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An 80-year-old Japanese woman had shown no indication of diabetes but regularly saw a primary-care physician for health management. Six months before her referral to our hospital, her HbA1c was 6.0%. She was referred to us for diabetic ketosis because she was urine ketone body-positive with a blood glucose level of 397 mg/dL and HbA1c of 14.6%. She was diagnosed with type 1 diabetes mellitus (T1DM) with glutamic acid decarboxylase (GAD) antibodies >2,000 U/mL (by ELISA) and IA-2 antibodies >30 U/mL. Insulin injections were introduced, and she was discharged. Laboratory tests during her hospitalization were negative for thyroid antibodies (TgAb, TPOAb). Elderly individuals with first-onset T1DM who are positive for IA-2 antibody are rare, and multiple-positive cases of pancreatic islet-associated autoantibodies are particularly rare. IA-2 antibodies have an approx. 60% positive rate in acute-onset T1DM, but they are more likely to be positive in children and adolescents and are known to turn negative earlier than anti-GAD antibodies. Although a large amount of insulin is needed in general in such cases, our patient was successfully treated with a small amount of insulin. IA-2 antibody has been reported to be positive even in GAD antibody-negative individuals. In some cases, IA-2 antibody and other antibodies are positive even in elderly-onset diabetes, and this contributes to the diagnosis of T1DM.
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Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Humanos , Niño , Femenino , Adolescente , Anciano , Anciano de 80 o más Años , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada , Autoanticuerpos , Insulina/uso terapéutico , Glutamato DescarboxilasaRESUMEN
Aims: Self-monitoring of blood glucose is a useful method for monitoring blood glucose. It is often a key role of a management plan to reduce glycemic variability and diabetic complications. Wireless monitoring systems to connect blood glucose and insulin pumps can facilitate glycemic control. In this study, we evaluated the accuracy of Contour® Next Link 2.4, a blood glucose monitoring system that cooperates wirelessly with most insulin pumps, in Japanese individuals. Methods: In this study, finger-stick samples from 59 individuals were collected at the Tokyo Saiseikai Central Hospital. Blood glucose concentrations were measured with the monitoring systems against an available reference. We evaluated the accuracy of the system based on the ISO 15197:2013 Section 6.3 accuracy criteria. Results: In the present study, 100% of the results fulfilled the ISO 15197:2013 Section 6.3 accuracy criteria (95% within ± 15 mg/dL or ± 15% of reference for glucose < 100 and ≥ 100 mg/dL, respectively). The Parkes-Consensus Error Grid analysis showed that 100% of the results fulfilled within Zone A. Conclusions: The Contour® Next Link 2.4 blood glucose monitoring system fulfilled the ISO 15197:2013 accuracy criteria limit and the consensus error grid criterion. Therefore, this monitoring system for observing blood glucose levels is accurate for Japanese individuals.
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Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene. Patients with ALD show progressive central nervous system demyelination and primary adrenal insufficiency. In Japan, most reported ALD cases were childhood-onset, and only one case of an adult patient with Addison's disease form of ALD has ever been reported. Herein, we present a case of a 29-year-old man with Addison's disease form of ALD. The patient had anorexia, weight loss, and skin pigmentation from 18 years of age. At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old. Endocrinological examination showed low serum cortisol (1.2 µg/dL) with high plasma ACTH (4,750 pg/mL), and abdominal computed tomography showed normal adrenal glands. Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state. He had no significant neurological findings on physical examination and no white matter lesions on brain magnetic resonance imaging (MRI). He was diagnosed with ALD presenting as Addison's disease, and glucocorticoid replacement therapy was initiated. Four years after the diagnosis, he still did not show any neurological findings and any white matter lesions on brain MRI. Evaluating VLCFA levels for ALD diagnosis is important in young adult men with idiopathic primary adrenal insufficiency as well as in children. Early diagnosis enables more rational approaches including the early detection of neurological complications and might improve the prognosis of patients.
