MARIA LUCIA CARDILLO CORREA GIANNELLA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/18 - Laboratório de Carboidratos e Radioimunoensaios, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/18 - Laboratório de Carboidratos e Radioimunoensaios, Hospital das Clínicas, Faculdade de Medicina - Líder
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- Diabetes induces tri-methylation at lysine 9 of histone 3 at Slc2a4 gene in skeletal muscle: A new target to improve glycemic control(2019) YONAMINE, Caio Y.; ALVES-WAGNER, Ana B.; V, Joao Esteves; OKAMOTO, Maristela M.; CORREA-GIANNELLA, Maria L.; GIANNELLA-NETO, Daniel; MACHADO, Ubiratan F.Expression of the glucose transporter GLUT4, encoded by Slc2a4 gene, is reduced in both type 1 and type 2 diabetes (T1D and T2D), contributing to glycemic impairment. The present study investigated epigenetic regulations at the Slc2a4 promoter in skeletal muscle of T1D- and T2D-like experimental models. Slc2a4/GLUT4 repression was observed in T1D and T2D and that was reversed by insulin and resveratrol treatments, respectively. In both T1D-like and T2D-like animals, tri-methylation at lysine 9 of histone 3 (H3K9me3) increased in the Slc2a4 enhancer segment, whereas MEF2A/D binding into this segment was reduced; all effects were reversed by respective treatments. This study reveals that increased H3K9me3 in the Slc2a4 promoter enhancer segment contributes to reduce GLUT4 expression in skeletal muscle and to worse glycemic control in diabetes, pointing to the H3K9me3 of Slc2a4 promoter as a potential target for development of new approaches for treating diabetes.
- Insulin Glargine U100 Improved Glycemic Control and Reduced Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3 and 4(2019) BETONICO, Carolina C.; TITAN, Silvia Maria O.; LIRA, Aecio; PELAES, Tatiana S.; CORREA-GIANNELLA, Maria Lucia C.; NERY, Marcia; QUEIROZ, MarciaPurpose: Glycemic control in patients with chronic kidney disease (CKD) is particularly hard to achieve because of a slower insulin degradation by the kidney. It might modify the long-acting insulin analogue pharmacokinetics, increasing its time-action and the risk of hypoglycemia. However, because this insulin has no peak action, it might be a more tolerable approach to patients with CKD. This hypothesis remains to be tested, because no study has thus far examined the efficacy and safety profile of long-acting basal analogues in patients with significant loss of renal function. The purpose of this study was to compare the glycemic response to treatment with glargine U100 or neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus (T2DM) and CKD stages 3 and 4. Methods: Thirty-four patients were randomly assigned to glargine U100 or NPH insulin after a 2-way crossover open-label design. The primary end point was the difference in glycosylated hemoglobin (HbA(1c)) and in the number of hypoglycemic events between weeks 1 and 24, whereas secondary end points included changes in glycemic patterns, weight and body mass index, and total daily dose of insulin. HbA(1)(c) was determined by ion-exchange HPLC, and hypoglycemia was defined as glucose concentration of 54 mg/dL (3.0 mmol/L) detected by self-monitoring of plasma glucose or continuous glucose monitoring. Findings: After 24 weeks, mean HbA(1c )decreased on glargine U100 treatment (-0.91%; P < 0.001), but this benefit was not observed for NPH (0.23%; P = 0.93). Moreover, incidence of nocturnal hypoglycemia was 3 times lower with glargine than with NPH insulin (P = 0.047). (C) 2019 Published by Elsevier Inc.
