Endocrinology of Diabetes and Fertility (EnDF)

• Induction of pancreatic β-cell proliferation and differentiation by modulation of Dyrk1A kinase activity. Convincing studies in human pancreas have demonstrated that there is a significant β-cell mass decreases in advanced type 2 diabetes (T2D). This is due to decreased proliferation and increased apoptosis, probably caused by gluco- and lipotoxicity. This loss of β-cells contributes to inadequate insulin secretion, a central aspect of the development of T2D. To counter this phenomenon, β-cell regeneration and islet preservation are seen as potential therapeutic strategies. In line with our long-lasting activities to identify molecular targets for the stimulation of β-cell regeneration, and in continuation of our previous work on GSK3β (Figeac et al. 2010, Am J Physiol Metab, 2010; Figeac et al. Mol Ther 2012; Pitasi et al. J Endocrinol, 2020), we have focused our research on Dyrk1A, an enzyme in close interaction with GSK3β. In partnership with the biotech company Perha Pharmaceuticals, Dyrk1A inhibitors are being tested in animal models (GK diabetic rats and db/db mice). These studies aim to investigate the effects of inhibitors on β-cell regeneration and identify the signaling pathways involved. The results could lead to the development of new therapies to preserve β-cell function and restore β-cell mass in T2D. Movassat (PI), B. Uzan (PI), S. Tolu, D.Picot. Collaborators: L. Meijer (Perha Pharmaceuticals), J. Dairou (LCBPT, UMR 8601), P. Cattan (Hôp. Saint-Louis, Paris 10). Fundings: Eurostars 2021, ANR PRCE 2022.
• Impact of the microenvironment on the regulation of healthy and diabetic ß-cell function. Several experimental and clinical studies have reported structural and functional alterations in the micro-vascularization of rodent and human islets during diabetic disease. This loss of exchanges between ß-cells and the circulation is thought to be a key factor in ß-cell dysfunction and the loss of regulation of the glucose response that characterizes T2D. One of the glucotoxic consequences of chronic hyperglycemia is excessive ATP production, leading to increased activation of P2-type purinergic signaling. The literature indicates a role for this P2-receptors (P2X) in the deleterious modulation of various tissues (adipose tissue and nerve cells) as well as in retinal and renal micro-vascularization in animal models of T2D. In continuation of our previous work (Quinault et al. Biochem Biophys Acta, 2016; Mesto et al. J Cell Physiol, 2022), our work aims to better understand the possible impact of purinergic signaling affecting ß-cell-endothelial cell interactions in the islet of Langherans in a glucotoxic environment (such as T2D). C. Tourrel-Cuzin (PI), B. Uzan, S. Tolu, J. Movassat, D. Picot.

• Disrupted hematopoiesis and immune cell infiltration in islets during diabetes. The bone marrow (BM) is the main site of blood cell production and contains hematopoietic stem and progenitor cells (HSPCs). Obesity is known to cause chronic inflammation in adipose tissue, which stimulates HSPC proliferation and increases myeloid cell production. However, the impact of diabetes without obesity on hematopoiesis has not yet been studied. Taking advantage of the Goto-Kakizaki (GK) rat model of T2D, which mimics the β-cell loss and islet inflammation present in diabetic patients, the aim is to characterize hematopoietic phenotypes in the BM and blood of GK rats at different stages of the disease (pre-diabetic and confirmed diabetic). In addition, we aim to understand how diabetes affects hematopoiesis and how a disrupted population of BM cells might influence islet inflammation and β-cell dysfunction in the pancreas (BM transplantations between GK and Wistar (healthy) rats). Subsequently, altered molecular pathways in the hematopoietic populations of GK rats at different stages of the disease will be analyzed to better understand the mechanisms underlying these abnormalities. B. Uzan (PI), C. Tourrel-Cuzin, J. Movassat, D. Picot, S. Tolu.

Environmental programming of metabolic diseases

The general awareness of the impact of the maternal nutritional and toxicological environment on offspring health has grown considerably in our societies in recent decades (Portha et al. Nutrients, 2019). However, the environmental inheritance (non-genetic transmission) of diseases, through the paternal lineage, remains underexplored. We have recently developed new projects on this emerging topic and shown that paternal protein-rich diet alters insulin sensitivity in their offspring in a sex-dependent manner (Gong et al. Biomolecules, 2021). As an extension of our research in this field, we are developing a project to understand the role of the toxicological environment, in response to current societal concerns linked to widespread exposure to environmental pollutants (endocrine disruptors, air pollution). We are studying the impact of paternal pre-conceptional exposure to endocrine disruptors on the metabolic health of offspring. We are studying the profile of small non-coding RNAs in the sperm of male progenitors exposed to BPS, as well as the epigenetic modifications occurring in the pancreatic, muscular, hepatic and adipose tissues of their fetal and adult offspring (Collaboration with Dr. Valérie Grandjean). This study will provide further evidence that changes in the paternal environment prior to conception could have a significant impact on the metabolic health of their offspring in adulthood. J. Movassat (PI), D. L’Hôte, B. Uzan, C. Tourrel-Cuzin, D. Picot, S. Tolu. Collaborations : V. Grandjean (C3M – Inserm U1065).  Financement:Société Francophone du Diabète

The link between T2D and neurodegenerative diseases. The islet/brain axis.

Epidemiological data suggest an increased risk of developing Alzheimer’s disease (AD) in individuals with T2D. With the aging of the population, the socio-economic and human burden of these diseases are expected to increase considerably. Despite the large body of epidemiological evidence linking AD and T2D, the molecular mechanisms underlying this association are still unknown. In collaboration with Dr N Janel (BFA, team 1), we recently demonstrated that diabetic GK rats display several circulating Alzheimer’s-like markers (Movassat et al. Front Neurol, 2019). We will now analyze some of the brain and pancreatic features linking T2D to neurodegenerative diseases, in collaboration with Dr. N. Janel and Dr. J. Dairou (LCBPT, UMR 8601). The identification of shared molecular mechanisms between AD and T2D is crucial, as it could lead to the identification of common therapeutic targets for the treatment of these two interconnected diseases. J. Movassat (PI), S. Tolu, B. Uzan, D. Bailbé, C. Tourrel-Cuzin, D. Picot.  Collaborators: N. Janel (BFA, Team1), J. Dairou (LCBPT, CNRS UMR 8601).