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Enfermedad de Addison/diagnóstico , Adrenoleucodistrofia/diagnóstico , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Enfermedad de Addison/complicaciones , Enfermedad de Addison/tratamiento farmacológico , Enfermedad de Addison/genética , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/patología , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/tratamiento farmacológico , Adrenoleucodistrofia/genética , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Diagnóstico Precoz , Glucocorticoides/administración & dosificación , Terapia de Reemplazo de Hormonas , Humanos , Hidrocortisona/administración & dosificación , MasculinoRESUMEN
This paper details the development of a precise assembly of two supermirrors for neutron-focusing, designed for installation in neutron reflectometer SOFIA at BL16 in J-PARC MLF to intensify the illumination for small samples. The supermirrors are sputtered on two metal substrates, whose surfaces are coated with amorphous Ni-P plating, and are figured by diamond cutting and polished to subnanometer roughness. Special care is taken while polishing the substrates to reduce waviness and surface roughness for achieving a sharp focusing spot and uniform neutron reflectivity. The supermirror could converge the neutrons into a focal spot with a width of 0.13 mm in the full width at half maximum.
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The characterization of radionuclides in Fukushima is important to determine their origins and current state in the environment. Radionuclides exist as fine particles and are mixed with other constituents. A measurement method with both micro-imaging capability and highly selective element detection is necessary to analyze these particles. We developed such an imaging technique using a time-of-flight secondary ion mass spectrometry and wavelength-tunable Ti:Sapphire lasers for the resonance ionization of target elements without mass interference. This is called resonant laser ionization sputtered neutral mass spectrometry. The instrument has a high lateral resolution and a higher ionization selectivity using two-step resonance excitation of Cs with two lasers at different wavelengths. Optimization of the wavelength for resonance ionization using a Cs compound was performed, and a real environmental particle containing radioactive Cs was analyzed. Isotope images of three kinds of Cs were successfully obtained without interfere from Ba isotopes for the first time.
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It is difficult to distinguish the onset of renal function decline from the typical variation in estimated glomerular filtration rate (eGFR) measurements in clinical practice. In this study, we used data analysis incorporating smoothing techniques to identify significant trends despite large amounts of noise. We identified the starting points of meaningful eGFR decline based on eGFR trajectories. This was a retrospective observational study of 2533 type 2 diabetes patients. We calculated 1-year eGFR decline rates from the difference between each eGFR value and that of the previous year. We examined the prediction capacity of 1-year eGFR decline rate for renal prognosis. When we performed receiver operating characteristic analysis, the area under the curve of 1-year eGFR decline rate was 0.963 (95% confidence interval: 0.953-0.973). With a cut-off value of more than 7.5% eGFR decline during a 1-year period, the sensitivity was 98.8% and specificity was 82.3%. The predictive accuracy of 1-year eGFR decline rate for renal prognosis was high.
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Diabetes Mellitus Tipo 2/complicaciones , Tasa de Filtración Glomerular , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Insuficiencia Renal/complicaciones , Estudios Retrospectivos , Factores de TiempoRESUMEN
This paper details methods for the precision design and fabrication of neutron-focusing supermirrors, based on electroless nickel plating. We fabricated an elliptic mirror for neutron reflectometry, which is our second mirror improved from the first. The mirror is a 550-millimeter-long segmented mirror assembled using kinematic couplings, with each segment figured by diamond cutting, polished using colloidal silica, and supermirror coated through ion-beam sputtering. The mirror was evaluated with neutron beams, and the reflectivity was found to be 68-90% at a critical angle. The focusing width was 0.17 mm at the full width at half maximum.
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AIMS: Hepatosteatosis is mainly induced by obesity and metabolic disorders, but various medications also induce hepatosteatosis. The administration of anti-CD3 antibody was shown to induce hepatosteatosis, but changes in lipid and glucose metabolism remain unclear. We investigated the mechanism of hepatosteatosis induced by anti-CD3 antibody and the effects of glucagon-like peptide-1 (GLP-1) receptor agonist that was recently shown to affect immune function in metabolic disorders. METHODS: Anti-CD3 antibody was administered to female BALB/c and C.B-17-scid mice with or without reconstitution by naïve CD4-positive splenocytes. Hepatic lipid content, serum lipid profile and glucose tolerance were evaluated. Splenic CD4-positive T lymphocytes were stimulated with the GLP-1R agonist, liraglutide, and cytokine production was measured. The effect of liraglutide on metabolic parameters in vivo was investigated in a T-cell activation-induced hepatosteatosis model. RESULTS: The administration of anti-CD3 antibody induced hepatosteatosis, hyperlipidemia, and glucose intolerance. C.B-17-scid mice reconstituted with CD4-positive T lymphocytes developed hepatosteatosis induced by anti-CD3 antibody. Liraglutide suppressed CD4-positive T lymphocyte cytokine expression in vitro and in vivo, and improved hepatosteatosis, glucose tolerance, and insulin sensitivity. CONCLUSIONS: Liraglutide suppressed the activation of CD4-positive T lymphocytes, and improved hepatosteatosis and metabolic disorders induced by T-cell activation in female mice.
