RESUMO
Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.
Assuntos
Genética Médica , Genoma , Genômica , Pesquisa , Bases de Dados Genéticas , Revelação , Genômica/métodos , Humanos , Japão , Farmacogenética , Projetos Piloto , Projetos de PesquisaRESUMO
BACKGROUND: A high-molecular-weight form of insulin-like growth factor-2 (IGF-2), known as "big" IGF-2, is occasionally produced by various tumor types, leading to hypoglycemia. Although solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, it has been estimated that 4-6% of SFT patients develop hypoglycemia due to circulating big IGF-2. The mean time elapsed from tumor detection until the onset of hypoglycemia is reportedly less than one year (8.5 ± 1.9 months). CASE PRESENTATION: A 68-year-old man was hospitalized for exacerbation of recurring hypoglycemic episodes. He had been diagnosed with an SFT 17 years before the onset of hypoglycemia, and the SFT had already been very large at that time. The tumor, which was non-resectable and refractory to chemotherapies, had slowly increased in size since the initial diagnosis. Half a year before the hypoglycemic episodes manifested, another tumor, adjacent to the left kidney, was newly identified. Fluorodeoxyglucose positron emission tomography-computed tomography scanning, revealed the left peri-renal tumor to show much higher fluorodeoxyglucose uptake than the preexisting SFT, suggesting that it was unlikely to be a metastasis from the SFT. Abundant serum big IGF-2 was detected by western immunoblot analysis, indicating it to be the cause of the hypoglycemia. Since the 17 years between SFT detection and the onset of IGF-2-induced hypoglycemia was an extremely long period as compared with those in previous reports, we initially suspected that the new, peri-renal tumor had produced big IGF-2, but transcatheter arterial embolization of its feeding arteries did not suppress hypoglycemia. Notably, by measuring the tumor volume doubling time, the peri-renal tumor growth was shown to be markedly accelerated in parallel with exacerbation of the hypoglycemia. The patient died of heart failure 21 months after the onset of hypoglycemia. Unexpectedly, autopsy revealed that big IGF-2 had been produced only by the preexisting SFT, not the peri-renal tumor, and that the peri-renal tumor was a dedifferentiated liposarcoma. CONCLUSIONS: We should keep in mind that even a long-inactive SFT can undergo transformation to produce big IGF-2, which then acts on both insulin and IGF-1 receptors, possibly leading to both hypoglycemia and the development/growth of another tumor, respectively.
Assuntos
Hipoglicemia/patologia , Fator de Crescimento Insulin-Like II/metabolismo , Lipossarcoma/patologia , Tumores Fibrosos Solitários/complicações , Idoso , Humanos , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Lipossarcoma/etiologia , Lipossarcoma/metabolismo , Masculino , Prognóstico , Tumores Fibrosos Solitários/metabolismoRESUMO
AIM: Macrovesicular steatosis around the central vein (zone 3) is one of the pathological features of non-alcoholic fatty liver disease or steatohepatitis (NAFLD/NASH). The aim of this study is to elucidate precisely the association between the area of lipid droplets (LDs) and the plasma metabolic parameters in patients with NAFLD/NASH. METHODS: Eighty patients with NAFLD/NASH diagnosed by needle biopsy were enrolled. The LDs around zone 3 were counted automatically by image processing software, the total area of LDs (TLDs), the maximum area of LDs (MAXLDs), the average area of LDs (AVELDs) and the heterogeneity by the coefficient of variation (CV [%]) were quantified. The correlations between these values and plasma metabolic parameters were analyzed. We evaluated the association between branched chain amino acids (BCAAs) and the heterogeneity of LDs in hepatocytes in vitro and in vivo. RESULTS: The MAXLDs was significantly correlated with more metabolic parameters than AVELDs and TLDs. The level of BCAAs was independently associated with the CV among the metabolic parameters. In early stage NAFLD, aspartate and alanine aminotransferase were significantly higher in the high CV group than in the low CV group. The high concentration of BCAAs increased the CV of LDs in hepatocytes accompanied by the expression of phosphor-p70 S6 kinase and sterol regulatory element-binding protein 1 in vitro. A high BCAA diet induced high heterogeneity of LDs around zone 3 in ob/ob mice. CONCLUSIONS: The levels of BCAAs were associated with the LD heterogeneity of hepatocytes around zone 3 in patients with NAFLD/NASH.
