Epigenetic Modifications Linked to T2D, the Heritability Gap, and Potential Therapeutic Targets.

With the pandemic of type 2 diabetes (T2D), there is an ever-increasing need to fully understand the underlying mechanisms of the disease. Type 2 diabetes shows a high heritability risk (25-80%); however, genes account only for 10% of this risk. From all the risk factors for diabetes, epigenetic mechanisms have the highest statistical scoring in explaining the disease. A multitude of organ-specific epigenomic changes have been linked to type 2 diabetes. Nutritional influences, mainly in the early life, physical activity level, environmental toxins act as epigenetic factors and the recognized epigenetic changes can represent a therapeutical target, new drugs being currently in development for this application. Our current review focuses on the most common epigenetic modifications linked to type 2 diabetes or insulin resistance, the potentially emerging epigenetic-related interventions and pharmacoepigenetic knowledge.

Genetic Approaches to the Study of Gene Variants and Their Impact on the Pathophysiology of Type 2 Diabetes.

Diabetes mellitus is an incurable progressive disease, characterized by elevated blood glucose levels, which lead to the development of micro- and macrovascular complications. Although the etiopathology of the disease remains unclear, it seems to be multifactorial, with an important interaction between genetics and environmental causes. Currently, the genetics of type 2 diabetes (T2D) is poorly understood. The recent advance of the genetic technologies and with a better understanding of genetics, more than 120 distinct genetic loci, with more than 150 variants, have been identified that may be involved in the pathogenesis of T2D. However, as these variants can account for only approximately 20% of the heritability of T2D, there is an obvious need for additional approaches to identify susceptibility genes or genetic mechanisms involved in the development of this disease. There is a growing number of genes found to be related to T2D; however, their individual impact on the pathogenesis of the disease appears to be low, while silencing of protective genes may also contribute to the development of this disease. The present review attempts to summarize our current knowledge in the field of genetics of T2D, highlighting the possible practical applications for each approach.

[Poor sleep quality and inadequate sleep duration related to obesity in two Roma subgroups in Transylvania]. / Elhízással összefüggo csökkent alvásminoség és nem megfelelo alvásidotartam két erdélyi roma alcsoportban.

Introduction: Short sleep duration and poor sleep quality may be associated with weight gain; this association has not yet been studied in Roma (Gipsy) population. Aim: Our aim was to study sleep patterns in two adult Roma subgroups (the wealthy Gabor and the poor Lovari Roma), compared to the majority of Hungarian population, in relation to obesity, knowing that Roma population has specific socio-cultural characteristics, with a rapidly changing lifestyle. Method: A population-based cross-sectional survey was conducted in a rural region in Transylvania, where the above groups are cohabiting. The groups were age- and gender-matched. Results: Sleep duration was 7.18 ± 1.6 hours in the Gabor Roma, 7.67 ± 1.5 hours in the Lovari Roma and 7.37 ± 1.5 hours in the non-Roma group. In average, 70% of them had enough sleep (≥7 hours). 38.6% of Gabor Roma, 27.1% of Lovari Roma and 23.5% of non-Roma had poor-quality sleep (p = 0.05). Gabor Roma had significantly higher body mass index (31.1 ± 4.6 versus 27.4 ± 5.2 and 28.66 ± 5.7 kg/m2, p = 0.004), and this correlated inversely with sleep duration (F = 14.85, p<0.000). Conclusion: Gabor Roma had significantly higher percentage of poor-quality sleep. Sleep duration and sleep quality were linked with obesity, mainly in the Roma population. Orv Hetil. 2019; 160(32): 1279-1283.

FDG PET is superior to CT in the prediction of viable tumour in post-chemotherapy seminoma residuals.

