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In this real-world pilot study, we evaluated the metabolic and endocrinological effects in patients with adult growth hormone deficiency (AGHD) who switched from daily growth hormone (GH) replacement therapy to weekly GH replacement therapy using somapacitan. Eleven patients with AGHD, whose medical treatment aside from GH replacement therapy did not change, were enrolled. We investigated the metabolic and endocrinological parameters between at switching and 6 months after switching from daily GH formulation to somapacitan. The results showed that body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (FPG), and liver functions were significantly improved 6 months after switching compared to those at switching (each P < .05). Besides, the improvement in HOMA-IR was significantly associated with the period of daily GH replacement therapy before switching (P = .048), while age, sex, improvement in BMI or liver functions, presence of any hormonal deficiency, and the existence of any hormonal replacement therapy significantly associated (P > .05). In addition, switching to GH replacement therapy did not affect endocrinological parameters. In conclusion, this study might indicate that weekly GH replacement therapy with somapacitan could have more beneficial points than daily GH replacement therapy. Considering the cohort of this study was small, future studies with larger cohorts should be necessary to confirm the results of this study.
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Endocrinología , Hormona de Crecimiento Humana , Humanos , Adulto , Proyectos Piloto , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/uso terapéuticoRESUMEN
Primary triglyceride deposit cardiomyovasculopathy (P-TGCV), caused by a rare genetic mutation in PNPLA2 encoding adipose triglyceride lipase (ATGL), exhibits severe cardiomyocyte steatosis and heart failure. Here, we report the case of a 51-year-old man with P-TGCV homozygous for a novel PNPLA2 mutation (c.446C > G, P149R) in the catalytic domain of ATGL. Analyses of endomyocardial biopsy specimens and in vitro expression experiments showed mutant protein expression with conserved lipid binding, but reduced lipolytic activity, indicating mutation pathogenicity.
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Pituitary apoplexy is an uncommon syndrome that often results in spontaneous hemorrhage or infarction of pituitary tumors or glands. We previously reported pituitary apoplexy occurred most frequently in nonfunctional pituitary adenomas among all types of pituitary incidentalomas. In the present study, we aimed to investigate the characteristics of pituitary apoplexy in patients with incidental nonfunctional pituitary adenomas. 65 patients with pituitary incidentaloma were enrolled. All patients underwent clinical/endocrinological/pathological investigations. As a result, 33 patients were diagnosed with nonfunctional pituitary adenomas. Of these, 12.1% of patients had pituitary apoplexy. There was no difference in tumor diameter, age, or sex between the apoplexy and the non-apoplexy groups. However, the liver enzymes aspartate transaminase and alanine aminotransferase were significantly higher, and plasma sodium and chloride levels were significantly lower in the apoplexy group than in the non-apoplexy group (each Pâ <â .05). In addition, low-density lipoprotein-cholesterol was significantly higher in the apoplexy group than in the non-apoplexy group (Pâ <â .05). Besides, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin deficiencies were significantly more frequent in the apoplexy group than in the non-apoplexy group (each Pâ <â .05), and growth hormone and adrenocorticotropic hormone deficiencies were more frequent in the apoplexy group than in the non-apoplexy group (Pâ =â .09 and.08, respectively). Furthermore, tumor diameter was not associated with pituitary apoplexy, whereas thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone deficiencies were significantly associated with the apoplexy group (each Pâ <â .05). Hence, the present study indicated that pituitary apoplexy could not be related to tumor diameter. Moreover, hormonal deficiencies, hepatic dysfunction, hyponatremia or hypochloremia, and dyslipidemia might be indicators of pituitary apoplexy. There could be the possibility the treatment for dyslipidemia prevents pituitary apoplexy.
