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    Determining the importance of glycemic variability in gestational diabetes mellitus using various techniques
    (İstanbul Üniversitesi Yayınevi, 2023) Öztop, Nida; Kubat Üzüm, Ayşe; Çelik, Selda; İdiz, Cemile; Bağdemir, Elif; Dinççağ, Nevin; N/A; Tütüncü, Yıldız; Faculty Member; School of Medicine; 239430
    Objective: The study aims to determine glycemic variation in patients with GDM and to evaluate the effect on the fetal growth using a continuous glucose monitoring system (CGMS) and to investigate the correlation between glucose variation through biomarkers including HbA1c, fructosamine (FRM), and 1.5-Anhy-droglucitol (1.5-AG). Materials and Methods: The study involves 31 women with GDM at gestational week >= 35 who'd only had diettherapy. Blood glucose levels were monitored for three consecutive days using CGMS to evaluate mean blood glucose levels and mean absolute difference (MAD). Self-monitoring of blood glucose (SMBG) was required from the patients while having the CMGS on their body. Blood sam-ples were collected to measure serum 1.5-AG, HbA1c, and FRM.Results: The mean levels were HbA1c=5.0 +/- 0.3%, FRM=2.1 +/- 0.2 mu mol/L, 1.5-AG=17.0 +/- 4.9 ng/ml, and 3-day average max-min glu-cose range=131.1 +/- 22.5 and 54.7 +/- 11.6 mg/dl (MAD=6.7 +/- 3.1%). The mean glucose levels measured using SMBG and CGMS were similar (82.9 +/- 10.2 vs 86.1 +/- 10.3 mg/dL). No correlation occurred between CMGS and biomarkers. The baby weight at birth and head circumference was determined to be lower for patients with glucose fluctuations.Conclusion: Biomarkers do not reflect glycemic fluctuation, and regular SMBG is required to achieve the desired glucose level, even in diet-regulated GDM. Lower head circumference and birth weight were determined in GDM mothers with high glycemic fluctuations, and CGMS may be an alternative method despite its cost and application difficulties. / Amaç: Gestasyonel Diabetes Mellitus (GDM) da gün içi glukoz dalgalanmaları ve bunun bebek üzerine etkisini belirlemek; ayrıca, glukozdaki dalgalanmaların HbA1c, fruktozamin (FRM) ve 1,5-Anhidroglucitol (1,5-AG) ile korelasyonunu saptamaktır. Gereç ve Yöntem: Sadece diyetle takip edilen GDM tanısı alan ve ≥35 gebelik haftasındaki 31 hastada devamlı glukoz ölçüm sistemi (CGMS) ile 72 saatlik glisemik değişkenlikler (ortalama mutlak değer %MAD ve ortalama glukoz değeri) ölçüldü, ayrıca hastalardan, CGMS takılı olduğu günler, kendi kendine glukoz ölçüm sistemi (SMBG) her öğün öncesinde ve birinci saat sonrasında parmak ucundan kan glukoz düzeylerini ölçmeleri istendi. 1,5 AG, Hba1c ve FRM düzeyleri CGMS çıkarıldığı üçüncü gün hastalardan alındı. Bulgular: Hastaların ortalama HbA1c, FRM ve 1,5-AG sırasıyla %5,0±0,3, 2,1±0,2 μmol/L, ve 17,0±4,9 ng/mL idi. Üç günlük izlemde maximum-minimum glukoz düzeyi ortalaması 131,1±22,5 ve 54,7±11,6 mg/dL iken %MAD değeri %6,7±3,1 idi. SMBG ve CGMS ile ölçülen ortalama glukoz değeri birbiri ile koreleyken (82,9±10,2 ve 86,1±10,3 mg/dL); glukoz dalgalanması ile FRM, HbA1c ve 1,5-AG arasında anlamlı korelasyon yoktu. Hastaların glikoz dalgalanmaları varsa doğumdaki bebek ağırlığının ve baş çevresinin düşük olduğu belirlendi. Sonuç: Çalışmamızda biyobelirteçlerin glisemik dalgalanmayı yansıtmadığı; istenilen glukoz seviyesinin sağlanması için, diyetle regüle GDM de bile, SMBG’un sık, düzenli olarak yapılmasının gerekliliği saptanmıştır; ancak glisemik dalgalanmaları fazla olan GDM’li annenin bebeğinde baş çevresi ve doğum kilosu daha düşük saptanmıştır ve glisemik dalgalanmayı daha yakından gösteren CGMS’ in her ne kadar maliyet ve uygulama zorluğu olsa da, SMBG’ ye alternatif yöntem olabileceği gösterilmiştir.
