Relations intercellulaires dans les îlots de Langerhans et leur rôle dans la sécrétion du glucagon

Les îlots de Langerhans sont de mini-organes comprenant des interactions cellulaires complexes et nécessaires à la régulation de la glycémie dans l'organisme. Toutefois, les mécanismes permettant de coordonner les différents types cellulaires de l'îlot sont nombreux et encore mal connus. Afin de mieux comprendre l'importance de ces interactions cellulaires, nous avons effectué deux études différentes. Dans notre première étude, nous avons pu constater que les cellules delta et PP présentent une distribution asymétrique au sein des îlots humains. En effet, les cellules PP sont majoritairement localisées aux bords des vaisseaux périphériques de l'îlot tandis que les cellules delta se trouvent majoritairement aux bords des vaisseaux qui s'invaginent à l'intérieur de l'îlot. Notre seconde étude a quant à elle permis de mettre en évidence le rôle essentiel des cellules bêta et des contacts cellulaires directs dans la régulation de la sécrétion du glucagon lors d'un challenge hypoglycémique

Facilitators and barriers of women's participation in HIV clinical research in Switzerland: A qualitative study

Objectives: Women are underrepresented in most HIV clinical trials in Western countries, but their participation remains crucial as the lack of information on sex-and gender-specific effects may hinder the safety and efficacy of antiretroviral treatments. The aim of this study was to identify barriers to and facilitators of women's participation in HIV clinical trials in Switzerland. Methods: We conducted semi-structured interviews among 20 women with HIV to explore factors associated with non-participation in clinical trials. The interviewer presented to participants a clinical trial's description and discussed it with them. Lexicometric analysis on transcribed interviews identified three themes and eight sub-themes related to the pros and cons of participation in HIV clinical trials. Results: Participants evoked mainly decision-making drivers, concerns for women living with HIV and treatment side-effects. They highlighted the need for extensive information provided by trusted healthcare professionals on the research process as central to the decision to enrol in HIV clinical trials. Familial responsibilities were clearly identified as barriers to their participation, but not pregnancy. Additional preoccupations were other health concerns and comorbidities and the consequences of stopping ongoing antiretroviral treatments. Conclusions: To overcome the barriers to the participation of women living with HIV in clinical research in Western countries, healthcare professionals and researchers should increase women's research literacy by involving them in the study design and by tailoring clinical trials to their social roles and health concerns. Trust in professionals is a facilitator of enrolment of women living with HIV that should be maintained.</p

Cell rearrangement in transplanted human islets

The major feature of the human pancreatic islet architecture is the organization of endocrine cells into clusters comprising central β cells and peripheral α cells surrounded by vasculature. To have an insight into the mechanisms that govern this unique islet architecture, islet cells were isolated, and reaggregation of α and β cells into islet-like structures (pseudoislets) after culture or transplantation into mice was studied by immunohistology. The pseudoislets formed in culture displayed an unusual cell arrangement, contrasting with the transplanted pseudoislets, which exhibited a cell arrangement similar to that observed in native pancreatic islet subunits. The pattern of revascularization and the distribution of extracellular matrix around transplanted pseudoislets were alike to those observed in native pancreatic islets. This organization of transplanted pseudoislets occurred also when revascularization was abolished by treating mice with an anti-VEGF antibody, but not when contact with extracellular matrix was prevented by encapsulation of pseudoislets within alginate hydrogel. These results indicate that the maintenance of islet cell arrangement is dependent on in vivo features such as extracellular matrix but independent of vascularization.-Lavallard, V., Armanet, M., Parnaud, G., Meyer, J., Barbieux, C., Montanari, E., Meier, R., Morel, P., Berney, T., Bosco, D. Cell rearrangement in transplanted human islets

The Role of Inflammation in β-cell Dedifferentiation

Chronic inflammation impairs insulin secretion and sensitivity. β-cell dedifferentiation has recently been proposed as a mechanism underlying β-cell failure in T2D. Yet the effect of inflammation on β-cell identity in T2D has not been studied. Therefore, we investigated whether pro-inflammatory cytokines induce β-cell dedifferentiation and whether anti-inflammatory treatments improve insulin secretion via β-cell redifferentiation. We observed that IL-1β, IL-6 and TNFα promote β-cell dedifferentiation in cultured human and mouse islets, with IL-1β being the most potent one of them. In particular, β-cell identity maintaining transcription factor Foxo1 was downregulated upon IL-1β exposure. In vivo, anti-IL-1β, anti-TNFα or NF-kB inhibiting sodium salicylate treatment improved insulin secretion of isolated islets. However, only TNFα antagonism partially prevented the loss of β-cell identity gene expression. Finally, the combination of IL-1β and TNFα antagonism improved insulin secretion of ex vivo isolated islets in a synergistic manner. Thus, while inflammation triggered β-cell dedifferentiation and dysfunction in vitro, this mechanism seems to be only partly responsible for the observed in vivo improvements in insulin secretion

