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Title: Epigenetic mechanisms as new risk factors for the development of diabetic neuropathy in type 1 diabetes
Abstract:
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease in which absolute deficiency of endogenous insulin is observed. The treatment of choice is the lifetime administration of exogenous insulin by subcutaneous injection. The incidence of diabetes, including T1DM, has been increasing in recent years, and insufficient metabolic control can lead to the development of acute or chronic complications of diabetes, the risk of which increases with the duration of T1DM. According to the recommendations of the Polish Diabetes Association, prevention of the development of chronic complications of diabetes is one of the priorities of care for patient with diabetes. Diabetic neuropathy, the most commonly observed chronic complication, is divided into generalized polyneuropathies (including autonomic neuropathy) and focal neuropathies. Autonomic neuropathy concerns the control of the functioning of many internal systems such as cardiovascular (CAN), gastrointestinal tract or genitourinary. The occurrence of CAN is associated with a significantly higher risk of death from cardiovascular causes, and a significant reduction in the survival of patients with T1DM compared to patients without this complication. The reference diagnostic method for diagnosing CAN is the Ewing test battery. According to current PTD recommendations, tests for CAN should be performed in al ; l patients with T1DM as part of screening annually after five years after the diagnosis of diabetes. Risk factors for the development of diabetic neuropathy include: the duration of diabetes, lack of metabolic compensation, oxidative stress and chronic inflammatory process. Multi-year and multicenter studies (UKPDS and DCCT) have shown that improving metabolic control; through the use of intensive insulin therapy in people with diabetes; significantly reduces the incidence of chronic complications. On the other hand, those who had their treatment intensified with a delay were observed, despite optimizing metabolic compensation through the implementation of intensive insulin therapy, were still more likely to develop chronic complications compared to the group treated with intensive insulin therapy from the beginning. This situation was well described among patients in the EDIC study, which was a continuation of the observation of the patients’ fate from the DCCT study. Based on these observations, the theory of "metabolic memory" of hyperglycemia in diabetic patients was put forward, which contributed to the development of research on the role of non-genetic mechanisms in the etiopathogenesis of diseases, including diabetes and its complications. Studies of various populations and observations of monozygous twins have confirmed the role of not only genetics b ; ut also epigenetics, currently defined by numerous processes related to the control of gene expression as a result of modification of genetic material, not related to changes in the sequence of nucleotides in DNA, such as a change in the level of DNA methylation. Recently, there have been more and more reports about epigenetic factors conditioning the development of diabetes and its chronic complications. The association of a different metDNA profile with nerve fiber degeneration has been described in patients with T2DM and diabetic peripheral neuropathy. It should be noted that the previous works mainly concern T2DM. However, there is no information on the influence of the above epigenetic mechanisms on the development of neuropathy, and in particular CAN in patients with T1DM. Considering many questions and doubts about the mechanisms of "metabolic memory" leading to the development and progression of chronic organ complications; the aim of this study was to test the hypothesis whether epigenetic mechanisms have an impact on the development of autonomic diabetic neuropathy of the cardiovascular system in patients with T1DM. OBJECTIVES The general objective of the doctoral dissertation was to test the hypothesis whether selected epigenetic mechanisms have an impact on the development of autonomic diabetic neuropathy of the cardiovascular system in patient ; s with type 1 diabetes. The specific objectives were: 1. Review of existing knowledge on etiopathogenesis, symptoms and the latest clinical studies on autonomic neuropathy of the cardiovascular system in the course of diabetes, mainly type 1. 2. Estimation of the incidence of autonomic neuropathy of the cardiovascular system, in the context of the model (multiple injections vs continuous subcutaneous insulin infusion) of treatment and metabolic control and clinical characteristics of patients of individual T1DM therapy groups. 3. Determination of possible changes in the expression of genes included in the molecular pathways that may be responsible for the initiation of destruction of nerve tissue in the course of type 1 diabetes. 4. To investigate the hypothesis that DNA methylation (one of the epigenetic mechanisms) is involved in the regulation of the expression of genes responsible for the destruction/regeneration of nerve cells and may play a key role in the pathogenesis of diabetic neuropathy, based on the DNA model of peripheral blood cells. METHODOLOGY AND TEST RESULTS 1. Cardiovascular autonomic neuropathy in the course of diabetes - the review of actual knowledge. Gastoł J, Pawliński Ł, Kieć-Wilk B. Postepy Biochem. 2019 Dec 30;65(4):306-312. doi: 10.18388/pb.2019_287. Review. Polish. (review paper) The paper provided a review of the available lit ; erature on etiopathogenesis, diagnostics, symptoms, and the therapeutic possibilities of CAN. In addition to well-established risk factors such as HbA1c or the duration of diabetes, epigenetic dysregulation of gene expression is also important in the etiopathogenesis of neuropathy, which may be expressed, among others, by a different metDNA profile. The gold diagnostic standard of CAN remains to conduct tests using the so-called Ewing batteries. This method allows to assess the functioning of both the sympathetic and parasympathetic system. The diagnosis of CAN is made when min. 2 of the battery tests are incorrect. In addition, the advancement of CAN is evidenced by the number of incorrect tests (staging). 