Type 2 Diabetes Mellitus: A Comprehensive Review of Pathophysiology, Comorbidities, and Emerging Therapies

Comprehensive physiology, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 1, 2025

ABSTRACT Humans are perhaps evolutionarily engineered to get deeply addicted sugar, as it not only provides energy but also helps in storing fats, which survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel‐good factor, they trigger secretion of serotonin dopamine brain, associated with reward sensation, uplifting mood general. However, when consumed excess, contributes imbalance, weight gain, obesity, leading onset a complex metabolic disorder, generally referred diabetes. Type 2 diabetes mellitus (T2DM) is one most prevalent forms diabetes, nearly affecting all age groups. T2DM clinically diagnosed cardinal sign chronic hyperglycemia (excessive sugar blood). Chronic hyperglycemia, coupled dysfunctions pancreatic β‐cells, insulin resistance, immune inflammation, further exacerbate pathology T2DM. Uncontrolled T2DM, major public health concern, significantly toward progression several micro‐ macrovascular diseases, such diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, cardiovascular including cancer. The current review discusses epidemiology, causative factors, pathophysiology, comorbidities, existing emerging therapies related It future roadmap for alternative drug discovery management

Язык: Английский

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Tryptophan and its metabolites in normal physiology and cancer etiology

FEBS Journal, Год журнала: 2021, Номер 290(1), С. 7 - 27

Опубликована: Окт. 23, 2021

Within the growing field of amino acid metabolism, tryptophan (Trp) catabolism is an area increasing interest. Trp essential for protein synthesis, and its metabolism gives rise to biologically active catabolites including serotonin numerous metabolites in kynurenine (Kyn) pathway. In normal tissues, production directly regulated by tissue‐specific expression Trp‐metabolizing enzymes. Alterations these enzymes cancers can shift balance lead increased specific byproducts that function as oncometabolites. For example, enzyme indoleamine 2,3‐dioxygenase, which converts into Kyn, leads increase Kyn levels cancers. functions oncometabolite cancer cells promoting activity transcription factor aryl hydrocarbon receptor, regulates progrowth genes. Moreover, also inhibits T‐cell thus allows evade clearance immune system. Therefore, targeting pathway has become a therapeutic focus novel means abrogate tumor growth resistance. This review summarizes biological role regulation with emphasis on cell evasion outlines areas future research focus.

Язык: Английский

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An Overview of Cell-Based Assay Platforms for the Solute Carrier Family of Transporters

Frontiers in Pharmacology, Год журнала: 2021, Номер 12

Опубликована: Авг. 10, 2021

The solute carrier (SLC) superfamily represents the biggest family of transporters with important roles in health and disease. Despite being attractive druggable targets, majority SLCs remains understudied. One major hurdle research on is lack tools, such as cell-based assays to investigate their biological role for drug discovery. Another challenge disperse anecdotal information assay strategies that are suitable SLCs. This review provides a comprehensive overview state-of-the-art cellular technologies SLC discusses relevant characteristics enabling choice an optimal technology. Innovative Medicines Initiative consortium RESOLUTE intends accelerate by providing scientific community high-quality reagents, data sets, ultimately unlock

Язык: Английский

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Membrane lipids and transporter function

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2021, Номер 1867(5), С. 166079 - 166079

Опубликована: Янв. 19, 2021

Transport proteins are essential for cells in allowing the exchange of substances between and their environment across lipid bilayer forming a tight barrier. Membrane lipids modulate function transmembrane such as transporters two ways: Lipids tightly specifically bound to transport addition they from bulk proteins. This overview summarizes currently available information at ultrastructural level on impact altered membrane composition. Human diseases leading homeostasis will lead composition, which turn affect transporter

Язык: Английский

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Investigation of fiber utilization in the rumen of dairy cows based on metagenome-assembled genomes and single-cell RNA sequencing

Microbiome, Год журнала: 2022, Номер 10(1)