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Anticuerpos/efectos adversos , Complejo CD3/inmunología , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Liraglutida/uso terapéutico , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Células Cultivadas , Femenino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones SCIDRESUMEN
Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.
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Ácido Aminolevulínico/administración & dosificación , Intolerancia a la Glucosa/tratamiento farmacológico , Fuerza Muscular/efectos de los fármacos , Sarcopenia/tratamiento farmacológico , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/genética , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/fisiopatología , Humanos , Ratones , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/metabolismo , Fuerza Muscular/fisiología , Resistencia Física/efectos de los fármacos , Factores de Riesgo , Sarcopenia/metabolismo , Sarcopenia/fisiopatologíaRESUMEN
BACKGROUND: Bile acid binding resin (BAR) absorbs intestinal bile acids, and improves obesity and metabolic disorders, but the precise mechanism remains to be clarified. Recent findings reveal that obesity is associated with skewed intestinal microbiota. Thus, we investigated the effect of BAR on intestinal microbiota and the role of microbiota in the prevention of obesity in high-fat diet-induced obesity in mice. PROCEDURES: Male Balb/c mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD with BAR (HFD+BAR), and then metabolic parameters, caecal microbiota, and metabolites were investigated. The same interventions were conducted in germ-free and antibiotic-treated mice. MAIN FINDINGS: The frequency of Clostridium leptum subgroup was higher in both HFD-fed and HFD+BAR-fed mice than in LFD-fed mice. The frequency of Bacteroides-Prevotella group was lower in HFD-fed mice than in LFD-fed mice, but the frequency was higher in HFD+BAR-fed mice than in HFD-fed mice. Caecal propionate was lower in HFD-fed mice than in LFD-fed mice, and higher in HFD+BAR-fed mice than in HFD-fed mice. HFD+BAR-fed mice showed lower adiposity than HFD-fed mice, and the reduction was not observed in germ-free or antibiotic-treated mice. Colonized germ-free mice showed a reduction in adiposity by BAR administration. Energy expenditure was lower in HFD-fed mice and higher in HFD+BAR-fed mice, but the increments induced by administration of BAR were not observed in antibiotic-treated mice. CONCLUSIONS: Modulation of intestinal microbiota by BAR could be a novel therapeutic approach for obesity.
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Ácidos y Sales Biliares/metabolismo , Resina de Colestiramina/farmacología , Grasas de la Dieta/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad/prevención & control , Animales , Carga Bacteriana , Bacteroides/efectos de los fármacos , Ciego/microbiología , Clostridium/efectos de los fármacos , Dieta Alta en Grasa , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Prevotella/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
Objective. The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods. The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results. The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area (r = -0.411, p < 0.0001), fasting glucose (r = -0.330, p < 0.0001), HbA1c (r = -0.231, p = 0.0146), and systolic blood pressure (r = -0.224, p = 0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR (r = -0.416, p < 0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion. We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.
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Glucemia/metabolismo , Distribución de la Grasa Corporal , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Grasos/metabolismo , Intolerancia a la Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Resistencia a la Insulina , Grasa Intraabdominal/diagnóstico por imagen , Grasa Subcutánea Abdominal/diagnóstico por imagen , Pueblo Asiatico , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Japón , Modelos Lineales , Ácido Linoleico/metabolismo , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
A 26-year-old Japanese woman presented with adrenal insufficiency, and treatment was started with cortisone and fludrocortisone in 1975. A few years later, she presented with hypoparathyroidism and was diagnosed with autoimmune polyendocrine syndrome type I (APS I), and treatment with calcium and alfacalcidol was started. She was found to have subacute thyroiditis and relative adrenal failure in 2006. Her condition remained stable under treatment with cortisone, fludrocortisone, levothyroxine, calcium lactate, precipitated calcium carbonate and alfacalcidol. While antibodies against pancreatic glutamic acid decarboxylase (GAD) were strongly positive (7,690 U/ml), fasting glucose level was 4.9 mmol/L and HbA1c was 6.3% on admission. As GAD antibody showed a high-titer of >10,000 U/ml and fasting plasma glucose level showed a rising trend, we performed 75-g oral glucose tolerance test (OGTT) 6 years after discharge. Whereas OGTT in 2012 showed impaired glucose tolerance, glucose tolerance had reverted to normal in 2014. A patient with a high-titer GAD antibody does not always have progressive glucose intolerance. GAD antibody positivity is common in not only type 1 diabetes, but also APS I and stiff-person syndrome (SPS). There are differences in recognized epitopes among the three disorders. Epitopes for GAD65 antibody associated with type 1 diabetes are located in the middle region and the COOH-terminal of the GAD65 protein, whereas epitopes associated with SPS reside in the NH2-terminal in addition to the middle region and COOH-terminal. The present case suggests that these differences in epitopes may be related to various pathogenic mechanisms including glucose intolerance.