2. Is treatment of type 1 diabetes mellitus (insulin therapy, metabolic control) optimal for preventing cardiovascular autonomic neuropathy? Pawliński Ł, Gastoł J, Fiema M, Matejko B, Kieć-Wilk B. Endokrynol Pol. 2019;70(4):323-329. doi: 10.5603/EP.a2019.0011. (original work) The work was a retrospective assessment of a group of 93 patients treated in the Metabolic Clinic in the period 2011-2015. The therapeutic model used was intensive insulin therapy using multiple insulin injections (MDII) or continuous subcutaneous insulin infusion (CSII). Biochemical parameters were assessed on the basis of a sample of fasting venous blood and urine donated in the mo ; rning. An Ewing test battery was used to assess the presence and sophistication of CAN. In the T1DM group treated with CSII cardiovascular autonomic neuropathy was significantly less common than in the classical insulin pen group (p<0.001). The retrospective metabolic compensation rate (HbA1c) was significantly lower in the CSII-treated group (HbA1c 7.44±1.14% vs 8.55±1.67 p=0.049). Patients diagnosed with CAN had a longer duration of diabetes and co-occurrence of chronic kidney disease. In addition, in the analyzed population, 87% of patients over 40 years of age had elevated LDL cholesterol values, and more than 70% of patients also had elevated levels of non-HDL cholesterol. Patients treated with CSII had statistically significantly lower triglyceride levels. The use of modern technologies in the treatment of T1DM helps to achieve better metabolic control and thus reduce the risk of developing chronic complications, including CAN. 3. Specific gene expression in type 1 diabetic patients with and without cardiac autonomic neuropathy. Gastol J, Polus A, Biela M, Razny U, Pawlinski L, Solnica B, Kiec-Wilk B. Sci Rep. 2020 Mar 27;10(1):5554. doi: 10.1038/s41598-020-62498-7. (original work) 60 patients with T1DM were enrolled in the study, the control group consisted of 20 healthy volunteers. The diagnosis of CAN was documented on the basis of tests using Ewi ; ng batteries. The average duration of diabetes was 15 years. Microarray analysis, confirmed by qRTPCR, showed significant up-regulation of autophagy genes, mitochondrial quality, regulatory genes (mTOR, GABARAPL2),apoptosis, endocytoplasmic stress and inflammation in the T1DM group compared to the control group. On the other hand, down-regulation of genes of proteolytic enzymes of lysosomes (catepsins) and the gene encoding the subuued of the H+building protein - ATPase of the lysosome membrane was observed. There were no significant differences in gene expression between patients with T1DM+CAN and patients with T1DM-CAN. Microarray analysis comparing patients with T1DM and the control group showed activation of genes encoding enzymes involved in DNA repair, as well as inhibition of protein expression I and III of the complex as an evidence of impaired mitochondrial function. Analysis of gene expression showed activation of pathways associated with the inflammatory process, which was confirmed by the determination of IL-6 levels. In the group of patients with T1DM, a higher concentration of IL-6 was observed. The observed changes in gene expression and activation of intracellular metabolic pathways give a coherent picture of the important role of oxidative stress in the course of inflammation and activation of apoptosis and neuronal degeneration, constituting ; an important factor responsible for the pathogenesis and progression of diabetic autonomic neuropathy in patients with T1DM. The importance of inflammation, confirmed by elevated levels of the Il-6 marker in the pathomechanism of autonomic neuropathy of the cardiovascular system, has also been demonstrated in patients with properly treated type 1 diabetes. 4. Epigenetic mechanism in search for the pathomechanism of diabetic neuropathy development in diabetes mellitus type 1 (T1DM). Gastoł J, Kapusta P, Polus A, Pitera E, Biela M, Wołkow P, Pawliński Ł, Kieć-Wilk B. Endocrine. 2020 Apr;68(1):235-240. doi: 10.1007/s12020-019-02172-9. Epub 2020 Jan 4. (original work) The study enrolled 24 patients with T1DM+CAN, 25 patients with T1DM-CAN, and 25 healthy volunteers. Single-center study, homogeneous group of patients (T1DM) treated with intensive insulin therapy. Diagnostics for CAN were performed using a battery of Ewing tests (ProSciCard). The DNA material was obtained from fasting venous blood samples, then bisulfonated and hybridized using Infinium Methylation EPIC Kit, Illumina and imaged with Illumina HiScan. Changes in the expression of selected genes were verified using qRTPCR. Amplification was carried out using continuous fluorescence detection 7900 HT Fast Real-Time PCR system (Thermo Fisher Scientific). The clinical characteristics of the study population showe ; d a significantly lower proportion of HbA1c among patients without neuropathy, and CSII was a more common therapeutic model in this group. Analysis of the level of specific DNA methylation showed significant differences in the regions of genes responsible for the regeneration of nerve fibers (NINJ2) and the functioning of nerve cells (BRSK2, CLDN4). Compared to patients without diagnosed cardiovascular neuropathy, CAN+ patients had significantly higher NINJ2 methylation levels and lower BRSK2 and CLDN4 5'UTR methylation levels. QRT-PCR confirmed weaker expression of NINJ2 and CLDN4 in CAN+ patients. A different DNA methylation profile of genes responsible for the development and regeneration of nerve fibers in patients with T1DM and autonomic neuropathy of the cardiovascular system seems to confirm the role of epigenetic mechanisms involved in "metabolic memory", promoting the development of autonomic neuropathy, a chronic complication of type 1 diabetes. Due to the specificity of nerve tissue, further research on tissue cultures is advisable to better understand the subject of genes associated with neurons degeneration and regeneration (RAGs).
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Rada Dyscypliny Nauki medyczne
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Mar 22, 2024
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