RESUMO
BACKGROUND: Insulin injection, especially with insulin analogs, occasionally induces the production of insulin antibodies with high binding capacity and low affinity, similar to the insulin autoantibodies characteristic of insulin autoimmune syndrome (IAS). Production of these "IAS-like" insulin antibodies causes marked glycemic fluctuations with postprandial hyperglycemia and fasting hypoglycemia. CASE PRESENTATION: A 66-year-old man with a 27-year history of diabetes was admitted because of marked glycemic fluctuations. Human insulin treatment had been initiated at age 56, followed by multiple daily injections of insulin analogs 5 years later. After the initial year of insulin analog treatment, the patient began to experience frequent morning hypoglycemic attacks and day-time hyperglycemia. Marked hyperinsulinemia (4500 µU/mL) and high titers of insulin antibodies (80.4%) with high binding capacity and low affinity indicated that IAS-like insulin antibodies were causing severe glucose fluctuations. Altering insulin formulations (insulin aspart â regular human insulinâ insulin lispro) proved to be ineffective. After several therapeutic trials, cessation of exogenous insulin and addition of mitiglinide to liraglutide with voglibose finally attenuated glycemic fluctuations with increased postprandial insulin secretion. Continuous glucose monitoring revealed improvement of morning hypoglycemia and postprandial hyperglycemia with smaller mean amplitude of glycemic excursion. Therefore, compared to exogenously injected insulin, endogenously secreted insulin directly and rapidly acts on hepatocytes and suppresses postprandial glucose output. CONCLUSIONS: Proper enhancement of postprandial endogenous insulin aimed at suppressing postprandial glucose output without stimulating excessive glucose uptake in the periphery is potentially useful for treating diabetes with insulin antibody-induced glycemic instability.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Secreção de Insulina , Insulina/sangue , Período Pós-Prandial , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Quimioterapia Combinada , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hiperglicemia/etiologia , Hipoglicemia/etiologia , Inositol/análogos & derivados , Inositol/uso terapêutico , Insulina/uso terapêutico , Anticorpos Anti-Insulina/sangue , Isoindóis/uso terapêutico , Liraglutida/uso terapêutico , Masculino , Resultado do TratamentoRESUMO
Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1-3 litters of sweet beverages daily to quench his thirst. Therefore, "soft-drink diabetic ketosis" was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.
Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Cetoacidose Diabética/diagnóstico , Hipertrigliceridemia/diagnóstico , Xantomatose/diagnóstico , Ácido 3-Hidroxibutírico/sangue , Acetoacetatos/sangue , Adolescente , Apolipoproteína E2 , Apolipoproteína E4 , Bebidas Gaseificadas/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Cetoacidose Diabética/tratamento farmacológico , Cetoacidose Diabética/etiologia , Cetoacidose Diabética/metabolismo , Dieta com Restrição de Gorduras , Hemoglobinas Glicadas/metabolismo , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/dietoterapia , Hipertrigliceridemia/metabolismo , Hipoglicemiantes/uso terapêutico , Inositol/análogos & derivados , Inositol/uso terapêutico , Insulina/uso terapêutico , Cetose/diagnóstico , Cetose/etiologia , Masculino , Metformina/uso terapêutico , Obesidade/complicações , Obesidade/metabolismo , Xantomatose/etiologia , Xantomatose/patologiaRESUMO
Hypothalamic obesity is a clinical syndrome characterized by severe and refractory obesity that is caused by hypothalamic function impairment. Recently, bariatric surgery has been attempted for patients with hypothalamic obesity after craniopharyngioma, but experiences have not yet been accumulated in other hypothalamic disorders. Here, we report the case of a 39-year-old male patient with panhypopituitarism who received laparoscopic sleeve gastrectomy (LSG) after intracranial germinoma treatment. The patient was diagnosed with intracranial germinoma at age 15 and achieved complete remission after radiotherapy (total 50 Gy). He was obese during diagnosis [body mass index (BMI), 29.2 kg/m2], and his obesity gradually worsened after the intracranial germinoma treatment, and LSG was considered when his BMI was 48.6 kg/m2. After 1 month of hospitalized diet-exercise program, LSG was performed. After LSG, his BMI gradually decreased and reached 38.8 kg/m2 on the day of discharge (6 weeks after the surgery). Five months after LSG, his insulin resistance improved, but insulin hypersecretion remained. Fifteen months after the surgery, his BMI was 31.2 kg/m2, with marked decrease in visceral and subcutaneous fat areas (from 393.8 cm2 and 168.2 cm2 before the surgery to 111.5 cm2 and 56.3 cm2, respectively.). To our knowledge, this is the first case of LSG for hypothalamic obesity after intracranial germinoma treatment. Although the pathophysiology of hypothalamic obesity is different from that of primary obesity, LSG could be a successful therapeutic choice for patients with hypothalamic obesity after the intracranial germinoma treatment.