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Adenoma , Apoplejia Hipofisaria , Neoplasias Hipofisarias , Humanos , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/patología , Adenoma/complicaciones , Adenoma/patología , Hormona Folículo Estimulante , Hormona Luteinizante , Tirotropina , Apoplejia Hipofisaria/etiología , Apoplejia Hipofisaria/diagnósticoRESUMEN
Hypothalamic adrenal insufficiency (AI) is a rare but distinct type of AI. The leading cause of hypothalamic AI is a secondary side-effect of exogenous steroid intake, particularly in large amounts and/or long-term periods. The next cause would be the effect of the tumor in the hypothalamic lesions. We show here 9 cases of hypothalamic AI without any disorder on imagings and a history of steroid administration. All patients had general fatigue; 7 patients (77.8%) had a history of hypoglycemia; 5 patients (55.6%) had a history of hypotension. None of the patients had hyponatremia, hyperkalemia, or eosinophilia. Their morning plasma adrenocorticotropic hormone (ACTH) value was low at 8.5 ± 4.2 pg/mL, and serum cortisol value was low at 4.5 ± 1.3 µg/dL. All patients demonstrated normal responses during the corticotropin-releasing hormone loading (CRH) test but inadequate responses during the insulin tolerance test (ITT). After hydrocortisone replacement therapy, their morning plasma ACTH and serum cortisol values were significantly recovered (P < .05). Moreover, more than half of the patients were fine after discontinuing hydrocortisone replacement therapy. These results indicate that this unique type of hypothalamic AI has a curable clinical course making hydrocortisone replacement therapy a novel therapeutic option.
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Insuficiencia Suprarrenal , Hidrocortisona , Insuficiencia Suprarrenal/tratamiento farmacológico , Insuficiencia Suprarrenal/etiología , Hormona Adrenocorticotrópica , Hormona Liberadora de Corticotropina , Humanos , InsulinaRESUMEN
OBJECTIVE: Previous reports have demonstrated the association of serum bilirubin levels with the progression of diabetic nephropathy. The objective of this study is to assess the association of basal bilirubin levels with progressive renal decline (PRD) and end-stage kidney disease (ESKD). METHODS: A total of 298 patients with diabetes who visited Kyushu University Hospital (Japan) were recruited and followed up for 10 years. PRD was defined as a negative change in estimated glomerular filtration ratio (eGFR) >3.7%/year, 2.5th percentile. Logistic regression analysis was performed to evaluate the association of total bilirubin levels with PRD and its cut-off point was determined by receiver operating characteristic (ROC) analysis. Kaplan-Meier method and Cox hazard regression analysis were used to evaluate the predictive ability of its cut-off point for ESKD. RESULTS: Logistic regression model showed that total bilirubin levels were significantly associated with PRD, and ROC analysis showed that its cut-off point was 0.5 mg/dL. Kaplan-Meier method showed that the percent of patients who reached two endpoints, composite endpoint (ESKD or doubling of creatinine level) or 30% eGFR decline, was significantly higher in the low bilirubin group than in the high bilirubin group (18.5% vs 11.0%, P = 0.045; 49.1% vs 42.1%, P = 0.045, respectively, log-rank test). Cox hazard regression models confirmed the independence of the predictive ability of its cut-off point. CONCLUSIONS: Serum total bilirubin levels were negatively associated with PRD in diabetic nephropathy and its cut-off point was 0.5 mg/dL. It may be clinically useful for identifying patients at high risk of ESKD.
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Diabetes Mellitus , Nefropatías Diabéticas , Fallo Renal Crónico , Bilirrubina , Estudios de Cohortes , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Humanos , Japón/epidemiologíaRESUMEN
This study aimed to develop a simplified model for predicting end-stage kidney disease (ESKD) in patients with diabetes. The cohort included 2549 individuals who were followed up at Kyushu University Hospital (Japan) between January 1, 2008 and December 31, 2018. The outcome was a composite of ESKD, defined as an eGFR < 15 mL min-1 [1.73 m]-2, dialysis, or renal transplantation. The mean follow-up was 5.6 [Formula: see text] 3.7 years, and ESKD occurred in 176 (6.2%) individuals. Both a machine learning random forest model and a Cox proportional hazard model selected eGFR, proteinuria, hemoglobin A1c, serum albumin levels, and serum bilirubin levels in a descending order as the most important predictors among 20 baseline variables. A model using eGFR, proteinuria and hemoglobin A1c showed a relatively good performance in discrimination (C-statistic: 0.842) and calibration (Nam and D'Agostino [Formula: see text]2 statistic: 22.4). Adding serum albumin and bilirubin levels to the model further improved it, and a model using 5 variables showed the best performance in the predictive ability (C-statistic: 0.895, [Formula: see text]2 statistic: 7.7). The accuracy of this model was validated in an external cohort (n = 5153). This novel simplified prediction model may be clinically useful for predicting ESKD in patients with diabetes.
