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Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of...
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Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 30413

Special Issue Editors

Prof. Dr. Paula M. Macedo

E-Mail Website
Guest Editor
1. Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School/Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
2. Portuguese Diabetes Association - Education and Research Center (APDP-ERC), Lisbon, Portugal
3. Department of Medical Sciences, University of Aveiro, Aveiro, Portugal
Interests: prediabetes; diabetes; obesity; autonomic dysfunction; insulin resistance; insulin clearance; non-alcoholic fatty liver disease; metabolic associated liver disease; fibrosis; gut-liver cross talk; brain-liver cross talk; translational research; clinical research
Prof. John Jones

E-Mail Website
Guest Editor
1. Center of Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
2. Portuguese Diabetes Association - Education and Research Center (APDP-ERC), Lisbon, Portugal
Interests: metabolic flux analysis; noninvasive measurements of hepatic stable-isotope tracer metabolism; intermediary metabolism; type 1 and type 2 diabetes; fatty liver disease; rare metabolic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Some of the most prevalent metabolic diseases today, including Type 2 diabetes and non-alcoholic fatty liver disease, involve altered or disrupted communication between different tissues and/or organs. The communication modes include signaling events transmitted by endocrine hormones, cytokines, neurons, metabolites, and exosomes and can involve both constitutive tissues and commensal microbiota. Identifying and characterizing these processes in the clinical setting requires integrating hitherto unconnected disciplines and diagnostic methods: for example, imaging of liver fat and fibrosis with the characterization of intestinal microbiome activity to understand the role of intestinal dysbiosis in driving fatty liver disease.

This Special Issue of the Journal of Clinical Medicine will report new advances in the integration of epidemiology, natural history, and novel pathogenic mechanisms that enhance our understanding of biological cross-talk in disease settings with a strong focus on those measurements and methodologies that can be applied in the clinical setting. The implication of tissue cross-talk processes in clinical diagnosis and treatment will also be highlighted. Therefore, researchers in the area of metabolic diseases are welcome to submit original research articles, meta-analyses, or reviews to this Special Issue.

Prof. Paula M. Macedo
Prof. John Jones
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Noninvasive methods of diagnosis
  • Oxidative stress in metabolic organs
  • Lipotoxicity
  • Cell death mechanisms
  • Inflammation
  • Insulin Resistance
  • Organs Cross talk
  • Pancreas-liver axis
  • Gut-liver axis
  • Brain-liver axis
  • Glucidic and lipid metabolism
  • Metabolic organs dysfunction at the basis of risk factors for cardiovascular diseases
  • Fibrogenesis
  • In vitro/in vivo models of metabolic organs
  • Epidemiological aspects
  • Natural history of dysmetabolism
  • Emerging medical therapies

Published Papers (7 papers)

