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1.
Diabetes Obes Metab ; 22(5): 879-884, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31943645

RESUMO

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining popularity in the management of diabetes in solid organ transplant (SOT) recipients. There are no studies available comparing the two GLP-1RAs dulaglutide and liraglutide in SOT. We performed a retrospective chart review to assess the safety and effectiveness of these agents in adult SOT with diabetes at 6, 12 and 24 months. There were 63 and 25 recipients on dulaglutide and liraglutide, respectively. There was a sustained reduction in primary endpoints of weight, BMI and insulin requirement with dulaglutide when compared to liraglutide. Decrease in weight was 2%, 4% and 5.2% with dulaglutide and 0.09%, 0.87% and 0.89% with liraglutide at 6, 12 and 24 months respectively. BMI reduction followed the same trend in the two groups. The percentage reduction for insulin was 26% with dulaglutide and 3.6% with liraglutide. There was a 10% reduction in creatinine and a 15% increase in estimated glomerular filtration rate (eGFR) at the end of 24 months with dulaglutide. However, there was an increase in creatinine by 7% and an 8% decrease in eGFR at the end of 24 months with liraglutide.


Assuntos
Diabetes Mellitus Tipo 2 , Transplante de Órgãos , Adulto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Liraglutida/uso terapêutico , Proteínas Recombinantes de Fusão , Estudos Retrospectivos
2.
Diabetes Obes Metab ; 21(4): 1061-1065, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30565376

RESUMO

Published data regarding the approach to management of diabetes mellitus in solid organ transplant (SOT) recipients are limited. We performed a retrospective chart review of SOT recipients with diabetes, above 18 years of age, who were usisng dulaglutide. There was a sustained, statistically significant reduction in the primary endpoints of weight, body mass index (BMI) and insulin requirement in 63 SOT recipients at 6, 12 and 24 months, respectively. A total of 59, 50 and 13 recipients were followed during 6, 12 and 24 months, with a mean paired difference for weight reduction of 2.07 (P value <0.003), 4.007 (P value <0.001) and 5.23 (P value <0.034) kgs and a BMI reduction of 0.80 (P value <0.001), 1.35 (P value <0.005) and 2.015 (P value <0.045) kg/m2 , respectively. The mean paired difference for insulin reduction before and after dulaglutide treatment was 5.94 units (P value <0.0002). There was no increased risk of malignancy, cardiovascular morbidity, graft-failure or all-cause mortality. Gastrointestinal manifestations were rare, even in patients with advanced chronic kidney disease (CKD), and required no change in immunosuppressive agents. Thus, dulaglutide may be considered an important option for diabetes management in SOT.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Transplante de Órgãos , Proteínas Recombinantes de Fusão/uso terapêutico , Adulto , Idoso , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Hemoglobinas Glicadas/metabolismo , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Transplante de Coração , Humanos , Imunossupressores/uso terapêutico , Incretinas/uso terapêutico , Insulina/uso terapêutico , Transplante de Rim , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplantados
4.
J Biol Chem ; 290(6): 3793-802, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25538235

RESUMO

Metformin is the most widely prescribed oral anti-diabetic agent. Recently, we have shown that low metformin concentrations found in the portal vein suppress glucose production in hepatocytes through activation of AMPK. Moreover, low concentrations of metformin were found to activate AMPK by increasing the phosphorylation of AMPKα at Thr-172. However, the mechanism underlying the increase in AMPKα phosphorylation at Thr-172 and activation by metformin remains unknown. In the current study, we find that low concentrations of metformin promote the formation of the AMPK αßγ complex, resulting in an increase in net phosphorylation of the AMPK α catalytic subunit at Thr-172 by augmenting phosphorylation by LKB1 and antagonizing dephosphorylation by PP2C.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Multimerização Proteica , Animais , Linhagem Celular Tumoral , Células Cultivadas , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Camundongos , Fosforilação , Ligação Proteica , Proteína Fosfatase 2/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Subunidades Proteicas/metabolismo
5.
J Biol Chem ; 289(30): 20435-46, 2014 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-24928508

RESUMO

Metformin is a first-line antidiabetic agent taken by 150 million people across the world every year, yet its mechanism remains only partially understood and controversial. It was proposed that suppression of glucose production in hepatocytes by metformin is AMPK-independent; however, unachievably high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMP-activated protein kinase (AMPK)-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60-80 µM). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA pathway negatively regulates AMPK activity through phosphorylation at Ser-485/497 on the α subunit, which in turn reduces net phosphorylation at Thr-172. Because diabetic patients often have hyperglucagonemia, AMPKα phosphorylation at Ser-485/497 is a therapeutic target to improve metformin efficacy.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Gluconeogênese/efeitos dos fármacos , Glucose/biossíntese , Hepatócitos/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/citologia , Camundongos
6.
J Biol Chem ; 289(7): 4326-33, 2014 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24379407