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Diabetes Mellitus , Fallo Renal Crónico , Insuficiencia Renal Crónica , Bilirrubina , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Hemoglobina Glucada , Humanos , Proteinuria , Diálisis Renal , Factores de Riesgo , Albúmina SéricaRESUMEN
Context: Mutations in the NR0B1 gene, also well-known as the DAX1 gene, are known to cause congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism. The abnormal NR0B1 protein fails to suppress the transcription of promoters of steroidogenic enzymes, which are also targets of NR5A1 protein, also well-known as Ad4BP/SF-1 protein. Since NR5A1 and NR0B1 have antagonistic effects on steroidogenesis, the loss of function due to NR0B1 mutations may be compensated by inducing loss of function of NR5A1 protein. Patient: A middle-aged man was diagnosed with congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism and genetic analysis revealed him to have a novel NR0B1 mutation, c.1222C>T(p.Gln408Ter). Methods: NR0B1 activity was evaluated in CLK1/4 inhibitor-treated 293T cells via immunoblotting and luciferase assays of the STAR promoter. Results: TG003 treatment suppressed NR5A1 protein function to compensate for the mutant NR0B1 showing inhibited suppression of transcription. Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor. Conclusion: The specific reduction of NR5A1 phosphorylation by a CLK1/4 inhibitor may alleviate developmental defects in patients with NR0B1 mutations.
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INTRODUCTION: Cinacalcet is a calcimimetic that modulates the functions of calcium-sensing receptor and is currently used to treat patients with primary hyperparathyroidism (PHPT). Although it was reported that cinacalcet treatment reduced the size of hyperplastic parathyroid glands in patients with secondary hyperparathyroidism, whether or not cinacalcet treatment can reduce the size of parathyroid adenomas in patients with PHPT has been unknown. MATERIALS AND METHODS: We recruited nine (male: one, female: eight) patients with PHPT due to parathyroid adenomas who did not undergo parathyroidectomy. Cinacalcet was administered at a dose of 50 mg/day, and we evaluated the size of parathyroid adenomas (width × thickness) (mm2) using ultrasonography before and after 6 months of cinacalcet treatment. RESULTS: The mean age of the subjects was 58.1 ± 7.2 years old, and the mean serum intact parathyroid hormone (PTH) concentration was 134.8 ± 8.7 pg/ml. All participants showed hypercalcemia and osteopenia. After 6 months, the mean size of parathyroid adenomas was significantly decreased (baseline: 73.8 ± 33.4 mm2 vs. after 6 months: 52.5 ± 25.0 mm2, p = 0.045). Thus, 6-month cinacalcet treatment induced a 29% size reduction in parathyroid adenomas. Furthermore, the serum intact PTH concentration before cinacalcet treatment was positively correlated with the reduction in the size of parathyroid adenomas. CONCLUSION: The present study revealed that cinacalcet treatment reduces the size of parathyroid adenomas in patients with PHPT. The accumulation of more PHPT cases with cinacalcet therapy is required to confirm this finding.
