While the propensity of nucleation can be estimated from the lag time t(l), the efficiency of growth is represented by the growth rate k(g). Here, I have analysed the absolute k(g) and t(l) values from a total of 298 samples prepared from insulin, glucagon and different sequence variants of the Alzheimer's Abeta(1-40) peptide. Although these samples differ in the conditions of aggregation, systematic comparison reveals an overall similarity in the plot of k(g)versus t(l). The plot fits readily with the simple equation k(g)=alpha/t(l) and by using a proportionality factor alpha of 4.5. In contrast to the individual values of k(g) and t(l) that depend substantially on sequential and environmental parameters, alpha seems much less affected by such factors. These data suggest mechanistic similarities in the nucleation behaviour of different amyloid-like fibrils and aggregates.
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PMID:Absolute correlation between lag time and growth rate in the spontaneous formation of several amyloid-like aggregates and fibrils. 1714 Dec 69

Glucagon-like peptide-1 (GLP-1) has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus (T2DM). Both Alzheimer's disease (AD) and T2DM share some common pathophysiologic hallmarks, such as amyloid beta (Abeta), phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Abeta and tau protein. Combine these findings, GLP-1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP-1, communities between T2DM and AD, new progresses of GLP-1 in treating T2MD and improving some pathologic hallmarks of AD.
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PMID:Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer's disease? 1759 27

Alzheimer's disease (AD) is the most common form of dementia. Glucagon-like peptide-1 (GLP-1) gives a new genre in therapeutic targets for intervention in AD with its neurotrophic and neuroprotective functions. In previous work, we identified that geniposide is a novel agonist for GLP-1 receptor, which shows neurotrophic characteristics to induce the neuronal differentiation of PC12 cells. The aim of this study is to determine whether geniposide prevents neurons from oxidative damage, and to explore its signaling pathways. The results demonstrated that geniposide increased the expression of anti-apoptotic proteins, including Bcl-2 and heme oxygenase-1 (HO-1), to antagonize the oxidative damage in PC12 cells induced by hydrogen peroxide. LY294002 (a PI3K inhibitor) inhibited the effect of geniposide increasing of Bcl-2 level by activation of MAPK, MEK and c-Raf phosphorylation in hydrogen peroxide treated PC12 cells. U0126 (a selective inhibitor of MEK) also attenuated the enhancement of geniposide on Bcl-2 level by inhibiting the phosphorylation of p90RSK in the hydrogen peroxide treated PC12 cells. All these data demonstrate that geniposide, an agonist for GLP-1 receptor, regulates expression of anti-oxidative proteins including HO-1 and Bcl-2 by activating the transcriptor of p90RSK via MAPK signaling pathway in PC12 cells.
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PMID:Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway. 1762 57

The formation of amyloid fibrils and other polypeptide aggregates depends strongly on the physico-chemical environment. One such factor affecting aggregation is the presence and concentration of salt ions. We have examined the effects of salt ions on the aggregation propensity of Alzheimer's Abeta(1-40) peptide and on the structure of the dissolved and of the fibrillar peptide. All salts examined promote aggregation strongly. The most pronounced effect is seen within the cationic series, i.e. for MgCl2. Evaluation of different possible explanations suggests that Abeta(1-40) aggregation depends on direct interaction between ions and Abeta(1-40) peptide, and correlates with ion-induced changes of the surface tension. Salts have profound effects on the fibril structure. In the presence of salts, fibrils are associated with smaller diameters, narrower crossover distances and lower amide I maxima. Since Abeta(1-40) aggregation responds to salts in a manner unlike that for other polypeptides, such as glucagon, beta2-microglobulin or alpha-synuclein; these data argue that there is no fully uniform way in which salts affect aggregation of different polypeptide chains. These observations are important for understanding and predicting aggregation on the basis of simple physico-chemical properties.
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PMID:Effect of different salt ions on the propensity of aggregation and on the structure of Alzheimer's abeta(1-40) amyloid fibrils. 1790 5