RESUMO

FOXO1 is an important downstream mediator of the insulin signaling pathway. In the fed state, elevated insulin phosphorylates FOXO1 via AKT, leading to its nuclear exclusion and degradation. A reduction in nuclear FOXO1 levels then leads to suppression of hepatic glucose production. However, the mechanism leading to expression of Foxo1 gene in the fasted state is less clear. We found that Foxo1 mRNA and FOXO1 protein levels of Foxo1 were increased significantly in the liver of mice after 16 h of fasting. Furthermore, dibutyrl cAMP stimulated the expression of Foxo1 at both mRNA and protein level in hepatocytes. Because cAMP-PKA regulates hepatic glucose production through cAMP-response element-binding protein co-activators, we depleted these co-activators using adenoviral shRNAs. Interestingly, only depletion of co-activator P300 resulted in the decrease of Foxo1 mRNA and FOXO1 protein levels. In addition, inhibition of histone acetyltransferase activity of P300 significantly decreased hepatic Foxo1 mRNA and FOXO1 protein levels in fasted mice, as well as fasting blood glucose levels. By characterization of Foxo1 gene promoter, P300 regulates the Foxo1 gene expression through the binding to tandem cAMP-response element sites in the proximal promoter region of Foxo1 gene.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fatores de Transcrição Forkhead/biossíntese , Regulação da Expressão Gênica/fisiologia , Fígado/metabolismo , Animais , Bucladesina/farmacologia , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Jejum/metabolismo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/citologia , Camundongos
7.
JCEM Case Rep ; 2(6): luae097, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38911362

RESUMO

Pheochromocytomas (PCCs) and/or paragangliomas (PGLs) are a challenge to diagnose during pregnancy because of elusive signs and testing difficulties. We report a 25-year-old woman with no pertinent medical history who presented to the hospital with hypertension, vision loss, and weakness and was initially diagnosed with preeclampsia. Imaging showed hemangioblastomas in the medulla and thoracic spine, pancreatic cysts, and a renal cyst. The endocrinology service was consulted for possible PCCs associated with von Hippel-Lindau disease (VHL). Serum and urine normetanephrine levels were elevated despite the lack of overt PCCs/PGLs seen on magnetic resonance imaging and magnetic resonance angiography. The patient was medically managed with doxazosin and then labetalol. Despite successful resection of the hemangioblastoma in the medulla, the patient suffered respiratory distress requiring tracheostomy and venous-venous extracorporeal membrane oxygenation (V-V ECMO) and fetal demise. After 3 months, the patient was discharged to rehabilitation. Follow-up genetics were heterozygous for VHL and Lynch syndrome. DOTATATE positron emission tomography/computed tomography scan showed a small hepatic focus of a maximum standard uptake value of 12.1. Altogether, this case illustrates the importance of prompt diagnosis and proper management of PCCs/PGLs during pregnancy and incorporating genetic information during surveillance to lower morbidity and mortality.

8.
JCEM Case Rep ; 2(1): luad126, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38116162

RESUMO

Autoimmune diabetes mellitus (DM) due to pembrolizumab is a rare but reported complication of immune checkpoint inhibitors (ICIs). It is often missed for a long initial period, leading to unnecessary admissions and poor glucose management. We report a case of a 72-year-old woman with prior history of gastrointestinal stromal tumor (GIST) and current diagnosis of squamous cell carcinoma (SCC) of the lung, who upon presentation at the emergency department with symptoms of encephalopathy, was diagnosed as having sodium glucose cotransporter 2 inhibitor (SGLT-2i)-induced diabetic ketoacidosis (DKA). Upon further investigation, we learned that this patient had multiple hospitalizations for recurrent DKA over 2 years after being managed on metformin and SGLT-2i. Biochemical testing helped confirm pembrolizumab-induced autoimmune diabetes with significantly elevated glutamic acid decarboxylase-65 (GAD65) autoantibodies and an undetectable C-peptide level. The patient has had clinical improvement with insulin therapy without further DKA episodes. She continued to be managed by outpatient endocrinology with improved glucose control. Altogether, this case demonstrates the importance of keeping a high vigilance for possible new onset of autoimmune endocrine diseases, such as diabetes, in patients treated with ICIs, to enable earlier diagnosis and prompt initiation of correct therapy.