- MicroRNAs 1915-3p, 2861, and 4532 Are Associated with Long-Term Renal Function Decline in Type 1 Diabetes(2019) MONTEIRO, Maria Beatriz; SANTOS-BEZERRA, Daniele P.; PELAES, Tatiana S.; VAIDYA, Vishal S.; CORREA-GIANNELLA, Maria Lucia
- Glutathione peroxidase 4 functional variant rs713041 modulates the risk for cardiovascular autonomic neuropathy in individuals with type 1 diabetes(2019) ADMONI, Sharon Nina; SANTOS-BEZERRA, Daniele Pereira; PEREZ, Ricardo Vesoni; PATENTE, Thiago Andrade; MONTEIRO, Maria Beatriz; CAVALEIRO, Ana Mercedes; PARISI, Maria Candida; NETO, Arnaldo Moura; PAVIN, Elizabeth Joao; QUEIROZ, Marcia Silva; NERY, Marcia; CORREA-GIANNELLA, Maria LuciaCardiac autonomic neuropathy is a neglected diabetic chronic complication for which genetic predictors are rarely reported. Oxidative stress is implicated in the pathogenesis of microvascular complications, and glutathione peroxidase 4 is involved in the detoxification of peroxides and of reactive oxygen species. Thus, the association of a functional variant in the gene encoding glutathione peroxidase 4 (rs713041) with this diabetic complication was investigated in 341 individuals with type 1 diabetes evaluated for cardiac autonomic neuropathy status (61.7% women, 34 [27-42] years old; diabetes duration: 21 [15-27] years; HbA1c: 8.3% [7.4-9.4]; as median [interquartile interval]). Cardiac autonomic neuropathy was present in 29% of the participants. There was an inverse association of the minor T allele of rs713041 with cardiac autonomic neuropathy (odds ratio = 0.39; 95% confidence interval = 0.17-0.90; p = 0.0271) after adjustment for potential confounders. The functional glutathione peroxidase 4 variant rs713041 modulated the risk for cardiac autonomic neuropathy in the studied population with type 1 diabetes.
- Allelic variations in genes belonging to glutathione system increase proliferative retinopathy risk in type 1 diabetes individuals(2019) PEREZ, Ricardo Vessoni; MACHADO, Cleide Guimaraes; SANTOS-BEZERRA, Daniele Pereira; ADMONI, Sharon Nina; PATENTE, Thiago Andrade; MONTEIRO, Maria Beatriz; CAVALEIRO, Ana Mercedes; QUEIROZ, Marcia Silva; NERY, Marcia; CORREA-GIANNELLA, Maria LuciaAims: Given the participation of oxidative stress in the pathogenesis of diabetic complications, we evaluated, in type 1 diabetes (T1D) individuals, the association between diabetic retinopathy (DR) and functional single nucleotide polymorphisms (SNPs) in regulatory regions of two genes belonging to the antioxidant glutathione (GSH) system: rs17883901 in GCLC and rs713041 in GPX4. Methods: A cross-sectional case-control study included 288 individuals (61% women, 34[+/- 11] years old, diabetes duration of 22[+/- 9] years, mean [+/- SD]) sorted according to DR stages: absence of DR (ADR), non proliferative DR (NPDR) and proliferative DR (PDR). SNPs were genotyped by real-time PCR using fluorescent labelled probes. Logistic regression models with adjustment for confounding covariates were employed. Results: The presence of at least one T-allele of rs17883901 in GCLC was an independent risk factor for PDR (OR 4.13, 95% CI 1.38-13.66, p = 0.014) in a polytomous regression model (PDR versus ADR). The presence of at least one T-allele of rs713041 in GPX4 conferred protection against PDR (OR 0.30, 95% CI 0.11-0.80, p = 0.017) in female T1D individuals. Conclusion: The functional SNPs rs17883901 and rs713041 modulate the risk for PDR in the studied population of T1D individuals, widening the spectrum of candidate genes for this complication.