Assuntos
Neoplasias Encefálicas/radioterapia , Gastrectomia , Germinoma/radioterapia , Laparoscopia , Obesidade Mórbida/cirurgia , Adolescente , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Neoplasias Encefálicas/sangue , Germinoma/sangue , Teste de Tolerância a Glucose , Hospitalização , Humanos , Testes de Inteligência , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/patologia , Masculino , Obesidade Mórbida/sangue , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND & AIMS: Hypoxia-inducible factor 1α subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD increases the risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis. METHODS: We performed studies with mice with inducible disruption of Hif1a in hepatocytes via a Cre adenoviral vector (inducible hepatocyte-selective HIF1A knockout [iH-HIFKO] mice), and mice without disruption of Hif1a (control mice). Mice were fed a diet rich in cholesterol and cholate for 1 or 2 weeks; gallbladders were collected and the number of gallstones was determined. Livers and biliary tissues were analyzed by histology, quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunoblots. We measured concentrations of bile acid, cholesterol, and phospholipid in bile and rates of bile flow. Primary hepatocytes and cholangiocytes were isolated and analyzed. HIF1A was knocked down in Hepa1-6 cells with small interfering RNAs. Liver biopsy samples from patients with NAFLD, with or without gallstones, were analyzed by quantitative reverse-transcription polymerase chain reaction. RESULTS: Control mice fed a diet rich in cholesterol and cholate developed liver steatosis with hypoxia; levels of HIF1A protein were increased in hepatocytes around central veins and 90% of mice developed cholesterol gallstones. Only 20% of the iH-HIFKO mice developed cholesterol gallstones. In iH-HIFKO mice, the biliary lipid concentration was reduced by 36%, compared with control mice, and bile flow was increased by 35%. We observed increased water secretion from hepatocytes into bile canaliculi to mediate these effects, resulting in suppression of cholelithogenesis. Hepatic expression of aquaporin 8 (AQP8) protein was 1.5-fold higher in iH-HIFKO mice than in control mice. Under hypoxic conditions, cultured hepatocytes increased expression of Hif1a, Hmox1, and Vegfa messenger RNAs (mRNAs), and down-regulated expression of AQP8 mRNA and protein; AQP8 down-regulation was not observed in cells with knockdown of HIF1A. iH-HIFKO mice had reduced inflammation and mucin deposition in the gallbladder compared with control mice. Liver tissues from patients with NAFLD with gallstones had increased levels of HIF1A, HMOX1, and VEGFA mRNAs, compared with livers from patients with NAFLD without gallstones. CONCLUSIONS: In steatotic livers of mice, hypoxia up-regulates expression of HIF1A, which reduces expression of AQP8 and concentrates biliary lipids via suppression of water secretion from hepatocytes. This promotes cholesterol gallstone formation. Livers from patients with NAFLD and gallstones express higher levels of HIF1A than livers from patients with NAFLD without gallstones.
