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    An increasingly complex view of intestinal motility. Rao Meenakshi Nature reviews. Gastroenterology & hepatology 10.1038/s41575-019-0249-0
    Glial progenitor cell-based treatment and modeling of neurological disease. Goldman Steven A,Nedergaard Maiken,Windrem Martha S Science (New York, N.Y.) The diseases of myelin are among the most prevalent and disabling conditions in neurology. These diseases include both the vascular and inflammatory demyelinating disorders of adulthood, as well as the childhood leukodystrophies and cerebral palsy. These fundamentally glial disorders may be amenable to treatment by glial progenitor cells (GPCs), which give rise to astroglia and myelin-producing oligodendrocytes. Given the development of new methods for generating and isolating human GPCs, the myelin disorders may now be compelling targets for cell-based therapy. In addition, the efficient engraftment and expansion of human GPCs in murine hosts has led to the development of human glial chimeric mouse brains, which provides new opportunities for studying the species-specific roles of human glia in cognition, as well as in disease pathogenesis. 10.1126/science.1218071
    Endocrine cross-talk between the gut microbiome and glial cells in development and disease. Anbalagan Savani Journal of neuroendocrinology Glial cells make up the major cellular component of the nervous system. Glial development is usually investigated through perturbations of host genetics, although non-host-derived signalling molecules can also regulate glial cells. Indeed, gut microbiome colonisation and the presence of microbiome-derived factors in the blood coincide with glial cell development. Emerging data suggest that the gut microbiome can regulate gliogenesis, myelination and glial epigenetics. Neurodegenerative diseases are characterised by changes in the gut microbiome and glial dysfunction. This perspective discusses the ways in which microbiome-derived molecules can engage in cross-talk with glial cells during development and in dysfunctional glial diseases. 10.1111/jne.12924
    Role of Microbiota-Derived Extracellular Vesicles in Gut-Brain Communication. Cuesta Carlos M,Guerri Consuelo,Ureña Juan,Pascual María International journal of molecular sciences Human intestinal microbiota comprise of a dynamic population of bacterial species and other microorganisms with the capacity to interact with the rest of the organism and strongly influence the host during homeostasis and disease. Commensal and pathogenic bacteria coexist in homeostasis with the intestinal epithelium and the gastrointestinal tract's immune system, or GALT (gut-associated lymphoid tissue), of the host. However, a disruption to this homeostasis or dysbiosis by different factors (e.g., stress, diet, use of antibiotics, age, inflammatory processes) can cause brain dysfunction given the communication between the gut and brain. Recently, extracellular vesicles (EVs) derived from bacteria have emerged as possible carriers in gut-brain communication through the interaction of their vesicle components with immune receptors, which lead to neuroinflammatory immune response activation. This review discusses the critical role of bacterial EVs from the gut in the neuropathology of brain dysfunctions by modulating the immune response. These vesicles, which contain harmful bacterial EV contents such as lipopolysaccharide (LPS), peptidoglycans, toxins and nucleic acids, are capable of crossing tissue barriers including the blood-brain barrier and interacting with the immune receptors of glial cells (e.g., Toll-like receptors) to lead to the production of cytokines and inflammatory mediators, which can cause brain impairment and behavioral dysfunctions. 10.3390/ijms22084235
    A metabolic and functional overview of brain aging linked to neurological disorders. Baquer Najma Z,Taha Asia,Kumar Pardeep,McLean P,Cowsik S M,Kale R K,Singh R,Sharma Deepak Biogerontology Close correlations have recently been shown among the late onset complications encountered in diabetes and aging linked to neurobiological disorders. Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's disease and Parkinson's disease, dementia, cognitive dysfunction and hypernatremia. Beside the sex hormones other hormonal changes are also known to occur during aging and many common problems encountered in the aging process can be related to neuroendocrine phenomena. Diabetes mellitus is associated with moderate cognitive deficits and neurophysiologic and structural changes in the brain, a condition that may be referred to as diabetes encephalopathy; diabetes increases the risk of dementia especially in the elderly. The current view is that the diabetic brain features many symptoms that are best described as accelerated brain aging. This review presents and compares biochemical, physiological, electrophysiological, molecular, and pathological data from neuronal tissue of aging and hormone treated control and diabetic animals to arrive at the similarities among the two naturally occuring physiological conditions. Animal models can make a substantial contribution to understanding of the pathogenesis, which share many features with mechanism underlying brain aging. By studying the pathogenesis, targets for pharmacology can be identified, finally leading to delay or prevention of these complications. Antiaging strategies using hormone therapy, chemical and herbal compounds were carried out for reversal of aging effects. Neuronal markers have been presented in this review and similarities in changes were seen among the aging, diabetes and hormone treated (estrogen, DHEA and insulin) brains from these animals. A close correlation was observed in parameters like oxidative stress, enzyme changes, and pathological changes like lipofuscin accumulation in aging and diabetic brain. 10.1007/s10522-009-9226-2
    The importance of BDNF and RAGE in diabetes-induced dementia. Kim Oh Yoen,Song Juhyun Pharmacological research Diabetes-induced dementia is an emerging neurodisorder all over the world. The prevalence rates of dementia and diabetes have been gradually increasing worldwide. Diabetes has been known to lead to oxidative stress, inflammation aggravation, and hyperglycemia conditions in the brain. Various diabetic implications cause the lower secretion of brain-derived neurotrophic factor (BDNF) and the increase of receptor for advanced glycation end products (RAGE), ultimately leading to both cerebrovascular dysfunction and cognitive decline. Here, we summarized the significant evidences highlighting the specific mechanisms between BDNF and RAGE and cerebrovascular dysfunction and memory function and how these relate to diabetes-induced dementia. Especially, we review that the association between BDFN and RAGE in neuroinflammation, the reduction of long-term potentiation, and the vascular implications in brain. 10.1016/j.phrs.2020.105083
    Effect of natural products on diabetes associated neurological disorders. Patel Sita Sharan,Udayabanu Malairaman Reviews in the neurosciences Diabetes mellitus, a metabolic disorder, is associated with neurological complications such as depression, anxiety, hypolocomotion, cognitive dysfunction, phobias, anorexia, stroke, pain, etc. Traditional system of medicine is long known for its efficient management of diabetes. The current review discusses the scope of some common medicinal herbs as well as secondary metabolites with a special focus on diabetes-mediated central nervous system complications. Literatures suggest that natural products reduce diabetes-mediated neurological complications partly by reducing oxidative stress and/or inflammation or apoptosis in certain brain regions. Natural products are known to modulate diabetes-mediated alterations in the level of acetylcholinesterase, choline acetyltransferase, monoamine oxidase, serotonin receptors, muscarinic receptors, insulin receptor, nerve growth factor, brain-derived neurotrophic factor, and neuropeptide in brain. Further, there are several natural products reported to manage diabetic complications with unknown mechanism. In conclusion, medicinal plants or their secondary metabolites have a wide scope and possess therapeutic potential to effectively manage neurological complications associated with chronic diabetes. 10.1515/revneuro-2016-0038
    Iron metabolism in diabetes-induced Alzheimer's disease: a focus on insulin resistance in the brain. Chung Ji Yeon,Kim Hyung-Seok,Song Juhyun Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine Alzheimer's disease (AD) is characterized by an excessive accumulation of toxic amyloid beta (Aβ) plaques and memory dysfunction. The onset of AD is influenced by age, genetic background, and impaired glucose metabolism in the brain. Several studies have demonstrated that diabetes involving insulin resistance and glucose tolerance could lead to AD, ultimately resulting in cognitive dysfunction. Even though the relationship between diabetes and AD was indicated by significant evidences, the critical mechanisms and metabolic alterations in diabetes induced AD are not clear until now. Recently, iron metabolism has been shown to play multiple roles in the central nervous system (CNS). Iron deficiency and overload are associated with neurodegenerative diseases. Iron binds to Aβ and subsequently regulates Aβ toxicity in the CNS. In addition, previous studies have shown that iron is involved in the aggravation of insulin resistance. Considering these effects of iron metabolism in CNS, we expect that iron metabolism may play crucial roles in diabetic AD brain. Thus, we review the recent evidence regarding the relationship between diabetes-induced AD and iron metabolism. 10.1007/s10534-018-0134-2
    Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer's Disease. Sun Yanan,Ma Cao,Sun Hui,Wang Huan,Peng Wei,Zhou Zibo,Wang Hongwei,Pi Chenchen,Shi Yingai,He Xu Journal of diabetes research As a chronic metabolic disease, diabetes mellitus (DM) is broadly characterized by elevated levels of blood glucose. Novel epidemiological studies demonstrate that some diabetic patients have an increased risk of developing dementia compared with healthy individuals. Alzheimer's disease (AD) is the most frequent cause of dementia and leads to major progressive deficits in memory and cognitive function. Multiple studies have identified an increased risk for AD in some diabetic populations, but it is still unclear which diabetic patients will develop dementia and which biological characteristics can predict cognitive decline. Although few mechanistic metabolic studies have shown clear pathophysiological links between DM and AD, there are several plausible ways this may occur. Since AD has many characteristics in common with impaired insulin signaling pathways, AD can be regarded as a metabolic disease. We conclude from the published literature that the body's diabetic status under certain circumstances such as metabolic abnormalities can increase the incidence of AD by affecting glucose transport to the brain and reducing glucose metabolism. Furthermore, due to its plentiful lipid content and high energy requirement, the brain's metabolism places great demands on mitochondria. Thus, the brain may be more susceptible to oxidative damage than the rest of the body. Emerging evidence suggests that both oxidative stress and mitochondrial dysfunction are related to amyloid- (A) pathology. Protein changes in the unfolded protein response or endoplasmic reticulum stress can regulate A production and are closely associated with tau protein pathology. Altogether, metabolic disorders including glucose/lipid metabolism, oxidative stress, mitochondrial dysfunction, and protein changes caused by DM are associated with an impaired insulin signal pathway. These metabolic factors could increase the prevalence of AD in diabetic patients via the promotion of A pathology. 10.1155/2020/4981814
    Diabetes mellitus and dementia. Pasquier F,Boulogne A,Leys D,Fontaine P Diabetes & metabolism Alzheimer's disease (AD) and diabetes mellitus (DM) are two of the most common and devastating health problems in the elderly. They share a number of common features amongst which high prevalence after 65 years, important impact of patient's quality of life, substantial health care costs. Reviews on the epidemiological studies on cognitive impairment in patients with DM found evidence of cross-sectional and prospective associations between type 2 DM and moderate cognitive impairment, on memory and executive functions. There is also evidence for an elevated risk of both vascular dementia and AD in patients with type 2 DM, albeit with strong interaction of other factors such as hypertension, dyslipidaemia and ApoE genotype. DM is an independent predictor of post-stroke dementia. DM being an atherogenic risk factor, it may increase the risk of dementia through associations with stroke, causing vascular dementia. In addition, vascular reactivity may be adversely affected by advanced glycosylation end products resulting in more subtle perfusion abnormalities. Cerebrovascular disease may exacerbate AD through direct interactions between the two pathological processes or through cognitive impairment secondary to cerebrovascular disease "unmasking" AD at an earlier stage than it would otherwise become apparent. The increased risk of AD may also be mediated by the exacerbation of B-amyloid neurotoxicity by advanced glycosylation end products identified in the matrix of neurofibrillary tangles and amyloid plaques in AD brains, or associations with insulin functions. Decreased cholinergic transport across the blood-brain barrier observed in diabetic animals may exacerbate cognitive impairment in AD. Many interventions could reduce the cognitive decline associated with DM, yet not enough are taken into account so far. 10.1016/s1262-3636(07)70298-7