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Research

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15 pages, 3192 KiB  
Article
Sex-Specific Signature in the Circulating NLRP3 Levels of Saudi Adults with Metabolic Syndrome
by Nasser M. Al-Daghri, Kaiser Wani, Hind AlHarthi, Amani Alghamdi, Abdullah M. Alnaami and Sobhy M. Yakout
J. Clin. Med. 2021, 10(15), 3288; https://doi.org/10.3390/jcm10153288 - 26 Jul 2021
Cited by 7 | Viewed by 3709
Abstract
Recently, inflammasomes such as NLRP3 as cytosolic pattern-recognition receptors have been implicated in the development of inflammation; however, limited investigations report the circulating levels of this protein. The objective, thus, was to investigative circulating NLRP3 levels in Saudi patients with a low-grade inflammatory [...] Read more.
Recently, inflammasomes such as NLRP3 as cytosolic pattern-recognition receptors have been implicated in the development of inflammation; however, limited investigations report the circulating levels of this protein. The objective, thus, was to investigative circulating NLRP3 levels in Saudi patients with a low-grade inflammatory disorder called metabolic syndrome (MetS). Two hundred Saudi adults aged 30–65, with or without MetS diagnosed on the basis of National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) criteria, were randomly recruited. Five MetS components were established according to the diagnostic criteria in the study subjects. Circulating levels of NLRP3 and known inflammation markers, such as tumor necrosis factor α (TNF-α), C-reactive protein (CRP) and interleukins (IL-1β and IL-18), were measured in the blood samples taken from the study subjects. Gender-based analysis showed a significant elevated circulating levels of NLRP3 in non-MetS men compared to non-MetS females (p < 0.001). Moreover, an increase in circulating levels of NLRP3 with a number of MetS components (p = 0.038) was observed only in females. A significant positive correlation of NLRP3 levels with age (r = 0.20, p = 0.04), BMI (r = 0.32, p < 0.01) and waist (r = 0.24, p = 0.02) and a significant negative correlation between NLRP3 and HDL-cholesterol (r= −0.21, p = 0.03) were also observed in females. Logistic regression analysis also yielded a sex-specific positive association of NLRP3 with MetS in females, with this association influenced mostly by central obesity and dyslipidemia components of MetS. In conclusion, this study suggests a sexual disparity in the circulating levels of NLRP3, with a trend of increasing circulating NLRP3 levels with increasing MetS components observed only in females, influenced mostly by adiposity and dyslipidemia components of MetS. Longitudinal studies with a larger sample size and investigating sex-specific hormones with NLRP3 would be needed to establish a causal relationship of NLRP3 with MetS. Full article
(This article belongs to the Special Issue Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases)
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10 pages, 1694 KiB  
Article
Clinical Epidemiology of Systolic and Diastolic Orthostatic Hypotension in Patients on Peritoneal Dialysis
by Claudia Torino, Rocco Tripepi, Maria Carmela Versace, Antonio Vilasi, Giovanni Tripepi and Vincenzo Panuccio
J. Clin. Med. 2021, 10(14), 3075; https://doi.org/10.3390/jcm10143075 - 12 Jul 2021
Cited by 1 | Viewed by 2200
Abstract
Blood pressure changes upon standing reflect a hemodynamic response, which depends on the baroreflex system and euvolemia. Dysautonomia and fluctuations in blood volume are hallmarks in kidney failure requiring replacement therapy. Orthostatic hypotension has been associated with mortality in hemodialysis patients, but neither [...] Read more.
Blood pressure changes upon standing reflect a hemodynamic response, which depends on the baroreflex system and euvolemia. Dysautonomia and fluctuations in blood volume are hallmarks in kidney failure requiring replacement therapy. Orthostatic hypotension has been associated with mortality in hemodialysis patients, but neither this relationship nor the impact of changes in blood pressure has been tested in patients on peritoneal dialysis. We investigated both these relationships in a cohort of 137 PD patients. The response to orthostasis was assessed according to a standardized protocol. Twenty-five patients (18%) had systolic orthostatic hypotension, and 17 patients (12%) had diastolic hypotension. The magnitude of systolic and diastolic BP changes was inversely related to the value of the corresponding supine BP component (r = −0.16, p = 0.056 (systolic) and r = −0.25, p = 0.003 (diastolic), respectively). Orthostatic changes in diastolic, but not in systolic, BP were linearly related to the death risk (HR (1 mmHg reduction): 1.04, 95% CI 1.01–1.07, p = 0.006), and this was also true for CV death (HR: 1.08, 95% CI 1.03–1.12, p = 0.001). The strength of this association was not affected by further data adjustment (p ≤ 0.05). These findings suggest that independent of the formal diagnosis of orthostatic hypotension, even minor orthostatic reductions in diastolic BP bear an excess death risk in this population. Full article