9.
Nutr Clin Pract ; 39(1): 86-99, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38213274

RESUMO

Total pancreatectomy with islet autotransplantation (TPIAT) is a surgical treatment option for patients with chronic pancreatitis who have not responded to other therapies. TP offers pain relief whereas IAT preserves beta cell mass to reduce endocrine insufficiency. During the surgical procedure, the entire pancreas is removed. Islet cells from the pancreas are then isolated, purified, and infused into the liver via the portal vein. Successful TPIAT relieves pain for a majority of patients but is not without obstacles, specifically gastrointestinal, exocrine, and endocrine challenges. The postoperative phase can be complicated by gastrointestinal symptoms causing patients to have difficulty regaining adequate oral intake. Enteral nutrition is frequently provided as a bridge to oral diet. Patients undergoing TPIAT must be monitored for macronutrient and micronutrient deficiencies following the procedure. Exocrine insufficiency must be treated lifelong with pancreatic enzyme replacement therapy. Endocrine function must be monitored and exogenous insulin provided in the postoperative phase; however, a majority of patients undergoing TPIAT require little or no long-term insulin. Although TPIAT can be a successful option for patients with chronic pancreatitis, nutrition-related concerns must be addressed for optimal recovery.


Assuntos
Transplante das Ilhotas Pancreáticas , Pancreatite Crônica , Humanos , Pancreatectomia/efeitos adversos , Transplante Autólogo , Transplante das Ilhotas Pancreáticas/métodos , Pancreatite Crônica/cirurgia , Pancreatite Crônica/complicações , Insulina , Dor/complicações , Dor/cirurgia , Resultado do Tratamento
10.
J Biol Chem ; 287(38): 32069-77, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-22815486

RESUMO

A major cause of fasting hyperglycemia in diabetes mellitus is unregulated hepatic glucose production (HGP). Insulin suppresses HGP by phosphorylating CBP and disassembling the CREB-CBP complex from gluconeogenic genes. p300 is closely related to CBP; but in contrast to CBP, p300 binds constitutively to CREB due to the absence of phosphorylation site found in CBP. In a phosphorylation-competent p300(G442S) knock-in mouse model, we demonstrate that HGP is now exquisitely sensitive to insulin suppression. p300(G422S) and hepatic-deleted p300 mice exhibited significant lower blood glucose levels in the fasted and post-prandial states, indicating a role for p300 in maintaining basal HGP.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Gluconeogênese , Fígado/metabolismo , Transcrição Gênica , Fatores de Transcrição de p300-CBP/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Glucose/metabolismo , Técnica Clamp de Glucose , Hepatócitos/metabolismo , Insulina/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação , Fosforilação , Regiões Promotoras Genéticas
11.
J Diabetes Res ; 2020: 9282310, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33426086

RESUMO

Chronic pancreatitis (CP) is a progressive disease that leads to eventual loss of endocrine and exocrine function. Total pancreatectomy and islet autotransplantation (TPIAT) is a treatment option for patients with CP; however, predicting postoperative metabolic outcomes remains elusive. In this single-center retrospective study, we report pre-TPIAT characteristics, beta cell function indices, islet yield, and post-TPIAT glucose management data to further understand their relationship. Islet yield, glucose level, and insulin requirement for 72 hours postoperatively were collected for a total of 13 TPIAT recipients between 9-2013 and 9-2018. In addition, their glucose control and basal insulin requirements at 3, 6, and 12 months post-TPIAT were analyzed. All 13 subjects had normal baseline fasting glucose levels. Median islet yield was 4882 IEq/kg (interquartile range 3412 to 8987). Median postoperative total insulin requirement on day 3 was 0.43 units/kg. Pre-TPIAT baseline glucose, insulin, or c-peptide level did not have a significant correlation with the islet yield. Similarly, there was no correlation between islet yield and insulin requirement at 72-hour postoperatively. However, there was an inverse correlation between the absolute islet yield (IEq) and insulin requirement at 6 months and 12 months following post-TPIAT. Further analysis of the relationship between 72-hour post-op insulin requirement and insulin requirement at discharge, 3, 6, and 12 months showed a positive correlation. Despite the finding of inverse correlation of islet yield with long-term basal insulin requirement, this study was not able to detect a correlation between the preoperative parameters to postoperative short-term or long-term outcome as noted in other studies. The 72-hour postoperative insulin requirement is a helpful postoperative predictor of patients needing long-term insulin management following TPIAT. This observation may identify a high-risk group of patients in need of more intensive diabetes education and insulin treatment prior to hospital discharge.