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Adenoma/complicaciones , Adenoma/tratamiento farmacológico , Cinacalcet/uso terapéutico , Hiperparatiroidismo Primario/complicaciones , Neoplasias de las Paratiroides/complicaciones , Neoplasias de las Paratiroides/tratamiento farmacológico , Adenoma/sangre , Adenoma/diagnóstico por imagen , Calcio/sangre , Cinacalcet/efectos adversos , Femenino , Humanos , Hiperparatiroidismo Primario/sangre , Hiperparatiroidismo Primario/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Neoplasias de las Paratiroides/sangre , Neoplasias de las Paratiroides/diagnóstico por imagen , Paratiroidectomía , Carga Tumoral , UltrasonografíaRESUMEN
Due to its rarity, adrenal hemorrhage is difficult to diagnose, and its precise etiology has remained unknown. One of the pivotal mechanisms of adrenal hemorrhage is the thrombosis of the adrenal vein, which could be due to thrombophilia. However, detailed pathological evaluation of resected adrenal glands is usually required for definitive diagnosis. Here, we report a case of a cortisol-secreting adenoma with concomitant foci of hemorrhage due to antiphospholipid syndrome diagnosed both clinically and pathologically. In addition, the tumor in this case was pathologically diagnosed as cortisol-secreting adenoma, although the patient did not necessarily fulfill the clinical diagnostic criteria of full-blown Cushing or sub-clinical Cushing syndrome during the clinical course, which also did highlight the importance of detailed histopathological investigations of resected adrenocortical lesions.
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Adenoma , Síndrome Antifosfolípido , Síndrome de Cushing , Adenoma/complicaciones , Adenoma/diagnóstico , Adenoma/cirugía , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/diagnóstico , Síndrome de Cushing/complicaciones , Síndrome de Cushing/etiología , Hemorragia/complicaciones , Hemorragia/etiología , Humanos , HidrocortisonaRESUMEN
Genetic deficiency of adipose triglyceride lipase (ATGL), a rate-limiting enzyme for intracellular triglyceride (TG) hydrolysis, causes TG-deposit cardiomyovasculopathy (TGCV), a recently identified rare cardiovascular disorder (ORPHA code: 565612) in humans. One of the major characteristics of TGCV is a novel type of diffuse and concentric coronary atherosclerosis with ATGL-deficient smooth muscle cells (SMCs). Patients with TGCV have intractable coronary artery disease. Therefore, it is crucial to investigate the mechanisms underlying vascular lesions in ATGL deficiency using animal models. Cuff injury is an experimental procedure to induce vascular remodeling with neointimal formation with SMCs after placing a cuff around the adventitial side of the artery without direct influence on endothelium. We report the effect of cuff injury on femoral arteries of ATGL-knockout (ATGLâ»/â») mice. Cuff-induced concentric neointimal formation with migrating SMCs was exacerbated in ATGLâ»/â» mice, mimicking atherosclerotic lesions in patients with TGCV. In the media, cell death of SMCs and loss of elastic fibers increased. Perivascular infiltrating cells expressing tumor necrosis factor-α (TNF-α) were more prominent in ATGLâ»/â» mice than in wild-type (WT) mice. In Boyden chamber experiments, a greater number of ATGLâ»/â» SMCs migrated in response to TNF-α compared to WT SMCs. These data, for the first time, demonstrated that outside-in signaling by cuff-induced neointimal formation where paracrine stimuli from adventitial infiltrating cells may lead to neointimal formation and mediolysis in ATGL-deficient conditions. Cuff injury might be a valuable model for understanding the mechanisms underlying the development of atherosclerotic lesions in patients with TGCV.