(This article belongs to the Special Issue Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases)
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12 pages, 3009 KiB  
Article
Effects of Meal Fructose/Glucose Composition on Postprandial Glucose Appearance and Hepatic Glycogen Synthesis in Healthy Subjects
by Cristina Barosa, Rogério T. Ribeiro, Rita Andrade, João F. Raposo and John G. Jones
J. Clin. Med. 2021, 10(4), 596; https://doi.org/10.3390/jcm10040596 - 5 Feb 2021
Cited by 2 | Viewed by 2256
Abstract
Dietary fructose overshadows glucose in promoting metabolic complications. Intestinal fructose metabolism (IFM) protects against these effects in rodents, by favoring gluconeogenesis, but the extent of IFM in humans is not known. We therefore aimed to infer the extent of IFM by comparing the [...] Read more.
Dietary fructose overshadows glucose in promoting metabolic complications. Intestinal fructose metabolism (IFM) protects against these effects in rodents, by favoring gluconeogenesis, but the extent of IFM in humans is not known. We therefore aimed to infer the extent of IFM by comparing the contribution of dietary fructose to systemic glucose and hepatic glycogen appearance postprandially. Twelve fasting healthy subjects ingested two protein meals in random order, one supplemented with 50 g 5/95 fructose/glucose (LF) and the other with 50 g 55/45 fructose/glucose (HF). Sources of postprandial plasma glucose appearance and hepatic glycogen synthesis were determined with deuterated water. Plasma glucose excursions, as well as pre- and post-meal insulin, c-peptide, and triglyceride levels were nearly identical for both meals. The total gluconeogenic contribution to plasma glucose appearance was significantly higher for HF versus LF (65 ± 2% vs. 34 ± 3%, p < 0.001). For HF, Krebs cycle anaplerosis accounted for two-thirds of total gluconeogenesis (43 ± 2%) with one-third from Triose-P sources (22 ± 1%). With LF, three-quarters of the total gluconeogenic contribution originated via Krebs cycle anaplerosis (26 ± 2%) with one-quarter from Triose-P sources (9 ± 2%). HF and LF gave similar direct and indirect pathway contributions to hepatic glycogen synthesis. Increasing the fructose/glucose ratio had significant effects on glucose appearance sources but no effects on hepatic glycogen synthesis sources, consistent with extensive IFM. The majority of fructose carbons were converted to glucose via the Krebs cycle. Full article
(This article belongs to the Special Issue Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases)
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14 pages, 2147 KiB  
Article
Metabolic Footprint, towards Understanding Type 2 Diabetes beyond Glycemia
by Ana F. Pina, Rita S. Patarrão, Rogério T. Ribeiro, Carlos Penha-Gonçalves, João F. Raposo, Luís Gardete-Correia, Rui Duarte, José M. Boavida, José L. Medina, Roberto Henriques and Maria P. Macedo
J. Clin. Med. 2020, 9(8), 2588; https://doi.org/10.3390/jcm9082588 - 10 Aug 2020
Cited by 9 | Viewed by 2804
Abstract
Type 2 diabetes (T2D) heterogeneity is a major determinant of complications risk and treatment response. Using cluster analysis, we aimed to stratify glycemia within metabolic multidimensionality and extract pathophysiological insights out of metabolic profiling. We performed a cluster analysis to stratify 974 subjects [...] Read more.
Type 2 diabetes (T2D) heterogeneity is a major determinant of complications risk and treatment response. Using cluster analysis, we aimed to stratify glycemia within metabolic multidimensionality and extract pathophysiological insights out of metabolic profiling. We performed a cluster analysis to stratify 974 subjects (PREVADIAB2 cohort) with normoglycemia, prediabetes, or non-treated diabetes. The algorithm was informed by age, anthropometry, and metabolic milieu (glucose, insulin, C-peptide, and free fatty acid (FFA) levels during the oral glucose tolerance test OGTT). For cluster profiling, we additionally used indexes of metabolism mechanisms (e.g., tissue-specific insulin resistance, insulin clearance, and insulin secretion), non-alcoholic fatty liver disease (NAFLD), and glomerular filtration rate (GFR). We found prominent heterogeneity within two optimal clusters, mainly representing normometabolism (Cluster-I) or insulin resistance and NAFLD (Cluster-II), at higher granularity. This was illustrated by sub-clusters showing similar NAFLD prevalence but differentiated by glycemia, FFA, and GFR (Cluster-II). Sub-clusters with similar glycemia and FFA showed dissimilar insulin clearance and secretion (Cluster-I). This work reveals that T2D heterogeneity can be captured by a thorough metabolic milieu and mechanisms profiling—metabolic footprint. It is expected that deeper phenotyping and increased pathophysiology knowledge will allow to identify subject’s multidimensional profile, predict their progression, and treat them towards precision medicine. Full article
(This article belongs to the Special Issue Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases)
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Review