    GLP-1 mimetics and cognition. Yaribeygi Habib,Rashidy-Pour Ali,Atkin Stephen L,Jamialahmadi Tannaz,Sahebkar Amirhossein Life sciences Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic drugs that improve the glycaemia via several molecular pathways. Recent evidence suggest that they also have additional effects modulating pathophysiologic pathways included in cognitive disorders. Since some forms of cognitive dysfunction such as Alzheimer's disease are more common among diabetic patients than in the normal population, antidiabetic drugs that have neuroprotective effects affording protection for cognitive disorders would be of benefit. Therefore, we reviewed the pharmacologic effects of GLP-1 analogues and found that they may have the additional benefit of improving cognitive performance via at least eight molecular mechanisms. 10.1016/j.lfs.2020.118645
    Early Biomarkers of Neurodegenerative and Neurovascular Disorders in Diabetes. Gasecka Aleksandra,Siwik Dominika,Gajewska Magdalena,Jaguszewski Miłosz J,Mazurek Tomasz,Filipiak Krzysztof J,Postuła Marek,Eyileten Ceren Journal of clinical medicine Diabetes mellitus (DM) is a common disease worldwide. There is a strong association between DM and neurovascular and neurodegenerative disorders. The first group mainly consists of diabetic retinopathy, diabetic neuropathy and stroke, whereas, the second group includes Alzheimer's disease, Parkinson's disease, mild cognitive impairment and dementia. The aforementioned diseases have a common pathophysiological background including insulin resistance, oxidative stress, atherosclerosis and vascular injury. The increasing prevalence of neurovascular and neurodegenerative disorders among diabetic patients has resulted in an urgent need to develop biomarkers for their prediction and/or early detection. The aim of this review is to present the potential application of the most promising biomarkers of diabetes-related neurodegenerative and neurovascular disorders, including amylin, β-amyloid, C-reactive protein (CRP), dopamine, gamma-glutamyl transferase (GGT), glycogen synthase kinase 3β, homocysteine, microRNAs (mi-RNAs), paraoxonase 1, phosphoinositide 3-kinases, tau protein and various growth factors. The most clinically promising biomarkers of neurovascular and neurodegenerative complications in DM are hsCRP, GGT, homocysteine and miRNAs. However, all biomarkers discussed in this review could become a part of the potential multi-biomarker screening panel for diabetic patients at risk of neurovascular and neurodegenerative complications. 10.3390/jcm9092807
    Brain injury with diabetes mellitus: evidence, mechanisms and treatment implications. Hamed Sherifa A Expert review of clinical pharmacology INTRODUCTION:Diabetes mellitus is a risk for brain injury. Brain injury is associated with acute and chronic hyperglycaemia, insulin resistance, hyperinsulinemia, diabetic ketoacidosis (DKA) and hypoglycaemic events in diabetic patients. Hyperglycemia is a cause of cognitive deterioration, low intelligent quotient, neurodegeneration, brain aging, brain atrophy and dementia. Areas covered: The current review highlights the experimental, clinical, neuroimaging and neuropathological evidence of brain injury induced by diabetes and its associated metabolic derangements. It also highlights the mechanisms of diabetes-induced brain injury. It seems that the pathogenesis of hyperglycemia-induced brain injury is complex and includes combination of vascular disease, oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, reduction of neurotrophic factors, acetylcholinesterase (AChE) activation, neurotransmitters' changes, impairment of brain repair processes, impairment of brain glymphatic system, accumulation of amyloid β and tau phosphorylation and neurodegeneration. The potentials for prevention and treatment are also discussed. Expert commentary: We summarize the risks and the possible mechanisms of DM-induced brain injury and recommend strategies for neuroprotection and neurorestoration. Recently, a number of drugs and substances [in addition to insulin and its mimics] have shown promising potentials against diabetes-induced brain injury. These include: antioxidants, neuroinflammation inhibitors, anti-apoptotics, neurotrophic factors, AChE inhibitors, mitochondrial function modifiers and cell based therapies. 10.1080/17512433.2017.1293521
    Diabetes-Related Neurological Implications and Pharmacogenomics. Rojas-Carranza Camilo Andres,Bustos-Cruz Rosa Helena,Pino-Pinzon Carmen Juliana,Ariza-Marquez Yeimy Viviana,Gomez-Bello Rosa Margarita,Canadas-Garre Marisa Current pharmaceutical design Diabetes mellitus (DM) is the most commonly occurring cause of neuropathy around the world and is beginning to grow in countries where there is a risk of obesity. DM Type II, (T2DM) is a common age-related disease and is a major health concern, particularly in developed countries in Europe where the population is aging. T2DM is a chronic disease which is characterised by hyperglycemia, hyperinsulinemia and insulin resistance, together with the body's inability to use glucose as energy. Such metabolic disorder produces a chronic inflammatory state, as well as changes in lipid metabolism leading to hypertriglyceridemia, thereby producing chronic deterioration of the organs and premature morbidity and mortality. The pathology's effects increase cerebral damage, leading to the rapid onset of neurodegenerative diseases. Hyperglycemia causes oxidative stress in tissues which are susceptible to the complications involved in diabetes, including peripheral nerves. Other additional mechanisms include activation of polyol aldose reductase signalling accompanied by protein kinase C (PKC)-ß activation, poly(ADP ribose) polymerase activation, cyclooxygenase (COX) 2 activation, endothelial dysfunction, altered Na+/K+ ATPase pump function, dyslipidaemia and perturbation of calcium balance. All the forgoing has an impact on neuron activity, mitochondrial function, membrane permeability and endothelial function. These biochemical processes directly affect the neurons and endothelial tissue, thereby accelerating cerebral aging by means of peroxidation of the polyunsaturated fatty acids and thus injuring cell membrane integrity and inducing apoptosis in the glial cells. The Central Nervous System (CNS) includes two types de glial cells: microglia and macroglia (astrocytes, oligodendrocytes and radial cells which include Bergmann cells and Müller cells). Glial cells constitute more than 90% of the CNS cell population. Human studies have shown that some oral antidiabetic drugs can improve cognition in patients suffering mild cognitive impairment (MCI) and dementia [1, 2]. While it is still unclear whether diabetes management will reduce MCI and Alzheimer's disease (AD), incidence, emerging evidence suggests that diabetes therapies may improve cognitive function. This review focuses three aspects: the clinical manifestation of diabetes regarding glial and neuronal cells, the association between neurodegeneration and diabetes and summarises some of the pharmacogenomic data obtained from studies of T2DM treatment, focusing on polymorphisms in genes affecting pharmacokinetics, pharmacodynamics and treatment outcome of the most commonly-prescribed oral anti-diabetic drugs (OADs). 10.2174/1381612823666170317165350
    Altered brain metabolites in patients with diabetes mellitus and related complications - evidence from H MRS study. Zhao Xue,Han Qing,Gang Xiaokun,Wang Guixia Bioscience reports In recent years, diabetes mellitus (DM) has been acknowledged as an important factor for brain disorders. Significant alterations in brain metabolism have been demonstrated during the development of DM and its complications. Magnetic resonance spectroscopy (MRS), a cutting-edge technique used in biochemical analyses, non-invasively provides insights into altered brain metabolite levels This review aims to discuss current MRS data describing brain metabolite levels in DM patients with or without complications. Cerebral metabolites including -acetylaspartate (NAA), creatine (Cr), choline (Cho), -inositol (mI), glutamate, and glutamine were significantly altered in DM patients, suggesting that energy metabolism, neurotransmission, and lipid membrane metabolism might be disturbed during the progression of DM. Changes in brain metabolites may be non-invasive biomarkers for DM and DM-related complications. Different brain regions presented distinct metabolic signatures, indicating region-specific diabetic brain damages. In addition to serving as biomarkers, MRS data on brain metabolites can also shed light on diabetic treatment monitoring. For example, exercise may restore altered brain metabolite levels and has beneficial effects on cognition in DM patients. Future studies should validate the above findings in larger populations and uncover the mechanisms of DM-induced brain damages. 10.1042/BSR20180660
    Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes. Bai Litao,Gao Jialiang,Wei Fan,Zhao Jing,Wang Danwei,Wei Junping Frontiers in pharmacology Ginseng, one of the oldest traditional Chinese medicinal herbs, has been used widely in China and Asia for thousands of years. Ginsenosides extracted from ginseng, which is derived from the roots and rhizomes of C. A. Meyer, have been used in China as an adjuvant in the treatment of diabetes mellitus. Owing to the technical complexity of ginsenoside production, the total ginsenosides are generally extracted. Accumulating evidence has shown that ginsenosides exert antidiabetic effects. and tests revealed the potential of ginsenoside Rg1, Rg3, Rg5, Rb1, Rb2, Rb3, compound K, Rk1, Re, ginseng total saponins, malonyl ginsenosides, Rd, Rh2, F2, protopanaxadiol (PPD) and protopanaxatriol (PPT)-type saponins to treat diabetes and its complications, including type 1 diabetes mellitus, type 2 diabetes mellitus, diabetic nephropathy, diabetic cognitive dysfunction, type 2 diabetes mellitus with fatty liver disease, diabetic cerebral infarction, diabetic cardiomyopathy, and diabetic erectile dysfunction. Many effects are attributed to ginsenosides, including gluconeogenesis reduction, improvement of insulin resistance, glucose transport, insulinotropic action, islet cell protection, hepatoprotective activity, anti-inflammatory effect, myocardial protection, lipid regulation, improvement of glucose tolerance, antioxidation, improvement of erectile dysfunction, regulation of gut flora metabolism, neuroprotection, anti-angiopathy, anti-neurotoxic effects, immunosuppression, and renoprotection effect. The molecular targets of these effects mainly contains GLUTs, SGLT1, GLP-1, FoxO1, TNF-α, IL-6, caspase-3, bcl-2, MDA, SOD, STAT5-PPAR gamma pathway, PI3K/Akt pathway, AMPK-JNK pathway, NF-κB pathway, and endoplasmic reticulum stress. Rg1, Rg3, Rb1, and compound K demonstrated the most promising therapeutic prospects as potential adjuvant medicines for the treatment of diabetes. This paper highlights the underlying pharmacological mechanisms of the anti-diabetic effects of ginsenosides. 10.3389/fphar.2018.00423
    The effect of type 1 diabetes on the developing brain. Cameron Fergus J,Northam Elisabeth A,Ryan Christopher M The Lancet. Child & adolescent health The effect of type 1 diabetes on the developing brain is a topic of primary research interest. A variety of potential dysglycaemic insults to the brain can cause cellular and structural injury and lead to altered neuropsychological outcomes. These outcomes might be subtle in terms of cognition but appear to persist into adult life. Age and circumstance at diagnosis appear to play a substantial role in potential CNS injury. A history of diabetic ketoacidosis and chronic hyperglycaemia appear to be more injurious than previously suspected, whereas a history of severe hypoglycaemia is perhaps less injurious. Neurocognitive deficits manifest across multiple cognitive domains, including executive function and speed of information processing. Some evidence suggests that subtle brain injury might directly contribute to psychological and mental health outcomes. Impaired executive function and mental health, in turn, could affect patients' adherence and the ability to make adaptive lifestyle choices. Impaired executive functioning creates a potential feedback loop of diabetic dysglycaemia leading to brain injury, further impaired executive function and mental health, which results in suboptimal adherence, and further dysglycaemia. Clinicians dealing with patients with suboptimal glycaemic outcomes should be aware of these potential issues. 10.1016/S2352-4642(19)30055-0
    Blood Brain Barrier Injury in Diabetes: Unrecognized Effects on Brain and Cognition. Bogush Marina,Heldt Nathan A,Persidsky Yuri Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology Diabetes mellitus (DM) is a disorder due to the inability properly to metabolize glucose associated with dysregulation of metabolic pathways of lipids and proteins resulting in structural and functional changes of various organ systems. DM has detrimental effects on the vasculature, resulting in the development of various cardiovascular diseases and stemming from microvascular injury. The blood brain barrier (BBB) is a highly specialized structure protecting the unique microenvironment of the brain. Endothelial cells, connected by junctional complexes and expressing numerous transporters, constitute the main cell type in the BBB. Other components, including pericytes, basement membrane, astrocytes and perivascular macrophages, join endothelial cells to form the neurovascular unit (NVU) and contribute to the proper function and integrity of the BBB. The role of the BBB in the pathogenesis of diabetic encephalopathy and other diabetes-related complications in the central nervous system is apparent. However, the mechanisms, timing and consequences of BBB injury in diabetes are not well understood. The importance of further studies related to barrier dysfunction in diabetes is dictated by its potential involvement in the cognitive demise associated with DM. This review summarizes the impact of DM on BBB/NVU integrity and function leading to neurological and cognitive complications. 10.1007/s11481-017-9752-7