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Arteria Femoral/lesiones , Lipasa/genética , Lipasa/metabolismo , Transducción de Señal , Animales , Aterosclerosis/fisiopatología , Movimiento Celular , Hidrólisis , Inmunohistoquímica , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía FluorescenteRESUMEN
PURPOSE: In this retrospective study, we investigated the status and validity of endoscopic transsphenoidal surgery (eTSS) for pituitary incidentalomas (PIs) as well as the value of basing the indication for surgery on the PI guidelines. METHODS: Patients who underwent eTSS at Fukuoka University Chikushi Hospital between 2012 and 2018 were divided into the PI group and the non-PI group in accordance with the PI guideline of the Endocrine Society and their clinicopathological characteristics and outcomes were compared and analyzed. RESULTS: A total of 59 patients were enrolled, with 35 patients in the PI group and 24 patients in the non-PI group. The diagnoses in the PI group were of non-functioning pituitary adenoma (NFPA) (nâ=â12, 34%), gonadotropin-producing pituitary adenoma (nâ=â8, 23%), Rathke cleft cyst (nâ=â7, 20%), meningioma (nâ=â4, 11%), and growth hormone-producing pituitary adenoma (nâ=â3, 9%); those in the non-PI group were of NFPA (nâ=â6, 25%), gonadotropin-producing pituitary adenoma (nâ=â3, 13%), Rathke cleft cyst (nâ=â3, 13%), growth hormone-producing pituitary adenoma (nâ=â3, 13%), and prolactin producing pituitary adenoma (nâ=â3, 13%). Regarding the preoperative factors, 1 patient in the PI group with panhypopituitarism was diagnosed with pituitary apoplexy (pure infarction) of an NFPA. The rates of postoperative anterior pituitary hormonal deficiencies (14% vs 46%, Pâ=â.015), residual tumor size (2â±â5 vs 6â±â7âmm, Pâ=â.008), and reoperation (nâ=â0, 0% vs nâ=â5, 21%, Pâ=â.005) were significantly different between the PI and non-PI groups. CONCLUSIONS: This study showed that, postoperatively, the incidence of anterior pituitary hormonal deficiencies was lower in the PI than in the non-PI group, although it was comparable between the 2 groups before the operation. The patients in the PI group also had smaller residual tumors and a lower risk of reoperation than those in non-PI group. PIs could have a better postoperative clinical outcome than non-PIs when the indication for eTSS is based on preoperative scrutiny according to the PI guidelines and eTSS is performed by an experienced pituitary surgeon. Hence, more aggressive scrutiny and treatment for PIs might be desirable.
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Endocrinología/normas , Endoscopía/métodos , Neoplasias Hipofisarias/cirugía , Guías de Práctica Clínica como Asunto , Adulto , Anciano , Femenino , Humanos , Hallazgos Incidentales , Masculino , Persona de Mediana Edad , Selección de Paciente , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/patología , Hueso Esfenoides/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: This study aimed to verify the safety and efficacy, including glycemic control, of the selective dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes. METHODS: This study used a multi-center, open-label, prospective observational design. Type 2 diabetes patients who were undergoing dietary therapy and/or exercise therapy alone without sufficient glycemic control (hemoglobin A1c (HbA1c) ≥ 6.5% and < 10%) were administered alogliptin (25 mg/day). The long-term effects (6 and 12 months) on blood glucose, blood pressure, heart rate, body weight and lipids were assessed. RESULTS: A final 50 patients were included with a high prevalence of hypertension (77%) and dyslipidemia (72%), and a mean duration of diabetes of 4.5 years. Pre-treatment HbA1c was 7.5% and was significantly decreased at 6 and 12 months (6M: 6.4%, 12M: 6.2%; P < 0.02 vs. 0M, respectively). Body weight, blood pressure and low-density lipoprotein cholesterol were significantly decreased by 6 months and maintained at 12 months. Triglycerides showed a significant decrease at 12 months. No significant differences were observed in HbA1c decrease for different grade of age, duration of diabetes, body mass index and renal function. The degree of decrease in HbA1c was most strongly correlated with pre-treatment HbA1c. Adverse events were noted in three patients, with no serious outcomes. CONCLUSION: The blood glucose-lowering effect and safety of alogliptin were demonstrated regardless of baseline HbA1c, although its effect appeared stronger with higher pre-treatment HbA1c values. Additionally, alogliptin appears useful for managing atherosclerotic risk factors such as body weight and blood pressure.