AIM: In advanced seminoma the management of residuals after completion of chemotherapy is controversial. Some centres routinely perform surgery for lesions > or =3 cm diameter, others recommend surgery solely if the residual fail to shrink or show even growth. This study prospectively investigates whether FDG PET can improve the prediction of viable tumour in post-chemotherapy seminoma residuals. MATERIALS AND METHODS: After an expansion of a previous study population, 54 patients from eight centres with metastatic seminoma and a CT-documented mass after chemotherapy were included in the study. Six patients were excluded from evaluation because of protocol violations. After PET, the patients underwent either surgery or were followed clinically. On follow-up the lesions were considered to be non-viable when there was unequivocal shrinking, or when the lesion remained morphologically stable for at least 24 months. Any lesion growth was assumed to be malignant. PET results were compared to CT discrimination (< or > or =3 cm) of the residual masses. RESULTS: Fifty-two PET scans were evaluable. After adequate chemotherapy, there were 74 CT-documented residual masses ranging in size from 1 to 11 cm (median, 2.2 cm). Their dignities were confirmed histologically in 13 lesions, or by follow-up CT in 61 lesions. Four of forty-seven lesions <3 cm and 11/27 lesions > or =3 cm were viable. PET was true positive in one lesion <3 cm and in 11 lesions > or =3 cm, false negative in three lesions <3 cm, and true negative in 59 lesions (43 lesions <3 cm). No PET scan was false positive. In detecting viability the sensitivity and specificity was 73% (95% CI, 44-88), and 73% (59-83), respectively, for CT (< or > or =3 cm); and 80% (51-95), and 100% (93-100), respectively, for PET (specificity, P < 0.001). CONCLUSION: In post-chemotherapy seminoma residuals, a positive PET is highly predictive for the presence of viable tumour. The specificity of PET is significantly higher than that of CT when using a > or =3 cm cut-off. A negative PET scan is excellent for the exclusion of disease in lesions > or =3 cm, with a somewhat higher sensitivity than CT (n.s.). PET can contribute to the management of residual seminoma lesions, especially in terms of avoiding unnecessary additional treatment for patients with lesions > or =3 cm.

Imaging of advanced neuroendocrine tumors with (18)F-FDOPA PET.

UNLABELLED: Nuclear medicine plays an important role in the imaging of neuroendocrine tumors (NETs). Somatostatin receptor scintigraphy (SRS) with (111)In-labeled somatostatin receptor analogs is a standard procedure for the detection and staging of NET. Based on the ability of NETs to store biogenic amines, this study evaluated whether 6-(18)F-fluoro-L-DOPA ((18)F-FDOPA) is a suitable PET tracer for NETs. METHODS: Twenty-three patients with histologically verified NETs in advanced stages were consecutively enrolled in the study. All patients underwent PET with (18)F-FDOPA, CT, and SRS within 6 wk. In patients with discrepancies between nuclear medicine and radiologic methods, follow-up investigations were performed by CT, MRI, and ultrasound. (18)F-FDOPA PET with attenuation correction was done 30 and 90 min after injection from the neck to the upper legs. SRS was performed with (111)In-DOTA-D-Phe(1)-Tyr(3)-octreotide at 6 and 24 h. All images were read without knowledge of the results of the other modalities. In every patient, the following regions were evaluated separately: bones, mediastinum, lungs, liver, pancreas, and others, including the abdominal and supraclavicular lymph nodes, spleen, and soft- tissue lesions. The findings were confirmed by clinical examination. The nuclear medicine methods were compared against morphologic imaging, which was considered as gold standard. RESULTS: The most frequently involved organs or regions were the liver (prevalence, 70%) and bone (52%), followed by mediastinal foci (31%), the lungs (22%), and the pancreas (13%). Fifty-two percent of patients had various lymphatic lesions. (18)F-FDOPA was most accurate in detecting skeletal lesions (sensitivity, 100%; specificity, 91%) but was insufficient in the lung (sensitivity, 20%; specificity, 94%); SRS yielded its best results in the liver (sensitivity, 75%; specificity, 100%); however, it was less accurate than PET in all organs. In about 40%, initial CT failed to detect bone metastases shown by PET that were later on verified by radiologic follow-up. CONCLUSION: (18)F-FDOPA PET performs better than SRS in visualizing NETs and may even do better than CT for bone lesions. SRS is essential to establish the usefulness of therapy with somatostatin analogs, yet is less accurate than (18)F-FDOPA PET for staging.