Assuntos
Glicemia/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/transplante , Insulina/uso terapêutico , Transplante das Ilhotas Pancreáticas , Pancreatectomia , Pancreatite Crônica/cirurgia , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Feminino , Humanos , Células Secretoras de Insulina/metabolismo , Transplante das Ilhotas Pancreáticas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ohio , Pancreatectomia/efeitos adversos , Pancreatite Crônica/diagnóstico , Estudos Retrospectivos , Fatores de Tempo , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
12.
Proc (Bayl Univ Med Cent) ; 37(4): 583, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38910829
13.
Thyroid ; 29(8): 1115-1124, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31154940

RESUMO

Background: The Afirma Gene Expression Classifier (GEC) has been used to further characterize cytologically indeterminate (cyto-I) thyroid nodules into either benign or suspicious categories. However, its relatively low positive predictive value (PPV) limited its use as a classifier for patients with suspicious results. The Afirma Gene Sequencing Classifier (GSC) was developed to improve PPV while maintaining a high negative predictive value (NPV), yet real-world assessment of its performance is lacking. Methods: We analyzed all patients who had cyto-I nodules and molecular testing with either GEC or GSC between 2011 and 2018 at a single academic medical center. Clinical information was obtained for 343 GEC-tested nodules and 164 GSC-tested nodules. Results: The GSC had a statistically significant higher benign call rate (76.2% vs. 48.1%, p < 0.001), PPV (60.0% vs. 33.3%, p = 0.01), and specificity (94.3% vs. 61.4%, p < 0.001) than the GEC. Improvement was statistically significant in both Bethesda III and Bethesda IV nodules. In particular, the benign call rate of GSC was significantly higher in nodules with Hürthle cell changes (88.8% vs. 25.7%, p < 0.01). The rate of surgical intervention in the indeterminate nodule cohort has decreased by 66.4% since switching to the GSC; 52.5% of indeterminate nodules went to surgery while using the GEC compared with 17.6% with the GSC (p < 0.001). This reduction was statistically significant in nodules with Bethesda III diagnoses, demonstrating a 70.9% decrease (GEC 51.3% vs. GSC 14.9%, p < 0.001), and in nodules with Bethesda IV cytology, a 39.2% decrease was noted (GEC 54.8% vs. GSC 33.3%, p = 0.003). Conclusions: Data from a single academic tertiary center show an improved specificity and PPV while maintaining high sensitivity and NPV for GSC compared with GEC. A statistically significant increase in benign call rates was observed in GSC compared with GEC, likely indicating fewer false positive results. After implementation of GSC, surgical interventions have been reduced by 68%.


Assuntos
Perfilação da Expressão Gênica , Análise de Sequência de DNA , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/genética , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Adenoma Oxífilo/diagnóstico , Adenoma Oxífilo/genética , Adenoma Oxífilo/patologia , Adulto , Idoso , Biópsia por Agulha Fina , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia
14.
Cell Transplant ; 27(10): 1569-1573, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30203686

RESUMO

Hepatic parenchymal disease, including chronic viral hepatitis, has traditionally been considered a relative contraindication to islet transplantation as the islets are infused into the recipient's liver. We present a case study of a patient with treated chronic hepatitis C infection (HCV) who safely received an autologous islet transplant following total pancreatectomy with excellent clinical outcomes. The patient was a 60-year-old woman diagnosed with debilitating abdominal pain secondary to chronic pancreatitis and with preserved islet function. She had previously been treated >10 years prior to surgical evaluation with interferon monotherapy for 1 year that led to sustained virologic response, including at the time of surgical evaluation for total pancreatectomy and islet autotransplantation (TPIAT). She underwent comprehensive preoperative evaluation of the liver, including liver biopsy, which showed no significant portal inflammation or fibrosis. Following a multidisciplinary meeting and discussion of the potential risks for the patient, the decision was made to proceed with TPIAT. The patient underwent a standard total pancreatectomy, and an autologous islet dose of 6638 islet equivalents/kg body weight was infused into the liver via the portal vein. Portal vein pressure was monitored throughout the infusion with a transient peak pressure of 27 cm H2O (basal pressure of 14 cm H2O) and final pressure of 23 cm H20 at 10 min post-infusion. Aside from a transient transaminitis, liver enzymes were normal at the time of hospital discharge. At greater than 1 year of follow-up, the patient has improved quality of life, with reduction in narcotic analgesia, remains insulin independent (with normal islet function), and has normal liver function. This case illustrates that islet autotransplant into the liver can be safely performed and suggests that carefully selected patients with liver disease may be eligible for TPIAT.