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    Examining the hepatic immune system in children with liver disease with fine needle aspiration
    (Lippincott Williams & Wilkins, 2022) N/A; N/A; N/A; N/A; N/A; N/A; N/A; Yüksel, Muhammed; Demirbaş, Burak; Mizikoğlu, Özlem; Tütüncü, Yıldız; Kanmaz, Turan; Oğuzkurt, Levent; Arıkan, Çiğdem; Researcher; Doctor; Researcher; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/A; N/A; School of Medicine; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; N/A; N/A; N/A; 239430; 275799; 13559; 240198
    Objectives: Liver biopsy is the standard in diagnosing liver diseases. Yet, it provides little space to perform comprehensive immune profiling of the liver. Hence, we explored whether fine needle aspirates (FNAs) could be used to elucidate the hepatic immunity in children. Methods: We enrolled 74 children undergoing diagnostic (n = 17) or protocol biopsy (n = 57) following liver transplantation (LT). Matched blood and FNAs were obtained. Additionally, explant liver tissue was collected from children (n = 14) undergoing LT. Immune cells were isolated from peripheral blood, FNAs and explanted livers. Immune-phenotypical profiling was done by flow cytometry. Results: Biopsied patients (58% female) were at a median age of 46 months (interquartile range [IQR]: 12–118) and LT patients (71% female) were 48 months (IQR: 21–134, P = 0.78) old. CD69+, a hallmark of tissue-resident immune cells was expressed in 1.3% of CD3+ T cells from blood being higher in FNA (20%) and tissue (49%, P < 0.001). CD4+ T-cell frequencies in tissue (13%) and FNAs (20%) were lower compared to blood (35%, P < 0.001) whereas CD8+ T cells in tissue (33.5%) and FNA (32%) were higher than in blood (25%, P < 0.01). Mucosal associated invariant T cells were enriched in liver tissue (8.8%) and in the FNA (4.4%) compared to blood (1.7%, P < 0.001). Whereas the percentage of total Tregs (CD4+CD25+FOXP3+CD127low/−) decreased, the proportion of activated Tregs (CD4+CD45RA-FOXP3high) increased in FNA and explant. Breg (CD19+CD20+CD24highCD38high) frequencies were similar in all groups. Conclusion: FNA is a practical method to sample the liver immune system collecting even small cell subsets such as regulatory T/B cells.
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    Precision diagnosis of maturity-onset diabetes of the young with next-generation sequencing: findings from the mody-ist study in adult patients
    (Mary Ann Liebert, Inc., 2022) Aydogan, Hulya Yilmaz; Gul, Nurdan; Demirci, Deniz Kanca; Mutlu, Ummu; Gulfidan, Gizem; Arga, Kazim Yalcin; Ozder, Aclan; Camli, Ahmet Adil; Ozturk, Oguz; Cacina, Canan; Darendeliler, Feyza; Poyrazoglu, Sukran; Satman, Ilhan; N/A; Tütüncü, Yıldız; Faculty Member; School of Medicine; 239430
    Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as "deleterious" as well as those predicted as "benign." Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.
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    Inflammatory markers are associated with the progression of gestational diabetes to metabolic syndrome
    (Taylor and Francis Inc, 2022) Can, Bulent; Can, Busra; Keskin, Havva; Bekpinar, Seldag; Dinccag, Nevin; N/A; Tütüncü, Yıldız; Faculty Member; School of Medicine; 239430
    The progression of gestational diabetes mellitus (GDM) to metabolic syndrome (MetS) is associated with systemic inflammation. The aim of this study was to compare the levels of inflammatory markers in former GDM patients with and without MetS. Medical records were screened retrospectively for patients who were diagnosed with GDM 10 (±2) years ago. Former GDM patients were invited to the hospital for an assessment of their current health status. Of 52 women with former GDM, 27 (52%) had MetS. C-reactive protein (CRP), interleukin-6 and plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in the MetS group while adiponectin was significantly lower (p < .001, p = .037, p = .002 and p = .013, respectively). There was no significant difference in plasma levels of visfatin and tumour necrosis factor-α. Interleukin-6, CRP, PAI-1 and adiponectin may be used as biomarkers to detect MetS in the pre-clinical phase. With timely diagnosis, early interventions can be implemented.
