Îlot de Langerhans

Résumé

right|thumb|Un îlot de Langerhans|upright=1.2 Les cellules des îlots de Langerhans (ou îlots pancréatiques, insulae pancreaticae) sont des cellules endocrines (produisant des hormones) du pancréas regroupées en petits amas (ou îlots) disséminés entre les acini séreux (cavités arrondies débouchant sur le canal pancréatique.) Historique Ces îlots furent décrits en 1868 par le biologiste allemand Paul Langerhans (1847-1888). Ils furent nommés « îlots de Langerhans » en son honneur par Édouard Laguesse, par ailleurs créateur du mot « endocrine ». Structure Les îlots de Langerhans représentent environ 1 à 2 % de la masse du pancréas, soit . Un adulte possède entre , la plupart situés à l'arrière du pancréas. D'une taille comprise entre , l'îlot est ainsi constitué de quelques cellules pour les plus petits îlots, et d'environ cellules pour les plus grands. Les hormones produites par les îlots de Langerhans sont sécrétées directement dans la circulation sanguine par

Source officielle

https://fr.wikipedia.org/wiki/%C3%8Elot_de_Langerhans

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Pancreatic beta cells play a major role in the regulation of glucose homeostasis by secreting insulin in response to elevated blood glucose levels. A gradual deterioration of functional beta cell mass and the chronic elevation of blood glucose levels are central to development of type 2 diabetes. While the etiologies of Type 2 diabetes and age-related metabolic complications are complex, they are often associated with a decline of intracellular nicotinamide adenine dinucleotide (NAD+). NAD+ levels are maintained through the balance between its synthesis from NAD+ precursors and its degradation by several families of enzymes, including the sirtuin family of protein deacetylases, the ADP-ribosyl transferase enzymes (ARTDs or PARPs) and cADP ribose hydrolases (CD38). NAD+ declines are mostly associated with increased NAD+ consumption, which can be counteracted by dietary supplementation of NAD+ precursors. However, our knowledge on how different tissues utilize and respond to different NAD+ precursors for NAD+ synthesis is still incomplete. This, in turn, limits our ability to provide therapeutic benefits in clinical settings. In this project, we aim to understand the relevance of a particular NAD+ precursor, nicotinamide riboside (NR), in beta cell physiology and its potential use to treat beta cell dysfunction. To do so, we have used mice that are deficient for nicotinamide riboside kinase 1 (NRK1), the first and rate-limiting enzyme for the transformation of NR into NAD+. We demonstrate that NRK1 whole body knockout mice exhibit impaired insulin secretion after a meal or upon glucose challenge when fed a high fat diet. However, NRK1 deficiency in beta cell was not the causality for beta cell failure as differences observed in the NRK1 whole body KO mice were not phenocopied in NRK1 beta cell specific KO mice. Aged NRK1 whole body KO mice also exhibited dysfunctional beta cells and significant loss of insulin content and beta cell mass. Furthermore, NRK1 deficiency exacerbates the decline of NAD+ bioavailability and mitochondria function with age, even promoting fibrosis in multiple tissues. Together, our data suggests that endogenous NR metabolism is critical in maintaining whole body NAD+ homeostasis and to protect against mitochondria dysfunction and stress-related cell responses in pancreatic beta cells.

EPFL2022

Chargement

Role of metabolism and mitochondria during glucose sensing and glucose-induced dysfunction in human pancreatic beta-cells

Isabelle Chareyron

Glucose sensing and regulation of insulin secretion are the two main functions performed by the pancreatic beta-cell. Together these processes contribute to the tight control of blood glucose in our body. Compromising the ability of the beta-cells to properly secrete insulin can lead to the development of Type 2 diabetes. Mitochondria play an important role in beta-cell function, by integrating nutrients signals and modulating insulin secretion. In this thesis, we aimed at better understanding the role of metabolism and mitochondria during glucose sensing and glucose-induced dysfunction in human pancreatic beta-cells. To that end, we designed three studies looking at different aspects of beta-cell mitochondrial function. In the first one, we developed an in vitro model of glucose overload in human islet. We report an over activation of the mitochondria when returned to basal conditions after a 4 day culture in elevated glucose. Additionally, these mitochondria only poorly responded to nutrient stimulation. Impaired metabolism secretion coupling and insulin secretion indicated a partial loss of beta-cell function, despite the increased mitochondrial activity. After 4 days of elevated glucose treatment, unusually high levels of glycerol-3-phosphate and pyruvate, even in sub-stimulatory extracellular glucose concentrations, were observed. We propose that the accumulation of these metabolites renders beta-cells blind to subsequent glucose stimulation. After removing the glucose stress for 24 hours the mitochondrial energy metabolism was fully restored and metabolism-secretion coupling was normalized. In the second approach, we measured for the first time the matrix pH in primary human pancreatic beta-cells. We showed that the mitochondrial pH in beta-cell is more acidic than in other cell types. Furthermore, in response to glucose, the beta-cell mitochondrial matrix slightly acidifies, possibly due to uptake and metabolism of pyruvate. Lastly, we observed that adenoviruses used to deliver the genetically encoded pH sensor can have an intrinsic impact on mitochondrial pH and calcium signaling. It must be used at low infection units per cell in the study of primary beta-cells. In the third project, we tried to modify the mitochondrial energy metabolism in beta-cells by inhibiting mitochondrial protein synthesis. We used different antibiotics to achieve this, in particular chloramphenicol, known to interfere with the activity of the mitochondrial ribosome. Surprisingly, we observe that when mitochondrial protein synthesis is inhibited, the respiration of insulin-secreting cells (INS-1E cells, human islets) is not affected. Expression of mtDNA encoded respiratory chain subunits is reduced and a mitochondrial unfolded protein response initiated without reducing respiratory rates. This raises the possibility that limited activation of unfolded protein response has a positive effect on the cells. This doctoral thesis provides novel insights into various aspects of mitochondrial behavior in pancreatic beta-cells, both during physiological and pathophysiological conditions. Additional work is needed to better understand the molecular mechanisms underlying the mitochondrial adaptation to nutrient overload and the associated beta-cell dysfunction leading to the accelerated impairment of glucose homeostasis during the development of Type 2 diabetes.

EPFL2019

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Microencapsulation of Langerhans islets by laser induced photopolymerization

Olivier Jordan

EPFL1996

Chargement

EPFL2022

Role of metabolism and mitochondria during glucose sensing and glucose-induced dysfunction in human pancreatic beta-cells

Isabelle Chareyron

EPFL2019