Assuntos
Hepatite C/complicações , Transplante das Ilhotas Pancreáticas/métodos , Pancreatectomia/métodos , Pancreatite Crônica/complicações , Pancreatite Crônica/terapia , Antivirais/uso terapêutico , Glicemia/análise , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C/sangue , Hepatite C/tratamento farmacológico , Humanos , Insulina/sangue , Interferons/uso terapêutico , Pessoa de Meia-Idade , Pancreatite Crônica/sangue , Transplante Autólogo/métodos
15.
J Endocrinol ; 221(3): 363-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24639469

RESUMO

Metformin is a first-line, anti-diabetic agent prescribed to over 150 million people worldwide. The main effect of metformin is to suppress glucose production in the liver; however, there is no reliable biomarker to assess the effectiveness of metformin administration. Our previous studies have shown that phosphorylation of CBP at S436 is important for the regulation of hepatic glucose production by metformin. In current study, we found that CBP could be phosphorylated in white blood cells (WBCs), and CBP phosphorylation in the liver and in WBCs of mice had a similar pattern of change during a fasting time course experiment. These data suggests that CBP phosphorylation in WBCs may be used as a biomarker of metformin action in the liver.


Assuntos
Biomarcadores/metabolismo , Proteína de Ligação a CREB/metabolismo , Hepatócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Metformina/farmacologia , Adolescente , Adulto , Animais , Proteína de Ligação a CREB/genética , Células Cultivadas , Jejum/sangue , Feminino , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Immunoblotting , Leucócitos/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Mutação , Obesidade/sangue , Fosforilação/efeitos dos fármacos , Serina/metabolismo
16.
Mol Endocrinol ; 27(8): 1322-32, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23770612

RESUMO

Because hepatic glycogenolysis maintains euglycemia during early fasting, proper hepatic glycogen synthesis in the fed/postprandial states is critical. It has been known for decades that gluconeogenesis is essential for hepatic glycogen synthesis; however, the molecular mechanism remains unknown. In this report, we show that depletion of hepatic p300 reduces glycogen synthesis, decreases hepatic glycogen storage, and leads to relative hypoglycemia. We previously reported that insulin suppressed gluconeogenesis by phosphorylating cAMP response element binding protein-binding protein (CBP) at S436 and disassembling the cAMP response element-binding protein-CBP complex. However, p300, which is closely related to CBP, lacks the corresponding S436 phosphorylation site found on CBP. In a phosphorylation-competent p300G422S knock-in mouse model, we found that mutant mice exhibited reduced hepatic glycogen content and produced significantly less glycogen in a tracer incorporation assay in the postprandial state. Our study demonstrates the important and unique role of p300 in glycogen synthesis through maintaining basal gluconeogenesis.


Assuntos
Gluconeogênese/fisiologia , Glicogênio Hepático/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Glicemia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Hipoglicemia/genética , Fígado/metabolismo , Glicogênio Hepático/biossíntese , Camundongos , Período Pós-Prandial/fisiologia , Interferência de RNA , RNA Interferente Pequeno , Fatores de Transcrição de p300-CBP/deficiência
17.
Am J Nephrol ; 25(4): 311-7, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15956781

RESUMO

Reactive oxygen species (ROS) are elevated in humans with hypertension many of which develop end-stage renal disease (ESRD), and antioxidant capacity is decreased. About one-half of essential hypertensives have a salt-sensitive type of hypertension, and the amount of renal damage that occurs in salt-sensitive hypertensives greatly exceeds that of non-salt-sensitive hypertensives. Antioxidant therapy can improve cardiovascular outcomes in humans but only if sufficient doses are used. Salt-sensitive hypertensive animal models, especially Dahl salt-sensitive rats, have been used to investigate the relationship between hypertension, ROS and end-stage renal damage. In experimental salt-sensitive hypertension, ROS increase and significant renal damage occur. In the Dahl salt-sensitive (S) rat on high Na for 3 weeks, renal damage is mild, renal levels of superoxide dismutase are decreased, and treatment with Tempol reduces arterial pressure. In the Dahl S rat on high Na for 5 weeks, renal damage is severe, GFR and renal plasma flow are decreased, and renal superoxide production is high. Treatment with vitamins C and E decreases renal superoxide production and renal damage and prevents the decrease in renal hemodynamics. Antioxidant treatment reduces arterial pressure, aortic superoxide production and renal inflammation in DOCA-salt rats, and decreases blood pressure and aortic superoxide release and increases bioactive nitric oxide in SHR stroke-prone rats. In conclusion, in both human and experimental salt-sensitive hypertension, superoxide production and renal damage are increased, antioxidant capacity is decreased, and antioxidant therapy can be helpful.