    Review of the Effect of Natural Compounds and Extracts on Neurodegeneration in Animal Models of Diabetes Mellitus. Infante-Garcia Carmen,Garcia-Alloza Monica International journal of molecular sciences Diabetes mellitus is a chronic metabolic disease with a high prevalence in the Western population. It is characterized by pancreas failure to produce insulin, which involves high blood glucose levels. The two main forms of diabetes are type 1 and type 2 diabetes, which correspond with >85% of the cases. Diabetes shows several associated alterations including vascular dysfunction, neuropathies as well as central complications. Brain alterations in diabetes are widely studied; however, the mechanisms implicated have not been completely elucidated. Diabetic brain shows a wide profile of micro and macrostructural changes, such as neurovascular deterioration or neuroinflammation leading to neurodegeneration and progressive cognition dysfunction. Natural compounds (single isolated compounds and/or natural extracts) have been widely assessed in metabolic disorders and many of them have also shown antioxidant, antiinflamatory and neuroprotective properties at central level. This work reviews natural compounds with brain neuroprotective activities, taking into account several therapeutic targets: Inflammation and oxidative stress, vascular damage, neuronal loss or cognitive impairment. Altogether, a wide range of natural extracts and compounds contribute to limit neurodegeneration and cognitive dysfunction under diabetic state. Therefore, they could broaden therapeutic alternatives to reduce or slow down complications associated with diabetes at central level. 10.3390/ijms20102533
    Potential Biochemical Mechanisms of Brain Injury in Diabetes Mellitus. Ma Wei-Xing,Tang Jing,Lei Zhi-Wen,Li Chun-Yan,Zhao Li-Qing,Lin Chao,Sun Tao,Li Zheng-Yi,Jiang Ying-Hui,Jia Jun-Tao,Liang Cheng-Zhu,Liu Jun-Hong,Yan Liang-Jun Aging and disease The goal of this review was to summarize current biochemical mechanisms of and risk factors for diabetic brain injury. We mainly summarized mechanisms published in the past three years and focused on diabetes induced cognitive impairment, diabetes-linked Alzheimer's disease, and diabetic stroke. We think there is a need to conduct further studies with increased sample sizes and prolonged period of follow-ups to clarify the effect of DM on brain dysfunction. Additionally, we also think that enhancing experimental reproducibility using animal models in conjunction with application of advanced devices should be considered when new experiments are designed. It is expected that further investigation of the underlying mechanisms of diabetic cognitive impairment will provide novel insights into therapeutic approaches for ameliorating diabetes-associated injury in the brain. 10.14336/AD.2019.0910
    Microvascular Dysfunction and Hyperglycemia: A Vicious Cycle With Widespread Consequences. Stehouwer Coen D A Diabetes Microvascular and metabolic physiology are tightly linked. This Perspective reviews evidence that ) the relationship between hyperglycemia and microvascular dysfunction (MVD) is bidirectional and constitutes a vicious cycle; ) MVD in diabetes affects many, if not all, organs, which may play a role in diabetes-associated comorbidities such as depression and cognitive impairment; and ) MVD precedes, and contributes to, hyperglycemia in type 2 diabetes (T2D) through impairment of insulin-mediated glucose disposal and, possibly, insulin secretion. Obesity and adverse early-life exposures are important drivers of MVD. MVD can be improved through weight loss (in obesity) and through exercise. Pharmacological interventions to improve MVD are an active area of investigation. 10.2337/dbi17-0044
    Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. McNay Ewan C,Recknagel Andrew K Neurobiology of learning and memory Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding, to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cognitive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients. 10.1016/j.nlm.2011.08.005
    A contemporary biological pathway of islet amyloid polypeptide for the management of diabetic dementia. Sah Sushil Kumar,Samuel Vijaya Paul,Dahiya Sunita,Singh Yogendar,Gilhotra Ritu M,Gupta Gaurav,Mishra Anurag,Sharma Rakesh Kumar,Kumar Gubbiyappa Shiva,SreeHarsha Nagaraja,Chellappan Dinesh Kumar,Dua Kamal Chemico-biological interactions Major challenges of dealing elder patients with diabetes mellitus (DM) are the individualization of consideration in persons with various comorbid types of conditions. In spite of the fact that microvascular and macrovascular problems associated with DM are well documented, there is only a few numbers of reports viewing different conditions, for example, cognitive dysfunction. Cognitive dysfunction is of specific significance due to its effect on self-care and quality of life. All in all, the etiology of cognitive dysfunction in the maturing populace is probably going to be the grouping of ischemic and degenerative pathology. It is likewise trusted that Hyperglycemia is engaged with the system of DM-related cognitive dysfunction. At present, it isn't certain in the case of enhancing glycemic control or utilizing therapeutic agents can enhance the risk of cognitive decay. Amylin was later characterized as an amyloidogenic peptide, confined from a beta cell tumor and called islet amyloid polypeptide (IAPP), and after that, amylin. Conversely, we investigate the beneficial role and hypothesizing the mechanism of amylin related expanding the level and activation of CGRP receptor to enhance the cognition declination amid diabetic dementia. 10.1016/j.cbi.2019.04.022
    Morphological and Pathological Characteristics of Brain in Diabetic Encephalopathy. Chen Rui,Shi Jiangwei,Yin Qingsheng,Li Xiaojin,Sheng Yanyuan,Han Juan,Zhuang Pengwei,Zhang Yanjun Journal of Alzheimer's disease : JAD Diabetes mellitus is a metabolic disease often accompanied by a series of complications, such as diabetic nephropathy, retinopathy, and diabetic foot. The survival time of diabetics has been significantly prolonged due to advancements in medicine. However, the prolonged survival time for diabetics can increase the prevalence of diabetic central nervous system disease. Diabetic encephalopathy (DE) has become one of the main complications of the disease, and the main clinical manifestation of DE is cognitive dysfunction. However, the typical morphological and pathological characteristics of the brain in DE are rarely systematically reported. Thus, this phenomenon severely restricts the diagnosis and treatment of DE. This article presents a description of the pathology characteristics of DE, including atrophy of the brain (gray matter, white matter, and hippocampus), changes in cerebrovascular morphology and function, impairment of synaptic plasticity, and dysfunction of neuroglia. In addition, abnormalities in the glymphatic clearance system of the brain are closely related to the progression of DE. A review of typical brain morphological and pathological characteristics would aid in the diagnosis and treatment of DE. 10.3233/JAD-180314
    Diabetes and cognitive dysfunction. McCrimmon Rory J,Ryan Christopher M,Frier Brian M Lancet (London, England) Cognitive dysfunction in type 1 and type 2 diabetes share many similarities, but important differences do exist. A primary distinguishing feature of type 2 diabetes is that people with this disorder often (but not invariably) do poorly on measures of learning and memory, whereas deficits in these domains are rarely seen in people with type 1 diabetes. Chronic hyperglycaemia and microvascular disease contribute to cognitive dysfunction in both type 1 and type 2 diabetes, and both disorders are associated with mental and motor slowing and decrements of similar magnitude on measures of attention and executive functioning. Additionally, both types are characterised by neural slowing, increased cortical atrophy, microstructural abnormalities in white matter tracts, and similar, but not identical, changes in concentrations of brain neurometabolites. Disconcertingly, the rapid rise in obesity and type 2 diabetes in all age groups might result in a substantial increase in prevalence of diabetes-related cognitive dysfunction. 10.1016/S0140-6736(12)60360-2
    Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: associations and a hypothesis. Domínguez R O,Pagano M A,Marschoff E R,González S E,Repetto M G,Serra J A Neurologia (Barcelona, Spain) INTRODUCTION:Epidemiological studies have demonstrated that patients with diabetes mellitus have an increased risk of developing Alzheimer disease, but the relationship between the 2 entities is not clear. DEVELOPMENT:Both diseases exhibit similar metabolic abnormalities: disordered glucose metabolism, abnormal insulin receptor signalling and insulin resistance, oxidative stress, and structural abnormalities in proteins and β-amyloid deposits. Different hypotheses have emerged from experimental work in the last two decades. One of the most comprehensive relates the microvascular damage in diabetic polyneuritis with the central nervous system changes occurring in Alzheimer disease. Another hypothesis considers that cognitive impairment in both diabetes and Alzheimer disease is linked to a state of systemic oxidative stress. Recently, attenuation of cognitive impairment and normalisation of values in biochemical markers for oxidative stress were found in patients with Alzheimer disease and concomitant diabetes. Antidiabetic drugs may have a beneficial effect on glycolysis and its end products, and on other metabolic alterations. CONCLUSIONS:Diabetic patients are at increased risk for developing Alzheimer disease, but paradoxically, their biochemical alterations and cognitive impairment are less pronounced than in groups of dementia patients without diabetes. A deeper understanding of interactions between the pathogenic processes of both entities may lead to new therapeutic strategies that would slow or halt the progression of impairment. 10.1016/j.nrl.2013.05.006
    Inside the Diabetic Brain: Role of Different Players Involved in Cognitive Decline. Gaspar Joana M,Baptista Filipa I,Macedo M Paula,Ambrósio António F ACS chemical neuroscience Diabetes mellitus is the most common metabolic disease, and its prevalence is increasing. A growing body of evidence, both in animal models and epidemiological studies, has demonstrated that metabolic diseases like obesity, insulin resistance, and diabetes are associated with alterations in the central nervous system (CNS), being linked with development of cognitive and memory impairments and presenting a higher risk for dementia and Alzheimer's disease. The rising prevalence of diabetes together with its increasing earlier onset suggests that diabetes-related cognitive dysfunction will increase in the near future, causing substantial socioeconomic impact. Decreased insulin secretion or action, dysregulation of glucose homeostasis, impairment in the hypothalamic-pituitary-adrenal axis, obesity, hyperleptinemia, and inflammation may act independently or synergistically to disrupt neuronal homeostasis and cause diabetes-associated cognitive decline. However, the crosstalk between those factors and the mechanisms underlying the diabetes-related CNS complications is still elusive. During the past few years, different strategies (neuroprotective and antioxidant drugs) have emerged as promising therapies for this complication, which still remains to be preventable or treatable. This Review summarizes fundamental past and ongoing research on diabetes-associated cognitive decline, highlighting potential contributors, mechanistic mediators, and new pharmacological approaches to prevent and/or delay this complication. 10.1021/acschemneuro.5b00240
    The Impact of Microbiota-Gut-Brain Axis on Diabetic Cognition Impairment. Xu Youhua,Zhou Hua,Zhu Quan Frontiers in aging neuroscience Progressive cognitive dysfunction is a central characteristic of diabetic encephalopathy (DE). With an aging population, the incidence of DE is rising and it has become a major threat that seriously affects public health. Studies within this decade have indicated the important role of risk factors such as oxidative stress and inflammation on the development of cognitive impairment. With the recognition of the two-way communication between gut and brain, recent investigation suggests that "microbiota-gut-brain axis" also plays a pivotal role in modulating both cognition function and endocrine stability. This review aims to systemically elucidate the underlying impact of diabetes on cognitive impairment. 10.3389/fnagi.2017.00106
    The role of traditional Chinese medicine in the treatment of cognitive dysfunction in type 2 diabetes. Meng Jinni,Zhu Yafei,Ma Huixia,Wang Xiaobo,Zhao Qipeng Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Diabetic cognitive dysfunction (DCD) is mainly one of the complications of type 2 diabetes mellitus (T2DM) with complex and obscure pathogenesis. Extensive evidence has demonstrated the effectiveness and safety of traditional Chinese medicine (TCM) for DCD management. AIM OF THE STUDY:This review attempted to systematically summarize the possible pathogenesis of DCD and the current Chinese medicine on the treatment of DCD. MATERIALS AND METHODS:We acquired information of TCM on DCD treatment from PubMed, Web of Science, Science Direct and CNKI databases. We then dissected the potential mechanisms of currently reported TCMs and their active ingredients for the treatment of DCD by discussing the deficiencies and giving further recommendations. RESULTS:Most TCMs and their active ingredients could improve DCD through alleviating insulin resistance, microvascular dysfunction, abnormal gut microbiota composition, inflammation, and the damages of the blood-brain barrier, cerebrovascular and neurons under hyperglycemia conditions. CONCLUSIONS:TCM is effective in the treatment of DCD with few adverse reactions. A large number of in vivo and in vitro, and clinical trials are still needed to further reveal the potential quality markers of TCM on DCD treatment. 10.1016/j.jep.2021.114464
