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Control of insulin secretion: Methylglyoxal (MGO)-modification of intracellular CD59 impairs insulin secretion by ß-cells.

Projectomschrijving

Versuikering van een eiwit

Hoe komt het dat mensen met diabetes type 2 minder insuline maken? Deze onderzoekers bekijken de rol van een versuikerd eiwit in de insulineproducerende cellen.

Minder insuline door kapotte brugfunctie

Bij het ontstaan van diabetes type 2 maakt de alvleesklier steeds minder insuline aan. Onlangs ontdekte dr. Van Greevenbroek (Universiteit Maastricht) dat een bepaald eiwit in de insulineproducerende cellen versuikerd raakt bij mensen met prediabetes of diabetes type 2, en niet meer goed werkt. Dit eiwit speelt een belangrijke rol in de uitscheiding van insuline.
Bij gezonde mensen vormt dit eiwit, CD59, een brug tussen de blaasjes in de insulineproducerende cel waarin insuline is opgeslagen en het celmembraan, waarna de inhoud van de blaasjes (insuline) wordt uitgescheiden.

De hypothese van dr. Van Greevenbroek was dat wanneer CD59 versuikerd raakt, het deze brugfunctie niet meer kan vervullen waardoor er minder insuline vrijkomt. Dat zou een indicatie zijn dat, indien er een manier gevonden wordt de versuikering van het eiwit te remmen, dit gunstig kan zijn voor insulineproductie.

Insulineproductie verhogen

Uit het onderzoek is duidelijk geworden dat het stofje Methylglyoxal (MGO) eiwitten zoals CD59 kan versuikeren. De onderzoeker vond dat mensen die meer van dat stofje in hun bloed hebben, inderdaad minder goed insuline uit kunnen scheiden. Verder onderzoek zal uitwijzen of deze twee bevindingen een oorzakelijk verband hebben.

Verslagen


Samenvatting van de aanvraag

In this project I will focus on a newly-identified molecule in the ß-cell that has been classified as a novel player in the secretion of insulin from its secretory granules. The main goal of this project is to investigate how modifications of this protein, CD59, in prediabetes and (early) diabetes can impair the insulin secretion process. In the past 10 years, complement activation has been implicated in the development of insulin resistance and type 2 diabetes. Exciting data in the literature now provoked the idea that complement activation does not only lead to type 2 diabetes via induction of insulin resistance, but also via impaired insulin secretion. It was shown that the extracellular complement regulator CD59, which protects cells against unwanted complement-induced lysis, has an unexpected and important intracellular role in ß-cells: Depletion of CD59 from ß-cells resulted in a 60% reduction in glucose-stimulated insulin secretion and CD59 was shown to be essential for the release of insulin from its secretory granules in the ß-cell. CD59 on the secretory granules acts as a bridge between the granules and the plasma membrane in the process of insulin secretion. Noteworthy, it has been previously shown that glycation of extracellular CD59 impairs its protective potential against cell lysis. In this breakthrough project I propose a completely novel mechanism for the progression of ß-cell dysfunction in individuals with prediabetes and early stages of type 2 diabetes. I hypothesize that increased concentrations of the glucose-derived a-dicarbonyl methylglyoxal (MGO) in the ß-cell, as occur during (postprandial) episodes of hyperglycaemia, affect the function of intracellular CD59 via modification of its arginine residues by MGO. This impairs the bridge-function of CD59 in the release of insulin from its storage granules. This results in insufficient insulin secretion and, consequently, leads to development and progression of type 2 diabetes. I intend to address this hypothesis in 3 steps. Step1: Proof on concept in vitro - Herein I will investigate the formation of MGO adducts on CD59 in ß-cells and evaluate how this affects insulin secretion. Step 2: Proof of concept in vivo - I will evaluate the extent to which MGO-adducts are present in CD59 in the pancreas of rodents that were exposed to MGO. Step 3: Proof of concept in humans - I will evaluate the relevance of this hypothesis for human (pre)diabetes. For this I will study, in a prospective human cohort, how whole body MGO stress is related to (impaired) ß-cell function If the hypothesis is correct, it will have important implications: - it will substantially strengthen the potential for the relief of glucose-induced a-dicarbonyl stress as a target to prevent progression of prediabetes to diabetes. Substances to relief a-dicarbonyl, such as pyridoxamine, are already studied in the context of diabetes complications, but their impact may be much more substantial, and extend to the preservation of ß-cell function. - the results of this project have the potential to reach beyond ß-cell (patho)physiology since exocytosis of insulin-containing secretory granules from ß-cells is similar to secretion of neurotransmitter from their storage granules at the synaptic end of neurons. Hence, the implications of this breakthrough project extend to (a) the neurological complications of diabetes, and (b) neurological consequences of other diseases that are characterized by a-dicarbonyl stress. I consider myself to be the right person to execute this breakthrough project successfully within the dedicated one-year period because I am trained as a Medical Biologist and as an Epidemiologist and have extensive hands-on experience in both areas of expertise, I have a very solid background in complement research, and I have excellent contacts in the field of both complement research and glycation research. Thus, my personal expertise, scientific embedding and scientific network are ideally suited for the current project in which complement and glycation enter the field of ß-cell (patho)fysiology.

Kenmerken

Projectnummer:
459001017
Looptijd: 100%
Looptijd: 100 %
2018
2021
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. M.M.J. van Greevenbroek PhD
Verantwoordelijke organisatie:
Maastricht University