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Autoanticuerpos/sangre , Glutamato Descarboxilasa/sangre , Poliendocrinopatías Autoinmunes/inmunología , Adulto , Glucemia/análisis , Epítopos/inmunología , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Poliendocrinopatías Autoinmunes/sangre , Poliendocrinopatías Autoinmunes/diagnóstico , Síndrome de la Persona Rígida/sangre , Síndrome de la Persona Rígida/diagnósticoRESUMEN
AIMS: Sufficient consultation time is important for establishing good doctor-patient relationship. We examined the factors that affect consultation length in Japanese diabetes practice. METHODS: This was a cross-sectional study performed at a diabetes clinic in central Tokyo, Japan. Regular diabetes consultations of 1197 patients with 22 physicians were analyzed. Consultation time and clinical characteristics were obtained from the electronic records. A negative binomial model, which included patient and physician characteristics, was constructed to examine the association of the variables with consultation length. RESULTS: Of the 1197 patients (mean age, 66; women, 25%; type 1 diabetes, 10%), the mean consultation time was 10.1min. In the multivariate model, longer consultation time was recorded in patients with type 1 diabetes, higher glycated hemoglobin (HbA1c), use of insulin injections, and use of hypnotics/anxiolytics. The consultation time was longer in patients with HbA1c of ⩾7.0 to <8.0% (⩾53 to <64mmol/mol), ⩾8.0 to <9.0% (⩾64 to <75mmol/mol) and ⩾9.0% (⩾75mmol/mol), compared to those with HbA1c of <7.0% (<53mmol/mol) with the ratios of 1.03 (95% confidence interval (CI)=0.96-1.10), 1.16 (95% CI=1.07-1.26) and 1.17 (95% CI=1.06-1.29), respectively. Body mass index was also associated with long consultation. Older and female physicians provided longer consultation. CONCLUSIONS: Clinical consultation length in diabetes practice was associated with certain patient and physician characteristics. The findings can be used for making diabetes consultation more efficacious, which could eventually lead to the provision of the most appropriate consultation time for individual patients.
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Diabetes Mellitus Tipo 1/terapia , Relaciones Médico-Paciente , Derivación y Consulta , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Insulina/sangre , Japón/epidemiología , Masculino , Persona de Mediana Edad , Derivación y Consulta/estadística & datos numéricos , Factores de Tiempo , Tokio/epidemiologíaRESUMEN
Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM), believed to be caused by ß-cell destruction through islet-cell autoimmunity, gradually progresses to an insulin-dependent state over time. Although the presence of anti-glutamic acid decarboxylase antibody (GADA) is required for the diagnosis of SPIDDM, a recent change in the GADA assay kit from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) yields mismatched GADA test results between the two kits, leading to confusion in understanding the pathological conditions of SPIDDM in Japan. Thus, this study aimed to clarify the difference in the clinical characteristics of GADA-ELISA-positive and GADA-ELISA-negative patients originally diagnosed as SPIDDM by GADA-RIA test. As a result, 42 of 63 original GADA-RIA-positive SPIDDM patients (66.7%) were found to be GADA-ELISA-positive, whereas the remaining 21 patients (33.3%) were found to be GADA-ELISA-negative. In patients with shorter disease duration, GADA-ELISA-positive patients showed significantly lower serum C-peptide levels than GADA-ELISA-negative patients. Meanwhile, in patients with longer disease duration, serum C-peptide levels were comparably decreased in GADA-ELISA-positive and GADA-ELISA-negative patients. A significant inverse correlation between serum C-peptide level and disease duration was observed in GADA-ELISA-negative patients, but not in GADA-ELISA-positive patients, suggesting that insulin secretory capacity may be gradually impaired over time also in GADA-ELISA-negative SPIDDM patients. In conclusion, physicians should be aware that GADA-ELISA-positive SPIDDM may be strongly associated with a future insulin-dependent state. Meanwhile, physicians should be careful in treating GADA-ELISA-negative SPIDDM patients diagnosed as type 2 DM, and cautiously follow the clinical course, in accordance with SPIDDM.
