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Studies have pointed to insulin resistance as pathogenic factor in fatty liver; the role of beta-cell function, even if generally accepted, is unexplored. This study was undertaken to test whether fasting indexes of beta-cell function were related to the intra-hepatic fat (IHF) content in non-diabetic humans. IHF content was measured by means of ¹H-Magnetic Resonance Spectroscopy (MRS), and insulin sensitivity and beta-cell function were estimated based on fasting plasma glucose, insulin and C-peptide in 31 patients with fatty liver and 62 individuals with matched anthropometric features (age: 36±8 vs. 36±7 years, BMI: 27.4±3.8 vs. 26.7±3.2 kg/m²). Patients with fatty liver had higher fasting glucose (P<0.05), insulin (P<0.01), c-peptide (P<0.005) and insulin resistance (HOMA2-%S: 56±24% vs. 77±38%; P=0.008). Fasting insulin secretion (383±168 vs. 284±107 pmol/L; P=0.007) and the beta-cell insulin sensitivity (HOMA2-%B: 171 ± 41% vs. 152±43%; P=0.04) were also increased in patients with fatty liver. A subgroup analysis, performed matching also for HOMA2-%S (including only those <70%; n=25 and n=30 in subjects with and without fatty liver: 47±12% vs. 49±12; P=0.56), confirmed increased insulin secretion (408±178 vs. 266±107 pmol/L; P=0.002) and HOMA2-%B (174±62% ys. 136±56%; P=0.02) in the individuals with fatty liver. In univariate analysis including the entire population fasting insulin explained 14% of the IHF content variability (P<0.000); in multivariate analysis the inclusion of fasting C-peptide increased it more than two-fold (to 32%; P<0.000); inclusion of age, sex, BMI and glucose in this model was not useful. Logistic regression showed that the insulin*C-peptide product was associated with the likelihood of having fatty liver (P<0.001). In conclusion, nondiabetic individuals with fatty liver are characterized not only by reduced insulin sensitivity but also by features of enhanced fasting beta-cell function, which is an independent meaningful factor. [ABSTRACT FROM AUTHOR]

Protocadherins, a family of adhesion molecules with crucial role in cell-cell interactions, have emerged as key players in neurodevelopmental and psychiatric disorders. In particular, growing evidence links genetic alterations in Protocadherin 9 ( PCDH9 ) gene with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory cortex, accompanied by sensorimotor and memory impairment. However, the synaptic and molecular mechanisms of PCDH9 in the brain remain largely unknown, particularly concerning its impact on brain pathology. To address this question, we conducted a comprehensive investigation of PCDH9 role in the male mouse hippocampus at the ultrastructural, biochemical, transcriptomic, electrophysiological and network level. We show that PCDH9 mainly localizes at glutamatergic synapses and its expression peaks in the first week after birth, a crucial time window for synaptogenesis. Strikingly, Pcdh9 KO neurons exhibit oversized presynaptic terminal and postsynaptic density (PSD) in the CA1. Synapse overgrowth is sustained by the widespread up-regulation of synaptic genes, as revealed by single-nucleus RNA-seq (snRNA-seq), and the dysregulation of key drivers of synapse morphogenesis, including the SHANK2/CORTACTIN pathway. At the functional level, these structural and transcriptional abnormalities result into increased excitatory postsynaptic currents (mEPSC) and reduced network activity in the CA1 of Pcdh9 KO mice. In conclusion, our work uncovers Pcdh9 pivotal role in shaping the morphology and function of CA1 excitatory synapses, thereby modulating glutamatergic transmission within hippocampal circuits. Significance statement Converging evidence indicates that genetic alterations in Protocadherin 9 ( PCDH9 ) gene are associated with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). However, our understanding of PCDH9 physiological role and molecular mechanisms in the brain, as well as its connection to synaptic dysfunction and brain pathology, remains limited. Here we demonstrate that Pcdh9 regulates the transcriptional profile, morphology and function of glutamatergic synapses in the CA1, thereby tuning hippocampal network activity. Our results elucidate the molecular and synaptic mechanisms of a gene implicated in neurodevelopmental and psychiatric disorders, and suggest potential hippocampal alterations contributing to the cognitive deficits associated with these conditions., (Copyright © 2024 the authors.)

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-d-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of (13)C-glucose and conversion to (13)C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMP-activated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD., (Copyright © 2016 by the American Society of Nephrology.)

Objective: The aims of this article are to present the main features of MRI of cardiomyopathy and to show selected images of cardiomyopathies., Conclusion: Cardiomyopathy is a frequent reason for cardiac MRI evaluation, which is now considered the most appropriate imaging technique for the diagnosis and follow-up of this wide range of myocardial diseases.