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Evidence of beta cell dedifferentiation in human type 2 diabetes
No full textRecenti studi sugli animali hanno dimostrato che le cellule β del pancreas nei modelli murini di diabete di tipo 2, diventano dedifferenziate in risposta all’iperglicemia, ritornando ad uno stato simile alla cellula progenitrice. Inoltre, le cellule β si convertono in altre cellule endocrine, comprese cellule che producono glucagone, dette "α-like", fornendo così una potenziale spiegazione per l’ iperglucagonemia che accompagna il diabete.
Partendo dai risultati ottenuti con il modello murino, abbiamo analizzato, con tecniche di immunofluorescenza al confocale e microscopia elettronica, campioni di pancreas umani fissati e inclusi in OCT di 15 donatori sani e 15 donatori con diabete di tipo 2 (M/F 9/6 vs 7/8 NS; età (±SD) 56±18 vs 66±17 NS; BMI (kg/m2) 26±6 vs 29±6 NS; anni dalla diagnosi di diabete di tipo 2 12±8).
All’esito di tali analisi abbiamo rilevato, nei soggetti diabetici, un aumento di quasi tre volte del numero di cellule delle isole pancreatiche che non producono più nessuno dei quattro principali ormoni pancreatici, ma che ancora conservano le caratteristiche di cellule endocrine (positività per Sinaptofisina e Cromogranina A).
Tali cellule rappresentavano il 31,9% delle cellule β nei diabetici rispetto all’8,7% dei controlli, e costituivano il 16,8% di tutte le cellule endocrine nelle isole dei diabetici, contro il 6,5% dei controlli (p <0.001).
Inoltre, l’espressione dei fattori di trascrizione FOXO1 e NKX6.1, marcatori della β cellula matura, sono risultati diminuiti o dislocalizzati (dal nucleo al citoplasma) nelle cellule β dei diabetici, confermando che la disfunzione β cellulare si accompagna ad una perdita della maturità della cellula stessa.
Un 15% delle cellule glucagone-positive nei diabetici è risultato positivo per FOXO1 citoplasmatico, con un aumento di 7 volte rispetto ai controlli (p=0.005). Poiché FOXO1 citoplasmatico è inattivo, i risultati sono compatibili con la spiegazione che queste cellule rappresentano antiche cellule β che, attraverso la perdita di funzione di FOXO1, sono in fase di conversione in cellule che producono glucagone-"α-like".
Infine, nei roditori le cellule β dedifferenziate ritornano ad una fase di cellula progenitrice, caratterizzata dall’espressione del fattore di trascrizione Neurogenin3. Neurogenin3 è assente nel pancreas umano adulto. Tuttavia, utilizzando le informazioni raccolte dal profilo di espressione genica di modelli animali di de-differenziazione β cellulare, abbiamo scoperto che ALDH1A3 rappresenta un nuovo marker di tale popolazione cellulare.
Abbiamo trovato un aumento di quasi quattro volte del numero di cellule positive per ALDH1A3 con NKX6.1 citoplasmatico (marker esclusivo della β cellula) nei diabetici rispetto ai controlli (p=0.009). Inoltre, queste cellule erano insulino-negative.
Questi dati sono coerenti con la possibilità che, allorché le cellule β perdono la loro identità (indicato dalla perdita di insulina e trasferimento di NKX6.1 nel citoplasma), esse acquisiscono l’immunoreattività per ALDH1A3, presentando un aspetto dedifferenziato.
I nostri dati sostengono quindi i risultati ottenuti dai modelli sperimentali, suggerendo che, nel diabete di tipo 2, le cellule β non si perdono in modo permanente e in parte si convertono in cellule α, potendo quindi giustificare l’iperglucagonemia che si riscontra nei soggetti diabetici.
In conclusione, l'ipotesi è che le cellule β sottoposte allo stress iperglicemico dedifferenzino per trovare riposo (sleeping cells), preservando la ri-differenziazione a condizioni metaboliche più favorevoli.Context. Diabetes is associated with a deficit of insulin-producing beta cells. Animal studies show that beta cells become dedifferentiated in diabetes, reverting to a progenitor-like stage, and partly converting to other endocrine cell types.
Objective. To determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 non-diabetic organ donors.
Design. We scored dedifferentiation using markers of endocrine lineage, beta cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3 (ALDH1A3).
Results. By these criteria, dedifferentiated cells accounted for 31.9% of beta cells in type 2 diabetics vs. 8.7% in controls, and for 16.8% vs. 6.5% of all endocrine cells (p<0.001). The number of ALDH1A3-positive/hormone-negative cells was threefold higher in diabetics compared to controls. Moreover, beta cell-specific transcription factors were ectopically found in glucagon- and somatostatin-producing cells of diabetic subjects.