Isotopic renal function studies in severe hypothyroidism and after thyroid hormone replacement therapy.

AIM: To investigate the possible changes in the renal tubular function in severe short-term hypothyroidism using (99m)Tc-MAG(3) renography. METHODS: 27 consecutive thyroidectomized patients (7 males and 20 females) aged 19-79 (mean 53) years were included in the present study. (99m)Tc-MAG(3) renography was performed in all patients before and after thyroid hormone replacement therapy. In addition, (51)Cr-EDTA clearance and serum creatinine concentrations were determined. RESULTS: The serum creatinine concentrations were significantly increased in hypothyroidism as compared with the concentrations after thyroxine substitution (1.30 +/- 0.44 vs. 1.04 +/- 0.32 mg/dl, p < 0.05). According to the (51)Cr-EDTA clearance, the glomerular filtration rate was significantly lower in hypothyroidism than after treatment (61 +/- 18 vs. 75 +/- 23 ml/min). In contrast, we did not find any significant change in the renographic parameters for (99m)Tc-MAG(3) before and after treatment (total excreted activity 20 min after administration 51 +/- 12 vs. 54 +/- 14%; T(max) left:right 4.2 +/- 1.77 : 3.91 +/- 1.06 min vs. 4.1 +/- 1.66 : 4.4 +/- 1.96 min). CONCLUSIONS: We did not find any influence of thyroid hormones on the outcome of (99m )Tc-MAG(3) renography. As (99m)Tc-MAG(3) reflects the tubular function, it seems that the renal hemodynamic changes in severe hypothyroidism mainly affect the glomerular function. In general, the glomerular filtration rate reduction seems to be reversible after hormone substitution therapy; however, care has to be taken in patients with renal insufficiency.

Brain tumour imaging with PET: a comparison between [18F]fluorodopa and [11C]methionine.

Imaging of amino acid transport in brain tumours is more sensitive than fluorine-18 2-fluoro-deoxyglucose positron emission tomography (PET). The most frequently used tracer in this field is carbon-11 methionine (MET), which is unavailable for PET centres without a cyclotron because of its short half-life. The purpose of this study was to evaluate the performance of 3,4-dihydroxy-6-[(18)F]fluoro-phenylalanine (FDOPA) in this setting, in comparison with MET. Twenty patients with known supratentorial brain lesions were referred for PET scans with FDOPA and MET. The diagnoses were 18 primary brain tumours, one metastasis and one non-neoplastic cerebral lesion. All 20 patients underwent PET with FDOPA (100 MBq, 20 min p.i.), and 19 of them also had PET scans with MET (800 MBq, 20 min p.i.). In all but one patient a histological diagnosis was available. In 15 subjects, histology was known from previous surgical interventions; in five of these patients, as well as in four previously untreated patients, histology was obtained after PET. In one untreated patient, confirmation of PET was possible solely by correlation with MRI; a histological diagnosis became available 10 months later. MET and FDOPA images matched in all patients and showed all lesions as hot spots with higher uptake than in the contralateral brain. Standardised uptake value ratios, tumour/contralateral side (mean+/-SD), were 2.05+/-0.91 for MET and 2.04+/-0.53 for FDOPA (NS). The benign lesion, which biopsy revealed to be a focal demyelination, was false positive, showing increased uptake of MET and FDOPA. We conclude that FDOPA is accurate as a surrogate for MET in imaging amino acid transport in malignant cerebral lesions for the purpose of visualisation of vital tumour tissue. It combines the good physical properties of (18)F with the pharmacological properties of MET and might therefore be a valuable PET radiopharmaceutical in brain tumour imaging.