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    Monogenic childhood diabetes: dissecting clinical heterogeneity by next-generation sequencing in maturity-onset diabetes of the young
    (Mary Ann Liebert, Inc, 2021) Demirci, Deniz Kanca; Darendeliler, Feyza; Poyrazoglu, Sukran; Al, Asli Derya Kardelen; Gul, Nurdan; Gulfidan, Gizem; Arga, Kazim Yalcin; Cacina, Canan; Ozturk, Oguz; Aydogan, Hulya Yilmaz; Satman, Ilhan; N/A; Tütüncü, Yıldız; Faculty Member; School of Medicine; 239430
    Diabetes is a common disorder with a heterogeneous clinical presentation and an enormous burden on health care worldwide. About 1-6% of patients with diabetes suffer from maturity-onset diabetes of the young (MODY), the most common form of monogenic diabetes with autosomal dominant inheritance. MODY is genetically and clinically heterogeneous and caused by genetic variations in pancreatic beta-cell development and insulin secretion. We report here new findings from targeted next-generation sequencing (NGS) of 13 MODY-related genes. A sample of 22 unrelated pediatric patients with MODY and 13 unrelated healthy controls were recruited from a Turkish population. Targeted NGS was performed with Miseq 4000 (Illumina) to identify genetic variations in 13 MODY-related genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11. The NGS data were analyzed adhering to the Genome Analysis ToolKit (GATK) best practices pipeline, and variant filtering and annotation were performed. In the patient sample, we identified 43 MODY-specific genetic variations that were not present in the control group, including 11 missense mutations and 4 synonymous mutations. Importantly, and to the best of our knowledge, the missense mutations NEUROD1 p.D202E, KFL11 p.R461Q, BLK p.G248R, and KCNJ11 p.S385F were first associated with MODY in the present study. These findings contribute to the worldwide knowledge base on MODY and molecular correlates of clinical heterogeneity in monogenic childhood diabetes. Further comparative population genetics and functional genomics studies are called for, with an eye to discovery of novel diagnostics and personalized medicine in MODY. Because MODY is often misdiagnosed as type 1 or type 2 diabetes mellitus, advances in MODY diagnostics with NGS stand to benefit diabetes overall clinical care as well.
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    PublicationOpen Access
    The predictors of long-COVID in the cohort of Turkish Thoracic Society-TURCOVID multicenter registry: one year follow-up results
    (Wolters Kluwer, 2022) Barış, Serap Argün; Toprak, Oya Baydar; Çetinkaya, Pelin Duru; Fakili, Füsun; Köktürk, Nurdan; Kul, Seval; Azak, Emel; Kuluöztürk, Mutlu; Yıldız, Pınar Aysert; Deniz, Pelin Pınar; Kılınç, Oğuz; Başyiğit, İlknur; Boyacı, Haşim; Hanta, İsmail; Köse, Neslihan; Sağcan, Gülseren; Cuhadaroğlu, Cağlar; Okur, Hacer; Özger, Hasan; Ergan, Begüm; Hafızoğlu, Mehtap; Sayıner, Abdullah; Temel, Esra Nurlu; Öztürk, Önder; Çiftçi, Tansu Ulukavak; Oğuzülgen, İpek Kıvılcım; Oğuz, Vildan Avkan; Bayraktar, Fırat; Ataoğlu, Özlem; Erçelik, Merve; Gülhan, Pınar Yıldız; Erdem, Aysegül Tomruk; Tor, Müge Meltem; Itil, Oya; Tütüncü, Yıldız; Kayalar, Özgecan; Bayram, Hasan; Faculty Member; Researcher; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 239430; N/A; 4890