Conclusions. The data support the view that pancreatic beta cells become dedifferentiated and convert to alpha- and delta-“like” cells in human type 2 diabetes. The findings should prompt a reassessment of goals in the prevention and treatment of beta cell dysfunction
Editorial: Cardiac energetic efficiency and cardiometabolic diseases
Full text linkIncreasing evidence have suggested that a compromised myocardial energetics is implicated in the pathogenesis of cardiovascular disease including ischemic cardiomyopathy, left ventricular hypertrophy and heart failure. The present Research Topic collects some of the last investigations evaluating the mechanisms underlying the link between an altered myocardial energetic efficiency and cardiovascular diseases, and the utility of pharmacological and non-pharmacological approaches targeting cardiac energetic metabolism to counteract cardiovascular disease progression.
The compilation starts with a cross-sectional study conducted by Liu et al. evaluating the association between coronary microvascular dysfunction and altered heart energetic efficiency and contractility. The Authors report that subjects with coronary microvascular dysfunction, defined as a reduced coronary flow reserve, exhibit a reduction in global work index, global contractive work, and global work efficiency and a higher global waste work, suggesting that coronary microvascular dysfunction may affect myocardial energetic efficiency and contractility. Additionally, the Authors also demonstrate that a reduced myocardial global work and efficiency may be a predictor of coronary microvascular dysfunction with a good diagnostic capacity, thus indicating that a compromised cardiac mechano-energetic efficiency may be a diagnostic tool for early identification of individuals with coronary artery disease.
Energetic metabolism of heat is a dynamic process depending of the availability of oxygen and several metabolic substrates such as glucose, fatty acids, ketone bodies and ammino acids. In order to gain insight into the metabolic alterations associated to a worse prognosis in subjects with coronary artery diseases, Na et al. conducted an observational study on 5,935 patients admitted to the cardiovascular department of Guang'anmen Hospital who were diagnosed with coronary heart disease and subdivided into two groups according to the occurrence of adverse myocardial events (MACEs) during the hospitalization. The Authors found that age, blood glucose, fatty acid, albumin, and ApoA1 levels at admission were associated with an increased risk of MACEs during the hospitalization. Decreased levels of blood glucose were associated with an increased risk of MACEs, whereas higher levels of glucose, making this energetic substrate more easily available, were protective. Higher levels of fatty acids and decreased values of Apo A1 were associated with an increased risk of MACEs, probably due to the accumulation of lipids in conditions of oxygen deprivation and their toxic effects on the heart. Additionally, decreased albumin concentrations were found to predict MACEs occurrence, indicating that a decreased availability of ammino acids for energetic supply may aggravates cardiac damage in conditions of myocardial hypoperfusion. The results of this study not only provide evidence that several energetic substrate changes occur in the heart of subjects with coronary artery disease but also demonstrate that metabolic alterations may predict MACEs, thus representing a tool for a better cardiovascular risk stratification and a potential therapeutic target.
Amongst chemical compound able to positively modulate energetic metabolism, polyphenols have attracted considerable attention. In their review Hedayati et al. describe the various benefic properties of polyphenols, including anti-inflammatory, antioxidant, antiapoptotic, and antiatherogenic effects thus suggesting that polyphenols may be promising adjutant approaches in the treatment of cardiovascular disease and heart failure.
The collection also includes preclinical studies with translational impact, providing new insights and interesting tools for clinical research on this topic field.
Raposo et al. report that intracoronary transfer of xenogeneic Human umbilical cord matrix-mesenchymal stromal cells (hUCM-MSC), shortly after reperfusion, improved left-ventricular systolic function. By using a swine randomized, sham- and placebo-controlled blinded trial, they demonstrated that improvement in mechanical performance may be depended to a favorable modification of myocardial interstitial fibrosis and downregulation of genes related to matrix remodeling, whereas the reduction of morphological infarct size seems to not be involved.
The treatment to protect heart function in post-myocardial infarction heart failure (post-MI HF) is still on debate. Tao et al. addressed this topic by testing the effect of the early administration of the SGLT-2i Dapagliflozin (DAPA) in rats post-MI HF compared to the combination of DAPA with sacubitril-valsartan (S/V) in different orders. They conclude that the most effective treatment strategy for rats with post-MI HF was the administration of DAPA during the first 2 weeks, followed by the addition of sacubitril-valsartan to DAPA later.