Assuntos
Colesterol/metabolismo , Cálculos Biliares/genética , Cálculos Biliares/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Aquaporinas/genética , Aquaporinas/metabolismo , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Colatos/administração & dosagem , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/metabolismo , Regulação para Baixo/genética , Feminino , Vesícula Biliar/patologia , Cálculos Biliares/patologia , Heme Oxigenase-1/genética , Hepatócitos/metabolismo , Humanos , Hipóxia/metabolismo , Inflamação/etiologia , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Mucinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , RNA Mensageiro/metabolismo , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética , Água/metabolismoRESUMO
BACKGROUND/OBJECTIVE: Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). SUBJECTS/METHODS: We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. RESULTS: In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. CONCLUSION: These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.
Assuntos
Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Biópsia , Estudos de Casos e Controles , Feminino , Humanos , Proteínas Substratos do Receptor de Insulina/análise , Proteínas Substratos do Receptor de Insulina/genética , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologiaRESUMO
Fulminant type 1 diabetes is characterized by remarkably rapid and complete ß-cell destruction. The established diagnostic criteria include the occurrence of diabetic ketosis soon after the onset of hyperglycemic symptoms, elevated plasma glucose with relatively low HbA1c at the first visit, and extremely low C-peptide. Serum C-peptide levels remain extremely low over a prolonged period. A 26-year-old-man with diabetic ketosis was admitted to our hospital. His relatively low HbA1c (7.6%), despite marked hyperglycemia (593 mg/dL) with marked ketosis, indicated abrupt onset. Islet-related autoantibodies were all negative. His data at onset, including extremely low serum C-peptide (0.11 ng/mL), fulfilled the diagnostic criteria for fulminant type 1 diabetes. However, his fasting serum C-peptide levels subsequently showed substantial recovery. While fasting C-peptide stayed below 0.30 ng/mL during the first two months post onset, the levels gradually increased and thereafter fluctuated between 0.60 ng/mL and 0.90 ng/mL until 24 months post onset. By means of multiple daily insulin injection therapy, his glycemic control has been well maintained (HbA1c approximately 6.0%), with relatively small glycemic fluctuations evaluated by continuous glucose monitoring. This clinical course suggests that, despite the abrupt diabetes onset with extremely low C-peptide levels, substantial numbers of ß-cells had been spared destruction and their function later showed gradual recovery. Diabetes has come to be considered a much more heterogeneous disease than the present subdivisions suggest. This case does not fit into the existing concepts of either fulminant type 1 or ketosis-prone diabetes, thereby further highlighting the heterogeneity of idiopathic type 1 diabetes.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Cetoacidose Diabética/terapia , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adulto , Glicemia/análise , Peptídeo C/sangue , Terapia Combinada , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Cetoacidose Diabética/prevenção & controle , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Insulina/uso terapêutico , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Japão , Masculino , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BTB and CNC homology 1 (Bach1) is a transcriptional repressor of antioxidative enzymes, such as heme oxygenase-1 (HO-1). Oxidative stress is reportedly involved in insulin secretion impairment and obesity-associated insulin resistance. However, the role of Bach1 in the development of diabetes is unclear. HO-1 expression in the liver, white adipose tissue, and pancreatic islets was markedly upregulated in Bach1-deficient mice. Unexpectedly, glucose and insulin tolerance tests showed no differences in obese wild-type (WT) and obese Bach1-deficient mice after high-fat diet loading for 6 wk, suggesting minimal roles of Bach1 in the development of insulin resistance. In contrast, Bach1 deficiency significantly suppressed alloxan-induced pancreatic insulin content reduction and the resultant glucose elevation. Furthermore, TUNEL-positive cells in pancreatic islets of Bach1-deficient mice were markedly decreased, by 60%, compared with those in WT mice. HO-1 expression in islets was significantly upregulated in alloxan-injected Bach1-deficient mice, whereas expression of other antioxidative enzymes, e.g., catalase, superoxide dismutase, and glutathione peroxidase, was not changed by either alloxan administration or Bach1 deficiency. Our results suggest that Bach1 deficiency protects pancreatic ß-cells from oxidative stress-induced apoptosis and that the enhancement of HO-1 expression plays an important role in this protection.