New avenues for GLP1 receptor agonists in the treatment of diabetes
Date
2021-10-11
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Abstract
Glükagoonilaadne peptiid 1 (GLP1) on hormoon, mis vabaneb soolestikust vastusena söömisele. GLP1-l on erinevates elundsüsteemides mitmeid toimeid. See osaleb vere glükoositaseme regulatsioonis: stimuleerides insuliini ja inhibeerides glükagooni vabanemist veresuhkru tase langeb. GLP1 toimel aeglustub mao motoorika ja tühjenemine. Kesknärvisüsteemis reguleerib GLP1 söögiisu ning seeläbi kehakaalu. GLP1 füsioloogilistel toimetel põhineb ravimklassi GLP1 retseptori agonistide kasutamine. Need on laialdaselt kasutatavad diabeediravimid, mis lisaks veresuhkru taseme langetamisele vähendavad söögiisu ja alandavad kehakaalu. Ravimklass on võrdlemisi ohutu, kuna hüpoglükeemia risk on väike. Lisaks on kõrvaltoimed võrdlemisi kerged, sagedasemateks iiveldus ja oksendamine.
GLP1 retseptori agonistide mõnede toimete suhtes kujuneb välja tolerantsus – näiteks mao motoorika aeglustumine väheneb ravimi kestval kasutusel. Samuti vähenevad ravimi korduval kasutamisel kõrvaltoimed, möödudes esimeste ravinädalatega. See, kas tolerantsus tekib ka GLP1 retseptori agonistide veresuhkru taset langetava toime suhtes, ei ole seni teada.
GLP1 retseptori agoniste on kasutatud haruldaste ühe geeni rikkest põhjustatud suhkurtõve vormide puhul. Wolframi sündroom on geneetiline haigus, mille käigus arenevad 1. tüüpi diabeet, magediabeet ja silmanärvi kahjustus. Seni ei ole haigusel spetsiifilist ravi ja suhkruhaiguse tekkel kasutatakse tavaliselt insuliini süste. Käesolevas töös uurisime, kas GLP1 retseptori agoniste saaks kasutada Wolframi sündroomi puhul tekkiva suhkurtõve raviks.
Uurimistöö eesmärkideks oli uurida GLP1 retseptori agonistide suhtes tekkivat tolerantsust hiirtel ja inimestel ning nende ravimite võimalikku toimet Wolframi sündroomi loommudelil. Eesmärkide saavutamiseks teostati loomkatseid hiirtel ning viidi läbi kliiniline uuring tervetel vabatahtlikel. Loomakatsete tulemused näitasid selget tolerantsuse teket hiirtel. Vastupidiselt loomkatsete tulemustele ei kujunenud aga tolerantsust välja inimeste puhul. Wolframi sündroomi loommudelis olid GLP1 retseptori agonistid efektiivsed veresuhkru langetajad, mis loob võimaluse nende kasutamiseks Wolframi sündroomi ravis.
Glucagon-like peptide 1 (GLP1) is a peptide hormone secreted from the gastrointestinal tract in response to food ingestion. Moreover, GLP1 is secreted from the nervous system, where it functions as a neurotransmitter and, surprisingly, from the endocrine pancreas during metabolic stress. GLP1 regulates several biological functions in different organ systems. As one of the incretins, GLP1 stimulates in a glucose-dependent manner insulin secretion and inhibits that of glucagon, leading to a decrease in blood glucose levels. It decelerates gastric motility and emptying, regulates feeding behavior and body weight. GLP1 receptor agonists (GLP1RAs) have become a popular tool for treating type 2 diabetes, displaying positive impact beyond antihyperglycemic action. The key benefits of GLP1RAs include lower risk of hypoglycemia and modest weight loss. The adverse effects, most frequently nausea and vomiting, are generally mild and subside with time. One of the adverse effects of GLP1RA administration is decreased gastric motility. Interestingly, it is well known that this effect subsides with prolonged treatment. Thus, there is clear evidence that some effects of GLP1RAs are subject to tolerance development. It is logical to ask whether these drugs' core effects on glucose regulation may also be affected. GLP1RAs have been successfully used to treat certain forms of monogenic diabetes. We have asked whether a rare type of diabetes associated with Wolfram syndrome may respond to GLP1RAs. This study aimed to elucidate whether tolerance develops toward GLP1RAs’ glucose-lowering effects in mice and humans, and to investigate the drug class effect in the animal model of Wolfram syndrome. The results from our animal experiments demonstrated that the glucose lowering effect of GLP1RAs were clearly weaker after prolonged treatment. Unlike in mice, in the small clinical trial in healthy volunteers, the effects of GLP1RAs did not wane after 3 weeks of administration. Thus, tolerance toward GLP1RAs’ glucose lowering-effect developed in mice but not in humans. In the animal model of Wolfram syndrome, GLP1RAs potently decreased glucose levels and, therefore, may have potential in the treatment of patients with Wolfram syndrome.
Glucagon-like peptide 1 (GLP1) is a peptide hormone secreted from the gastrointestinal tract in response to food ingestion. Moreover, GLP1 is secreted from the nervous system, where it functions as a neurotransmitter and, surprisingly, from the endocrine pancreas during metabolic stress. GLP1 regulates several biological functions in different organ systems. As one of the incretins, GLP1 stimulates in a glucose-dependent manner insulin secretion and inhibits that of glucagon, leading to a decrease in blood glucose levels. It decelerates gastric motility and emptying, regulates feeding behavior and body weight. GLP1 receptor agonists (GLP1RAs) have become a popular tool for treating type 2 diabetes, displaying positive impact beyond antihyperglycemic action. The key benefits of GLP1RAs include lower risk of hypoglycemia and modest weight loss. The adverse effects, most frequently nausea and vomiting, are generally mild and subside with time. One of the adverse effects of GLP1RA administration is decreased gastric motility. Interestingly, it is well known that this effect subsides with prolonged treatment. Thus, there is clear evidence that some effects of GLP1RAs are subject to tolerance development. It is logical to ask whether these drugs' core effects on glucose regulation may also be affected. GLP1RAs have been successfully used to treat certain forms of monogenic diabetes. We have asked whether a rare type of diabetes associated with Wolfram syndrome may respond to GLP1RAs. This study aimed to elucidate whether tolerance develops toward GLP1RAs’ glucose-lowering effects in mice and humans, and to investigate the drug class effect in the animal model of Wolfram syndrome. The results from our animal experiments demonstrated that the glucose lowering effect of GLP1RAs were clearly weaker after prolonged treatment. Unlike in mice, in the small clinical trial in healthy volunteers, the effects of GLP1RAs did not wane after 3 weeks of administration. Thus, tolerance toward GLP1RAs’ glucose lowering-effect developed in mice but not in humans. In the animal model of Wolfram syndrome, GLP1RAs potently decreased glucose levels and, therefore, may have potential in the treatment of patients with Wolfram syndrome.
Description
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Keywords
diabetes mellitus, diabetes mellitus, 2. type, Wolfram syndrome, pharmacotherapy, antidiabetic agents, drug tolerance, animal models