Role and regulation of Islet Brain 1 in B-cells failure evoked by diabetogenic environmental factors – DiabIB

The project will be achieved by following three specific tasks. The task 1 is dedicated to investigate the mechanism underlying the loss of IB1 in beta cells challenged with diabetes environmental stressors. This will undertaken using the state of the art of molecular biology tools. The task2 aims at delineating the kinases tethered by IB1 involved in the JNK activation evoked by environmental stressors. In particular we emphazise the contribution of the MAP3K Dual leucine zipper kinase in JNK activation triggered by IB1. In this task we postulate that IB1 ochestrates the assembly of the pro-survival JNK pathway. To reach this objective, interaction of IB1 with DLK and JNK will be examined in the cells either in basal or challenged with a stressful condition. This will be realized using immunoprecipitation (IP) experiments and mass spectroscopy. The goal of the task 3 is to understand how IB1 controls glucose-induced insulin secretion. In particular we aimed at determining the role of IB1 in the control of annexin A2 and the role of this latter in beta cell function.

Our findings unveil the role endoplasmic reticulum stress, as the potential repressor responsible of the diminution in the IB1. The latter preserves beta cells function and survival from adverse effects of environmental stress by inhibiting JNK activity. At present, the kinases that elicit JNK activation in beta cells are well known. In this respect, our work highlight the dual leucine zipper kinase (DLK) as a major MAP3K activating JNK3 through IB1. DLK, IB1 and JNK3 interacts each other. Silencing of DLK suppresses JNK3 activation in beta cells cultured with cytokines, and this is associated with a loss of insulin production, insulin secretion and increased apoptosis. Suppression of IB1 alter the annexin2 (anxA2) level. The latter regulates exocytosis and its silencing of AnxA2 mimicks the effects of IB1 silencing on glucose-induced insulin secretion. Understanding the mechanism whereby the expression of IB1 decreases in response to diabetogenic factors is crucial for combating the beta cell failure in diabetes. Furthermore, we do believe that elucidating the mechanism through which IB1 regulates the JNK pathway, and more generally, beta cell function, could help to refine existing therapies and/or to explore innovative therapeutic to counteract beta cell defects.

Overall the project addresses some important issues related to beta cell failure in T2D. Activation of JNK is a major determinant that account for beta cell loss in this disease. There is a wealth of in vivo and in vitro data that clearly show that blocking the JNK pathway markedly prevent cell death and thus emphasize the need to investigate new inhibitors of this pathway. Our former findings have revealed the requirement for the IB1 levels in the potent effects of a new recent class of anti-diabetic drug, namely the long acting agonists of the GLP-1R. We think that understanding the precise mechanisms by which IB1 acts in beta cells help in exploring novel concepts for medical research by improving beta cell life and number in T2D. Loss of the islets viability in the early steps of isolation is a major concern for transplantation purpose in type 1 diabetes before transplantation. Activation of JNK pathway largely contributes for reduction of islets numbers during isolation. We also believe that our research line will permit to find out strategies to increase islet viability and thereby to increase islet numbers to transplant in T1D. The present application takes the opportunity of the creation of the EGID in Lille. EGID groups three of the most relevant leaders in diabetes research in view of improving the critical mass and unifying independent but complementary experimental expertises. Research in beta cells is consistently a requirement for finding out efficient therapy to improve production of insulin in subjects with diabetes. The recent application of the GLP-1 mimetics and GLP-1 stabilizers as medicines for treatment of beta cell failure in patients with diabetes supports this statement. Thus our relative long term goal is to strengthen the research in diabetes in EGID and to create a pole for beta cell research in this institute. Toward this ambitious but feasible perspective this application is timely.

5 articles have been published so far 1) Jacovetti C, Abderrahmani A, Parnaud G, Jonas JC, Peyot ML, Cornu M, Laybutt R, Meugnier E, Rome S, Thorens B, Prentki M, Bosco D, Regazzi R. MicroRNAs contribute to compensatory ß cell expansion during pregnancy and obesity. J Clin Invest. Oct 1;122(10):3541-51, 2012. 2) Favre D, Le Gouill E, Fahmi D, Verdumo C, Chinetti-Gbaguidi G, Staels B, Caiazzo R, Pattou F, Lê K-A, Tappy L, Regazzi R, Giusti V, Vollenweider P, Waeber G and Abderrahmani A. Impaired expression of the inducible cAMP early repressor accounts for sustained adipose CREB activity in obesity. Diabetes. Dec;60(12):3169-74, 2011 3) Favre D, Niederhauser G, Fahmi D, Plaisance V, Brajkovic S, Beeler N, Allagnat F, Haefliger JA, Regazzi R, Waeber G, Abderrahmani A. Role for inducible cAMP early repressor in promoting pancreatic beta cell dysfunction evoked by oxidative stress in human and rat islets. Diabetologia. Sep;54(9):2337-46, 2011. 4) Abderrahmani A, Béraud-Dufour S, Noel J, Brau F, Waeber G, Mazella J, Coppola T. Neurotensin is a regulator of insulin secretion in pancreatic beta-cells. Int J Biochem Cell Biol. Oct;42(10):1681-1688, 2010.

Diabetes epidemic poses a major socio-economic burden over worldwide. The disease manifests when islets beta-cells from endocrine pancreas fail to release sufficient insulin to compensate for insulin resistance in target tissues. Impairment of beta-cell activity includes loss of glucose-induced insulin secretion and reduction in beta-cell mass. Beside genetic factor, prolonged exposure of beta-cells to an excess of environmental demands such as glucose, unsaturated fatty acids, pro-inflammatory cytokines and oxidized LDL accounts for a large part for development of beta-cell failure in diabetes. The adverse effects of all the stressors rely on activation of the JNK pathway, which is subsequent of the loss of expression of the islet brain 1 (IB1), a JNK scaffold protein that regulates insulin contents, nutrients-induced insulin secretion and cell survival. While IB1 tightly controls the insulin levels and cell survival by inhibiting the JNK pathway, regulation of insulin secretion achieved by the scaffold protein rule out the implication of the pathway. Our findings assume the ATF3, a transcription factor elicited by endoplasmic reticulum stress, as the potential repressor responsible of the diminution in the IB1. Furthermore we highlight the dual leucine zipper kinase (DLK) and annexin2 (anxA2) as keys whereby the scaffold protein exerts its regulatory activity on JNK activity and insulin secretion, respectively. Understanding the mechanism whereby the expression of IB1 decreases in response to diabetogenic factors is crucial for combating the beta cell failure in diabetes. Furthermore, we do believe that elucidating the mechanism through which IB1 regulates the JNK pathway, and more generally, beta cell function, could help to refine existing therapies and/or to explore innovative therapeutic to counteract beta cell defects.