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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- Variant rs17619600 in the gene encoding serotonin receptor 2B (HTR2B) increases the risk of gestational diabetes mellitus: a case-control study(2023) PENNO, Juliana Regina Chamlian Zucare; SANTOS-BEZERRA, Daniele Pereira; CAVALEIRO, Ana Mercedes; SOUSA, Ana Maria da Silva; ZACCARA, Tatiana Assuncao; COSTA, Rafaela Alkmin da; FRANCISCO, Rossana Pulcineli Vieira; CORREA-GIANNELLA, Maria LuciaBackgroundDuring pregnancy, the increase in maternal insulin resistance is compensated by hyperplasia and increased function of maternal pancreatic beta cells; the failure of this compensatory mechanism is associated with gestational diabetes mellitus (GDM). Serotonin participates in beta cell adaptation, acting downstream of the prolactin pathway; the blocking of serotonin receptor B (HTR2B) signaling in pregnant mice impaired beta cell expansion and caused glucose intolerance. Thus, given the importance of the serotoninergic system for the adaptation of beta cells to the increased insulin demand during pregnancy, we hypothesized that genetic variants (single nucleotide polymorphisms [SNPs]) in the gene encoding HTR2B could influence the risk of developing GDM.MethodsThis was a case-control study. Five SNPs (rs4973377, rs765458, rs10187149, rs10194776, and s17619600) in HTR2B were genotyped by real-time polymerase chain reaction in 453 women with GDM and in 443 pregnant women without GDM.ResultsOnly the minor allele C of SNP rs17619600 conferred an increased risk for GDM in the codominant model (odds ratio [OR] 2.15; 95% confidence interval [CI] 1.53-3.09; P < 0.0001) and in the rare dominant model (OR 2.32; CI 1.61-3.37; P < 0.0001). No associations were found between the SNPs and insulin use, maternal weight gain, newborn weight, or the result of postpartum oral glucose tolerance test (OGTT). In the overall population, carriers of the XC genotype (rare dominant model) presented a higher area under the curve (AUC) of plasma glucose during the OGTT, performed for diagnostic purposes, compared with carriers of the TT genotype of rs17619600.ConclusionsSNP rs17619600 in the HTR2B gene influences glucose homeostasis, probably affecting insulin release, and the presence of the minor allele C was associated with a higher risk of GDM.
- Dual SGLT1/SGLT2 Inhibitor Phlorizin Ameliorates Non-Alcoholic Fatty Liver Disease and Hepatic Glucose Production in Type 2 Diabetic Mice(2020) DAVID-SILVA, Aline; ESTEVES, Joao Victor; MORAIS, Mychel Raony P. T.; FREITAS, Helayne Soares; ZORN, Telma Maria; CORREA-GIANNELLA, Maria Lucia; MACHADO, Ubiratan FabresPurpose: NAFLD is a hepatic component of type 2 diabetes mellitus (T2D), in which impaired hepatic glucose production plays an important role. Inhibitors of sodium glucose transporter 2 (SGLT2) reduce glycemia and exert beneficial effects on diabetic complications. Recently, dual SGLT1/2 inhibition has been proposed to be more effective in reducing glycemia. We hypothesized that improving hepatic glucose metabolism induced by SGLT1/2 inhibition could be accompanied by beneficial effects on NAFLD progression. Methods: Glycemic homeostasis, hepatic glucose production and NAFLD features were investigated in obese T2D mice, treated with SGLT1/2 inhibitor phlorizin for 1 week. Results: T2D increased glycemia; insulinemia; hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase) and glucose transporter 2 (Sle2a2 gene); hepatocyte nuclear factors 1A/4A/3B-binding activity in Sle2a2; endogenous glucose production; liver weight, plasma transaminase concentration as well as hepatic inflammation markers, and induced histological signals of non-alcoholic steatohepatitis (NASH, according to NASH-CRN Pathology Committee System). Phlorizin treatment restored all these parameters (mean NASH score reduced from 5.25 to 2.75 P<0.001); however, plasma transaminase concentration was partially reverted and some hepatic inflammation markers remained unaltered. Conclusion: NAFLD accompanies altered hepatic glucose metabolism in T2D mice and that greatly ameliorated through short-term treatment with the dual SGLT1/2 inhibitor. This suggests that altered hepatic glucose metabolism participates in T2D-related NAFLD and highlights the pharmacological inhibition of SGLTs as a useful approach not only for controlling glycemia but also for mitigating development and/or progression of NAFLD.