    The diabetic brain and cognition. Riederer Peter,Korczyn Amos D,Ali Sameh S,Bajenaru Ovidiu,Choi Mun Seong,Chopp Michael,Dermanovic-Dobrota Vesna,Grünblatt Edna,Jellinger Kurt A,Kamal Mohammad Amjad,Kamal Warda,Leszek Jerzy,Sheldrick-Michel Tanja Maria,Mushtaq Gohar,Meglic Bernard,Natovich Rachel,Pirtosek Zvezdan,Rakusa Martin,Salkovic-Petrisic Melita,Schmidt Reinhold,Schmitt Angelika,Sridhar G Ramachandra,Vécsei László,Wojszel Zyta Beata,Yaman Hakan,Zhang Zheng G,Cukierman-Yaffe Tali Journal of neural transmission (Vienna, Austria : 1996) The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) is increasing with the aging of the population. Studies from the last several years have shown that people with diabetes have an increased risk for dementia and cognitive impairment. Therefore, the authors of this consensus review tried to elaborate on the role of diabetes, especially diabetes type 2 (T2DM) in both AD and VaD. Based on the clinical and experimental work of scientists from 18 countries participating in the International Congress on Vascular Disorders and on literature search using PUBMED, it can be concluded that T2DM is a risk factor for both, AD and VaD, based on a pathology of glucose utilization. This pathology is the consequence of a disturbance of insulin-related mechanisms leading to brain insulin resistance. Although the underlying pathological mechanisms for AD and VaD are different in many aspects, the contribution of T2DM and insulin resistant brain state (IRBS) to cerebrovascular disturbances in both disorders cannot be neglected. Therefore, early diagnosis of metabolic parameters including those relevant for T2DM is required. Moreover, it is possible that therapeutic options utilized today for diabetes treatment may also have an effect on the risk for dementia. T2DM/IRBS contribute to pathological processes in AD and VaD. 10.1007/s00702-017-1763-2
    Cognitive dysfunction: an emerging concept of a new diabetic complication in the elderly. Umegaki Hiroyuki,Hayashi Toshio,Nomura Hideki,Yanagawa Madoka,Nonogaki Zen,Nakshima Hirotaka,Kuzuya Masafumi Geriatrics & gerontology international The incidence of type 2 diabetes mellitus (T2DM) has risen, and this trend is likely to continue. Recent advances suggest that T2DM is a risk factor for cognitive decline. We are now encountering novel complications of T2DM, namely cognitive dysfunction and dementia. Although the treatment strategy for diabetic patients with neurocognitive dysfunction has received a great deal of attention, the appropriate level of glycemic control for the prevention of the development and/or progression of cognitive decline in elderly diabetic patients remains to be elucidated. Another issue in diabetic treatment in patients with cognitive dysfunction is the selection of medicines. The best choice and combination of antidiabetic medications for the preservation of cognition should also be studied. Ample studies suggest that exercise helps to preserve cognitive function, although existing evidence does not necessarily indicate its effectiveness exclusively in diabetic patients. Exercise is a helpful non-pharmacological therapy. Considering the progressive aging of the worldwide population, more research to investigate the best way to manage this population is important. 10.1111/j.1447-0594.2012.00922.x
    Targeting Insulin Resistance to Treat Cognitive Dysfunction. Molecular neurobiology Dementia is a devastating disease associated with aging. Alzheimer's disease is the most common form of dementia, followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus, characterized by chronic hyperglycemia and insulin resistance, as a risk factor for Alzheimer's disease and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported by recent clinical and preclinical studies. The findings from these studies suggest that antidiabetic drugs have the potential to be used to treat dementia. In this review, we discuss the physiological functions of insulin in the brain, studies on the evaluation of cognitive function under conditions of insulin resistance, and reports on the beneficial actions of antidiabetic drugs in the brain. This review covers clinical studies as well as investigations in animal models and will further highlight the emerging link between insulin resistance and neurodegenerative disorders. 10.1007/s12035-021-02283-3
    Chinese Medicinal Herbs in the Treatment of Diabetic Cognitive Impairment: A Systematic Review and Meta-Analysis. Yan Bin,Wang Jingbo,Xue Zhigang,Tian Guoqing Evidence-based complementary and alternative medicine : eCAM BACKGROUND:Diabetic cognitive impairment (DCI), a serious complication of diabetes mellitus (DM), is gaining more acceptance and attention. The learning and memory function of diabetics always decreases. Traditional Chinese medicine (TCM) has been demonstrated to be effective in treating the symptoms in China, and thereinto Chinese medicinal herbs (CMH) are the most widely used. The objective of the present study was to review and analyze the existing data about reducing the symptoms in CMH treatment for DCI. METHODS:Electronic literature databases (PubMed, EMBASE, CNKI, SinoMed, and Wan fang) were searched for randomized controlled trials conducted in China, comparing CMH with western medicines in the treatment of DCI, up to April 1, 2018. We applied standard meta-analytic techniques to analyze data from papers that reached acceptable criteria. RESULT:Nine randomized controlled trials (n = 576) on CMH were included. We found moderate evidence that CMH used alone or in combination with western medicines was more effective than western medicines alone in reliving the symptoms for DCI (total effective rate, odds radio (OR) = 4.64 (2.60, 8.29), and 95% confidence interval, P<0.00001). Besides, CMH along or in combination with western medicines showed more beneficial effects on Montreal Cognitive Assessment (MoCA) scale (mean difference (MD) = 1.31(0.75, 1.87), P<0.00001), Mini-Mental State Examination (MMSE) scale (MD = 2.07 (0.86, 3.28), P<0.00001, and TCM symptom score (TCMSS) (MD = -4.89 (-8.44, -1.34), P = 0.007). Most of the included studies showed that there was not a significant difference in the adverse events. CONCLUSIONS:These findings demonstrated that CMH used alone or in combination with western medicines were apparently better than western medicines alone in the treatment of DCI. Because of the poor quality of the studies that were available for the present meta-analysis, further researches are still needed to support these early findings. 10.1155/2018/7541406
    SIRT1 Regulates Cognitive Performance and Ability of Learning and Memory in Diabetic and Nondiabetic Models. Cao Yue,Yan Zi,Zhou Tong,Wang Guixia Journal of diabetes research Type 2 diabetes mellitus is a complex age-related metabolic disease. Cognitive dysfunction and learning and memory deficits are main characteristics of age-related metabolic diseases in the central nervous system. The underlying mechanisms contributing to cognitive decline are complex, especially cognitive dysfunction associated with type 2 diabetes mellitus. SIRT1, as one of the modulators in insulin resistance, is indispensable for learning and memory. In the present study, deacetylation, oxidative stress, mitochondrial dysfunction, inflammation, microRNA, and tau phosphorylation are considered in the context of mechanism and significance of SIRT1 in learning and memory in diabetic and nondiabetic murine models. In addition, future research directions in this field are discussed, including therapeutic potential of its activator, resveratrol, and application of other compounds in cognitive improvement. Our findings suggest that SIRT1 might be a potential therapeutic target for the treatment of cognitive impairment induced by type 2 diabetes mellitus. 10.1155/2017/7121827
    Neuronal damage and cognitive impairment associated with hypoglycemia: An integrated view. Languren Gabriela,Montiel Teresa,Julio-Amilpas Alberto,Massieu Lourdes Neurochemistry international The aim of the present review is to offer a current perspective about the consequences of hypoglycemia and its impact on the diabetic disorder due to the increasing incidence of diabetes around the world. The main consequence of insulin treatment in type 1 diabetic patients is the occurrence of repetitive periods of hypoglycemia and even episodes of severe hypoglycemia leading to coma. In the latter, selective neuronal death is observed in brain vulnerable regions both in humans and animal models, such as the cortex and the hippocampus. Cognitive damage subsequent to hypoglycemic coma has been associated with neuronal death in the hippocampus. The mechanisms implicated in selective damage are not completely understood but many factors have been identified including excitotoxicity, oxidative stress, zinc release, PARP-1 activation and mitochondrial dysfunction. Importantly, the diabetic condition aggravates neuronal damage and cognitive failure induced by hypoglycemia. In the absence of coma prolonged and severe hypoglycemia leads to increased oxidative stress and discrete neuronal death mainly in the cerebral cortex. The mechanisms responsible for cell damage in this condition are still unknown. Recurrent moderate hypoglycemia is far more common in diabetic patients than severe hypoglycemia and currently important efforts are being done in order to elucidate the relationship between cognitive deficits and recurrent hypoglycemia in diabetics. Human studies suggest impaired performance mainly in memory and attention tasks in healthy and diabetic individuals under the hypoglycemic condition. Only scarce neuronal death has been observed under moderate repetitive hypoglycemia but studies suggest that impaired hippocampal synaptic function might be one of the causes of cognitive failure. Recent studies have also implicated altered mitochondrial function and mitochondrial oxidative stress. 10.1016/j.neuint.2013.06.018
    A systematic review of the association of diabetic retinopathy and cognitive impairment in people with Type 2 diabetes. Crosby-Nwaobi R,Sivaprasad S,Forbes A Diabetes research and clinical practice A systematic review of studies reporting data on the relationship between diabetic eye disease and cognitive impairment in Type 2 diabetes was conducted. The increase in cognitive impairment has mirrored the global increase in diabetes. The aim of the systematic review was to determine the level of association between diabetic retinopathy and cognitive impairment. Item selection, data extraction and critical appraisal were undertaken using standard procedures and independently verified by two researchers. 3 out of 10 potentially relevant studies were included. All studies showed a level of association between diabetic retinopathy and cognitive impairment, suggesting a near threefold increased risk of cognitive impairment in patients with diabetic retinopathy compared to those without. An association of cognitive impairment and severity of diabetic retinopathy was found in males. Diabetic retinopathy was more strongly linked to impairment in the cognitive domains of verbal learning and recent memory. An increased risk of cognitive impairment in patients with diabetic retinopathy was found in the reviewed studies. However, the relationship of severity of diabetic retinopathy and cognitive impairment has not been established. Further studies with standardized measurements for cognitive impairment and diabetic retinopathy are required to delineate this relationship and the role of other factors in this relationship. 10.1016/j.diabres.2011.11.010
    Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders. Chen Qian,Cao Ting,Li NaNa,Zeng Cuirong,Zhang Shuangyang,Wu Xiangxin,Zhang Bikui,Cai Hualin Frontiers in pharmacology Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized. 10.3389/fphar.2021.667874
    Cognitive impairment in diabetic patients: Can diabetic control prevent cognitive decline? Kawamura Takahiko,Umemura Toshitaka,Hotta Nigishi Journal of diabetes investigation It is well recognized that the prevalence of dementia is higher in diabetic patients than non-diabetic subjects. The incidence of diabetes has been increasing because of dramatic changes in lifestyles, and combined with longer lifespans as a result of advances in medical technology, this has brought about an increase in the number of elderly diabetic patients. Together, aging and diabetes have contributed to dementia becoming a serious problem. Progression to dementia reduces quality of life, and imposes a burden on both patients themselves and the families supporting them. Therefore, preventing the complication of dementia will become more and more important in the future. Although many mechanisms have been considered for an association between diabetes and cognitive dysfunction, glucose metabolism abnormalities such as hyperglycemia and hypoglycemia, and insulin action abnormalities such as insulin deficiency and insulin resistance can be causes of cognitive impairment. Recent large-scale longitudinal studies have found an association between glycemic control and cognitive decline, although it is still unclear how cognitive decline might be prevented by good glycemic control. However, at an early stage, it is necessary to detect moderate cognitive dysfunction and try to reduce the risk factors for it, which should result in prevention of dementia, as well as vascular events. In the present review, in addition to outlining an association between diabetes and cognitive function, we discuss how glycemic control and cognitive decline are related. 10.1111/j.2040-1124.2012.00234.x
    A promising structural magnetic resonance imaging assessment in patients with preclinical cognitive decline and diabetes mellitus. Dong Yulan,Wang Qi,Yao Hailun,Xiao Yawen,Wei Jiaohong,Xie Peihan,Hu Jun,Chen Wen,Tang Yan,Zhou Hong,Liu Jincai Journal of cellular physiology Subjective cognitive decline (SCD) is frequently reported in diabetic patients. Diabetes mellitus (DM) is associated with changes in the microstructure of the brain arise in diabetic patients, including changes in gray matter volume (GMV). However, the underlying mechanisms of changes in GMV in DM patients with cognitive impairment remain uncertain. Here, we present an overview of amyloid-β-dependent cognitive impairment in DM patients with SCD. Moreover, we review the evolving insights from studies on the GMV changes in GMV and cognitive dysfunction to which provide the mechanisms of cognitive impairment in T2DM. Ultimately, the novel structural magnetic resonance imaging (MRI) protocol was used for detecting neuroimaging biomarkers that can predict the clinical outcomes in diabetic patients with SCD. A reliable MRI protocol would be helpful to detect neurobiomarkers, and to understand the pathological mechanisms of preclinical cognitive impairment in diabetic patients. 10.1002/jcp.28359
