Rescuing Pancreatic Beta Cells to Treat Diabetes: Strategies and Hurdles

Editors

Teresa Pereira

Uppsala University

Erwin Ilegems

Karolinska Institutet (KI)

Impact

Original Research

19 April 2023

Small molecule glucagon release inhibitors with activity in human islets

Michael A. Kalwat

, 7 more and

Melanie H. Cobb

2,231 views

1 citations

EndoC-betaH1 cells were lipofected with scramble (Scr) or ADA1 siRNA. Two days later cells were treated with 1 mM adenosine (Ado 1 mM) (left panel) or with palmitate + high glucose (P + HG) (right panel). The next day cells were analysed by flow cytometry.

Original Research

25 January 2023

Metabolic stress-induced human beta-cell death is mediated by increased intracellular levels of adenosine

Anongnad Ngamjariyawat

, 4 more and

Nils Welsh

1,950 views

3 citations

P2X receptors are ionotropic, ligand-gated ion channel receptors which are permeable to Na+, K+ and Ca2+ ions after activation by ATP. To date, seven subunits (P2X1→7) has been identified. Their impact on insulin secretion is quite controversial, with stimulatory and/or inhibitory effects described. P2Y receptors are metabotropic receptors from the large family of G protein-coupled receptors. They can activated by ATP but also by ADP, UTP and UDP. Eight receptor subtypes have been identified and subdivided into two P2Y receptor subfamilies: P2Y1, 2, 4 and 6 which are mainly coupled to Gq proteins and activate phospholipase C β pathway (PLCβ). P2Y11 can also be coupled to Gs proteins and thus stimulate adenylate cyclase (AC) and the synthesis of the second messenger, cAMP. The second group includes the P2Y12, 13 and 14 isoforms and are mainly coupled to Gi proteins and inhibit adenylate cyclase and cAMP synthesis. A study done by our team has showed that P2Y activation can stimulate glucose-induced insulin secretion by acting on the distal steps of insulin exocytosis including the subcortical actin network and insulin granules exocytosis. However, the mechanisms involved in this stimulation remains unknown.

Mini Review

09 December 2022

P2-type purinergic signaling in the regulation of pancreatic β-cell functional plasticity as a promising novel therapeutic approach for the treatment of type 2 diabetes?

Nour Mesto

, 1 more and

Cécile Tourrel-Cuzin

2,276 views

2 citations

(A–D). barplot of gene ontology terms enriched for biological processes for clusters 1, 4, 5 and 6 using the R package clusterProfiler. (E). Venn diagram of genes belong to cluster 1 (grey circle) and 6 (blue circle) with previously reported TOP-RNAs (white circle).

Original Research

05 August 2022

Glucose controls co-translation of structurally related mRNAs via the mTOR and eIF2 pathways in human pancreatic beta cells

Manuel Bulfoni

, 7 more and

Bertrand Cosson

Pancreatic beta cell response to glucose is critical for the maintenance of normoglycemia. A strong transcriptional response was classically described in rodent models but, interestingly, not in human cells. In this study, we exposed human pancreatic beta cells to an increased concentration of glucose and analysed at a global level the mRNAs steady state levels and their translationalability. Polysome profiling analysis showed an early acute increase in protein synthesis and a specific translation regulation of more than 400 mRNAs, independently of their transcriptional regulation. We clustered the co-regulated mRNAs according to their behaviour in translation in response to glucose and discovered common structural and sequence mRNA features. Among them mTOR- and eIF2-sensitive elements have a predominant role to increase mostly the translation of mRNAs encoding for proteins of the translational machinery. Furthermore, we show that mTOR and eIF2α pathways are independently regulated in response to glucose, participating to a translational reshaping to adapt beta cell metabolism. The early acute increase in the translation machinery components prepare the beta cell for further protein demand due to glucose-mediated metabolism changes.

2,733 views

7 citations

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