- Exercise Training Favorably Modulates Gene and Protein Expression That Regulate Arterial Cholesterol Content in CETP Transgenic Mice(2018) PINTO, Paula R.; SILVA, Karolline S. da; IBORRA, Rodrigo T.; OKUDA, Ligia S.; GOMES-KJERULF, Diego; FERREIRA, Guilherme S.; MACHADO-LIMA, Adriana; ROCCO, Debora D. F. M.; NAKANDAKARE, Edna R.; MACHADO, Ubiratan F.; CORREA-GIANNELLA, Maria L.; CATANOZI, Sergio; PASSARELLI, MarisaAerobic exercise training (AET) improves the reverse cholesterol transport (RCT) in cholesteryl ester transfer protein-transgenic (CETP-tg) mice. We aimed at investigating the role of AET in the expression of genes and proteins involved in lipid flux in the aorta and macrophages of CETP-tg mice. Three-month-old male mice were randomly divided into trained (T; treadmill 15 m/min; 30 min/day) and sedentary (S) groups. After 6 weeks, peritoneal macrophages and the aortic arch were obtained immediately (0 h) or 48 h after the last exercise session. mRNA was determined by RT-qPCR, protein levels by immunoblot and C-14-cholesterol efflux determined in macrophages. AET did not change body weight, plasma cholesterol, triglycerides, glucose and CETP activity. In macrophages, at time 0 h, a higher expression of genes that encode PPAR gamma, ABCA-1 and a lower expression of MCP-1 and IL-10, was observed in T as compared to S. After 48 h, lower expressions of MCP-1 and PPAR gamma genes were observed in T mice. Increase in ABCA-1, SR-BI and IL-6 and decrease of LOX-1, MCP-1, TNF and IL-10 gene expression was observed in the aorta of T compared to S mice (0 h) and LOX-1 and MCP-1 remained diminished after 48 h. The protein level of MCP-1 and SR-BI in the aortic arch was unchanged in T animals after 48 h as compared to S, but LOX-1 was reduced confirming data of gene expression. The apo A-I and the HDL2 mediated-cholesterol efflux (8 and 24 h) were not different between T and S animals. In the presence of CETP, AET positively influences gene expression in the arterial wall and macrophages of CETP-tg mice contributing to the RCT and prevention of atherosclerosis. These changes were perceptible immediately after the exercise session and were influenced by the presence of CETP although independent of changes in its activity. Reductions in gene and protein expression of LOX-1 were parallel and reflect the ability of exercise training in reducing the uptake of modified LDL by the arterial wall macrophages.
- MTP-493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients(2012) SIQUEIRA, E. R. F.; OLIVEIRA, C. P. M. S.; CORREA-GIANNELLA, M. L.; STEFANO, J. T.; CAVALEIRO, A. M.; FORTES, M. A. H. Z.; MUNIZ, M. T. C.; SILVA, F. S.; PEREIRA, L. M. M. B.; CARRILHO, F. J.The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8% of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3% of the patients with fibrosis grade 1+2 (OR = 1.8; 95%CI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95%CI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients.
