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Diabetic kidney disease (DKD) is the first cause of end-stage kidney disease in patients with diabetes and its prevalence is increasing worldwide. It encompasses histological alterations that mainly affect the glomerular filtration unit, which include thickening of the basement membrane, mesangial cell proliferation, endothelial alteration, and podocyte injury. These morphological abnormalities further result in a persistent increase of urinary albumin-to-creatinine ratio and in a reduction of the estimated glomerular filtration rate. Several molecular and cellular mechanisms have been recognized, up to date, as major players in mediating such clinical and histological features and many more are being under investigation. This review summarizes the most recent advances in understanding cell death mechanisms, intracellular signaling pathways and molecular effectors that play a role in the onset and progression of diabetic kidney damage. Some of those molecular and cellular mechanisms have been already successfully targeted in preclinical models of DKD and, in some cases, strategies have been tested in clinical trials. Finally, this report sheds light on the relevance of novel pathways that may become therapeutic targets for future applications in DKD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: The purine nucleotide adenosine triphosphate (ATP) is released into extracellular spaces as extracellular ATP (eATP) as a consequence of cell injury or death and activates the purinergic receptors. Once released, eATP may facilitate T-lymphocyte activation and differentiation. The purpose of this review is to elucidate the role of ATP-mediated signaling in the immunological events related to type 1 diabetes (T1D)., Recent Findings: T lymphocytes mediate immune response during the onset of T1D and promote pancreatic islet or whole pancreas rejection in transplantation. Recent data suggest a potential role for eATP in early steps of T1D onset and of allograft rejection. In different preclinical experimental models and clinical trials, several drugs targeting purinergic signaling have been employed to abrogate lymphocyte activation and differentiation, thus representing an achievable treatment to prevent/revert T1D or to induce long-term islet allograft function., Summary: In preclinical and clinical settings, eATP-signaling inhibition induces immune tolerance in autoimmune disease and in allotransplantation. In this view, the purinergic system may represent a novel therapeutic target for auto- and allo-immunity., Competing Interests: Conflicts of interests P.F. is owner of patent n. 11452781. All other authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dapagliflozin has been demonstrated to improve glycemic control, blood pressure, and body weight in type 2 diabetes mellitus (T2D); indeed, it can also reduce the risk of progression to renal failure, of hospitalization for heart failure and of cardiovascular death. We aim to investigate the acute effect of Dapagliflozin on kidney function in the common clinical practice in T2D. This is a study including 1402 patients with T2D recruited from 11 centers in Lombardia, Italy, who were evaluated at baseline and after 6 months of treatment with Dapagliflozin 10 mg per day. The primary outcome of the study was the change in HbA1c, while the secondary outcomes were modification of weight, BMI, systolic and diastolic pressure, creatinine, eGFR and albuminuria status. After 24 weeks of treatment with Dapagliflozin, a reduction in Hb1Ac was observed (-0.6 ± 1.8%) as well as in BMI (-1.5 ± 5.2 kg/m 2 ). Statistically significant changes were also found for systolic and diastolic blood pressure, cholesterol and triglycerides. Interestingly, a statistically significant acute improvement of kidney function was evident. Our analyses confirm the beneficial effects of dapagliflozin after 6 months of therapy, with improvements of glycemic and lipid profiles, blood pressure, BMI. Finally, an acute positive effect on albuminuria and KIDGO classes was observed during a 6 months treatment with dapagliflozin in patients with T2D., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In the last few years, a great interest has emerged in investigating the pleiotropic effects of Glucagon Like Peptide-1 Receptor Agonists (GLP-1RAs). While GLP-1RAs ability to lower plasma glucose and to induce weight loss has allowed them to be approved for the treatment of diabetes and obesity, consistent evidences from in vitro studies and preclinical models suggested that GLP-1RAs have anti-inflammatory properties and that may modulate the immune-system. Notably, such anti-inflammatory effects target different pathways in different tissues, underling the broad spectrum of GLP-1RAs actions. This review examines some of the currently proposed molecular mechanisms of GLP-1RAs actions and explores their potential benefits in reducing inflammatory responses, which may well suggest a future therapeutic use of GLP-1RAs in new indications., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Obesity is frequently a comorbidity of type 2 diabetes. