Background The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. Scope of review In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Major conclusions Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders

https://spiral.imperial.ac.uk/bitstream/10044/1/74273/2/Glucagon-like%20peptide%201%20%28GLP-1%29%20Molecular%20Metabolism.pdf

Glucagon-like peptide 1 (GLP-1)

β-glucan is a non-starch soluble polysaccharide widely present in yeast, mushrooms, bacteria, algae, barley, and oat. β-Glucan is regarded as a functional food ingredient due to its various health benefits. The high molecular weight (Mw) and high viscosity of β-glucan are responsible for its hypocholesterolemic and hypoglycemic properties. Thus, β-glucan is also used in the food industry for the production of functional food products. The inherent gel-forming property and high viscosity of β-glucan lead to the production of low-fat foods with improved textural properties. Various studies have reported the relationship between the molecular structure of β-glucan and its functionality. The structural characteristics of β-glucan, including specific glycosidic linkages, monosaccharide compositions, Mw, and chain conformation, were reported to affect its physiochemical and biological properties. Researchers have also reported some chemical, physical, and enzymatic treatments can successfully alter the molecular structure and functionalities of β-glucan. This review article attempts to review the available literature on the relationship of the molecular structure of β-glucan with its functionalities, and future perspectives in this area.

/pdf/a-concise-review-on-the-molecular-structure-and-function-2h25g9b1lv.pdf

A Concise Review on the Molecular Structure and Function Relationship of β-Glucan

Type 2 diabetes is a risk factor for developing Alzheimer’s disease (AD). The underlying mechanism that links up the two conditions seems to be the de-sensitization of insulin signaling. In patients with AD, insulin signaling was found to be de-sensitized in the brain, even if they did not have diabetes. Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common – they induce a chronic inflammation response in the brain. Pro-inflammatory cytokines block growth factor signaling and enhance oxidative stress. The underlying molecular processes for this are described in the review. Treatments to re-sensitize insulin signaling in the brain are also described, such as nasal insulin tests in AD patients, or treatments with re-sensitizing hormones, such as leptin, ghrelin, glucagon-like peptide 1 (GLP-1),and glucose-dependent insulinotropic polypeptide (GIP). The first clinical trials show promising results and are a proof of concept that utilizing such treatments is valid.

/pdf/insulin-signaling-impairment-in-the-brain-as-a-risk-factor-rkfbkdqflg.pdf

Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer's Disease.

Glucagon-like peptide 1 (GLP-1) is a target for treatment of diabetes; however, its function in the brain is not well studied. In this systematic review, we aimed to analyze the neuroprotective role of GLP-1 and its defined mechanisms. Methods: We searched 'Web of Science' and 'Pubmed' to identify relevant studies using GLP-1 as the keyword. Two hundred and eighty-nine clinical and preclinical studies have been included. Data have been presented by grouping neurodegenerative, neurovascular and specific cell culture models. Results: Recent literature shows that GLP-1 and its agonists, DPP-4 inhibitors and combined GLP-1/GIP molecules are effective in partially or fully reversing the effects of neurotoxic compounds, neurovascular complications of diabetes, neuropathological changes related with Alzheimer's disease, Parkinson's disease or vascular occlusion. Possible mechanisms that provide neuroprotection are enhancing the viability of the neurons and restoring neurite outgrowth by increased neurotrophic factors, increasing subventricular zone progenitor cells, decreasing apoptosis, decreasing the level of pro-inflammatory factors, and strengthening blood-brain barrier. Conclusion: Based on the preclinical studies, GLP-1 modifying agents are promising targets for neuroprotection. On the other hand, the number of clinical studies that investigate GLP-1 as a treatment is low and further clinical trials are needed for a benchside to bedside translation of recent findings.

GLP-1's role in neuroprotection: a systematic review.

Structure, preparation, modification, and bioactivities of β-glucan and mannan from yeast cell wall: A review.