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20 pages, 1419 KiB  
Review
Crosstalk between Tryptophan Metabolism via Kynurenine Pathway and Carbohydrate Metabolism in the Context of Cardio-Metabolic Risk—Review
by Małgorzata Kiluk, Janina Lewkowicz, Dariusz Pawlak and Anna Tankiewicz-Kwedlo
J. Clin. Med. 2021, 10(11), 2484; https://doi.org/10.3390/jcm10112484 - 4 Jun 2021
Cited by 24 | Viewed by 3804
Abstract
Scientific interest in tryptophan metabolism via the kynurenine pathway (KP) has increased in the last decades. Describing its metabolites helped to increase their roles in many diseases and disturbances, many of a pro-inflammatory nature. It has become increasingly evident that KP can be [...] Read more.
Scientific interest in tryptophan metabolism via the kynurenine pathway (KP) has increased in the last decades. Describing its metabolites helped to increase their roles in many diseases and disturbances, many of a pro-inflammatory nature. It has become increasingly evident that KP can be considered an important part of emerging mediators of diabetes mellitus and metabolic syndrome (MS), mostly stemming from chronic systemic low-grade inflammation resulting in the aggravation of cardiovascular complications. An electronic literature search of PubMed and Embase up to March 2021 was performed for papers reporting the effects of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), anthranilic acid (AA), and quinolinic acid (QA), focusing on their roles in carbohydrate metabolism and the cardiovascular system. In this review, we discussed the progress in tryptophan metabolism via KP research, focusing particular attention on the roles in carbohydrate metabolism and its complications in the cardiovascular system. We examined the association between KP and diabetes mellitus type 2 (T2D), diabetes mellitus type 1 (T1D), and cardiovascular diseases (CVD). We concluded that tryptophan metabolism via KP serves as a potential diagnostic tool in assessing cardiometabolic risk for patients with T2D. Full article
(This article belongs to the Special Issue Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases)
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14 pages, 1272 KiB  
Review
Insights into Macrophage/Monocyte-Endothelial Cell Crosstalk in the Liver: A Role for Trem-2
by Inês Coelho, Nádia Duarte, Maria Paula Macedo and Carlos Penha-Gonçalves
J. Clin. Med. 2021, 10(6), 1248; https://doi.org/10.3390/jcm10061248 - 17 Mar 2021
Cited by 7 | Viewed by 5177
Abstract
Liver disease accounts for millions of deaths worldwide annually being a major cause of global morbidity. Hepatotoxic insults elicit a multilayered response involving tissue damage, inflammation, scar formation, and tissue regeneration. Liver cell populations act coordinately to maintain tissue homeostasis and providing a [...] Read more.
Liver disease accounts for millions of deaths worldwide annually being a major cause of global morbidity. Hepatotoxic insults elicit a multilayered response involving tissue damage, inflammation, scar formation, and tissue regeneration. Liver cell populations act coordinately to maintain tissue homeostasis and providing a barrier to external aggressors. However, upon hepatic damage, this tight regulation is disrupted, leading to liver pathology which spans from simple steatosis to cirrhosis. Inflammation is a hallmark of liver pathology, where macrophages and endothelial cells are pivotal players in promoting and sustaining disease progression. Understanding the drivers and mediators of these interactions will provide valuable information on what may contribute to liver resilience against disease. Here, we summarize the current knowledge on the role of macrophages and liver sinusoidal endothelial cells (LSEC) in homeostasis and liver pathology. Moreover, we discuss the expanding body of evidence on cell-to-cell communication between these two cell compartments and present triggering receptor expressed on myeloid cells-2 (Trem-2) as a plausible mediator of this cellular interlink. This review consolidates relevant knowledge that might be useful to guide the pursue of successful therapeutic targets and pharmacological strategies for controlling liver pathogenesis. Full article
(This article belongs to the Special Issue Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases)
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44 pages, 2206 KiB  
Review
Liver Steatosis, Gut-Liver Axis, Microbiome and Environmental Factors. A Never-Ending Bidirectional Cross-Talk
by Agostino Di Ciaula, Jacek Baj, Gabriella Garruti, Giuseppe Celano, Maria De Angelis, Helen H. Wang, Domenica Maria Di Palo, Leonilde Bonfrate, David Q-H Wang and Piero Portincasa
J. Clin. Med. 2020, 9(8), 2648; https://doi.org/10.3390/jcm9082648 - 14 Aug 2020
Cited by 88 | Viewed by 9414
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in [...] Read more.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and parallels comorbidities such as obesity, metabolic syndrome, dyslipidemia, and diabetes. Recent studies describe the presence of NAFLD in non-obese individuals, with mechanisms partially independent from excessive caloric intake. Increasing evidences, in particular, point towards a close interaction between dietary and environmental factors (including food contaminants), gut, blood flow, and liver metabolism, with pathways involving intestinal permeability, the composition of gut microbiota, bacterial products, immunity, local, and systemic inflammation. These factors play a critical role in the maintenance of intestinal, liver, and metabolic homeostasis. An anomalous or imbalanced gut microbial composition may favor an increased intestinal permeability, predisposing to portal translocation of microorganisms, microbial products, and cell wall components. These components form microbial-associated molecular patterns (MAMPs) or pathogen-associated molecular patterns (PAMPs), with potentials to interact in the intestine lamina propria enriched in immune cells, and in the liver at the level of the immune cells, i.e., Kupffer cells and stellate cells. The resulting inflammatory environment ultimately leads to liver fibrosis with potentials to progression towards necrotic and fibrotic changes, cirrhosis. and hepatocellular carcinoma. By contrast, measures able to modulate the composition of gut microbiota and to preserve gut vascular barrier might prevent or reverse NAFLD. Full article
(This article belongs to the Special Issue Clinical Insights on Cross-Talk between Tissues/Organs in the Setting of Metabolic Diseases)
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