    Cognitive impairments in type 2 diabetes, risk factors and preventive strategies. Sharma Garima,Parihar Arti,Talaiya Tanay,Dubey Kirti,Porwal Bhagyesh,Parihar Mordhwaj S Journal of basic and clinical physiology and pharmacology Mild cognitive impairment (MCI) is a modifiable risk factor in progression of several diseases including dementia and type 2 diabetes. If cognitive impairments are not reversed at an early stage of appearance of symptoms, then the prolonged pathogenesis can lead to dementia and Alzheimer's disease (AD). Therefore, it is necessary to detect the risk factors and mechanism of prevention of cognitive dysfunction at an early stage of disease. Poor lifestyle, age, hyperglycemia, hypercholesterolemia, and inflammation are some of the major risk factors that contribute to cognitive and memory impairments in diabetic patients. Mild cognitive impairment was seen in those individuals of type 2 diabetes, who are on an unhealthy diet. Physical inactivity, frequent alcohol consumptions, and use of packed food products that provides an excess of cheap calories are found associated with cognitive impairment and depression in diabetic patients. Omega fatty acids (FAs) and polyphenol-rich foods, especially flavonoids, can reduce the bad effects of an unhealthy lifestyle; therefore, the consumption of omega FAs and flavonoids may be beneficial in maintaining normal cognitive function. These functional foods may improve cognitive functions by targeting many enzymes and molecules in cells chiefly through their anti-inflammatory, antioxidant, or signaling actions. Here, we provide the current concepts on the risk factors of cognitive impairments in type 2 diabetes and the mechanism of prevention, using omega FAs and bioactive compounds obtained from fruits and vegetables. The knowledge derived from such studies may assist physicians in managing the health care of patients with cognitive difficulties. 10.1515/jbcpp-2019-0105
    The neuroprotective effect and action mechanism of polyphenols in diabetes mellitus-related cognitive dysfunction. Zhang Shenshen,Xue Ran,Hu Ruizhe European journal of nutrition BACKGROUND:Diabetes mellitus (DM) is a complex and prevalent metabolic disorder worldwide. Strong evidence has emerged that DM is a risk factor for the accelerated rate of cognitive decline and the development of dementia. Though traditional pharmaceutical agents are efficient for the management of DM and DM-related cognitive decrement, long-term use of these drugs are along with undesired side effects. Therefore, tremendous studies have focused on the therapeutic benefits of natural compounds at present. Ample evidence exists to prove that polyphenols are capable to modulate diabetic neuropathy with minimal toxicity and adverse effects. PURPOSE:To describe the benefits and mechanisms of polyphenols on DM-induced cognitive dysfunction. In this review, we introduce an updated overview of associations between DM and cognitive dysfunction. The risk factors as well as pathological and molecular mechanisms of DM-induced cognitive dysfunction are summarized. More importantly, many active polyphenols that possess preventive and therapeutic effects on DM-induced cognitive dysfunction and the potential signaling pathways involved in the action are highlighted. CONCLUSIONS:The therapeutic effects of polyphenols on DM-related cognitive dysfunction pave a novel way for the management of diabetic encephalopathy. 10.1007/s00394-019-02078-2
    Cognitive impairment and dementia: a new emerging complication of type 2 diabetes-The diabetologist's perspective. Simó Rafael,Ciudin Andreea,Simó-Servat Olga,Hernández Cristina Acta diabetologica Type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) are two of the most common diseases of aging around the world. Given the frequency with which T2D and AD occur, the notion that people with T2D may be at increased risk for AD has large societal consequences, and understanding the mechanistic links between these diseases is imperative for the development of effective AD prevention and treatment strategies. Apart from being an accelerator of AD, T2D is associated with a progressive cognitive decline. Impaired insulin signaling, inflammation, the accumulation of advanced glycation end-products and oxidative stress all play an essential role in the pathogenesis of both AD and diabetic complications. Therefore, it is reasonable to postulate that these pathways are involved in the increased risk of dementia that occurs in the T2D population. The early diagnosis of cognitive impairment and the identification of the subset of patients at a higher risk of developing AD is a challenge for healthcare providers, and meeting it will permit us to implement a personalized medicine, which is an essential issue in diabetes care with significant therapeutic implications. The main gaps that should be filled to achieve this objective are examined. 10.1007/s00592-017-0970-5
    The Contribution of Kidney Disease to Cognitive Impairment in Patients with Type 2 Diabetes. Ghoshal Shivani,Allred Nicholette D,Freedman Barry I Current diabetes reports PURPOSE OF REVIEW:This review focuses on the relationships between diabetes, cognitive impairment, and the contribution of kidney disease. RECENT FINDINGS:We review the independent contributions of parameters of kidney disease, including albuminuria, glomerular filtration, bone/mineral metabolism, and vitamin D synthesis, on cognitive performance in patients with diabetes. Potential pathophysiologic mechanisms underlying these associations are discussed highlighting gaps in existing knowledge. Finally, effects of the dialysis procedure on the brain and cognitive performance are considered. Emphasis is placed on novel non-invasive screening tools with the potential to preserve cerebral perfusion during hemodialysis and limit cognitive decline in patients with diabetic ESKD. Patients with type 2 diabetes and advanced chronic kidney disease suffer a higher prevalence of cognitive impairment. This is particularly true in patients with diabetes and end-stage kidney disease (ESKD). 10.1007/s11892-020-01333-9
    Vascular cognitive impairment and dementia in type 2 diabetes mellitus: An overview. Lyu Fan,Wu Dan,Wei Changwei,Wu Anshi Life sciences Type 2 diabetes mellitus (T2DM) as well as vascular cognitive impairment and dementia (VCID), are both chronic diseases, severely affecting patients, families, and society. A growing number of studies have found that T2DM may double the incidence of cognitive impairment. To help patients with T2DM prevent cognitive dysfunction more scientifically, as well as providing researchers with clearer research ideas, we summarized the risk factors, mechanisms and prevention methods of VCID which is induced by T2DM. This is a great significance for patients with T2DM to prevent the occurrence of VCID, meanwhile, it provides a reference for future researches on the relationship between T2DM and VCID. 10.1016/j.lfs.2020.117771
    Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease. Jash Kavya,Gondaliya Piyush,Kirave Prathibha,Kulkarni Bhagyashri,Sunkaria Aditya,Kalia Kiran Drug development research Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age-related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie-ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro-RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same. 10.1002/ddr.21579
    Cerebral microbleeds, cognitive impairment, and MRI in patients with diabetes mellitus. Zhou Hong,Yang Juan,Xie Peihan,Dong Yulan,You Yong,Liu Jincai Clinica chimica acta; international journal of clinical chemistry Cerebral microbleeds (CMBs), a typical imaging manifestation marker of sporadic cerebral small vessel disease, play a critical role in vascular cognitive impairment, which is often accompanied by diabetes mellitus (DM). Hence, CMBs may, in part, be responsible for the occurrence and development of cognitive impairment in patients with diabetes. Novel magnetic resonance imaging (MRI) sequences, such as susceptibility-weighted imaging and T2*-weighted gradient-echo, have the capability of noninvasively revealing CMBs in the brain. Moreover, a correlation between CMBs and cognitive impairment in patients with diabetes has been suggested in applications of functional MRI (fMRI). Since pathological changes in the brain occur prior to observable decline in cognitive function, neuroimaging may help predict the progression of cognitive impairment in diabetic patients. In this article, we review the detection of CMBs using MRI in diabetic patients exhibiting cognitive impairment. Future studies should emphasize the development and establishment of a novel MRI protocol, including fMRI, for diabetic patients with cognitive impairment to detect CMBs. A reliable MRI protocol would also be helpful in understanding the pathological mechanisms of cognitive impairment in this important patient population. 10.1016/j.cca.2017.04.019
    Spatiotemporal variations of vascular endothelial growth factor in the brain of diabetic cognitive impairment. Yin Qingsheng,Ma Jing,Han Xu,Zhang Hanyu,Wang Fang,Zhuang Pengwei,Zhang Yanjun Pharmacological research Although it is feared that diabetes-induced cognitive impairment (DCI) will become a major clinical problem worldwide in the future, its detailed pathological mechanism is not well known. Because patients with diabetes have various complications of vascular disease, vascular disorders in the brain are considered to be one of the main mechanisms of DCI. Mounting evidence suggests that the vascular endothelial growth factor (VEGF) family plays a crucial role in the development of DCI. In this review, we summarized the changes and functions of VEGF during the development of DCI, and speculated that it was characterized by spatiotemporal variations in DCI progression. Considering the complexity of DCI pathogenesis and the diversity of VEGF function, we focused on the interrelationship of DCI and VEGF spatiotemporal variations during DCI development. During the progression of DCI, hyperglycemia, abnormal brain insulin signals, advanced glycation end products (AGEs) and consequently hypoxia, oxidative stress, and inflammation are the main pathophysiological changes; hypoxia-inducible factor (HIF), reactive oxygen species (ROS), and nuclear factor kappa beta (NF-κB) play major roles in DCI-related VEGF spatiotemporal regulation. Furthermore, spatiotemporal variations in VEGF-mediated pathological cerebral neovascularization, repair and regeneration of dural lymphatic vessels, increased blood-brain barrier (BBB) permeability and slight neuroprotection are increasing emphasized as potential targets in the treatment of DCI. 10.1016/j.phrs.2020.105234
    Deconstructing Mechanisms of Diet-Microbiome-Immune Interactions. Alexander Margaret,Turnbaugh Peter J Immunity Emerging evidence suggests that the effect of dietary intake on human health and disease is linked to both the immune system and the microbiota. Yet, we lack an integrated mechanistic model for how these three complex systems relate, limiting our ability to understand and treat chronic and infectious disease. Here, we review recent findings at the interface of microbiology, immunology, and nutrition, with an emphasis on experimentally tractable models and hypothesis-driven mechanistic work. We outline emerging mechanistic concepts and generalizable approaches to bridge the gap between microbial ecology and molecular mechanism. These set the stage for a new era of precision human nutrition informed by a deep and comprehensive knowledge of the diverse cell types in and on the human body. 10.1016/j.immuni.2020.07.015
    Gastrointestinal biofilms in health and disease. Nature reviews. Gastroenterology & hepatology Microorganisms colonize various ecological niches in the human habitat, as they do in nature. Predominant forms of multicellular communities called biofilms colonize human tissue surfaces. The gastrointestinal tract is home to a profusion of microorganisms with intertwined, but not identical, lifestyles: as isolated planktonic cells, as biofilms and in biofilm-dispersed form. It is therefore of major importance in understanding homeostatic and altered host-microorganism interactions to consider not only the planktonic lifestyle, but also biofilms and biofilm-dispersed forms. In this Review, we discuss the natural organization of microorganisms at gastrointestinal surfaces, stratification of microbiota taxonomy, biogeographical localization and trans-kingdom interactions occurring within the biofilm habitat. We also discuss existing models used to study biofilms. We assess the contribution of the host-mucosa biofilm relationship to gut homeostasis and to diseases. In addition, we describe how host factors can shape the organization, structure and composition of mucosal biofilms, and how biofilms themselves are implicated in a variety of homeostatic and pathological processes in the gut. Future studies characterizing biofilm nature, physical properties, composition and intrinsic communication could shed new light on gut physiology and lead to potential novel therapeutic options for gastrointestinal diseases. 10.1038/s41575-020-00397-y