According to WHO data more than 180 million people suffer from diabetes mellitus worldwide and this number could double within 15 years. Normal function of the brain is dependent on continuous supply of glucose. In hypoglycemia, production of counterregulatory hormones (glucagon, epinephrine, growth hormone, and cortisol) increases, the sympathetic system becomes stimulated, and features of neuroglycopenia appear in order to save the homeostasis. Hypoglycemia is an alarming, actually life threatening condition, but the exposure to chronic hyperglycemia has a more detrimental effect on the brain than recurrent exposure to severe hypoglycemia. The active neural response to hyperglycemia induces changes in gene expression and function. The first steps against hyperosmolality are initially adaptive, but later hyperactivation of the hypothalamic magnocellular neurosecretory cells leads to their structural damage. Changes in hippocampal gene transcription are partially implicated in the deterioration of declarative memory. Neurologically passive shunting of excess glucose through alternative cellular metabolic pathways induces atherogenic, vascular lesions, free radicals, leukoencephalopathy and atrophy of the brain and thus leading to cognitive deficits. In physiological conditions insulin has neuroprotective effect. However, insulin resistance in the central nervous system correlates with insulin resistance in the periphery. Loss of responsiveness to insulin could render neurons more susceptible to neurotoxic insults, the protective effect of insulin diminishes, and apoptosis, neurodegeneration and the resultant cognitive decline are all increased in insulin-resistant patients. Some unclear relations appear between diabetes mellitus and Alzheimer's disease. Diabetic patients with APOE-4 gene have an increased risk for Alzheimer's disease. Prevalence of depression is higher in patients with diabetes mellitus and in turn, depression is a risk factor for diabetes mellitus. Simultaneous presence of depression and diabetes mellitus tends to worsen the course of both.
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PMID:[Cerebral complications of diabetes mellitus]. 1805 61

Glucagon-like peptide-1 (GLP-1) is a glucoincretin hormone most intensively studied for its actions on insulin secreting beta-cells. GLP-1 and its receptor are also found in brain and accumulating evidence indicates that GLP-1 has neuroprotective actions. Here, we investigated whether GLP-1 protects neuronal cells from death evoked by nerve growth factor (NGF) withdrawal. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer disease to diabetic neuropathies. We report that GLP-1 provides sustained protection of cultured neuronal PC12 cells and sympathetic neurons from degeneration and death caused by NGF deprivation. Past work shows that NGF deprivation induces the pro-apoptotic protein Bim which contributes to neuron death. Here, we find that GLP-1 suppresses Bim induction promoted by NGF deprivation. Thus, GLP-1 may protect neurons, at least in part, by suppressing Bim induction. Our findings support the idea that drugs that mimic or elevate GLP-1 represent potential therapeutics for neurodegenerative diseases.
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PMID:Glucagon-like peptide-1 (GLP-1) diminishes neuronal degeneration and death caused by NGF deprivation by suppressing Bim induction. 1835 62

Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease, and insulin signalling is often impaired in Alzheimer's disease, contributing to the neurodegenerative process. One potential strategy to help prevent this is the normalisation of insulin signalling in the brain. Therefore, the present study was designed to test the effects of the insulin-releasing gut hormone, glucagon-like peptide 1 (GLP-1). A protease-resistant form of GLP-1, (Val8)GLP-1, was also tested. Effects of both native GLP-1 and (Val8)GLP-1 on synaptic plasticity (LTP) in the hippocampus (15 nmol i.c.v.) were examined and results demonstrated for the first time that both peptides have enhancing effects on LTP. In sharp contrast, the inactive truncated form of GLP-1, GLP-1(9-36), had no effect on LTP. Injection of beta-amyloid (25-35) (100 nmol or 10 nmol i.c.v.), a peptide that aggregates in brains of Alzheimer's disease patients, impaired LTP. The injection of (Val8)GLP-1 (15 nmol i.c.v.) 30 min prior to injection of amyloid (25-35) (100 nmol i.c.v.) fully reversed the impairment of LTP induced by beta-amyloid. When (Val8)GLP-1 was administered 15 min prior to or simultaneously with beta-amyloid, no such reversal was observed. These results demonstrate for the first time that GLP-1 not only directly modulates neurotransmitter release and LTP formation, but also protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation. Therefore, longer-acting GLP-1 agonists show great potential as a novel treatment for preventing neurodegenerative processes in neurodegenerative disorders.
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PMID:GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. 1846 98


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