Last, the collection ends with a study to test the efficacy of supplementation of cardioplegia with sildenafil in a piglet model of cardiopulmonary bypass and arrest, using both cold and warm cardioplegia protocols. Previous investigations into whether sildenafil has a cardiac inotropic effect have proved controversial. Several human studies have found no evidence of an inotropic effect of sildenafil, either in vivo or in vitro, while others have reported that sildenafil administration is associated with increases in cardiac index. This study demonstrated that supplementation of cardioplegia with sildenafil has beneficial metabolic effects. Since cardioprotection for paediatric patients is currently not as effective as in adult patients and for a long time has been described as inadequate, these findings may represent an exciting step towards improving cardioprotection for this highly vulnerable group of patients.
In conclusion, the article Collection provides new insights for the role of myocardial energetic efficiency in the pathogenesis of cardiovascular diseases and explores the mechanisms affecting cardiac mechano-energetic performance providing potential solutions for clinical practice
The Endocrine Adipose Organ: A System Playing a Central Role in COVID-19
Full text linkIn the last 30 years the adipose cell has been object of several studies, turning its reputation from an inert cell into the main character involved in the pathophysiology of multiple diseases, including the ongoing COVID-19 pandemic, which has changed the clinical scenario of the last two years. Composed by two types of tissue (white and brown), with opposite roles, the adipose organ is now classified as a real endocrine organ whose dysfunction is involved in different diseases, mainly obesity and type 2 diabetes. In this mini-review we aim to retrace the adipose organ history from physiology to physiopathology, to provide therapeutic perspectives for the prevention and treatment of its two main related diseases (obesity and type 2 diabetes) and to summarize the most recent discoveries linking adipose tissue to COVID-19
Crescita e apprendimento attraverso il corpo in movimento
Full text linkL’attività motoria durante la crescita del bambino è uno strumento indispensabile per il corpo e per lo spirito. Diversi e molteplici studi dimostrano come grazie al movimento si instaurino rapporti con l’ambiente e con gli altri, si esprime il sé e le proprie emozioni, si forma l’identità, si minimizzano i rischi di incorrere in malattie metaboliche e cardiovascolari e si sviluppa la sfera cognitiva. Partendo da queste riflessioni siamo arrivate ad elaborare un quesito: l’attività fisica quanto incide sulle capacità cognitive e quanto supporta il rendimento scolastico? Nel presente elaborato proveremo a dare una risposta avvalorando il concetto secondo cui il movimento è cambiamento, crescita, vita
Diabetes Secondary to Pancreatic Diseases
No full textDiabetes secondary to pancreatic diseases is a well-known form of diabetes mellitus, classified as "diseases of the exocrine pancreas - other specific type of diabetes," or Type 3c diabetes mellitus (T3cDM) Exocrine pancreatic diseases underlying T3cDM include benign and malign conditions, of any etiology, that diffusely injure the pancreas. Due to the heterogeneity of its underlying causes, it is rarely considered in everyday clinical practice, but it could be more common than generally thought. An early diagnosis of a pancreatic disease may substantially change the patient's prognosis. Finally, endocrinologists should become more acquainted with pancreatic diseases, while all other specialists should attribute the deserved importance to diabetes and hyperglycemia, even in the apparently mild forms. A schematic revision of causes, clinical diagnoses and management will be discussed in the chapter
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
β-Cell Fate in Human Insulin Resistance and Type 2 Diabetes: A Perspective on Islet Plasticity
No full textAlthough it is well established that type 2 diabetes (T2D) is generally due to the progressive loss of β-cell insulin secretion against a background of insulin resistance, the actual correlation of reduced β-cell mass to its defective function continues to be debated. There is evidence that a compensatory increase in β-cell mass, and the consequent insulin secretion, can effectively cope with states of insulin resistance, until hyperglycemia supervenes. Recent data strongly indicate that the mechanisms by which islets are able to compensate in response to insulin resistance in peripheral tissues is secondary to hyperplasia, as well as the activation of multiple cellular machineries with diverse functions. Importantly, islet cells exhibit plasticity in altering their endocrine commitment; for example, by switching from secretion of glucagon to secretion of insulin and back (transdifferentiation) or from an active secretory state to a nonsecretory quiescent state (dedifferentiation) and back. Lineage tracing (a method used to track each cell though its differentiation process) has demonstrated these potentials in murine models. A limitation to drawing conclusions from human islet research is that most studies are derived from human autopsy and/or organ donor samples, which lack in vivo functional and metabolic profiling. In this review, we specifically focus on evidence of islet plasticity in humans—from the normal state, progressing to insulin resistance to overt T2D—to explain the seemingly contradictory results from different cross-sectional studies in the literature. We hope the discussion on this intriguing scenario will provide a forum for the scientific community to better understand the disease and in the long term pave the way for personalized therapies
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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