    The Gut Microbiome Influences Host Endocrine Functions. Rastelli Marialetizia,Cani Patrice D,Knauf Claude Endocrine reviews The gut microbiome is considered an organ contributing to the regulation of host metabolism. Since the relationship between the gut microbiome and specific diseases was elucidated, numerous studies have deciphered molecular mechanisms explaining how gut bacteria interact with host cells and eventually shape metabolism. Both metagenomic and metabolomic analyses have contributed to the discovery of bacterial-derived metabolites acting on host cells. In this review, we examine the molecular mechanisms by which bacterial metabolites act as paracrine or endocrine factors, thereby regulating host metabolism. We highlight the impact of specific short-chain fatty acids on the secretion of gut peptides (i.e., glucagon-like peptide-1, peptide YY) and other metabolites produced from different amino acids and regulating inflammation, glucose metabolism, or energy homeostasis. We also discuss the role of gut microbes on the regulation of bioactive lipids that belong to the endocannabinoid system and specific neurotransmitters (e.g., γ-aminobutyric acid, serotonin, nitric oxide). Finally, we review the role of specific bacterial components (i.e., ClpB, Amuc_1100) also acting as endocrine factors and eventually controlling host metabolism. In conclusion, this review summarizes the recent state of the art, aiming at providing evidence that the gut microbiome influences host endocrine functions via several bacteria-derived metabolites. 10.1210/er.2018-00280
    Gut microbiome stability and resilience: elucidating the response to perturbations in order to modulate gut health. Fassarella Marina,Blaak Ellen E,Penders John,Nauta Arjen,Smidt Hauke,Zoetendal Erwin G Gut The human gut microbiome is a complex ecosystem, densely colonised by thousands of microbial species. It varies among individuals and depends on host genotype and environmental factors, such as diet and antibiotics. In this review, we focus on stability and resilience as essential ecological characteristics of the gut microbiome and its relevance for human health. Microbial diversity, metabolic flexibility, functional redundancy, microbe-microbe and host-microbe interactions seem to be critical for maintaining resilience. The equilibrium of the gut ecosystem can be disrupted by perturbations, such as antibiotic therapy, causing significant decreases in functional richness and microbial diversity as well as impacting metabolic health. As a consequence, unbalanced states or even unhealthy stable states can develop, potentially leading to or supporting diseases. Accordingly, strategies have been developed to manipulate the gut microbiome in order to prevent or revert unhealthy states caused by perturbations, including faecal microbiota transplantation, supplementation with probiotics or non-digestible carbohydrates, and more extensive dietary modifications. Nevertheless, an increasing number of studies has evidenced interindividual variability in extent and direction of response to diet and perturbations, which has been attributed to the unique characteristics of each individual's microbiome. From a clinical, translational perspective, the ability to improve resilience of the gut microbial ecosystem prior to perturbations, or to restore its equilibrium afterwards, would offer significant benefits. To be effective, this therapeutic approach will likely need a personalised or subgroup-based understanding of individual genetics, diet, gut microbiome and other environmental factors that might be involved. 10.1136/gutjnl-2020-321747
    Brain-gut-microbiome interactions in obesity and food addiction. Gupta Arpana,Osadchiy Vadim,Mayer Emeran A Nature reviews. Gastroenterology & hepatology Normal eating behaviour is coordinated by the tightly regulated balance between intestinal and extra-intestinal homeostatic and hedonic mechanisms. By contrast, food addiction is a complex, maladaptive eating behaviour that reflects alterations in brain-gut-microbiome (BGM) interactions and a shift of this balance towards hedonic mechanisms. Each component of the BGM axis has been implicated in the development of food addiction, with both brain to gut and gut to brain signalling playing a role. Early-life influences can prime the infant gut microbiome and brain for food addiction, which might be further reinforced by increased antibiotic usage and dietary patterns throughout adulthood. The ubiquitous availability and marketing of inexpensive, highly palatable and calorie-dense food can further shift this balance towards hedonic eating through both central (disruptions in dopaminergic signalling) and intestinal (vagal afferent function, metabolic endotoxaemia, systemic immune activation, changes to gut microbiome and metabolome) mechanisms. In this Review, we propose a systems biology model of BGM interactions, which incorporates published reports on food addiction, and provides novel insights into treatment targets aimed at each level of the BGM axis. 10.1038/s41575-020-0341-5
    Interaction between drugs and the gut microbiome. Weersma Rinse K,Zhernakova Alexandra,Fu Jingyuan Gut The human gut microbiome is a complex ecosystem that can mediate the interaction of the human host with their environment. The interaction between gut microbes and commonly used non-antibiotic drugs is complex and bidirectional: gut microbiome composition can be influenced by drugs, but, vice versa, the gut microbiome can also influence an individual's response to a drug by enzymatically transforming the drug's structure and altering its bioavailability, bioactivity or toxicity (pharmacomicrobiomics). The gut microbiome can also indirectly impact an individual's response to immunotherapy in cancer treatment. In this review we discuss the bidirectional interactions between microbes and drugs, describe the changes in gut microbiota induced by commonly used non-antibiotic drugs, and their potential clinical consequences and summarise how the microbiome impacts drug effectiveness and its role in immunotherapy. Understanding how the microbiome metabolises drugs and reduces treatment efficacy will unlock the possibility of modulating the gut microbiome to improve treatment. 10.1136/gutjnl-2019-320204
    The Microbiome as a Modifier of Neurodegenerative Disease Risk. Fang P,Kazmi S A,Jameson K G,Hsiao E Y Cell host & microbe The gut microbiome is increasingly implicated in modifying susceptibility to and progression of neurodegenerative diseases (NDs). In this review, we discuss roles for the microbiome in aging and in NDs. In particular, we summarize findings from human studies on microbiome alterations in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We assess animal studies of genetic and environmental models for NDs that investigate how manipulations of the microbiome causally impact the development of behavioral and neuropathological endophenotypes of disease. We additionally evaluate the likely immunological, neuronal, and metabolic mechanisms for how the gut microbiota may modulate risk for NDs. Finally, we speculate on cross-cutting features for microbial influences across multiple NDs and consider the potential for microbiome-targeted interventions for NDs. 10.1016/j.chom.2020.06.008
    Metabolism and Metabolic Disorders and the Microbiome: The Intestinal Microbiota Associated With Obesity, Lipid Metabolism, and Metabolic Health-Pathophysiology and Therapeutic Strategies. Aron-Wisnewsky Judith,Warmbrunn Moritz V,Nieuwdorp Max,Clément Karine Gastroenterology Changes in the intestinal microbiome have been associated with obesity and type 2 diabetes, in epidemiological studies and studies of the effects of fecal transfer in germ-free mice. We review the mechanisms by which alterations in the intestinal microbiome contribute to development of metabolic diseases, and recent advances, such as the effects of the microbiome on lipid metabolism. Strategies have been developed to modify the intestinal microbiome and reverse metabolic alterations, which might be used as therapies. We discuss approaches that have shown effects in mouse models of obesity and metabolic disorders, and how these might be translated to humans to improve metabolic health. 10.1053/j.gastro.2020.10.057
    Gut-Brain Cross-Talk in Metabolic Control. Clemmensen Christoffer,Müller Timo D,Woods Stephen C,Berthoud Hans-Rudolf,Seeley Randy J,Tschöp Matthias H Cell Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics. 10.1016/j.cell.2017.01.025
    The role of short-chain fatty acids in microbiota-gut-brain communication. Dalile Boushra,Van Oudenhove Lukas,Vervliet Bram,Verbeke Kristin Nature reviews. Gastroenterology & hepatology Short-chain fatty acids (SCFAs), the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract, are speculated to have a key role in microbiota-gut-brain crosstalk. However, the pathways through which SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, research directly exploring the role of SCFAs as potential mediators of the effects of microbiota-targeted interventions on affective and cognitive functioning is sparse, especially in humans. This Review summarizes existing knowledge on the potential of SCFAs to directly or indirectly mediate microbiota-gut-brain interactions. The effects of SCFAs on cellular systems and their interaction with gut-brain signalling pathways including immune, endocrine, neural and humoral routes are described. The effects of microbiota-targeted interventions such as prebiotics, probiotics and diet on psychological functioning and the putative mediating role of SCFA signalling will also be discussed, as well as the relationship between SCFAs and psychobiological processes. Finally, future directions to facilitate direct investigation of the effect of SCFAs on psychological functioning are outlined. 10.1038/s41575-019-0157-3
    Neuropod Cells: The Emerging Biology of Gut-Brain Sensory Transduction. Annual review of neuroscience Guided by sight, scent, texture, and taste, animals ingest food. Once ingested, it is up to the gut to make sense of the food's nutritional value. Classic sensory systems rely on neuroepithelial circuits to convert stimuli into signals that guide behavior. However, sensation of the gut milieu was thought to be mediated only by the passive release of hormones until the discovery of synapses in enteroendocrine cells. These are gut sensory epithelial cells, and those that form synapses are referred to as neuropod cells. Neuropod cells provide the foundation for the gut to transduce sensory signals from the intestinal milieu to the brain through fast neurotransmission onto neurons, including those of the vagus nerve. These findings have sparked a new field of exploration in sensory neurobiology-that of gut-brain sensory transduction. 10.1146/annurev-neuro-091619-022657
    Gut-brain axis in 2016: Brain-gut-microbiota axis - mood, metabolism and behaviour. Dinan Timothy G,Cryan John F Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2016.200
    Neurogastroenterology: Improving glucose tolerance via the gut-brain axis. Weber Christine Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2015.204
    The entero-insular axis in type 2 diabetes--incretins as therapeutic agents. Creutzfeldt W Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association The search for intestinal factors regulating the endocrine secretion of the pancreas started soon after the discovery of secretin, i.e. nearly 100 years ago. Insulinotropic factors of the gut released by nutrients and stimulating insulin secretion in physiological concentrations in the presence of elevated blood glucose levels have been named incretins. Of the known gut hormones only gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1 [7-36] amide) fulfill this definition.--The incretin effect (i.e. the ratio between the integrated insulin response to an oral glucose load and an isoglycaemic intravenous glucose infusion) is markedly diminished in patients with type 2 diabetes mellitus, while the plasma levels of GIP and GLP-1 and their responses to nutrients are in the normal range. Therefore, a reduced responsiveness of the islet B-cells to incretins has been postulated. This insensitivity of the diabetic B-cells towards incretins can be overcome by supraphysiological (pharmacological) concentrations of GLP-1 [7-36], however not of GIP. Accordingly, fasting and postprandial glucose levels can be normalized in patients with type 2 diabetes by infusions of GLP-1 [7-36]. Further studies revealed that this is partially due to the fact that GLP-1 [7-36]--in addition to its insulinotropic effect--also inhibits glucagon secretion and delays gastric emptying. These three antidiabetic effects qualify GLP-1 [7-36] as an interesting therapeutic tool, mainly for type 2 diabetes. However, because of its short plasma half life time natural GLP-1 [7-36] is not suitable for subcutaneous application. At present methods are being developed to improve the pharmacokinetics of GLP-1 by inhibition of the cleaving enzyme dipeptidyl peptidase IV (DPP-IV) or by synthesis of DPP-IV resistant GLP-1 analogues. Also naturally occurring GLP-1 analogues (for instance exendin-4) with a much longer half life time than GLP-1 [7-36] are being tested.--Thus, after 100 years of speculations and experimentations, incretins and their analogues are emerging as new antidiabetic drugs. 10.1055/s-2001-18589
    Therapeutic mechanisms of traditional Chinese medicine to improve metabolic diseases via the gut microbiota. Zhang Hai-Yu,Tian Jia-Xing,Lian Feng-Mei,Li Min,Liu Wen-Ke,Zhen Zhong,Liao Jiang-Quan,Tong Xiao-Lin Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Metabolic diseases such as obesity, type 2 diabetes mellitus, and hyperlipidemia are associated with the dysfunction of gut microbiota. Traditional Chinese medicines (TCMs) have shown considerable effects in the treatment of metabolic disorders by regulating the gut microbiota. However, the underlying mechanisms are unclear. Studies have shown that TCMs significantly affect glucose and lipid metabolism by modulating the gut microbiota, particularly mucin-degrading bacteria, bacteria with anti-inflammatory properties, lipopolysaccharide- and short-chain fatty acid (SCFA)-producing bacteria, and bacteria with bile-salt hydrolase activity. In this review, we explored potential mechanisms by which TCM improved metabolic disorders via regulating gut microbiota composition and functional structure. In particular, we focused on the protection of the intestinal barrier function, modulation of metabolic endotoxemia and inflammatory responses, regulation of the effects of SCFAs, modulation of the gut-brain axis, and regulation of bile acid metabolism and tryptophan metabolism as therapeutic mechanisms of TCMs in metabolic diseases. 10.1016/j.biopha.2020.110857
