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

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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 36981

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Special Issue Editors

Prof. Dr. Paula M. Macedo

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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

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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
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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

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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

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Published Papers (7 papers)

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Research

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15 pages, 3192 KiB

Open AccessArticle

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 8 | Viewed by 4387

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 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

Open AccessArticle

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 2861

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 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

Open AccessArticle

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 2937

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 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

Open AccessArticle

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 11 | Viewed by 3371

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 (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

Open AccessReview

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 34 | Viewed by 4980

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 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

Open AccessReview

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 9 | Viewed by 6360

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 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

Open AccessReview

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 115 | Viewed by 10914

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 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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