Assuntos
Antioxidantes/uso terapêutico , Hipertensão/complicações , Falência Renal Crônica/etiologia , Estresse Oxidativo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Falência Renal Crônica/fisiopatologia , Modelos Animais , Ratos , Espécies Reativas de Oxigênio , Sais/efeitos adversos , Sódio na Dieta/efeitos adversos
18.
Hypertension ; 41(6): 1346-52, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12719439

RESUMO

The role of oxidative stress in the long-term regulation of arterial pressure, renal hemodynamics, and renal damage was studied in Dahl salt-sensitive rats. Twenty-eight Dahl S/Rapp strain rats, equipped with indwelling arterial and venous catheters, were subjected to a 3-week intravenous infusion of either low Na (0.9 mmol/d) or high Na (20.6 mmol/d) or the superoxide dismutase mimetic, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), at 125 micromol x kg(-1) x h(-1) plus low Na or high Na. After 21 days, mean arterial pressure was 140+/-3 mm Hg in the high-Na group, 118+/-1 mm Hg (P<0.05) in the high-Na/Tempol group, and unchanged in the low-Na/Tempol and low-Na groups. Tempol did not change renal blood flow, glomerular filtration rate, or glomerular cross-sectional area in rats subjected to the high-Na intake but did decrease urinary protein excretion, the percentage of sclerotic glomeruli, and the kidney weight to body weight ratio. In 15 additional Dahl S rats subjected to high or low Na intake for 3 weeks, renal cortical and medullary O2*- release increased significantly in the high-Na group when compared with the low-Na group. Tempol decreased both renal cortical and medullary O2*- release in the high- and low-Na rats, but the decrease in O2*- release was greater in high-Na rats. The data suggest that oxidative stress contributes to Dahl salt-sensitive hypertension and the accompanying renal damage.


Assuntos
Hipertensão/etiologia , Estresse Oxidativo , Animais , Pressão Sanguínea/efeitos dos fármacos , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/fisiopatologia , Infusões Intravenosas , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Glomérulos Renais/patologia , Masculino , Proteinúria/diagnóstico , Ratos , Ratos Endogâmicos Dahl , Esclerose , Sódio/urina , Marcadores de Spin , Superóxidos/metabolismo , Urina
19.
Am J Physiol Regul Integr Comp Physiol ; 283(3): R732-8, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12185008

RESUMO

The roles of oxidative stress and renal superoxide dismutase (SOD) levels and their association with renal damage were studied in Dahl salt-sensitive (S) and salt-resistant (R)/Rapp strain rats during changes in Na intake. After 3 wk of a high (8%)-Na diet in S rats, renal medullary Cu/Zn SOD was 56% lower and Mn SOD was 81% lower than in R high Na-fed rats. After 1, 2, and 3 wk of high Na, urinary excretion of F(2)-isoprostanes, an index of oxidative stress, was significantly greater in S rats compared with R rats. Plasma F(2)-isoprostane concentration increased in the 2-wk S high Na-fed group. After 3 wk, renal cortical and medullary superoxide production was significantly increased in Dahl S rats on high Na intake, and urinary protein excretion, an index of renal damage, was 273 +/- 32 mg/d in S high Na-fed rats and 35 +/- 4 mg/d in R high Na-fed rats (P < 0.05). In conclusion, salt-sensitive hypertension in the S rat is accompanied by marked decreases in renal medullary SOD and greater renal oxidative stress and renal damage than in R rats.


Assuntos
Córtex Renal/enzimologia , Medula Renal/enzimologia , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo , Animais , Antioxidantes/metabolismo , Dieta Hipossódica , F2-Isoprostanos/sangue , F2-Isoprostanos/urina , Hipertensão Renal/metabolismo , Masculino , Proteinúria/metabolismo , Ratos , Ratos Endogâmicos Dahl , Espécies Reativas de Oxigênio/metabolismo , Sódio na Dieta/farmacologia
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