Asymmetrical distribution of δ and PP cells in human pancreatic islets

The aim of this study was to evaluate the location of PP and δ cells in relation to the vascularization within human pancreatic islets. To this end, pancreas sections were analysed by immunofluorescence using antibodies against endocrine islet and endothelial cells. Staining in different islet areas corresponding to islet cells adjacent or not to peripheral or central vascular channels was quantified by computerized morphometry. As results, α, PP and δ cells were preferentially found adjacent to vessels. In contrast to α cells, which were evenly distributed between islet periphery and intraislet vascular channels, PP and δ cells had asymmetric and opposite distributions: PP staining was higher and somatostatin staining was lower in the islet periphery than in the area around intraislet vascular channels. Additionally, frequencies of PP and δ cells were negatively correlated in the islets. No difference was observed between islets from the head and the tail of the pancreas, and from type 2 diabetic and non-diabetic donors. In conclusion, the distribution of δ cells differs from that of PP cells in human islets, suggesting that vessels at the periphery and at the centre of islets drain different hormonal cocktails

Pharmacokinetic parameters and weight change in HIV patients newly switched to dolutegravir-based regimens in SIMPL'HIV clinical trial.

This study aims to evaluate the association between dolutegravir (DTG) pharmacokinetic parameters and weight changes in treatment-experienced people with HIV (PWHIV) from the Simpl'HIV study newly switched to a dual DTG-based regimen. We used multivariable linear regressions to evaluate the association between DTG pharmacokinetic parameters at week 48 (derived using an established model) and weight change between week 0 and week 48. We adjusted our model for potential confounders including CD4 nadir, female sex, African origin, age, weight at week 0 and presence of an NNRTI-based regimen before switch to DTG. The analysis included data from 39 PWHIV. An average significant weight gain of 2.4 kg was observed between baseline and week 48. DTG plasma exposure was not significantly associated with weight gain, even after adjusting for potential confounders (p=0.9). We found no significant association between DTG pharmacokinetic parameters and weight gain amongst PWHIV newly switched to a DTG-based dual regimen

Beta-cell-specific expression of NOX5 aggravates high fat diet-induced impairment of islet insulin secretion in mice

NADPH oxidases (NOX-es) produce reactive oxygen species and modulate β-cell insulin secretion. Islets of Type2 diabetic subjects present elevated expression of NOX5. Here we sought to characterize regulation of NOX5 expression in human islets in vitro and to uncover the relevance of NOX5 in islet function in vivo using a novel mouse model expressing NOX5 in doxycycline-inducible, β-cell-specific manner (RIP/rtTA/NOX5 mice). In situ hybridization and immunohistochemistry employed on pancreatic sections demonstrated NOX5 mRNA and protein expressions in human islets. In cultures of dispersed islets NOX5 protein was observed in somatostatin-positive (δ) cells in basal (2.8mM glucose) conditions. siRNA-mediated knock-down of NOX5 in human islets cultured in basal glucose concentrations resulted in diminished glucose-induced insulin secretion in vitro. However, when islets were preincubated in high (16.7mM) glucose media for 12 hours, NOX5 appeared also in insulin-positive (β) cells. In vivo, mice with β-cell NOX5 expression developed aggravated impairment of glucose-induced insulin secretion compared to control mice when challenged with 14 weeks of high-fat diet. Similarly, in vitro palmitate pre-incubation resulted in more severe reduction of insulin release in islets of RIP/rtTA/NOX5 mice compared to their control littermates. Decreased insulin secretion was most distinct in response to theophylline stimulation suggesting impaired cAMP-mediated signaling due to increased phophodiesterase activation. Our data provide the first insight into the complex regulation and function of NOX5 in islets implying an important role for NOX5 in δ-cell mediated intra-islet crosstalk in physiological circumstances but also identifying it as an aggravating factor in β-cell failure in diabetic conditions