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Triglyceride deposit cardiomyovasculopathy (TGCV) is a newly identified disease that was discovered in individuals who required cardiac transplantation in Japan in 2008. Defective intracellular lipolysis causes triglyceride (TG) accumulation in the myocardium and coronary artery vascular smooth muscle cells, which results in severe heart failure and coronary artery disease with poor prognosis. A known cause of TGCV is a genetic deficiency of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in the intracellular hydrolysis of TG. TGCV is classified into primary TGCV with ATGL mutations and idiopathic TGCV without ATGL mutations. Since its discovery, the Japan TGCV Study Group has attempted to elucidate its pathophysiology, develop diagnostic procedures, and specific treatment. Myocardial scintigraphy with iodine-123-ß-methyl iodophenyl-pentadecanoic acid (123I-BMIPP) is a unique imaging modality for evaluating myocardial lipolysis in vivo. The washout rate of 123I-BMIPP is an essential indicator for the diagnosis of TGCV. Along with our efforts to provide awareness of and insights into this disease concept, we found that the cumulative number of clinically diagnosed patients has reached >200 and the cases are distributed throughout Japan. In addition, we successfully completed three investigator-initiated clinical trials of a potential therapeutic agent (CNT-01) for TGCV, which was assigned by the Ministry of Health, Labour, and Welfare, Japan, under the SAKIGAKE Designation System in June 2020. Here, we provide the Diagnostic Criteria 2020 for TGCV in order to further promote this "rare and intractable disease" project.
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Cardiomiopatías/patología , Enfermedad de la Arteria Coronaria/patología , Insuficiencia Cardíaca/patología , Errores Innatos del Metabolismo Lipídico , Triglicéridos/metabolismo , Cardiomiopatías/etiología , Enfermedad de la Arteria Coronaria/etiología , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Adulto JovenRESUMEN
Objective: We purpose to confirm the effect of teneligliptin (Tenelia), a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, on glycemic control and non-glucose risk factors for macroangiopathy, including blood pressure, lipid metabolism, and body weight.Methods: In a prospective, multicenter, open-label, observational study, teneligliptin (20 mg/day) was administered to type 2 diabetic patients with poor glycemic control (HbA1c ≥ 6.5% to <10%) at our hospitals. The safety of teneligliptin and its impact on blood glucose, blood pressure, and the lipid profile were assessed after administration for 3 and 6 months.Results: One hundred and sixty-two patients were enrolled between February 2014 and August 2015. HbA1c was 7.6% at baseline and showed significant reduction to 7.1% after 3 months of treatment and to 6.9% after 6 months (both p < 0.01). Patients with poorly controlled hypertension (systolic blood pressure [SBP] ≥130 mmHg and/or diastolic blood pressure [DBP] ≥80 mmHg) at study initiation were extracted to investigate the effect of teneligliptin on blood pressure. SBP showed a significant decrease from 141.2 ± 9.8 mmHg at baseline to 131.1 ± 14.3 mmHg after 3 months and 133.9 ± 11.5 mmHg after 6 months (both p < 0.001). DBP also decreased significantly from 85.8 ± 5.7 mmHg at baseline to 78.4 ± 10.0 mmHg after 3 months and 79.7 ± 10.1 mmHg after 6 months (both p < 0.001). Adverse events were pruritus in four patients, and cerebral infarction was reported as a cerebrovascular event in one patient.Conclusions: Teneligliptin therapy was safe and improved glycemic control irrespective of baseline HbA1c. Blood pressure was also improved in patients with concomitant hypertension.
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Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/análisis , Hipertensión , Pirazoles , Tiazolidinas , Disponibilidad Biológica , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Quimioterapia Combinada/métodos , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Evaluación de Procesos y Resultados en Atención de Salud , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , Pirazoles/farmacocinética , Tiazolidinas/administración & dosificación , Tiazolidinas/efectos adversos , Tiazolidinas/farmacocinéticaRESUMEN
Osteoporosis is a complication of type 2 diabetes mellitus (T2DM). Blockade of receptor activator of nuclear factor kappa-B ligand (RANKL) improves osteoporosis, but might also improve glucose tolerance through reduction of hepatic insulin resistance. However, the effect of denosumab (a human monoclonal antibody of RANKL) upon glycemic and metabolic parameters is controversial. We revealed the effect of denosumab upon glycemic and metabolic parameters for 52 weeks. We evaluated 20 individuals diagnosed with both osteoporosis (male and female: postmenopausal) and T2DM. We measured glycemic and metabolic parameters before and 26/52 weeks after administration of denosumab (60âmg per 26 weeks) without changing any other medication each patient was taking. All patients completed the study without complications and the T-score (lumbar spine and femoral neck) improved significantly from baseline to 52 weeks after denosumab administration (Pâ<â.001, .001, respectively). None of the glycemic parameters changed significantly from baseline to 26 weeks after denosumab administration, but levels of glycated hemoglobin and homeostasis model assessment of insulin resistance improved significantly from baseline to 52 weeks after administration (Pâ=â.019, .008, respectively). The levels of liver enzymes did not change significantly from baseline to 26 weeks after denosumab administration, but levels of aspartate transaminase and alanine aminotransferase improved significantly from baseline to 52 weeks after administration (Pâ=â.014, .004, respectively). None of the markers of lipid metabolism and body mass index changed significantly from baseline to 26/52 weeks after denosumab administration. These data demonstrated that denosumab is useful for T2DM patients with osteoporosis for glycemic control via improvement of insulin resistance. Also, the effect of denosumab might be due to improvement of hepatic function.