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Diabetes Mellitus/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Heme Oxigenase-1/metabolismo , Células Secretoras de Insulina/metabolismo , Estresse Oxidativo/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Glicemia/metabolismo , Diabetes Mellitus/enzimologia , Heme Oxigenase-1/genética , Histocitoquímica , Marcação In Situ das Extremidades Cortadas , Insulina/sangue , Células Secretoras de Insulina/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Chronic stress is well known to affect metabolic regulation. However, molecular mechanisms interconnecting stress response systems and metabolic regulations have yet to be elucidated. Various physiological processes, including glucose/lipid metabolism, are regulated by the circadian clock, and core clock gene dysregulation reportedly leads to metabolic disorders. Glucocorticoids, acting as end-effectors of the hypothalamus-pituitary-adrenal (HPA) axis, entrain the circadian rhythms of peripheral organs, including the liver, by phase-shifting core clock gene expressions. Therefore, we examined whether chronic stress affects circadian expressions of core clock genes and metabolism-related genes in the liver using the chronic mild stress (CMS) procedure. In BALB/c mice, CMS elevated and phase-shifted serum corticosterone levels, indicating overactivation of the HPA axis. The rhythmic expressions of core clock genes, e.g., Clock, Npas2, Bmal1, Per1, and Cry1, were altered in the liver while being completely preserved in the hypothalamic suprachiasmatic nuculeus (SCN), suggesting that the SCN is not involved in alterations in hepatic core clock gene expressions. In addition, circadian patterns of glucose and lipid metabolism-related genes, e.g., peroxisome proliferator activated receptor (Ppar) α, Pparγ-1, Pparγ-coactivator-1α, and phosphoenolepyruvate carboxykinase, were also disturbed by CMS. In contrast, in C57BL/6 mice, the same CMS procedure altered neither serum corticosterone levels nor rhythmic expressions of hepatic core clock genes and metabolism-related genes. Thus, chronic stress can interfere with the circadian expressions of both core clock genes and metabolism-related genes in the liver possibly involving HPA axis overactivation. This mechanism might contribute to metabolic disorders in stressful modern societies.
Assuntos
Adaptação Fisiológica/fisiologia , Proteínas CLOCK/metabolismo , Relógios Circadianos/fisiologia , Regulação da Expressão Gênica/fisiologia , Fígado/metabolismo , Estresse Fisiológico/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the synthesis of γ-aminobutyric acid (GABA). Anti-GAD antibodies (GADA) are associated with the progression of stiff person syndrome and other neurological diseases, as well as the immune-mediated (type 1) diabetes. GABA is one of the most widely distributed neurotransmitters, but the non-motor symptoms of GADA-positive patients are not well understood. Diabetes is increasingly recognized as a risk factor for dementia; however, the relationship between diabetes and dementia is controversial.The objective of this study was to assess cognitive function in patients with GADA-positive diabetes using subjects with GADA-negative type 2 diabetes as controls. METHODS: Twenty-one patients with GADA-positive diabetes (mean age 52.5 ± 12.3 years, mean duration 7.7 ± 6.6 years) and 19 control subjects with GADA-negative type 2 diabetes (mean age 53.4 ± 8.9 years, mean duration 12.5 ± 6.7) were included in the study. The subjects underwent extensive neuropsychological testing and brain MRI. RESULTS: The neuropsychological test scores were lower in the GADA-positive group than the control group (GADA-negative). Twelve subjects (57%) in the GADA group and 4 subjects (21%) in the control group had low performances (p = 0.027). No statistically significant differences were found between the GADA and control groups regarding demographics, diabetic severity cardiovascular risks, cerebral T2 hyperintensities, white matter volume and gray matter volume. CONCLUSIONS: Our study showed that GADA-positive diabetic patients have an increased risk of cognitive decline compared to patients with type 2 diabetes of comparable diabetic severity. It also showed that GADA may be associated with isolated cognitive decline in the absence of other neurological complications.