In recent decades, various polysaccharides isolated from algae, mushrooms, yeast, and higher plants have attracted serious attention in the area of nutrition and medicine. The reasons include their low toxicity, rare negative side effects, relatively low price, and broad spectrum of therapeutic actions. The two most and best-studied polysaccharides are mannan and glucan. This review focused on their biological properties.

https://www.mdpi.com/1422-0067/20/13/3189/pdf

Glucan and Mannan-Two Peas in a Pod.

The search for lipid-lowering drugs is important for clinical medicine. This review summarizes our research findings regarding the hypolipidemic activity of polysaccharides. There are several validated agents altering lipid levels which reduce the risk of atherosclerotic cardiovascular events. Nonetheless, for many people, the risk of such an event remains unacceptably high despite treatment with these agents. This situation has prompted the search for new therapies to reduce the residual cardiovascular risk. The lipid-lowering effect of β-glucans consumed with food was demonstrated in patients with atherosclerosis. The mechanism of the protective effect of β-glucans is poorly studied. The effects of β-glucans are mediated by Toll-like receptors, by dectin-1, and possibly by other receptors. Nevertheless, the mechanism of the protective action of β-glucan in lipemic mice has been studied insufficiently. This review will present up-to-date information regarding experimental hypolipidemic polysaccharide compounds that hold promise for medicine. Phagocyte-specific chitotriosidase in humans contributes to innate immune responses against chitin-containing fungi. This enzyme has been first described in patients with Gaucher disease and serves as an important diagnostic biomarker. It has been reported that, in mice, chitin particles of certain size are recognized by macrophages through Toll-like receptors, dectin-1, and to a lesser extent through mannose receptor.

Hypolipidemic Effects of β-Glucans, Mannans, and Fucoidans: Mechanism of Action and Their Prospects for Clinical Application

β-Glucans have been studied in animal species, from earthworms to humans They form a heterogenous group of glucose polymers found in fungi, plants, bacteria, and seaweed β-Glucans have slowly emerged as an important target for the recognition of pathogens In the current review, we highlight the major roles of mushroom-derived β-glucans on cancer progression

Effects of Medicinal Fungi-Derived β-Glucan on Tumor Progression

Huntington’s disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

https://www.mdpi.com/1422-0067/19/9/2505/pdf

GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling

Autophagy attenuation has been found in neurodegenerative diseases, aging, diabetes mellitus, and atherosclerosis. In experimental models of neurodegenerative diseases, the correction of autophagy in the brain reverses neuronal and behavioral deficits and hence seems to be a promising therapy for neuropathologies. Our aim was to study the effect of an autophagy inducer, trehalose, on brain autophagy and behavior in a genetic model of diabetes with signs of neuronal damage (db/db mice). A 2% trehalose solution was administered as drinking water during 24 days of the experiment. Expressions of markers of autophagy (LC3-II), neuroinflammation (IBA1), redox state (NOS), and neuronal density (NeuN) in the brain were assessed by immunohistochemical analysis. For behavioral phenotyping, the open field, elevated plus-maze, tail suspension, pre-pulse inhibition, and passive avoidance tests were used. Trehalose caused a slight reduction in increased blood glucose concentration, considerable autophagy activation, and a decrease in the neuroinflammatory response in the brain along with improvements of exploration, locomotor activity, anxiety, depressive-like behavior, and fear learning and memory in db/db mice. Trehalose exerted some beneficial peripheral and systemic effects and partially reversed behavioral alterations in db/db mice. Thus, trehalose as an inducer of mTOR-independent autophagy is effective at alleviating neuronal and behavioral disturbances accompanying experimental diabetes.

Tatiana A. Korolenko

Papers

Glucan and Mannan-Two Peas in a Pod.

Hypolipidemic Effects of β-Glucans, Mannans, and Fucoidans: Mechanism of Action and Their Prospects for Clinical Application

Effects of Medicinal Fungi-Derived β-Glucan on Tumor Progression

GLP-1 Analogue Liraglutide Attenuates Mutant Huntingtin-Induced Neurotoxicity by Restoration of Neuronal Insulin Signaling

Treatment with Autophagy Inducer Trehalose Alleviates Memory and Behavioral Impairments and Neuroinflammatory Brain Processes in db/db Mice.