- Identification and performance of multiple clinical and laboratorial risk factors for diagnosis of cardiac autonomic neuropathy in type 1 diabetes patients(2019) RIGUETTO, Cinthia Minatel; TAKANO, Caroline Rigoleto; ADMONI, Sharon Nina; PARISI, Maria Candida Ribeiro; GIANNELLA, Maria Lucia Correa; PAVIN, Elizabeth Joao; MOURA NETO, ArnaldoPurpose The incidence of cardiac autonomic neuropathy (CAN) in patients with type 1 diabetes (T1D) is frequently underestimated. Individuals with T1D and CAN have an increased mortality risk, mainly from cardiovascular causes. The objectives of the present study were to assess the clinical and laboratory characteristics associated with CAN in patients with T1D and verify the ability of multiple clinical factors to help identify patients with this condition. Methods 102 patients with T1D were evaluated for CAN using standardized cardiovascular reflex testing. Clinical characteristics were used to compute a numerical score for CAN diagnosis and a ROC curve elaborated for assessment of the best cutoff to predict CAN. This score was then applied to the second sample of 120 patients. The sensitivity, specificity, and positive and negative predictive values were calculated. Results Prevalence of CAN was around 35% in the first sample of patients and just below 20% in the second sample. Hypertension, total cholesterol, triglycerides, postprandial sweating, diastolic blood pressure, abnormal right and left 10 g monofilament, retinopathy, and nephropathy were considered independent predictors of CAN. The CAN-score cut-off was 16.88. This yielded a sensitivity of 50%, specificity 73.8%, positive predictive value 22.9%, and negative predictive value 90.5%. Conclusion The use of a subset of clinical and laboratory characteristics can be more accessible than the cardiac reflex tests and more accurate than a single isolated characteristic.
- Genetic variants in DNMT1 and the risk of cardiac autonomic neuropathy in women with type 1 diabetes(2019) SANTOS-BEZERRA, Daniele Pereira; ADMONI, Sharon Nina; MORI, Rosana Cristina; PELAES, Tatiana Souza; PEREZ, Ricardo Vesoni; MACHADO, Cleide Guimaraes; MONTEIRO, Maria Beatriz; PARISI, Maria Candida; PAVIN, Elizabeth Joao; QUEIROZ, Marcia Silva; PASSARELLI, Marisa; MACHADO, Ubiratan Fabres; CORREA-GIANNELLA, Maria LuciaAims/Introduction Epigenetics participate in the pathogenesis of metabolic memory, a situation in which hyperglycemia exerts prolonged deleterious effects even after its normalization. We tested the hypothesis that genetic variants in an epigenetic gene could predispose to diabetes complications. Material and Methods We assessed the frequency of five single-nucleotide polymorphisms in the gene encoding deoxyribonucleic acid methytransferase 1 (DNMT1; rs8112895, rs7254567, rs11085721, rs17291414 and rs10854076), and their associations with diabetic kidney disease, retinopathy, distal polyneuropathy and autonomic cardiovascular neuropathy in 359 individuals with long-term type 1 diabetes. Results None of the single-nucleotide polymorphisms studied was significantly associated with the presence of chronic complications in the overall population. However, after sex stratification, the minor allele C of rs11085721 conferred risk for cardiovascular neuropathy in women after adjustment for confounding variables (odds ratio 2.32; 95% confidence interval 1.26-4.33; P = 0.006). Conclusions The fact that heterozygous mutations in DNMT1 are associated with hereditary sensory autonomic neuropathy provides plausibility to the present finding. If confirmed in independent samples, it suggests that genetic variants in epigenetic genes might predispose to more or fewer epigenetic changes in the face of similar metabolic derangements triggered by hyperglycemia, constituting the ""genetics of epigenetics"" for microvascular diabetes complications.