    The gut-brain axis: a major glucoregulatory player. Burcelin R Diabetes & metabolism Glucose homeostasis corresponds to the overall physiological, cellular, and molecular mechanisms which tightly maintain the glycaemia between ∼4.5 and ∼6 mM. The resulting blood glucose concentration is the consequence of a balance between the mechanisms that ensure the entry and the output of glucose in the blood. A dynamic balance needs hence to be perfectly achieved in order to maintain a physiological glycaemic concentration. Specialized cells from the intestine continuously detect changes in glucose concentration and send signals to peripheral tissues and the brain through the vagus nerve. The molecular mechanisms involved in glucose detection have not been perfectly defined but could resemble those from the insulin-secreting beta cells. The brain then integrates the enteric and circulating endocrine signals to generate a new signal towards peripheral tissues such as the pancreas, liver, muscles, and blood vessels. This metabolic reflex is called anticipatory since it allows the peripheral tissues to prepare for the adequate handling of nutrients. Diabetes is associated with an impaired anticipatory reflex, which hampers the proper detection of nutrients and leads to hyperglycaemic episodes. Recently, GLP-1-based therapies have demonstrated the improvement of glucose detection and their efficacy on glycaemic control. Although not yet fully demonstrated, GLP-1-based therapies regulate glucose sensors, which leads to the glycaemic improvement. Certainly other molecular targets could be identified to further generate new therapeutic strategies. 10.1016/S1262-3636(10)70468-7
    Gut Mechanisms Linking Intestinal Sweet Sensing to Glycemic Control. Kreuch Denise,Keating Damien J,Wu Tongzhi,Horowitz Michael,Rayner Christopher K,Young Richard L Frontiers in endocrinology Sensing nutrients within the gastrointestinal tract engages the enteroendocrine cell system to signal within the mucosa, to intrinsic and extrinsic nerve pathways, and the circulation. This signaling provides powerful feedback from the intestine to slow the rate of gastric emptying, limit postprandial glycemic excursions, and induce satiation. This review focuses on the intestinal sensing of sweet stimuli (including low-calorie sweeteners), which engage similar G-protein-coupled receptors (GPCRs) to the sweet taste receptors (STRs) of the tongue. It explores the enteroendocrine cell signals deployed upon STR activation that act within and outside the gastrointestinal tract, with a focus on the role of this distinctive pathway in regulating glucose transport function via absorptive enterocytes, and the associated impact on postprandial glycemic responses in animals and humans. The emerging role of diet, including low-calorie sweeteners, in modulating the composition of the gut microbiome and how this may impact glycemic responses of the host, is also discussed, as is recent evidence of a causal role of diet-induced dysbiosis in influencing the gut-brain axis to alter gastric emptying and insulin release. Full knowledge of intestinal STR signaling in humans, and its capacity to engage host and/or microbiome mechanisms that modify glycemic control, holds the potential for improved prevention and management of type 2 diabetes. 10.3389/fendo.2018.00741
    Incretins or anti-incretins? A new model for the "entero-pancreatic axis". Kamvissi V,Salerno A,Bornstein S R,Mingrone G,Rubino F Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme The role of incretins in glucose homeostasis is well known. Yet, in recent years, the sustained weight loss and rapid glycemic control following bariatric surgery has challenged our understanding of the intestinal-pancreatic interaction. This in turn led to the introduction of metabolic surgery, an innovative medical discipline in which a surgical manipulation of the gastrointestinal tract (e. g., through a Roux-en-Y gastric bypass, RYGB, or Bilio-Pancreatic-Diversion, BPD) yields a sustained remission of diabetes mellitus. The pathophysiological background of this metabolic effect is, amongst other things, based on the anti-incretin theory. This theory postulates that in addition to the well-known incretin effect, nutrient passage through the GI-tract could also activate negative feedback mechanisms (anti-incretins) to balance the effects of incretins and other postprandial glucose-lowering mechanisms (i. e., suppression of ghrelin, glucagon, and hepatic glucose production via activation of nutrient sensing). This in turn prevents postprandial hyperinsulinemic hypoglycemia. The bypass of the duodenum, the entire jejunum and the first portion of the ileum by BPD induce normalization of peripheral insulin sensitivity, while the bypass of a shorter intestinal tract by RYGB mainly improves the hepatic insulin sensitivity. In addition, RYGB greatly increases insulin secretion. Therefore, metabolic surgery highlights the important role of the small intestine in glucose homeostasis, while until few years ago, it was only the pancreas and the liver that were thought to represent the regulatory organs for glucose disposal. 10.1055/s-0034-1394374
    Gut-Pancreatic Axis AMPlified in Islets of Langerhans. Ryu Stacy H,Stappenbeck Thaddeus S Immunity Microbially derived metabolites in the intestine regulate host immunity and impact disease pathophysiology in various organs. Sun et al. (2015) suggest a direct effect of microbial metabolites on pancreatic endocrine cells in regulating type 1 diabetes pathophysiology. 10.1016/j.immuni.2015.08.003
    The Gut-Brain Axis, Including the Microbiome, Leaky Gut and Bacterial Translocation: Mechanisms and Pathophysiological Role in Alzheimer's Disease. Köhler Cristiano A,Maes Michael,Slyepchenko Anastasiya,Berk Michael,Solmi Marco,Lanctôt Krista L,Carvalho André F Current pharmaceutical design Alzheimer's disease (AD), the most common form of dementia, is a progressive disorder manifested by gradual memory loss and subsequent impairment in mental and behavioral functions. Though the primary risk factor for AD is advancing age, other factors such as diabetes mellitus, hyperlipidemia, obesity, vascular factors and depression play a role in its pathogenesis. The human gastrointestinal tract has a diverse commensal microbial population, which has bidirectional interactions with the human host that are symbiotic in health, and in addition to nutrition, digestion, plays major roles in inflammation and immunity. The most prevalent hypothesis for AD is the amyloid hypothesis, which states that changes in the proteolytic processing of the amyloid precursor protein leads to the accumulation of the amyloid beta (Aβ) peptide. Aβ then triggers an immune response that drives neuroinflammation and neurodegeneration in AD. The specific role of gut microbiota in modulating neuro-immune functions well beyond the gastrointestinal tract may constitute an important influence on the process of neurodegeneration. We first review the main mechanisms involved in AD physiopathology. Then, we review the alterations in gut microbiota and gut-brain axis that might be relevant to mediate or otherwise affect AD pathogenesis, especially those associated with aging. We finally summarize possible mechanisms that could mediate the involvement of gut-brain axis in AD physiopathology, and propose an integrative model.
    Healthy axis: Towards an integrated view of the gut-brain health. Boem Federico,Amedei Amedeo World journal of gastroenterology Despite the lack of precise mechanisms of action, a growing number of studies suggests that gut microbiota is involved in a great number of physiological functions of the human organism. In fact, the composition and the relations of intestinal microbial populations play a role, either directly or indirectly, to both the onset and development of various pathologies. In particular, the gastrointestinal tract and nervous system are closely connected by the so-called gut-brain axis, a complex bidirectional system in which the central and enteric nervous system interact with each other, also engaging endocrine, immune and neuronal circuits. This allows us to put forward new working hypotheses on the origin of some multifactorial diseases: from eating to neuropsychiatric disorders (such as autism spectrum disorders and depression) up to diabetes and tumors (such as colorectal cancer). This scenario reinforces the idea that the microbiota and its composition represent a factor, which is no longer negligible, not only in preserving what we call "health" but also in defining and thus determining it. Therefore, we propose to consider the gut-brain axis as the focus of new scientific and clinical investigation as long as the locus of possible systemic therapeutic interventions. 10.3748/wjg.v25.i29.3838
    Iron influences on the Gut-Brain axis and development of type 2 diabetes. Fernández Real José Manuel,Moreno-Navarrete José Maria,Manco Melania Critical reviews in food science and nutrition BACKGROUND:Microbiota/neuroendocrine interactions with health and disease are increasingly recognized. Main Body: Aging is associated with progressive iron storage and development of type 2 diabetes, which impacts on brain microstructure and function, mainly in obese subjects. Iron status is also mutually influencing the composition of the gut microbiota, which in turn may affect cognition through the gut-brain axis. Short Conclusion: In this article we update the possible role of iron in all these interactions. 10.1080/10408398.2017.1376616
    The gut microbiota to the brain axis in the metabolic control. Grasset Estelle,Burcelin Remy Reviews in endocrine & metabolic disorders The regulation of glycemia is under a tight neuronal detection of glucose levels performed by the gut-brain axis and an efficient efferent neuronal message sent to the peripheral organs, as the pancreas to induce insulin and inhibit glucagon secretions. The neuronal detection of glucose levels is performed by the autonomic nervous system including the enteric nervous system and the vagus nerve innervating the gastro-intestinal tractus, from the mouth to the anus. A dysregulation of this detection leads to the one of the most important current health issue around the world i.e. diabetes mellitus. Furthemore, the consequences of diabetes mellitus on neuronal homeostasis and activities participate to the aggravation of the disease establishing a viscious circle. Prokaryotic cells as bacteria, reside in our gut. The strong relationship between prokaryotic cells and our eukaryotic cells has been established long ago, and prokaryotic and eukaryotic cells in our body have evolved synbiotically. For the last decades, studies demonstrated the critical role of the gut microbiota on the metabolic control and how its shift can induce diseases such as diabetes. Despite an important increase of knowledge, few is known about 1) how the gut microbiota influences the neuronal detection of glucose and 2) how the diabetes mellitus-induced gut microbiota shift observed participates to the alterations of autonomic nervous system and the gut-brain axis activity. 10.1007/s11154-019-09511-1
    Central Nervous System Regulation of Intestinal Lipoprotein Metabolism by Glucagon-Like Peptide-1 via a Brain-Gut Axis. Farr Sarah,Baker Christopher,Naples Mark,Taher Jennifer,Iqbal Jahangir,Hussain Mahmood,Adeli Khosrow Arteriosclerosis, thrombosis, and vascular biology OBJECTIVE:Intestinal overproduction of atherogenic chylomicron particles postprandially is an important component of diabetic dyslipidemia in insulin-resistant states. In addition to enhancing insulin secretion, peripheral glucagon-like peptide-1 (GLP-1) receptor stimulation has the added benefit of reducing this chylomicron overproduction in patients with type 2 diabetes mellitus. Given the presence of central GLP-1 receptors and GLP-1-producing neurons, we assessed whether central GLP-1 exerts an integral layer of neuronal control during the production of these potentially atherogenic particles. APPROACH AND RESULTS:Postprandial production of triglyceride-rich lipoproteins was assessed in Syrian hamsters administered a single intracerebroventricular injection of the GLP-1 receptor agonist exendin-4. Intracerebroventricular exendin-4 reduced triglyceride-rich lipoprotein-triglyceride and -apolipoprotein B48 accumulation relative to vehicle-treated controls. This was mirrored by intracerebroventricular MK-0626, an inhibitor of endogenous GLP-1 degradation, and prevented by central exendin9-39, a GLP-1 receptor antagonist. The effects of intracerebroventricular exendin-4 were also lost during peripheral adrenergic receptor and central melanocortin-4 receptor inhibition, achieved using intravenous propranolol and phentolamine and intracerebroventricular HS014, respectively. However, central exendin9-39 did not preclude the effects of peripheral exendin-4 treatment on chylomicron output. CONCLUSIONS:Central GLP-1 is a novel regulator of chylomicron production via melanocortin-4 receptors. Our findings point to the relative importance of central accessibility of GLP-1-based therapies and compel further studies examining the status of this brain-gut axis in the development of diabetic dyslipidemia and chylomicron overproduction. 10.1161/ATVBAHA.114.304873
    Microbial Ecosystem in Diabetes Mellitus: Consideration of the Gastrointestinal System. Yehualashet Awgichew Shewasinad,Yikna Berhan Begashaw Diabetes, metabolic syndrome and obesity : targets and therapy Intestinal microbiota is established to be a crucial element in the control of human health, and keeping the symbiotic relationship between the human body and intestinal microbes will have paramount importance. A number of investigations illustrated that many chronic diseases are associated with intestinal micro-ecological disorders implying intestinal floras as an important component among the environmental factors, and perturbations in their composition are correlated with metabolic disorders, including obesity and diabetes mellitus (DM). Increased evidence suggests that alterations in the gut microbial ecosystem have been involved in part in the pathogenesis of both type 1 and type 2 DM. Short chain fatty acids (SCFAs), derived from microbiota, have been studied for their potential action in modulating CNS, gut barrier axis, and the immune system as a promising mechanism for the observed protective effects on diabetes pathogenesis. Besides, the role of bile acid (BA) stimulated receptors to have a significant role in liver metabolism, and pathophysiology of liver-based metabolic diseases has also been investigated. In the current review, we will try to summarize the correlation between intestinal microbiota and diabetes considering the existing current evidence revealing the role of gut microbiota in onset and disease progression. 10.2147/DMSO.S304497
