GLP-1 Analogue-Loaded Glucose-Responsive Nanoparticles as Allies of Stem Cell Therapies for the Treatment of Type I Diabetes.

Type 1 diabetes (T1D) is characterized by insufficient insulin secretion due to ß-cell loss. Despite exogenous insulin administration being a lifesaving treatment, many patients still experience severe glycemic lability. For these patients, a ß-cell replacement strategy through pancreas or pancreatic islet transplantation is the most physiological approach. However, donors' scarcity and the need for lifelong immunosuppressive therapy pose some challenges. This study proposes an innovative biomimetic pancreas, comprising ß- and α-cells differentiated from human induced pluripotent stem cells (hiPSCs) embedded in a biofunctional matrix with glucose-responsive nanoparticles (NPs) encapsulating a glucagon-like peptide 1 (GLP-1) analogue, which aims to enhance the glucose responsiveness of differentiated ß-cells. Herein, glucose-sensitive pH-responsive NPs encapsulating exenatide or semaglutide showed an average size of 145 nm, with 40% association efficiency for exenatide-loaded NPs and 55% for semaglutide-loaded NPs. Both peptides maintained their secondary structure after in vitro release and showed a similar effect on INS-1E cells' insulin secretion. hiPSCs were differentiated into ß- and α-cells, and insulin-positive cells were obtained (82%), despite low glucose responsiveness, as well as glucagon-positive cells (17.5%). The transplantation of the developed system in diabetic mice showed promising outcomes since there was an increase in the survival rate of those animals. Moreover, diabetic mice transplanted with cells and exenatide showed a decrease in their glucose levels. Overall, the biomimetic pancreas developed in this work showed improvements in diabetic mice survival rate, paving the way for new cellular therapies for T1D that explore the synergy of nanomedicines and stem cell-based approaches.

Targeting ß Cells with Cathelicidin Nanomedicines Improves Insulin Function and Pancreas Regeneration in Type 1 Diabetic Rats.

Type 1 diabetes (T1D) is an incurable condition with an increasing incidence worldwide, in which the hallmark is the autoimmune destruction of pancreatic insulin-producing ß cells. Cathelicidin-based peptides have been shown to improve ß cell function and neogenesis and may thus be relevant while developing T1D therapeutics. In this work, a cathelicidin-derived peptide, LLKKK18, was loaded in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), surface-functionalized with exenatide toward a GLP-1 receptor, aiming the ß cell-targeted delivery of the peptide. The NPs present a mean size of around 100 nm and showed long-term stability, narrow size distribution, and negative ζ-potential (-10 mV). The LLKKK18 association efficiency and loading were 62 and 2.9%, respectively, presenting slow and sustained in vitro release under simulated physiologic fluids. Glucose-stimulated insulin release in the INS-1E cell line was observed in the presence of the peptide. In addition, NPs showed a strong association with ß cells from isolated rat islets. After administration to diabetic rats, NPs induced a significant reduction of the hyperglycemic state, an improvement in the pancreatic insulin content, and glucose tolerance. Also remarkable, a considerable increase in the ß cell mass in the pancreas was observed. Overall, this novel and versatile nanomedicine showed glucoregulatory ability and can pave the way for the development of a new generation of therapeutic approaches for T1D treatment.

SARS-CoV-2 and diabetes: New challenges for the disease.

A novel small enveloped RNA virus with the typical characteristic of the family to which it belongs, a crown, hence the name coronavirus, appeared in December 2019 in Wuhan, China, and subdued the world to its influence. The particular severity of the disease and higher mortality rates in patients with associated morbidities, including hypertension, obesity and diabetes, increases the concern over the consequences of this pandemic. In this review, the features of SARS-CoV-2 will be addressed, as well as the reasons why it poses a particular challenge to diabetic patients. We will also highlight the recent treatment strategies being explored to control this pandemic. Emerging evidence demonstrates that the correct management of diabetes in those patients infected with SARS-CoV-2 is of utmost importance for the viral disease progression, therefore, the importance of blood glucose control will also be addressed.

Studies in the mouse model identify strain variability as a major determinant of disease outcome in Leishmania infantum infection.

BACKGROUND: Visceral leishmaniasis is a severe and potentially fatal disease caused by protozoa of the genus Leishmania, transmitted by phlebotomine sandflies. In Europe and the Mediterranean region, L. infantum is the commonest agent of visceral leishmaniasis, causing a wide spectrum of clinical manifestations, including asymptomatic carriage, cutaneous lesions and severe visceral disease. Visceral leishmaniasis is more frequent in immunocompromised individuals and data obtained in experimental models of infection have highlighted the importance of the host immune response, namely the efficient activation of host's macrophages, in determining infection outcome. Conversely, few studies have addressed a possible contribution of parasite variability to this outcome. METHODS: In this study, we compared three isolates of L. infantum regarding their capacity to grow in the organs of mice, the way they activate the host's macrophages and other components of the immune response and also their capacity to cope with host's antimicrobial mechanisms, namely reactive oxygen and nitrogen species. RESULTS: We found that the three parasite strains significantly differed regarding the degree to which they induced nitric oxide synthase (NOS2) and arginase expression in infected macrophages and the pattern of cytokine production they induced in the host, resulting in different degrees of inflammatory response in infected livers. Additionally, the three strains also significantly differed in their in vitro susceptibility to reactive oxygen and nitrogen species. This variability was reflected in the capacity of each strain to persist and proliferate in the organs of wild-type as well as NOS2- and phagocyte oxidase- deficient mice. CONCLUSIONS: The results obtained in this study show that parasite strain variability is an important determinant of disease outcome in L. infantum visceral leishmaniasis, with relevant implications for studies on host-pathogen interaction and also for leishmanicidal drug development.