- Micro-RNAs 518d-3p and 618 Are Upregulated in Individuals With Type 1 Diabetes With Multiple Microvascular Complications(2019) SANTOS-BEZERRA, Daniele P.; SANTOS, Aritania S.; GUIMARAES, Gabriel C.; ADMONI, Sharon N.; V, Ricardo Perez; MACHADO, Cleide G.; PELAES, Tatiana S.; PASSARELLI, Marisa; MACHADO, Ubiratan F.; QUEIROZ, Marcia S.; SILVA, Maria Elizabeth R. da; CORREA-GIANNELLA, Maria LuciaObjective: To compare the serum micro-RNAs (miRNAs) profile of individuals with type 1 diabetes without microvascular complications vs. those with multiple severe microvascular complications, in order to identify epigenetically modulated pathways in these two groups of individuals. Research Design and Methods: A total of 10 subjects were selected among individuals followed in the Diabetes Outpatient Clinic and sorted according to the absence or presence of all microvascular complications. Samples from these participants were used for evaluation of serum miRNA expression profile employing a qRT-PCR assay with hydrolysis probes based on the Taqman Low Density Arrays (TLDA) system. The top six most differentially expressed miRNAs between the aforementioned groups were validated by qRT-PCR in additional 47 type 1 diabetes individuals sorted according to the absence or presence of all microvascular complications and matched for age, sex, degree of metabolic control, diabetes duration, and age at diagnosis. Results: Twenty one out of three hundred and seventy seven miRNAs were upregulated in the group of individuals with all microvascular complications vs. the group without complications. The following miRs were validated: 518-3p, 34a-5p, 126-5p, 425-5p, 618, and 139-5p and logistic regression analyses showed that miRNA-518-3p and miRNA-618 were positively associated with multiple microvascular complications after adjustment for age, sex, diabetes duration, HbA(1)c and use of statin, angiotensin-converting enzyme inhibitors and amlodipine. Conclusions: In this cohort of type 1 diabetes individuals, serum miR-518d-3p and miR-618 were upregulated in those with diabetes kidney disease, diabetes retinopathy, peripheral neuropathy, and cardiovascular autonomic neuropathy in comparison to individuals with no microvascular complications.
- Reduced intestinal FADS1 gene expression and plasma omega-3 fatty acids following Roux-en-Y gastric bypass(2019) GARLA, Priscila; SALA, Priscila; TORRINHAS, Raquel Susana Matos; MACHADO, Natasha Mendonca; FONSECA, Danielle Cristina; SILVA, Mariane Marques da; RAVACCI, Graziela Rosa; BELARMINO, Giliane; ISHIDA, Robson Kiyoshi; GUARDA, Ismael Francisco Mota Siqueira; MOURA, Eduardo Guimardes Hourneaux de; SAKAI, Paulo; SANTO, Marco Aurelio; SILVA, Ismael Dale Cotrim Guerreiro da; PEREIRA, Claudia Cristina Alves; HEYMSFIELD, Steven; CORREA-GIANNELLA, Maria Lucia Cardillo; CALDER, Philip C.; WAITZBERG, Dan LinetzkyBackground & aims: Roux-en-Y gastric bypass (RYGB) limits food ingestion and may alter the intestinal expression of genes involved in the endogenous synthesis of polyunsaturated fatty acids (PUFAs). These changes may decrease the systemic availability of bioactive PUFA5 after RYGB. To study the impact of RYGB on the dietary ingestion and plasma concentration of PUFA5 and on the intestinal expression of genes involved in their endogenous biosynthesis in severely obese women with type 2 diabetes. Methods: Before, and 3 and 12 months after RYGB, obese women (n = 20) self-reported a seven-day dietary record, answered a food frequency query and provided plasma samples for alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic (DHA) and arachidonic (ARA) acid assessment by gas chromatography. Intestinal biopsies (duodenum, jejunum and ileum) were collected through double balloon endoscopy before and 3 months after RYGB for gene expression analysis by microarray (Human GeneChip 1.0 ST array) and RT-qPCR validation. Results: Compared to the preoperative period, patients had decreased intakes of PUFAs, fish and soybean oil (p < 0.05) and lower plasma concentrations of ALA and EPA (p < 0.001) 3 and 12 months after RYGB. FADS] gene expression was lower in duodenum (RT-qPCR fold change = 1.620, p < 0.05) and jejunum (RT-qPCR fold change = -1.549, p < 0.05) 3 months following RYGB, compared to before surgery. Conclusion: RYGB decreased PUFA ingestion, plasma ALA and EPA levels, and intestinal expression of FADS] gene. The latter encodes a key enzyme involved in endogenous biosynthesis of PUFA5. These data suggest that supplementation of omega-3 PUFAs may be required for obese patients undergoing RYGB. Clinical Trial Registry number and website: www.clinicaltrials.gov NCT01251016; Plataforma Brasil - 19339913.0.0000.0068. (C) 02018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.