    Nutrient-sensing mechanisms and pathways. Efeyan Alejo,Comb William C,Sabatini David M Nature The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids, lipids and surrogate metabolites are integrated and coordinated at the organismal level through hormonal signals. During food abundance, nutrient-sensing pathways engage anabolism and storage, whereas scarcity triggers homeostatic mechanisms, such as the mobilization of internal stores through autophagy. Nutrient-sensing pathways are commonly deregulated in human metabolic diseases. 10.1038/nature14190
    The New Biology and Pharmacology of Glucagon. Müller T D,Finan B,Clemmensen C,DiMarchi R D,Tschöp M H Physiological reviews In the last two decades we have witnessed sizable progress in defining the role of gastrointestinal signals in the control of glucose and energy homeostasis. Specifically, the molecular basis of the huge metabolic benefits in bariatric surgery is emerging while novel incretin-based medicines based on endogenous hormones such as glucagon-like peptide 1 and pancreas-derived amylin are improving diabetes management. These and related developments have fostered the discovery of novel insights into endocrine control of systemic metabolism, and in particular a deeper understanding of the importance of communication across vital organs, and specifically the gut-brain-pancreas-liver network. Paradoxically, the pancreatic peptide glucagon has reemerged in this period among a plethora of newly identified metabolic macromolecules, and new data complement and challenge its historical position as a gut hormone involved in metabolic control. The synthesis of glucagon analogs that are biophysically stable and soluble in aqueous solutions has promoted biological study that has enriched our understanding of glucagon biology and ironically recruited glucagon agonism as a central element to lower body weight in the treatment of metabolic disease. This review summarizes the extensive historical record and the more recent provocative direction that integrates the prominent role of glucagon in glucose elevation with its under-acknowledged effects on lipids, body weight, and vascular health that have implications for the pathophysiology of metabolic diseases, and the emergence of precision medicines to treat metabolic diseases. 10.1152/physrev.00025.2016
    Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Ahmad Tiara R,Haeusler Rebecca A Nature reviews. Endocrinology Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research. 10.1038/s41574-019-0266-7
    Gut-Brain Glucose Signaling in Energy Homeostasis. Soty Maud,Gautier-Stein Amandine,Rajas Fabienne,Mithieux Gilles Cell metabolism Intestinal gluconeogenesis is a recently identified function influencing energy homeostasis. Intestinal gluconeogenesis induced by specific nutrients releases glucose, which is sensed by the nervous system surrounding the portal vein. This initiates a signal positively influencing parameters involved in glucose control and energy management controlled by the brain. This knowledge has extended our vision of the gut-brain axis, classically ascribed to gastrointestinal hormones. Our work raises several questions relating to the conditions under which intestinal gluconeogenesis proceeds and may provide its metabolic benefits. It also leads to questions on the advantage conferred by its conservation through a process of natural selection. 10.1016/j.cmet.2017.04.032
    Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes. Fernández-Real José Manuel,McClain Donald,Manco Melania Diabetes care OBJECTIVE:The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. RESEARCH DESIGN AND METHODS:The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). RESULTS:The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate β-cells and insulin secretion, although this has been scarcely studied. CONCLUSIONS:Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted. 10.2337/dc14-3082
    Intestinal Adaptations after Bariatric Surgery: Consequences on Glucose Homeostasis. Cavin Jean-Baptiste,Bado André,Le Gall Maude Trends in endocrinology and metabolism: TEM The gastrointestinal (GI) tract can play a direct role in glucose homeostasis by modulating the digestion and absorption of carbohydrates and by producing the incretin hormones. In recent years, numerous studies have focused on intestinal adaptation following bariatric surgeries. Changes in the number of incretin (glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide) producing cells have been reported, which could result in the modified hormonal response seen after surgery. In addition, the rate of absorption and the intestinal regions exposed to sugars may affect the time course of appearance of glucose in the blood. This review gives new insights into the direct role of the GI tract in the metabolic outcomes of bariatric surgery, in the context of glucose homeostasis. 10.1016/j.tem.2017.01.002
    Multifaceted interplay among mediators and regulators of intestinal glucose absorption: potential impacts on diabetes research and treatment. Chan Leo Ka Yu,Leung Po Sing American journal of physiology. Endocrinology and metabolism Glucose is the prominent molecule that characterizes diabetes and, like the vast majority of nutrients in our diet, it is absorbed and enters the bloodstream directly through the small intestine; hence, small intestine physiology impacts blood glucose levels directly. Accordingly, intestinal regulatory modulators represent a promising avenue through which diabetic blood glucose levels might be moderated clinically. Despite the critical role of small intestine in blood glucose homeostasis, most physiological diabetes research has focused on other organs, such as the pancreas, kidney, and liver. We contend that an improved understanding of intestinal regulatory mediators may be fundamental for the development of first-line preventive and therapeutic interventions in patients with diabetes and diabetes-related diseases. This review summarizes the major important intestinal regulatory mediators, discusses how they influence intestinal glucose absorption, and suggests possible candidates for future diabetes research and the development of antidiabetic therapeutic agents. 10.1152/ajpendo.00373.2015
    Brain glucose sensing, glucokinase and neural control of metabolism and islet function. Ogunnowo-Bada E O,Heeley N,Brochard L,Evans M L Diabetes, obesity & metabolism It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel--emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases. 10.1111/dom.12334
    De novo formation of insulin-producing "neo-β cell islets" from intestinal crypts. Chen Yi-Ju,Finkbeiner Stacy R,Weinblatt Daniel,Emmett Matthew J,Tameire Feven,Yousefi Maryam,Yang Chenghua,Maehr Rene,Zhou Qiao,Shemer Ruth,Dor Yuval,Li Changhong,Spence Jason R,Stanger Ben Z Cell reports The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an in vivo screen by expressing three β cell "reprogramming factors" in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into "neoislets" below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia in diabetic mice. Moreover, PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into β-like cells. Our results thus demonstrate that the intestine is an accessible and abundant source of functional insulin-producing cells. 10.1016/j.celrep.2014.02.013
    Alpha-, Delta- and PP-cells: Are They the Architectural Cornerstones of Islet Structure and Co-ordination? Brereton Melissa F,Vergari Elisa,Zhang Quan,Clark Anne The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society Islet non-β-cells, the α- δ- and pancreatic polypeptide cells (PP-cells), are important components of islet architecture and intercellular communication. In α-cells, glucagon is found in electron-dense granules; granule exocytosis is calcium-dependent via P/Q-type Ca(2+)-channels, which may be clustered at designated cell membrane sites. Somatostatin-containing δ-cells are neuron-like, creating a network for intra-islet communication. Somatostatin 1-28 and 1-14 have a short bioactive half-life, suggesting inhibitory action via paracrine signaling. PP-cells are the most infrequent islet cell type. The embryologically separate ventral pancreas anlage contains PP-rich islets that are morphologically diffuse and α-cell deficient. Tissue samples taken from the head region are unlikely to be representative of the whole pancreas. PP has anorexic effects on gastro-intestinal function and alters insulin and glucagon secretion. Islet architecture is disrupted in rodent diabetic models, diabetic primates and human Type 1 and Type 2 diabetes, with an increased α-cell population and relocation of non-β-cells to central areas of the islet. In diabetes, the transdifferentiation of non-β-cells, with changes in hormone content, suggests plasticity of islet cells but cellular function may be compromised. Understanding how diabetes-related disordered islet structure influences intra-islet cellular communication could clarify how non-β-cells contribute to the control of islet function. 10.1369/0022155415583535
    Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells. Zhang Qin,Pan Ying,Zeng Benhua,Zheng Xiaojiao,Wang Haifang,Shen Xueying,Li Hui,Jiang Qian,Zhao Jiaxu,Meng Zhuo-Xian,Li Pingping,Chen Zhengjun,Wei Hong,Liu Zhihua Cell research Long-range communication between intestinal symbiotic bacteria and extra-intestinal organs can occur through circulating bacterial signal molecules, through neural circuits, or through cytokines or hormones from host cells. Here we report that Nod1 ligands derived from intestinal bacteria act as signal molecules and directly modulate insulin trafficking in pancreatic beta cells. The cytosolic peptidoglycan receptor Nod1 and its downstream adapter Rip2 are required for insulin trafficking in beta cells in a cell-autonomous manner. Mechanistically, upon recognizing cognate ligands, Nod1 and Rip2 localize to insulin vesicles, recruiting Rab1a to direct insulin trafficking through the cytoplasm. Importantly, intestinal lysozyme liberates Nod1 ligands into the circulation, thus enabling long-range communication between intestinal microbes and islets. The intestine-islet crosstalk bridged by Nod1 ligands modulates host glucose tolerance. Our study defines a new type of inter-organ communication based on circulating bacterial signal molecules, which has broad implications for understanding the mutualistic relationship between microbes and host. 10.1038/s41422-019-0190-3
    Ageing, metabolism and the intestine. Funk Maja C,Zhou Jun,Boutros Michael EMBO reports The intestinal epithelium serves as a dynamic barrier to the environment and integrates a variety of signals, including those from metabolites, commensal microbiota, immune responses and stressors upon ageing. The intestine is constantly challenged and requires a high renewal rate to replace damaged cells in order to maintain its barrier function. Essential for its renewal capacity are intestinal stem cells, which constantly give rise to progenitor cells that differentiate into the multiple cell types present in the epithelium. Here, we review the current state of research of how metabolism and ageing control intestinal stem cell function and epithelial homeostasis. We focus on recent insights gained from model organisms that indicate how changes in metabolic signalling during ageing are a major driver for the loss of stem cell plasticity and epithelial homeostasis, ultimately affecting the resilience of an organism and limiting its lifespan. We compare findings made in mouse and Drosophila and discuss differences and commonalities in the underlying signalling pathways and mechanisms in the context of ageing. 10.15252/embr.202050047
    Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium. Gribble Fiona M,Reimann Frank Annual review of physiology The enteroendocrine system orchestrates how the body responds to the ingestion of foods, employing a diversity of hormones to fine-tune a wide range of physiological responses both within and outside the gut. Recent interest in gut hormones has surged with the realization that they modulate glucose tolerance and food intake through a variety of mechanisms, and such hormones are therefore excellent therapeutic candidates for the treatment of diabetes and obesity. Characterizing the roles and functions of different enteroendocrine cells is an essential step in understanding the physiology, pathophysiology, and therapeutics of the gut-brain-pancreas axis. 10.1146/annurev-physiol-021115-105439
    Roles of the Gut in Glucose Homeostasis. Holst Jens Juul,Gribble Fiona,Horowitz Michael,Rayner Chris K Diabetes care The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. Gastric emptying is a highly regulated process, which normally ensures a limited and fairly constant delivery of nutrients and glucose to the proximal gut. The subsequent digestion and absorption of nutrients are associated with the release of a set of hormones that feeds back to regulate subsequent gastric emptying and regulates the release of insulin, resulting in downregulation of hepatic glucose production and deposition of glucose in insulin-sensitive tissues. These remarkable mechanisms normally keep postprandial glucose excursions low, regardless of the load of glucose ingested. When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. This article discusses the underlying mechanisms. 10.2337/dc16-0351