Assuntos
Anticorpos/metabolismo , Autoimunidade/fisiologia , Transtornos Cognitivos/imunologia , Transtornos Cognitivos/fisiopatologia , Glutamato Descarboxilase/imunologia , Adulto , Fatores Etários , Idoso , Análise de Variância , Encéfalo/patologia , Estudos de Casos e Controles , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/imunologia , Feminino , Humanos , Leucoencefalopatias , Imageamento por Ressonância Magnética , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Fibras Nervosas Mielinizadas/patologia , Exame Neurológico , Testes NeuropsicológicosAssuntos
Glucosídeos/uso terapêutico , Lipodistrofia/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose , Tiofenos/uso terapêutico , Adulto , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/etiologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Hemoglobinas Glicadas/análise , Humanos , Resistência à Insulina , Lipodistrofia/complicações , Lipodistrofia/congênito , MasculinoRESUMO
Sacubitril/valsartan, a novel therapy in chronic heart failure (CHF), inhibits the breakdown of various peptides. However, whether or not sacubitril/valsartan administration affects urinary C-peptide levels is unclear. We herein report a 70-year-old man with type 2 diabetes mellitus (T2DM) and hypertension coexisting with CHF and nephrotic syndrome. The patient's urinary C-peptide levels dramatically increased after sacubitril/valsartan administration and decreased after discontinuation of the drug. Furthermore, sacubitril/valsartan administration to five other patients with hypertension and T2DM markedly increased urinary C-peptide levels. Thus, the insulin secretory capacity of patients with T2DM receiving sacubitril/valsartan may be overestimated when their urinary C-peptide level is measured.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Hipertensão , Masculino , Humanos , Idoso , Peptídeo C , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Tetrazóis/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Valsartana , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Compostos de Bifenilo/uso terapêutico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Combinação de Medicamentos , Volume SistólicoRESUMO
Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter. Crossing these with tissue-specific Cre-expressing mice allows us to monitor the proliferation time course of pancreatic ß-cells, which are few in number and weakly proliferative, by measuring plasma luciferase activity. Physiological time courses, during obesity development, pregnancy and juvenile growth, as well as diurnal variation, of ß-cell proliferation, are clearly detected. Moreover, this strategy can be utilized for highly sensitive ex vivo screening for proliferative factors for targeted cells. Thus, these technologies may contribute to advancements in broad areas of biological and medical research.
Assuntos
Pesquisa Biomédica , Eritrócitos Anormais , Feminino , Gravidez , Animais , Camundongos , Aclimatação , Transporte Biológico , Proliferação de CélulasRESUMO
Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages.
Assuntos
Insulina , Leptina , Animais , Camundongos , Humanos , Leptina/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Peso Corporal , Hipotálamo/metabolismo , Camundongos Knockout , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Metabolismo Energético/genéticaRESUMO
The enhancement of insulin secretion and of the proliferation of pancreatic ß cells are promising therapeutic options for diabetes. Signals from the vagal nerve regulate both processes, yet the effectiveness of stimulating the nerve is unclear, owing to a lack of techniques for doing it so selectively and prolongedly. Here we report two optogenetic methods for vagal-nerve stimulation that led to enhanced glucose-stimulated insulin secretion and to ß cell proliferation in mice expressing choline acetyltransferase-channelrhodopsin 2. One method involves subdiaphragmatic implantation of an optical fibre for the photostimulation of cholinergic neurons expressing a blue-light-sensitive opsin. The other method, which suppressed streptozotocin-induced hyperglycaemia in the mice, involves the selective activation of vagal fibres by placing blue-light-emitting lanthanide microparticles in the pancreatic ducts of opsin-expressing mice, followed by near-infrared illumination. The two methods show that signals from the vagal nerve, especially from nerve fibres innervating the pancreas, are sufficient to regulate insulin secretion and ß cell proliferation.
