scholarly journals The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective

2020 ◽  
Vol 21 (9) ◽  
pp. 3240 ◽  
Author(s):  
Loranne Agius ◽  
Brian E. Ford ◽  
Shruti S. Chachra
Keyword(s):  
Molecular Mechanisms ◽  
Adenine Nucleotide ◽  
Clinical Use ◽  
Fructose Bisphosphatase ◽  
Ampk Activation ◽  
Allosteric Activation ◽  
Fructose 1,6 Bisphosphate ◽  
Gluconeogenic Substrate ◽  
Review Current

Metformin therapy lowers blood glucose in type 2 diabetes by targeting various pathways including hepatic gluconeogenesis. Despite widespread clinical use of metformin the molecular mechanisms by which it inhibits gluconeogenesis either acutely through allosteric and covalent mechanisms or chronically through changes in gene expression remain debated. Proposed mechanisms include: inhibition of Complex 1; activation of AMPK; and mechanisms independent of both Complex 1 inhibition and AMPK. The activation of AMPK by metformin could be consequent to Complex 1 inhibition and raised AMP through the canonical adenine nucleotide pathway or alternatively by activation of the lysosomal AMPK pool by other mechanisms involving the aldolase substrate fructose 1,6-bisphosphate or perturbations in the lysosomal membrane. Here we review current interpretations of the effects of metformin on hepatic intermediates of the gluconeogenic and glycolytic pathway and the candidate mechanistic links to regulation of gluconeogenesis. In conditions of either glucose excess or gluconeogenic substrate excess, metformin lowers hexose monophosphates by mechanisms that are independent of AMPK-activation and most likely mediated by allosteric activation of phosphofructokinase-1 and/or inhibition of fructose bisphosphatase-1. The metabolite changes caused by metformin may also have a prominent role in counteracting G6pc gene regulation in conditions of compromised intracellular homeostasis.

Translation Research for the Rehabilitation of Left Spatial Neglect and Associated Disorders of Attention in Stroke Patients

2008 ◽  
Vol 18 (2) ◽  
pp. 55-65 ◽  
Author(s):  
Nkiruka Arene ◽  
Argye E. Hillis
Keyword(s):  
Theoretical Basis ◽  
Attention Bias ◽  
Spatial Neglect ◽  
Clinical Use ◽  
Stroke Patients ◽  
Translation Research ◽  
Unilateral Neglect ◽  
Assessment And Treatment ◽  
Sound Theoretical Basis ◽  
Review Current

Abstract The syndrome of unilateral neglect, typified by a lateralized attention bias and neglect of contralateral space, is an important cause of morbidity and disability after a stroke. In this review, we discuss the challenges that face researchers attempting to elucidate the mechanisms and effectiveness of rehabilitation treatments. The neglect syndrome is a heterogeneous disorder, and it is not clear which of its symptoms cause ongoing disability. We review current methods of neglect assessment and propose logical approaches to selecting treatments, while acknowledging that further study is still needed before some of these approaches can be translated into routine clinical use. We conclude with systems-level suggestions for hypothesis development that would hopefully form a sound theoretical basis for future approaches to the assessment and treatment of neglect.

scholarly journals Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 629
Author(s):  
Jorge Gutiérrez-Cuevas ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Hugo Christian Monroy-Ramírez ◽  
Marina Galicia-Moreno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
White Adipocyte ◽  
Peroxisome Proliferator Activated Receptors ◽  
And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

scholarly journals Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

2021 ◽  
Vol 22 (2) ◽  
pp. 660
Author(s):  
María Aguilar-Ballester ◽  
Gema Hurtado-Genovés ◽  
Alida Taberner-Cortés ◽  
Andrea Herrero-Cervera ◽  
Sergio Martínez-Hervás ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Leukocyte Adhesion ◽  
Experimental Studies ◽  
Lipid Lowering ◽  
Foam Cell Formation ◽  
Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

scholarly journals The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

2021 ◽  
Vol 22 (2) ◽  
pp. 803
Author(s):  
Giuseppina Emanuela Grieco ◽  
Noemi Brusco ◽  
Giada Licata ◽  
Daniela Fignani ◽  
Caterina Formichi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Β Cell ◽  
Physiological Mechanisms ◽  
Effective Strategies ◽  
Chronic Hyperglycaemia ◽  
Shed Light

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.

scholarly journals Molecular mechanisms and the vital roles of resistin, TLR 4, and NF-κB in treating type 2 diabetic complications

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Venkataiah Gudise ◽  
Bimalendu Chowdhury
Keyword(s):  
Type 2 Diabetes ◽  
Effective Treatment ◽  
Diabetic Complications ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Vascular Complications ◽  
Diabetic Patients ◽  
Rapid Progression ◽  
Main Body

Abstract Background Type 2 diabetes in obese (≥ 25 and ≥ 30 kg/m2) patients is the foremost cause of cardiovascular complications like stroke, osteoarthritis, cancers (endometrial, breast, ovarian, liver, kidney, colon, and prostate), and vascular complications like diabetic neuropathy, diabetic and retinopathy, and diabetic nephropathy. It is recognized as a global burden disorder with high prevalence in middle-income nations which might lead to a double burden on health care professionals. Hence, this review emphasizes on understanding the complexity and vital signaling tracts involved in diabetic complications for effective treatment. Main body Type 2 diabetes in overweight patients induces the creation of specific ROS that further leads to changes in cellular proliferation, hypothalamus, and fringe. The resistin, TLR4, and NF-κB signalings are mainly involved in the progression of central and fringe changes such as insulin resistance and inflammation in diabetic patients. The overexpression of these signals might lead to the rapid progression of diabetic vascular complications induced by the release of proinflammatory cytokines, chemokines, interleukins, and cyclooxygenase-mediated chemicals. Until now, there has been no curative treatment for diabetes. Therefore, to effectively treat complications of type 2 diabetes, the researchers need to concentrate on the molecular mechanisms and important signaling tracts involved. Conclusion In this review, we suggested the molecular mechanism of STZ-HFD induced type 2 diabetes and the vital roles of resistin, TLR4, and NF-κB signalings in central, fringe changes, and development diabetic complications for its effective treatment. Graphical abstract

