Vpliv akutne hiperglikemije na delovanje kognitivnih področij možganov pri otrocih s sladkorno boleznijo tipa 1 ; The impact of acute hyperglycaemia on the function of cognitive areas in the brain in children with type 1 diabetes mellitus

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Titel: Vpliv akutne hiperglikemije na delovanje kognitivnih področij možganov pri otrocih s sladkorno boleznijo tipa 1 ; The impact of acute hyperglycaemia on the function of cognitive areas in the brain in children with type 1 diabetes mellitus

Beteiligte: Šuput Omladič, Jasna [Verfasser:in]

Erschienen: [Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 2021

Sprache: Slowenisch

Entstehung:

Hochschulschrift: Dissertation, 2021

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Beschreibung: POVZETEK 1.8. Uvod Sladkorna bolezen tipa 1 (SB1) je ena najpogostejših kroničnih bolezni otroštva. Slabo urejena sladkorna bolezen vpliva na delovanje možganov. Z raziskavami so ugotovili, da imajo bolniki s SB1 in SB2 med akutno hiperglikemijo nižje dosežke pri govornem in celostnem IQ preizkusu. Vzrok kognitivnega upada pri bolnikih s SB1 ni znan, predpostavlja se, da bi bil lahko povezan z oksidativnim stresom in vnetjem. Prav tako še ni znano, katera področja možganov so najbolj prizadeta. 1.9. Cilji Cilji raziskave so bili: ? s fMRI opredeliti vpliv akutne hiperglikemije (20 mmol/l) na področja možganov, povezanih z načrtovanjem, prostorskim spominom in impulzivnostjo pri otrocih in mladostnikih s SBT1 ; ? z 1 H-MRS opredeliti vpliv 2-urne hiperglikemije na koncentracijo glukoze, mioinozitola, N- acetilaspartata, holina v področjih možganov, ki so vključene pri nadzornih funkcijah (talamus, frontalna možganska skorja, frontalna bela možganovina) pri otrocih in mladostnikih s SBT1. ? opredeliti vpliv 2-urne hiperglikemije na raven vnetnih mediatorjev (IL-6, fibrinogen) v periferni krvi pri otrocih in mladostnikih s SBT1 1.10. Metode V raziskavi je sodelovalo 20 otrok s SB1, starih med 11 in 19 let, brez kliničnih zapletov SB1, s podobno urejenostjo SB 1 v zadnjih 3 letih (HbA1c), normalno prehranjenih (ITM), nekadilcev, zdravljenih z intenzivirano inzulinsko shemo ali z inzulinsko črpalko, brez diabetične ketoacidoze ali težke hipoglikemije v zadnjem letu, s trajanjem SB1 5-10 let ; ter 20 zdravih prostovoljcev, skladnih po starosti. Otroci s SB1 so med evglikemično in hiperglikemično zanko opravili tako fMRI (Flankerjeva naloga, Londonski stolp, kapaciteta delovnega spomina) kot tudi H 1 -MRS preiskave. Vse MR preiskave so bile opravljene na 3T tomografu. Otrokom s SB1 smo na tešče in po 120-minutni hiperglikemiji odvzeli periferno kri za določitev kazalcev vnetja (IL-6,fibrinogen). Zdravi prostovoljci opravili enake preiskave fMRI in H 1 -MRS kot otroci s SB1, dvakrat zapored v istem dnevu, brez vpliva na vrednost krvnega sladkorja. 1.11. Hipoteze Pričakovali smo, da bomo opredelili: ? povečano delovanje možgan med izvajanjem naloge načrtovanja (Londonski stolp) med kratkotrajno hiperglikemijo v primerjavi z evglikemijo ; ? povečano delovanje možgan med izvajanjem naloge prostorskega spomina med kratkotrajno hiperglikemijo v primerjavi z evglikemijo ; ? večjo impulzivnost med kratkotrajno hiperglikemijo v primerjavi z evglikemijo ; ? spremembo koncentracije nevrotransmiterjev v določenih področjih možgan, povezanih z nadzornimi funkcijami, kar bi kazalo na spremembe v prenosu signala, ter funkciji celičnih membrane med kratkotrajno hiperglikemijo v primerjavi z evglikemijo povečanje koncentracije kazalcev vnetja v periferni krvi po kratkotrajni hiperglikemiji 1.12. Pomembnost Zaenkrat še ni objave fMRI med akutno hiperglikemijo, z izjemo abstrakta predstavljanega na ADA srečanju leta 2015, ko so pokazali, da je med akutno hiperglikemijo v stanju mirovanja povišana aktivacija možgan (fMRI resting state), zato bodo rezultati naše raziskave povsem izvirni. Ocena možnih škodljivih vplivov akutne hiperglikemije na kognicijo je pomembna za nadaljnje smernice zdravljenja sladkorne bolezni tipa 1, v smislu intenzivnosti inzulinske terapije in ciljev glede urejenosti. 1.13. Rezultati Med nalogo prostorskega spomina smo zaznali zmanjšano zmogljivost prostorskega delovnega spomina med akutno hiperglikemijo in pomembne razlike v aktivaciji regij zanimanja v različnih fazah prostorskega delovnega spomina (p = 0,014). Prostornina sive možganovine (p <0,005) in površina možganske skorje sta bili znatno zmanjšani (p <0,05) pri udeležencih s SB1. Značilno se je povečala frakcijska anizotropija (FA) (p <y0,05), radialna (RD) in aksialna difuznost (AD) pa sta se znatno zmanjšali (p <0,05) pri udeležencih z SB1. Možganska povezljivost se je znatno povečala (p <0,002) v skupini s SB1. Med akutno hiperglikemijo pa je bila, v primerjavi z evglikemijo, zmanjšana (p <0,002). 