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Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Glutamato Descarboxilasa/inmunología , Insulina/uso terapéutico , Anciano , Autoinmunidad , Estudios Transversales , Diabetes Mellitus Tipo 1/patología , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoAsunto(s)
Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Fuerza de la Mano , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Anciano , Índice de Masa Corporal , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/sangre , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Factores de Riesgo , Transportador 2 de Sodio-Glucosa/metabolismo , Resultado del TratamientoRESUMEN
The objective was to clarify whether dietary palmitic acid supplementation affects glucose-stimulated insulin secretion (GSIS) and the endoplasmic reticulum (ER) stress pathway in pancreatic islets in mice. Eight-week-old male C57BL/6J mice were randomly divided into three treatment diet groups: control diet, palmitic acid-supplemented diet (PAL) and oleic acid-supplemented diet (OLE). After 2 weeks of treatment, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were performed. GSIS was assessed by pancreatic perfusion in situ with basal (100 mg/dL) glucose followed by a high (300 mg/dL) glucose concentration. We measured mRNA levels of ER stress markers such as C/EBP homologous protein (CHOP), immunoglobulin heavy-chain binding protein (BIP) and X-box binding protein (XBP)-1 using real-time polymerase chain reaction (PCR) analyses in isolated islets. Immunohistochemical staining was also performed. Mice fed PAL showed significantly decreased glucose tolerance (p < 0.05). In the perfusion study, GSIS was significantly suppressed in the PAL group (p < 0.05). Semi-quantitative RT-PCR revealed that islet CHOP, BIP, and XBP-1 mRNA expression were significantly increased in the PAL group (p < 0.05). TUNEL-positive ß-cells were not detected in all groups. Dietary palmitic acid-supplementation for 2 weeks might suppress GSIS and induce ER stress in pancreatic islets in mice, in the early stage of lipotoxicity.
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Grasas de la Dieta/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glucosa/farmacología , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Ácido Palmítico/farmacología , Animales , Dieta , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: This retrospective study evaluated the long-term efficacy of sitagliptin and the factors contributing to its glucose-lowering effect. METHODS: Six hundred and sixteen dipeptidyl peptidase-4 inhibitor-naïve outpatients with type 2 diabetes who began sitagliptin treatment between December 1, 2009 and December 31, 2011 were included in this study. The inclusion criteria were that the patient had regularly visited our hospital for a period of ≥700 days from the initiation of sitagliptin treatment and the measurement of hemoglobin A1c (HbA1c) had been performed at 0, 3, 6, 12, 18, and 24 months after the initiation of treatment. From the population of 616 patients, 447 and 169 had received sitagliptin for ≥700 and <700 days, respectively. The primary endpoint was ΔHbA1c at 24 months. The factors associated with the hypoglycemic effect of sitagliptin were also investigated. RESULTS: Sitagliptin treatment significantly decreased the level of HbA1c, and the hypoglycemic effect was sustained for at least 2 years. The baseline HbA1c level, duration of diabetes, Δbody weight value, and ΔHbA1c value at 3 months were independently associated with the hypoglycemic effect of sitagliptin. CONCLUSION: Sitagliptin has a long-term hypoglycemic effect in type 2 diabetes patients. A patient's ΔHbA1c at 3 months may be a predictor of their ΔHbA1c at 24 months.