    Objective: to evaluate long-term effects of COVID-19, and to determine the risk factors in long-COVID in a cohort of the Turkish Thoracic Society (TTS)-TURCOVID multicenter registry.Methods: thirteen centers participated with 831 patients; 504 patients were enrolled after exclusions. The study was designed in three-steps: (1) Phone questionnaire; (2) retrospective evaluation of the medical records; (3) face-to-face visit. Results: in the first step, 93.5% of the patients were hospitalized; 61.7% had a history of pneumonia at the time of diagnosis. A total of 27.1% reported clinical symptoms at the end of the first year. Dyspnea (17.00%), fatigue (6.30%), and weakness (5.00%) were the most prevalent long-term symptoms. The incidence of long-term symptoms was increased by 2.91 fold (95% CI 1.04-8.13, P=0.041) in the presence of chronic obstructive pulmonary disease and by 1.84 fold (95% CI 1.10-3.10, P=0.021) in the presence of pneumonia at initial diagnosis, 3.92 fold (95% Cl 2.29-6.72, P=0.001) of dyspnea and 1.69 fold (95% Cl 1.02-2.80, P=0.040) fatigue persists in the early-post-treatment period and 2.88 fold (95% Cl 1.52- 5.46, P=0.001) in the presence of emergency service admission in the post COVID period. In step 2, retrospective analysis of 231 patients revealed that 1.4% of the chest X-rays had not significantly improved at the end of the first year, while computed tomography (CT) scan detected fibrosis in 3.4%. In step 3, 138 (27.4%) patients admitted to face-to-face visit at the end of first year; at least one symptom persisted in 49.27% patients. The most common symptoms were dyspnea (27.60%), psychiatric symptoms (18.10%), and fatigue (17.40%). Thorax CT revealed fibrosis in 2.4% patients. Conclusions: COVID-19 symptoms can last for extended lengths of time, and severity of the disease as well as the presence of comorbidities might contribute to increased risk. Long-term clinical issues should be regularly evaluated after COVID-19.
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    PublicationOpen Access
    Cytokine profile in patients with maturity-onset diabetes of the young (MODY)
    (HighWire Press, 2022) Diren, A.; Demirci, D.K.; Gül, N.; Karacanlı, B.; Baykut, A.; Öztürk, O.; Satman, I.; Yılmaz Aydoğan, H.; Tütüncü, Yıldız; Faculty Member; School of Medicine; 239430
    Background/aim: high-sensitivity C-reactive protein (hs-CRP) is used in the differential diagnosis of maturity-onset diabetes of the young (MODY)-3, but other inflammatory markers have not been investigated in MODY patients. We aimed to compare the serum levels of anti-inflammatory and proinflammatory cytokines between MODY patients and healthy subjects and show the inflammatory features in MODY subtypes. Patients and methods: thirty patients with clinically suspected MODY and 34 healthy controls were included in this study. Next -generation sequencing (NGS) was used for the molecular diagnosis of MODY subtypes. Serum levels of cytokines were measured using a multiplexed cytokine assay and hs-CRP concentration was determined by the immunoturbidimetric assay. Results: the hs-CRP levels were higher in both NGS-confirmed (MODY, n=17) (p=0.009) and NGS-unconfirmed (non-MODY, n=13) patients (p<0.001) than those in controls. However, IL-1 beta (p=0.001), IL-6 (p=0.018), IL-31 (p=0.003), TNF-alpha (p<0.001), and sCD40L (p=0.007) levels of MODY patients and IL-1 beta (p=0.002), IL-31 (p<0.001), IL-22 (p=0.018), and sCD40L (p=0.039) levels of non-MODY patients were lower than those of controls. While hs-CRP levels were lower in MODY3 patients than non-MODY3 patients (p=0.009), IL-17A (p=0.006) and IL-23 (p=0.016) levels for the first time in this study were found to be higher in patients with MODY3 than in patients with other MODY subtypes (p<0.05). Conclusion: MODY patients had lower serum levels of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha, IL-31, and sCD40L compared to healthy controls. High IL-17A and IL-23 levels along with low hs-CRP levels may be potential markers to distinguish MODY3 from other MODY subtypes.