Опубликована: Янв. 20, 2022

Abstract Background Dairy cows utilize human-inedible, low-value plant biomass to produce milk, a low-cost product with rich nutrients and high proteins. This process largely relies on rumen microbes that ferment lignocellulose cellulose volatile fatty acids (VFAs). The VFAs are absorbed partly metabolized by the stratified squamous epithelium, which is mediated diverse cell types. Here, we applied metagenomic binning approach explore individual involved in fiber digestion performed single-cell RNA sequencing epithelial cells investigate subtypes contributing VFA absorption metabolism. Results 52 mid-lactating dairy our study (parity = 2.62 ± 0.91) had milk yield of 33.10 6.72 kg. We determined fermentation capacities 186 bacterial genomes using identified specific strong cellulose/xylan/pectin degradation capabilities were highly associated biosynthesis VFAs. Furthermore, constructed map consisting 18 based transcriptome 20,728 cells. A systematic survey expression profiles genes encoding candidates for transporters revealed IGFBP5 + cg-like spinous uniquely expressed SLC16A1 SLC4A9 , suggesting this type may play important roles absorption. Potential cross-talk between microbiome host their modulating key also identified. Conclusions discovered microbial digestion, uptake metabolism, respectively, rumen. integration these data enables us link single trophic system.

Язык: Английский

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Ageing induces tissue‐specific transcriptomic changes in Caenorhabditis elegans

The EMBO Journal, Год журнала: 2022, Номер 41(8)