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Glucemia/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Denosumab/farmacología , Denosumab/uso terapéutico , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Osteoporosis/metabolismo , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Masculino , Osteoporosis/etiología , Ligando RANK/inmunologíaRESUMEN
INTRODUCTION: Recently, the sodium-glucose cotransporter2 (SGLT2) inhibitor empagliflozin has been shown to lower cardiovascular risk among diabetic patients. It is intriguing that some SGLT2 inhibitors have been found to increase low-density lipoprotein (LDL) cholesterol levels, while the relevance to high-density lipoprotein (HDL) cholesterol is unknown. Although the inhibitory effect of SGLT2 inhibitors on glucose reabsorption may accelerate compensatory lipid metabolism and subsequently reduce body weight and affect the lipid profile, much remains unclear about this mechanism. Therefore, we conducted this study to investigate in detail how canagliflozin affects lipoprotein fractions including LDL and HDL subclasses. MATERIALS AND METHODS: This study is a multicenter prospective study. The participants were patients with 22 type 2 diabetes (60.7 ± 11.6 years, 59.1% of men) who had HbA1c ⩾ 7.0% and consented to participate in the study. They were administered 100 mg canagliflozin orally once per day. Biochemistry test and cholesterol levels of 20 lipoprotein fractions (G1-G20) using high performance liquid chromatography methods were examined before and after 12 weeks of treatment period. RESULTS: Significant decreases were observed in the participants' body weight (69.7 to 67.9 kg, P < .001), systolic blood pressure (129.3 to 119.5 mm Hg, P < .01), and HbA1c (8.5% to 7.4%, P < .001). Cholesterol levels in the 20 lipoprotein fractions increased for very large HDL (G14, G15) and large HDL (G16) (P < .05). CONCLUSIONS: Reduction in body weight, improvement of blood glucose levels, and increases in very large HDL and large HDL subclasses were observed after canagliflozin treatment. These beneficial changes might contribute to subsequent suppression of cardiovascular outcomes.
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Triglyceride deposit cardiomyovasculopathy (TGCV) is a phenotype primarily reported in patients carrying genetic mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) which releases long chain fatty acid (LCFA) as a major energy source by the intracellular TG hydrolysis. These patients suffered from intractable heart failure requiring cardiac transplantation. Moreover, we identified TGCV patients without PNPLA2 mutations based on pathological and clinical studies. We provided the diagnostic criteria, in which TGCV with and without PNPLA2 mutations were designated as primary TGCV (P-TGCV) and idiopathic TGCV (I-TGCV), respectively. We hereby report clinical profiles of TGCV patients. Between 2014 and 2018, 7 P-TGCV and 18 I-TGCV Japanese patients have been registered in the International Registry. Patients with I-TGCV, of which etiologies and causes are not known yet, suffered from adult-onset severe heart disease, including heart failure and coronary artery disease, associated with a marked reduction in ATGL activity and myocardial washout rate of LCFA tracer, as similar to those with P-TGCV. The present first registry-based study showed that TGCV is an intractable, at least at the moment, and heterogeneous cardiovascular disorder.