- Ocular Manifestations and Neuropathy in Type 2 Diabetes Patients With Charcot Arthropathy(2021) TRINDADE, Marilia; VASCONCELOS, Jessica Castro de; AYUB, Gabriel; GRUPENMACHER, Alex Treiger; HUARACHI, Delma Regina Gomes; VITURINO, Marina; CORREA-GIANNELLA, Maria Lucia; ATALA, Yeelen Ballesteros; ZANTUT-WITTMANN, Denise Engelbrecht; PARISI, Maria Candida; ALVES, MonicaObjective Diabetes can affect the eye in many ways beyond retinopathy. This study sought to evaluate ocular disease and determine any associations with peripheral neuropathy (PN) or cardiac autonomic neuropathy (CAN) in type 2 diabetes (T2D) and Charcot arthropathy (CA) patients. Design A total of 60 participants were included, 16 of whom were individuals with T2D/CA, 21 of whom were individuals with T2D who did not have CA, and 23 of whom were healthy controls. Ocular surface evaluations were performed, and cases of dry eye disease (DED) were determined using the Ocular Surface Disease Index (OSDI) questionnaire, ocular surface staining, Schirmer test, and Oculus Keratograph 5M exams. All variables were used to classify DED and ocular surface disorders such as aqueous deficiency, lipid deficiency, inflammation, and ocular surface damage. Pupillary and retinal nerve fiber measurements were added to the protocol in order to broaden the scope of the neurosensory ocular evaluation. PN and CAN were ascertained by clinical examinations involving the Neuropathy Disability Score (for PN) and Ewing's battery (for CAN). Results Most ocular variables evaluated herein differed significantly between T2D patients and controls. When the controls were respectively compared to patients with T2D and to patients with both T2D and CA, they differed substantially in terms of visual acuity (0.92 +/- 0.11, 0.73 +/- 0.27, and 0.47 +/- 0.26, p=0.001), retinal nerve fiber layer thickness (96.83 +/- 6.91, 89.25 +/- 10.44, and 80.37 +/- 11.67 mu m, p=0.03), pupillometry results (4.10 +/- 0.61, 3.48 +/- 0.88, and 2.75 +/- 0.81 mm, p=0.0001), and dry eye symptoms (9.19 +/- 11.71, 19.83 +/- 19.08, and 24.82 +/- 24.40, p=0.03). DED and ocular surface damage also differed between individuals with and without CA, and were associated with PN and CAN. Conclusion CA was found to be significantly associated with the severity of ocular findings. DED in cases of CA was also associated with PN and CAN. These findings suggest that intrinsic and complex neurosensory impairment in the eyes, peripheral sensory nerves, and the autonomic nervous system are somehow connected. Thus, a thorough ocular evaluation may be useful to highlight neurological complications and the impact of diabetes on ocular and systemic functions and structures.
- Differential expression of genes encoding proteins of the HGF/MET system in insulinomas(2015) MURAT, Cahue de Bernardis; ROSA, Paula Waki Lopes da; FORTES, Maria Angela Henriques Zanella; CORREA, Luciana; MACHADO, Marcel Cerqueira Cesar; NOVAK, Estela Maria; SIQUEIRA, Sheila Aparecida Coelho; PEREIRA, Maria Adelaide Albergaria; CORREA-GIANNELLA, Maria Lucia; GIANNELLA-NETO, Daniel; GIORGI, Ricardo RodriguesBackground: Insulinomas are the most common functional pancreatic neuroendocrine tumors, whereas histopathological features do not predict their biological behaviour. In an attempt to better understand the molecular processes involved in the tumorigenesis of islet beta cells, the present study evaluated the expression of genes belonging to the hepatocyte growth factor and its receptor (HGF/MET) system, namely, MET, HGF; HGFAC and ST14 (encode HGF activator and matriptase, respectively, two serine proteases that catalyze conversion of pro-HGF to active HGF); and SPINT1 and SPINT2 (encode serine peptidase inhibitors Kunitz type 1 and type 2, respectively, two inhibitors of HGF activator and of matriptase). Methods: Quantitative real-time reverse transcriptase polymerase chain reaction was employed to assess RNA expression of the target genes in 24 sporadic insulinomas: 15 grade 1 (G1), six grade 2 (G2) and three hepatic metastases. Somatic mutations of MET gene were searched by direct sequencing of exons 2, 10, 14, 16, 17 and 19. Results: Overexpression of MET was observed in the three hepatic metastases concomitantly with upregulation of the genes encoding HGF and matriptase and downregulation of SPINT1. A positive correlation was observed between MET RNA expression and Ki-67 proliferation index while a negative correlation was detected between SPINT1 expression and the mitotic index. No somatic mutations were found in MET gene. Conclusion: The final effect of the increased expression of HGF, its activator (matriptase) and its specific receptor (MET) together with a decreased expression of one potent inhibitor of matriptase (SPINT1) is probably a contribution to tumoral progression and metastatization in insulinomas.