Опубликована: Март 7, 2022

Resource7 March 2022Open Access Transparent process Ageing induces tissue-specific transcriptomic changes in Caenorhabditis elegans Xueqing Wang orcid.org/0000-0003-3136-2568 State Key Laboratory of Cell Biology, Shanghai Institute Biochemistry and Center for Excellence Molecular Science, Chinese Academy Sciences, Shanghai, China University Beijing, Contribution: Resources, Data curation, Formal analysis, Validation, ​Investigation, Visualization, Methodology, Writing - original draft, review & editing Search more papers by this author Quanlong Jiang CAS Computational Nutrition Health, Institutes Biological Peking-Tsinghua Life Advanced Interdisciplinary Studies, Quantitative Biology (CQB), Peking University, Software, Yuanyuan Song ​Investigation Zhidong He Hongdao Zhang orcid.org/0000-0003-2390-0450 Mengjiao Visualization Xiaona orcid.org/0000-0001-6479-3562 Yumin Dai Oezlem Karalay Max Planck Ageing, Cologne, Germany Cologne Cluster on Cellular Stress Responses Aging-Associated Diseases (CECAD), Christoph Dieterich Klaus Tschira Integrative Cardiology Department Internal Medicine III, Hospital Heidelberg, Adam Antebi Supervision, draft Ligang Wu Corresponding Author [email protected] orcid.org/0000-0003-4010-9118 Funding acquisition, Project administration Jing-Dong J Han orcid.org/0000-0002-9270-7139 Yidong Shen orcid.org/0000-0002-2841-7233 Conceptualization, administration, Information Wang1,2,†, Jiang3,4,†, Song1,2,†, He1,2, Zhang1,2, Song1,2, Dai1,2, Karalay5,6, Dieterich7, Antebi5,6, *,1,2, *,3,4 *,1,2 1State 2University 3CAS 4Peking-Tsinghua 5Max 6Cologne 7Klaus † These authors contributed equally to work *Corresponding author. Tel: +86 21 54921321; E-mail: 10 62757330; 54921171; The EMBO Journal (2022)41:e109633https://doi.org/10.15252/embj.2021109633 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions Figures Info Abstract is complex with common distinct features across tissues. Unveiling underlying processes driving ageing individual tissues indispensable decipher mechanisms organismal longevity. well-established model organism that has spearheaded research discovery numerous genetic pathways controlling its lifespan. However, it remains challenging dissect worm due limited description tissue pathology access molecular during ageing. In study, we isolated cells from five major young old worms profiled age-induced within these We observed striking diversity identified different sets longevity regulators therein. addition, found novel factors, irx-1 myrf-2, which control integrity intestinal barrier sarcomere structure respectively. This study demonstrates complexity highlights power profiling ageing, can serve as resource field. Synopsis Whether associated specific organs poorly addressed. Here, dissection analyses diverse C. provides insight into disting trajectories each them. Five somatic tissues—nervous system, hypodermis, intestine, coelomocyte body all muscle undergo Tissue-specific between are pronounced than regulates similar biological gene Transcription factors irx-1/IRX myrf-2/MYRF intestine wall muscle, Introduction causes systematic decline physiological functions therefore poses risk various severe diseases aged population (Campisi et al, 2019). Over past decades, cellular systems protect have been substantially charted pioneering studies organisms (Kenyon, 2010; Riera 2016; Campisi nematode among foremost models research, short lifespan only few weeks, but displaying phenotypes humans (Mack 2018). It was first shown regulated evolutionarily conserved signalling identification insulin/IGF-1 (IIS) pathway (Johnson, 1990; Kenyon 1993; Morris 1996; Ogg 1997; Kenyon, 2011). Mutations critical IIS genes, such FOXO3A, were later be human (Willcox 2008). Since then, also pioneered other milestone findings biology Mack 2018; or interventions induce evident (Lund 2002; McElwee 2003; Murphy Hou Li proposed represent (Murphy 2003). transcriptional information previous mainly whole animals ages mutants technical difficulty dissecting interest tiny (Corsi 2015). datasets provided key insights researchers using well organisms. Nevertheless, cannot solely analysed at level animal, since characteristic trajectory, driven unique (Rando Wyss-Coray, 2021). tissue–tissue communication plays an essential role systemic level, how occurs relationship remain elusive. order autonomous non-autonomous multicellular organisms, profile Yet, lack age-related significant gap our understanding. By improving protocol isolate embryonic neurons fluorescence-activated cell sorting (FACS) (Von Stetina 2007), lab GFP-labelled cells, enabling adult (Kaletsky 2016, Following their technique, further developed method micromanipulation (Zhou current (i.e. neuron, hypodermis coelomocytes) thereby From perspective differentially expressed regulators, results indicate remarkable not arise structures regulations same atlas tissues, two transcription myrf-2 deterioration sarcomere. provide foundation explore machinery Results Sequencing To transcriptomes labelled fluorescent markers dissociated. (BWM), identities hand-picked Neurons composed classes collected FACS 2016). day 1 adulthood (D1) considered young, whereas post-reproductive 8 (D8) aged. both subjected Smart-seq2 (Picelli 2013) (Fig 1A). viability validated indicators (Zhang 2011) EV1A). A battery genes examined qRT–PCR assess purity samples EV1B). type manually picked BWM, coelomocytes, expression corresponding detected, EV1C–F), indicating largely devoid contamination. With reports 2018), FACS-isolated neuron highly enriched EV1G). Figure 1. Worm A. flowchart depicting Isolated pooled Smart-seq2. B, Principal component analysis (B) hierarchical clustering (C) three replicates. D1: adulthood, D8: adulthood. Neu: Int: BWM: Hyp: Coel: coelomocyte. D. volcano plots showing Genes fold change > 1.5 P-value smaller 0.05 significantly changed numbers percentages Age-DEGs plots. Download figure PowerPoint Click here expand figure. EV1. validation assay cells. Cells neurons, GFP reporters. Dead preparations (RFP) ethidium homodimer-1 staining (RFP). preparation coelomocytes live RFP Calcein AM (GFP) Arrow heads denote interest. Scale bar: 20 µm. B. list used. C–F. RT–qPCR indicated (C), (D), (E) (F). ND: Ct 40. Mean ± SD. n = 3 G. (left) RNA-Seq reads (right) comparable previously reported. Unpaired t-test, two-tailed. As expected, underwent (Figs 1B–D EV2A). showed sequenced clustered types then 1B C), highlighting distinctive reported 2018) effects expression. When compared D1 counterparts, 3,744, 2,246, 1,189, 902 1,056 D8 respectively 1D Dataset EV1). ageing-regulated (Age-DEGs) comprise 21.5, 18.4, 7.4, 11.5 7.7% 1D) 50.1% orthologs mammals EV2B EV1), share EV2. heatmap conserved. comparison Different exhibit deteriorate whether ageing-induced other, those D7. Only small fraction tested altered 2A B EV3C). dataset D2 (Hou 2016) EV3A, D). Therefore, could signature 2. variable A, overlap upregulated (A) downregulated number ratio Venn diagrams. Hypergeometric test. drops increase X-axis denotes EV3. report al (2016), comparing WT 2 C, samples. (C): data obtained (Worm). (D): (2016). (Worm (H)). Red lines pursue hypothesis, speculated, substantial EV2C EV3C 82.8, 72.7, 61.7, 65.7 74.1% 2C EV2C). ratios 74.1, 69.3, 67.2, 59.3 57.6%, respectively, patterns necessarily restricted because most express (Appendix Fig S1A–F). regulate differently high specificities Age-DEGs, exhibited decrease 2D). surprisingly there no shared D, unlikely alter core group Taken together, specificity changes. portray next used WormCat, powerful tool analysing multiple datasets, examine functional (Holdorf 2020). WormCat categorises function (Category 1) location (Categories 3) Category 1, many (Age-BPs) worm. 74.2% 73.9% Age-BPs least 3A EV2). Among them some well-known hallmarks, stress response metabolism (Lopez-Otin 2013). Interestingly, up- implying impact 3. WormCat. Categories differentiated capitalisation bold fonts. below cyan blocks. detailed 3, facets general 2), consistently At 2, 62.0 58.2% Age-BPs, detected one tissue, were, 71.9 64.6% (Dataset Gene ontology (GO) analys