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Enfermedades Cardiovasculares/metabolismo , Enfermedades Raras/metabolismo , Triglicéridos/metabolismo , Adulto , Anciano , Aterosclerosis/genética , Aterosclerosis/metabolismo , Enfermedades Cardiovasculares/patología , Femenino , Humanos , Lipasa/genética , Lipasa/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Enfermedades Raras/patologíaRESUMEN
The recently discovered circular RNAs (circRNAs) are mostly formed by back-splicing where the downstream 5' splice site splices to the upstream 3' splice site by conventional pre-mRNA splicing. These circRNAs regulate gene expression by acting as sponges for micro-RNAs or RNA-binding proteins. Here we show that the NR5A1 (previously called Ad4BP or SF-1) gene which is exclusively expressed in the adrenal cortex and steroidogenic tissue can form atypical circRNAs by unconventional splicing. Two stem loops with inositol-requiring protein-1α (IRE1α) cleavage sites are connected by an IRE1α cleavage site to form a circRNA (circIRE RNA). From total RNA of normal human adrenal cortex, we detected a circIRE RNA with connected ends by IRE1α cleavage sites in exon 6 and exon 1 (circIRE NR5A1 ex6-1 RNA). circIRE NR5A1 ex6-1 RNA was not detected in the adrenocortical cancer cell line, H295R. When IRE1α was expressed in H295R cells a different circIRE NR5A1 RNA connecting IRE1-cleavage sites in exon 7 and exon 1 was detected (circIRE NR5A1 ex7-1 RNA). The expression of this circIRE RNA was inhibited by the IRE1 inhibitor 1, STF-083010, implicating that it was formed via the ER stress pathway, where IRE1α is a major factor. This is the first report of this type of circular RNA connected by IRE1-cleavage sites found to be expressed in mammalian cells in a tissue-specific manner. To our surprise, the concomitant expression of NR5A1 was increased by IRE1α implicating that NR5A1 was not subjected to IRE1-dependent decay of mRNA (RIDD) but rather activating a transcriptional regulatory network to cope with ER stress in steroidogenic tissue reminiscent to XBP1 in other tissue. We believe this is the first report of such tissue-specific transcriptional cascade responding to ER stress as well as the novel finding of circular RNAs connected by IRE1α cleavage sites expressed in mammalian tissue.
Asunto(s)
Corteza Suprarrenal/metabolismo , Endorribonucleasas/genética , Proteínas Serina-Treonina Quinasas/genética , ARN Circular/biosíntesis , ARN Circular/genética , Factor Esteroidogénico 1/genética , Corteza Suprarrenal/citología , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Secuencia de Bases , Sitios de Unión/genética , Línea Celular Tumoral , Estrés del Retículo Endoplásmico , Endorribonucleasas/antagonistas & inhibidores , Endorribonucleasas/metabolismo , Exones , Expresión Génica , Humanos , Modelos Biológicos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Empalme del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sulfonamidas/farmacología , Tiofenos/farmacologíaRESUMEN
Glucose intolerance is often observed in patients with pheochromocytoma. However, it remains controversial issue that glucose intolerance on pheochromocytoma is caused by impaired insulin secretion and/or by increased insulin resistance. We aimed to reveal the mechanism of glucose intolerance on pheochromocytoma with regard to the type and amount of catecholamines released. We evaluated 12 individuals diagnosed with pheochromocytoma and who underwent surgery to remove it. We examined glycemic parameters before and after surgery and investigated the association between the change of parameters of insulin secretion (homeostasis model assessment of ß-cell function (HOMA-ß)), insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) and that of urinary levels of metanephrine/normetanephrine before and after surgery. Overall, fasting plasma glucose, glycated hemoglobin (HbA1c), HOMA-ß, and HOMA-IR were improved significantly after surgery. Regression analysis showed that the improvement in HOMA-ß from before to after surgery was significantly positively associated with an improvement in urinary levels of metanephrine from before to after surgery and showed a significantly negative association with improvement in urinary levels of normetanephrine from before to after surgery. The improvement in HOMA-IR from before to after surgery was significantly positively associated with an improvement in urinary levels of normetanephrine from before to after surgery. Our results showed that pheochromocytoma extirpation improved glycemic parameters. Furthermore, the different effects elicited by excess amounts of adrenaline and noradrenaline on glucose intolerance were demonstrated.