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors in patients with type 2 diabetes, but lifestyle-based weight loss strategies are not long-term effective. There is an increasing need to consider pharmacological approaches to assist weight loss in the so called diabesity syndrome. Aim of this review is to analyze the weight-loss effect of non-insulin glucose lowering drugs in patients with type 2 diabetes., Material and Methods: A systematic analysis of the literature on the effect of non-insulin glucose lowering drugs on weight loss in patients with type 2 diabetes was performed. For each class of drugs, the following parameters were analyzed: kilograms lost on average, effect on body mass index and body composition., Results: Our results suggested that anti-diabetic drugs can be stratified into 3 groups based on their efficacy in weight loss: metformin, acarbose, empagliflozin and exenatide resulted in a in a mild weight loss (less than 3.2% of initial weight); canagliflozin, ertugliflozin, dapagliflozin and dulaglutide induces a moderate weight loss (between 3.2% and 5%); liraglutide, semaglutide and tirzepatide resulted in a strong weight loss (greater than 5%)., Conclusions: This study shows that new anti-diabetic drugs, particularly GLP1-RA and Tirzepatide, are the most effective in inducing weight loss in patients with type 2 diabetes. Interestingly, exenatide appears to be the only GLP1-RA that induces a mild weight loss., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To assess the effect of a fermented rice-flour obtained from Lactobacillus paracasei CBA L74 in managing infants with moderate to severe atopic dermatitis. Infants with moderate to severe atopic dermatitis, aged 6-36 months, were randomly assigned to receive once-daily consumption of rice flour containing heat-killed probiotic Lactobacillus paracasei CBA L74 or placebo for 12 weeks as supplementary approach to topical treatment. Primary outcome was SCORAD index change from baseline to 12 weeks; secondary outcomes were gut microbiota composition, as evaluated by the analysis of fecal samples, and serum cytokines at baseline and at the end of the intervention period in both groups, and steroid usage over the treatment period and one month after stopping it. V3-V4 region of the 16S ribosomal RNA gene was sequenced to evaluate changes in the gut microbiota. SCORAD index decreased over the treatment period in both groups. The difference in the SCORAD change was -2.1 (-5.5 to 1.3; p = 0.223) for the experimental vs. the placebo group, not reaching the minimal clinical difference of 8.7 units. The use of topical steroids, measured as finger tips units, decreased from 4 to 16 weeks, in both groups; the reduction was significantly higher in experimental than in placebo group (p value from Wilcoxon rank sum test = 0.031). No significant differences were observed for cytokines levels between groups. The composition of gut microbiota at the phylum and class taxonomic levels resulted very similar, at baseline and after intervention, in both groups. Similarly, no significant differences were observed in the relative abundance of bacterial genera between groups. In conclusion, though the heat-killed Lactobacillus paracaseiwas not proved to be effective in reducing the severity of atopic dermatitis, it showed a steroid sparing effect the value of which needs to be further investigated., (Copyright © 2020. Published by Elsevier Ltd.)

Type 2 diabetes (T2D) is a condition characterized by hyperglycemia and chronic complications. Antidiabetic drugs and lifestyle interventions are the current gold standard therapy for T2D; current therapies, however, can only delay long-term diabetic complications and can additionally be associated with beta cell failure. While the mechanism of beta cell failure is well-studied, little is known about the immunological and inflammatory events associated with antidiabetic agents. Here we studied the effects of three antidiabetic drugs (Metformin, Sitagliptin, and Liraglutide) on immune-relevant pathways in a human beta cell line. Costimulatory molecule expression, cytokine secretion, and gene expression profiles were evaluated at different time points following challenge with the aforementioned antidiabetic agents. Our results showed that these three antidiabetic agents, particularly Sitagliptin, downregulate HLA Class I and II expression and upregulate the immune-regulatory molecules PD-L1 and CTLA4. Metformin and Liraglutide were shown to elicit significantly greater release of TNFa, IL-6, and GM-CSF, while Sitagliptin had a lesser effect on pro-inflammatory cytokine production. Gene expression analysis confirmed the aforementioned observations and also demonstrated upregulation of NOS2, SIRT1, SITR3, POLRMT, MRPL43 and NFkB with antidiabetic agents. We conclude that Sitagliptin most effectively modulates beneficial immune-relevant pathways in a human beta cell line., (Copyright © 2019 Elsevier Ltd. All rights reserved.)