Язык: Английский

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Bile Acids Transporters of Enterohepatic Circulation for Targeted Drug Delivery

Molecules, Год журнала: 2022, Номер 27(9), С. 2961 - 2961

Опубликована: Май 5, 2022

Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across variety fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides systematic review on their transport processes within the enterohepatic circulation related processes. The focus is laid description specific or less-specific BA proteins localization. Initially, reader provided essential information about BAs′ properties, systemic flow, metabolism, functions. Later, described in detail schematically illustrated, moving step by from liver via bile ducts to gallbladder, small intestine, colon; this accompanied descriptions major known be involved transport. Spillage BAs into urine excretion also discussed. Finally, points out some less-studied areas circulation, which can crucial for development BA-related drugs, prodrugs, drug carrier systems.

Язык: Английский

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The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy

Pharmaceutics, Год журнала: 2023, Номер 15(2), С. 364 - 364

Опубликована: Янв. 21, 2023

Transporter-mediated drug resistance is a major obstacle in anticancer delivery and key reason for cancer therapy failure. Membrane solute carrier (SLC) transporters play crucial role the cellular uptake of drugs. The expression function SLC can be down-regulated cells, which limits drugs into tumor resulting inefficiency therapy. In this review, we summarize current understanding low-SLC-transporter-expression-mediated different types cancers. Recent advances SLC-transporter-targeting strategies include development transporter-utilizing prodrugs nanocarriers modulation transporter cells. These will an important future therapies by enabling efficient

Язык: Английский

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Maternal-fetal cross-talk via the placenta: influence on offspring development and metabolism

Development, Год журнала: 2023, Номер 150(20)

Опубликована: Окт. 13, 2023

ABSTRACT Compelling epidemiological and animal experimental data demonstrate that cardiometabolic neuropsychiatric diseases originate in a suboptimal intrauterine environment. Here, we review evidence suggesting altered placental function may, at least part, mediate the link between maternal environment changes fetal growth development. Emerging indicates placenta controls development of several tissues through nutrient sensing, modulation trophoblast transporters by altering number cargo released extracellular vesicles. In this Review, discuss functions maternal-placental-fetal interface (in humans mice) how cross-talk these compartments may be mechanism for utero programming, focusing on mechanistic target rapamycin (mTOR), adiponectin O-GlcNac transferase (OGT) signaling. We also diet stress influences metabolism restriction can result susceptibility to developing chronic disease later life. Finally, speculate interventions targeting offer unprecedented opportunities prevent future generations.

Язык: Английский

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Lipocalin 2 receptors: facts, fictions, and myths

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Авг. 11, 2023

The human 25-kDa Lipocalin 2 (LCN2) was first identified and purified as a protein that in part is associated with gelatinase from neutrophils. This shows high degree of sequence similarity the deduced sequences rat α2-microglobulin-related mouse 24p3. Based on its typical lipocalin fold, which consists an eight-stranded, anti-parallel, symmetrical β-barrel fold structure it initially thought LCN2 circulating functioning transporter small lipophilic molecules. However, studies Lcn2 null mice have shown has bacteriostatic properties plays key role innate immunity by sequestering bacterial iron siderophores. Numerous reports further involved control cell differentiation, energy expenditure, death, chemotaxis, migration, many other biological processes. In addition, important roles for health disease been multiple molecular pathways required regulation expression identified. Nevertheless, although six putative receptors proposed, there fundamental lack understanding how these cell-surface transmit amplify to cell. present review we summarize current knowledge discuss inconsistencies, misinterpretations false assumptions potential receptors.

Язык: Английский

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