Inhibition of xanthine oxidase ameliorates functional and metabolic impairment in type 2 diabetic hearts under pressure overload

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Igaki ◽  
A Osanami ◽  
M Tanno ◽  
T Sato ◽  
T Ogawa ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Xanthine Oxidase ◽  
Adenine Nucleotide ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Diabetic Control ◽  
Funding Source ◽  
National Budget ◽  
Adenine Nucleotide Pool

Abstract Background We recently reported that upregulated AMP deaminase (AMPD), via reduction in the tissue adenine nucleotide pool, contributes to exacerbation of diastolic dysfunction under pressure overload in OLETF, a rat model of obese type 2 diabetes (T2DM). Upregulated AMPD also possibly promotes xanthine oxidase (XO)-mediated ROS production, since AMPD deaminases AMP to IMP, which is further converted to inosine, providing substrates of XO, hypoxanthine and xanthine. Here, we examined the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction by suppression of ROS-mediated mitochondrial dysfunction and/or vascular dysfunction in T2DM rats. Methods and results Metabolomic analyses revealed that levels of xanthine and uric acid in the LV myocardium were significantly higher by 37% and 51%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of phenylephrine-induced pressure overloading (200–230 mmHg). Myocardial XO activity in OLETF was 57.9% higher than that in LETO, which may be attributed to 31% higher level of inosine, a positive regulator of XO, in OLETF than in LETO. The activity of XO was significantly attenuated by administration of topiroxostat, an XO inhibitor at 0.5 mg/kg/day for 14 days. Pressure volume loop analyses showed that the pressure overloading resulted in significantly higher LVEDP in OLETF than in LETO (18.3±1.5 vs. 12.2±1.3 mmHg, p<0.05, n=7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6±0.4 vs. 4.7±0.7 mmHg). Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3±1.5 vs. 11.3±1.1 mmHg, p<0.05) but not in LETO. Under the condition of pressure overloading, Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3±0.3 vs. 1.6±0.3, p<0.05), and it was also improved by topiroxostat in OLETF (1.2±0.2, p<0.05). Myocardial ATP content was lower in OLETF than in LETO (2966±400 vs. 1818±171 nmol/g wet tissue, p<0.05), and treatment with topiroxostat significantly restored the ATP level (2629±307 nmol/g wet tissue). The LV myocardium of OLETF under pressure overload showed significantly higher level of malondialdehyde and 4-hydroxynonenal, an indicator of lipid peroxidation, than that of LETO. Measurement of oxygen consumption rate by Seahorse XFe96 Analyzer in mitochondria isolated from LV tissues revealed that state 3 respiration was significantly suppressed in OLETF by 43% compared to LETO, and it was restored by treatment with topiroxostat. Conclusion Both activity and substrates of XO are increased in T2DM hearts, in which upregulation of AMPD may play a role. Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling in diabetic hearts, most likely through protection of mitochondrial function from ROS-mediated injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-aid for Scientific Research (#26461132, #17K09584) from the Japanese Society for the Promotion of Science

scholarly journals Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1236
Author(s):  
Jesús Burillo ◽  
Patricia Marqués ◽  
Beatriz Jiménez ◽  
Carlos González-Blanco ◽  
Manuel Benito ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Progressive Disease

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

scholarly journals Diabetes and Thrombosis: A Central Role for Vascular Oxidative Stress

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 706
Author(s):  
Aishwarya R. Vaidya ◽  
Nina Wolska ◽  
Dina Vara ◽  
Reiner K. Mailer ◽  
Katrin Schröder ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Cell Damage ◽  
National Health System ◽  
Vascular Damage ◽  
Circulating Cells ◽  
Environmental Causes ◽  
Vascular Oxidative Stress

Diabetes mellitus is the fifth most common cause of death worldwide. Due to its chronic nature, diabetes is a debilitating disease for the patient and a relevant cost for the national health system. Type 2 diabetes mellitus is the most common form of diabetes mellitus (90% of cases) and is characteristically multifactorial, with both genetic and environmental causes. Diabetes patients display a significant increase in the risk of developing cardiovascular disease compared to the rest of the population. This is associated with increased blood clotting, which results in circulatory complications and vascular damage. Platelets are circulating cells within the vascular system that contribute to hemostasis. Their increased tendency to activate and form thrombi has been observed in diabetes mellitus patients (i.e., platelet hyperactivity). The oxidative damage of platelets and the function of pro-oxidant enzymes such as the NADPH oxidases appear central to diabetes-dependent platelet hyperactivity. In addition to platelet hyperactivity, endothelial cell damage and alterations of the coagulation response also participate in the vascular damage associated with diabetes. Here, we present an updated interpretation of the molecular mechanisms underlying vascular damage in diabetes, including current therapeutic options for its control.

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