- Development and internal validation of an adrenal cortical carcinoma prognostic score for predicting the risk of metastasis and local recurrence(2013) FREIRE, Daniel Soares; SIQUEIRA, Sheila Aparecida Coelho; ZERBINI, Maria Claudia Nogueira; WAJCHENBERG, Bernardo Leo; CORREA-GIANNELLA, Maria Lucia; LUCON, Antonio Marmo; PEREIRA, Maria Adelaide AlbergariaObjective To develop and internally validate a prognostic score to predict the risk of metastases or recurrence in patients with adrenal cortical carcinomas (ACC). Design Clinical, laboratory and pathological data from 129 ACC patients, treated in a tertiary centre, were retrospectively reviewed. Results Using a multivariate binary logistic regression analysis, we developed a prognostic score with five covariates: a functional pattern other than isolated hyperandrogenism, a tumour size >75cm, a primary tumour classified as T3/T4, the presence of microscopic venous invasion and a mitotic index >5/50 high-power fields. The prognostic score was calibrated according to the Hosmer-Lemeshow goodness-of-fit test (P=09329) and exhibited excellent overall performance (Brier score=00738). Finally, the discriminatory ability of the model, determined by the area under the ROC curve (A(ROC)), was near perfect (A(ROC), 09611; 95% CI, 092676-099552). The prediction model was internally validated with 200 bootstrap resamples and achieved excellent performance for estimating the risk of metastasis and recurrence in eight additional patients with apparently localized disease at diagnosis. Conclusion We developed and internally validated a prognostic score based on the clinicopathological data that are readily available to any attending physician. Our model can be used to accurately estimate the risk of unfavourable outcomes in ACC patients. This score could be beneficial for both patient counselling and the identification of patients in whom adjuvant mitotane is justified.
conferenceObject BIOSAFE: A NOVEL BIOMATERIAL FOR PANCREATIC ISLETS ENCAPSULATION AND TYPE 1 DIABETES MELLITUS THERAPY.(2015) LEAL-LOPES, Camila; GRAZIOLI, Gisella; MARES-GUIA, Thiago R.; CORREA-GIANNELLA, Maria Lcia C.; SOGAYAR, Mari C.- Case report: Insulinomatosis: description of four sporadic cases and review of the literature(2024) JR, Delmar Muniz Lourenco; CORREA-GIANNELLA, Maria Lucia; SIQUEIRA, Sheila Aparecida Coelho; NERY, Marcia; RIBEIRO, Flavio Galvao; QUEDAS, Elizangela Pereira de Souza; ROCHA, Manoel de Souza; NASCIMENTO, Ramon Marcelino do; PEREIRA, Maria Adelaide AlbergariaThe best-known etiologies of hyperinsulinemic hypoglycemia are insulinoma, non-insulinoma pancreatogenous hypoglycemic syndrome, autoimmune processes, and factitious hypoglycemia. In 2009, a disease not associated with classic genetic syndromes and characterized by the presence of multiple pancreatic lesions was described and named insulinomatosis. We present the clinical and pathologic features of four patients with the diagnosis of insulinomatosis, aggregated new clinical data, reviewed extensively the literature, and illustrated the nature and evolution of this recently recognized disease. One of our patients had isolated (without fasting hypoglycemia) postprandial hypoglycemia, an occurrence not previously reported in the literature. Furthermore, we reported the second case presenting malignant disease. All of them had persistent/recurrent hypoglycemia after the first surgery even with pathology confirming the presence of a positive insulin neuroendocrine tumor. In the literature review, 27 sporadic insulinomatosis cases were compiled. All of them had episodes of fasting hypoglycemia except one of our patients. Only two patients had malignant disease, and one of them was from our series. The suspicion of insulinomatosis can be raised before surgery in patients without genetic syndromes, with multiple tumors in the topographic investigation and in those who had persistent or recurrent hypoglycemia after surgical removal of one or more tumors. The definitive diagnosis is established by histology and immunohistochemistry and requires examination of the ""macroscopically normal pancreas."" Our case series reinforces the marked predominance in women, the high frequency of recurrent hypoglycemia, and consequently, a definitive poor response to the usual surgical treatment.
- Bariatric surgery and gene expression in the gut(2018) SALA, Priscila; CORREA-GIANNELLA, M. L.; WAITZBERG, Dan L.Purpose of reviewThe current review provides an overview of recent literature on new findings related to bariatric surgery and gut gene expression.Recent findingsBariatric surgery modulates the expression of intestinal genes. Experimental and clinical investigations have demonstrated the association of gut rearrangement with changes in intestinal expression of genes related to glucose metabolism. Recent data suggest that bariatric surgery also affects expression of genes belonging to other pathways, including nutrient transporters and metabolism of vitamin B12, decreasing pathway-encoding genes that may contribute to vitamin B12 deficiency in the postoperative period.SummaryBariatric surgery is an effective intervention strategy against severe obesity, resulting in sustained weight loss and reduction of comorbidities. Nutritional genomic changes appear in response to bariatric surgery, possibly due to adaptive gut response. Improved understanding of the molecular pathways modulated by this intervention may facilitate weight and comorbidities management.