1.14. Zaključki Akutna hiperglikemija je negativno vplivala na sposobnost prostorskega delovnega spomina pri mladostnikih z SB1, ki je pomemben za vsakodnevno delovanje in akademsko uspešnost. Predlagani kompenzacijski mehanizem povečanih možganov povezljivost pri mladostnikih s SB1 med akutno hiperglikemijo ni učinkovit, kar ima negative vpliv na izvršilne funkcije. ; 1. ABSTRACT 1.1. Background Type 1 diabetes (T1D) is one of the most common chronic diseases of the childhood. Poor glycaemic control influences the brain function. Studies show lower intelligence quotient (IQ) scores in verbal and cognitive area in T1D and type 2 diabetes (T2D) patients during acute hyperglycaemic episodes. The cause of cognitive demise in T1D patients is not clear ; however, it could be related to oxidative stress and inflammation. It is also not clear which areas of the brain are the most affected. 1.2. Objective The goals of the study are studying the influence of 120 – minute hyperglycaemia on:  the function of cognitive areas in the brain by performing functional magnetic resonance imaging (fMRI),  inflammation (interleukin-6 (IL-6), fibrinogen) 1.3. Methods Twenty T1D patients, aged between 11 and 19 years, without chronic complication of T1D, similar values of glycated haemoglobin (HbA1c) in the last 3 years among the group, normal body mass index (BMI) for age and gender, non-smokers, on insulin pump treatment or treated with multiple daily injections (MDI), without diabetic ketoacidosis or severe hypoglycaemia in the last year, 5-10 years since T1D diagnosis, and 20 healthy volunteers matched for age participated in the study. T1D patients were subjected to euglycaemic and hyperglycaemic clamp. During both fMRI (Flanker task, Tower of London task, working memory capacity) and magnetic resonance spectroscopy (MRS) studies were performed using Philips MR. Blood samples were obtained in fasting state and after 120-minut of hyperglycaemia in order to measure inflammatory markers (IL-6,fibrinogen). The healthy volunteers performed the same fMRI and MRS studies as T1D patients twice in a row (on the same day) without any interventions regarding blood glucose levels. 1.4. Hypotheses We expected that:  more cognitive areas in the brain would be activated during planning task (Tower of London) in acute hyperglycaemia as compared to euglycaemic state  more cognitive areas in the brain would be activated during spatial memory task in acute hyperglycaemia as compared to euglycaemic state  the inhibition control would decrease during acute hyperglycaemia as compared to euglycaemic state  neurotransmitter levels (glucose, myoinositol, N- acetylaspartate, choline) would change in the brain (thalamus, frontal brain cortex, frontalna white matter) during acute hyperglycaemia, marking the change in signal transmission, increased cell membrane disintegration and dysfunction  the level of markers of inflammation in blood would increase during acute hyperglycaemia 1.5. Relevance To our knowledge no data describing fMRI during acute hyperglycaemia was published to date, apart from an abstract reporting increased activation in the brain in the resting state during acute hyperglycaemia, which is why the results of our research are completely original. Assessing the possible deleterious consequence of acute hyperglycaemia on cognitive function is relevant for future guidelines on insulin therapy and glucose control and may place the acute hyperglycaemia among clinically important acute complications of diabetes. 1.6. Results Lower spatial working memory (sWM) capacity during acute hyperglycaemia and significant differences in activation of regions of interest during different stages of the spatial working memory task (p=0.014) were observed. Grey matter volume (GMV) (p<0.005) and cortical surface area were significantly reduced (p<0.05) in participants withT1D. Fractional anisotropy (FA) was significantly increased (p<y0.05), radial (RD) and axial diffusivity (AD) were significantly decreased (p<0.05) in participants with T1D. Brain connectivity was significantly increased (p<0.002) in group with T1D. However, during acute hyperglycaemia, it was reduced (p<0.002) as compared to euglycaemia. 1.7. Conclusions Acute hyperglycaemia negatively affected sWM capacity in adolescents with T1D, which is relevant for daily functioning and academic performance. The proposed compensatory mechanism of increased brain connectivity in adolescents with T1D fails during acute hyperglycaemia, with possible deleterious effect on executive functions.

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