RESUMO
BACKGROUND: The processes of arteriosclerosis, including atherosclerosis and vascular remodeling, are affected by interactions among numerous biological pathways such as responses to inflammation, oxidative stress, and endoplasmic reticulum stress. C/EBP homologous protein (CHOP), which is well known to induce cellular apoptosis in response to severe endoplasmic reticulum stress, is reportedly upregulated in plaque lesions. METHODS AND RESULTS: We examined the effects of CHOP deficiency on 2 types of arteriosclerosis: cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerosis. Cuff injury-induced neointimal formation was markedly inhibited in CHOP(-/-) mice with suppressed aortic expression of inflammatory factors and smooth muscle cell proliferation-related proteins. A CHOP deficiency also inhibited aortic plaque formation in hypercholesterolemic apolipoprotein E(-/-) mice with suppressed aortic expression of inflammatory factors and oxidative stress markers. Bone marrow transplantation experiments revealed that recipient CHOP deficiency significantly suppressed both cuff injury-induced neointimal formation and hypercholesterolemia-induced atherosclerotic plaque formation to a greater extent than donor CHOP deficiency, suggesting the importance of CHOP in vascular cells for arteriosclerosis progression. Furthermore, in our in vitro experiments, in not only macrophages but also endothelial and smooth muscle cell lines, endoplasmic reticulum stress inducers upregulated inflammation-, adhesion-, or smooth muscle cell proliferation-related proteins, whereas decreased CHOP expression remarkably suppressed endoplasmic reticulum stress-induced upregulation of these proteins. CONCLUSIONS: In addition to the well-known signaling for apoptosis induction, CHOP may play important roles in augmenting potentially pathological biological stress responses. This noncanonical role of CHOP, especially that expressed in vascular cells, may contribute to the progression of vascular remodeling and atherosclerosis.
Assuntos
Arteriosclerose , Retículo Endoplasmático/metabolismo , Estresse Fisiológico/fisiologia , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Animais , Apolipoproteínas E/genética , Arteriosclerose/genética , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Feminino , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neointima/genética , Neointima/metabolismo , Neointima/patologia , RNA Interferente Pequeno , Vasculite/genética , Vasculite/metabolismo , Vasculite/patologiaRESUMO
Insulin like growth factor-1 (IGF-1) plays important roles in metabolic functions, especially in adulthood. Additionally, obese subjects are reportedly predisposed to having low absolute IGF-1 levels. However, the prevalence and clinical characteristics of obese subjects with low IGF-1 levels are unknown. We examined 64 obese subjects with a body mass index (BMI) ≥ 35 kg/m2, with no history of endocrinological disorders, receiving inpatient care. IGF-1 levels were interpreted based on the IGF-1 standard deviation score (SDS) clinically used and standardized by age and sex (low IGF-1 group; ≤ - 2.0 SDS and standard IGF-1 group; - 2.0 < and < + 2.0 SDS). Notably, 26.6% of the subjects had low IGF-1. Body fat mass and percentage, but not BMI, were significantly higher in the low than in the standard IGF-1 group. Furthermore, natural log-transformed high-sensitivity C-reactive protein, and the frequencies of dyslipidemia and hyperuricemia were higher in the low IGF-1 group. Moreover, among the subjects without diabetes, fasting glucose levels were significantly higher in the low IGF-1 group. Stepwise variable selection procedure revealed body fat percentage to be a parameter most strongly associated with low IGF-1. Thus, low IGF-1 levels may be an important marker of adiposity-associated metabolic disorders in obese patients.
Assuntos
Fator de Crescimento Insulin-Like I , Doenças Metabólicas , Humanos , Adulto , Estudos Retrospectivos , Japão/epidemiologia , Doenças Metabólicas/complicações , Doenças Metabólicas/epidemiologia , Comorbidade , Obesidade/complicações , Obesidade/epidemiologiaRESUMO
AIMS: Some studies have reported changes in glycemic control of patients with diabetes mellitus under lockdown. However, no previous study examined the impact of the pandemic on glycemic control in patients with diabetes in countries that did not introduce a lockdown such as Japan. This study aimed to assess changes in glycemic control during the pandemic in patients with type 2 diabetes treated at a Japanese clinic. METHODS: We conducted a historical cohort study, using electronic medical records of patients with type 2 diabetes who visited our clinic between January 2019 and August 2020. Differences in HbA1c values before and after the outbreak of COVID-19 were the primary outcome, examined using the linear mixed model. RESULTS: HbA1c values significantly increased from 7.45% to 7.53% after the state of emergency was introduced (n = 1,009). Furthermore, a deterioration in HbA1c values was observed in particular among women, patients aged ≥ 65 years, those with body mass index of ≥ 25 kg/m2, and those that were not using insulin. CONCLUSIONS: Glycemic control deteriorated in patients with type 2 diabetes during the pandemic even in a country without a national lockdown.