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Fosfato de Sitagliptina/uso terapéutico , Adulto , Peso Corporal , Diabetes Mellitus Tipo 2/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming one of the major therapeutic options for the treatment of type 2 diabetes mellitus (T2DM). This study was conducted as an exploratory analysis to clarify the effects of liraglutide, a GLP-1RA, on beta cell function, fat distribution and pancreas volume compared with metformin in Japanese overweight/obese patients with T2DM. METHODS: A subpopulation of the Keio study for Initial treatment of type 2 Diabetes with Liraglutide versus Metformin (KIND-LM) study participants (n = 20, 10 in oral metformin group and 10 in subcutaneous liraglutide group) who were enrolled at Keio University Hospital and underwent frequently sampled mixed meal tolerance test (MTT) and abdominal computed tomography (CT) at weeks 0 and 24 were included in this analysis. The patients were treated with either metformin or liraglutide throughout the 24-week study period. RESULTS: Changes in glycemic parameters such as glycated hemoglobulin (HbA1c), glycated albumin and 1,5-anhydroglucitol at week 24 were comparable between the groups. An oral minimal model based on MTT revealed that static-phase beta cell responsiveness (Φ s) and static-phase disposition index were significantly increased at week 24 in the liraglutide group but not in the metformin group. There was no significant change in fat distribution as well as body weight at week 24 in either group. Serum amylase and lipase levels modestly but significantly increased in the liraglutide group during the study; however, there was no incidence of pancreatitis and pancreas volume was not changed in the liraglutide group. CONCLUSION: Liraglutide monotherapy for 24 weeks improved beta cell responsiveness with no change in either body weight or fat distribution. Further investigation is needed to clarify the mechanism by which liraglutide increases serum pancreatic enzymes. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ ); UMIN000004243.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/enzimología , Liraglutida/farmacología , Metformina/farmacología , Obesidad/complicaciones , Sobrepeso/complicaciones , Amilasas/sangre , Glucemia/efectos de los fármacos , Distribución de la Grasa Corporal , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diabetes Mellitus Tipo 2/patología , Esquema de Medicación , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Células Secretoras de Insulina/citología , Lipasa/sangre , Liraglutida/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Obesidad/tratamiento farmacológico , Tamaño de los Órganos/efectos de los fármacos , Sobrepeso/tratamiento farmacológico , Radiografía , Resultado del TratamientoRESUMEN
AIMS: Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. METHODS: Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for ≥6 months. RESULTS: BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. CONCLUSIONS: BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol-LXR-IRS2 pathway.
Asunto(s)
Ácidos y Sales Biliares/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Resistencia a la Insulina , Hígado/efectos de los fármacos , Animales , Ácidos y Sales Biliares/administración & dosificación , Glucemia/metabolismo , Colesterol/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Femenino , Humanos , Hígado/metabolismo , Receptores X del Hígado , Masculino , Ratones , Ratones Endogámicos , Persona de Mediana Edad , Receptores Nucleares Huérfanos/agonistas , Estudios Retrospectivos , Triglicéridos/sangreRESUMEN
AIMS: This retrospective study aimed to determine the hypoglycaemic effect of 2 years of sitagliptin administration in terms of changes in HbA1c and C-peptide immunoreactivity (CPR) index (plasma CPR [ng/mL]/glucose [mg/dL]×100). METHODS: The inclusion criteria for DPP-4 inhibitor-naive outpatients with type 2 diabetes (n=285) were: continuation of sitagliptin for ≥700 days from initial administration and measurement of HbA1c, serum CPR, and plasma glucose levels at 0, 3, 6, 12, 18, and 24 months after sitagliptin initiation. Logistic regression analyses determined the factors contributing to the response to sitagliptin, based on responder (ΔHbA1c ≤-0.4% [≤-4 mmol/mol]) and non-responder (ΔHbA1c >-0.4% [>-4 mmol/mol]) groups. RESULTS: The HbA1c level decreased and CPR index increased from baseline to 3, 6, 12, 18, and 24 months after the start of sitagliptin administration (HbA1c: 7.4 ± 0.8% [57 ± 9 mmol/mol], 7.3 ± 0.9% [57 ± 9 mmol/mol], 7.4 ± 0.9% [58 ± 10 mmol/mol], 7.1 ± 0.8% [55 ± 9 mmol/mol], and 7.3 ± 0.9% [57 ± 10 mmol/mol], respectively, all P<0.001 vs. baseline [8.0 ± 1.0%, 64 ± 11 mmol/mol] and CPR index: 1.69 ± 0.96, 1.71 ± 1.10, 1.62 ± 0.96, 1.64 ± 0.92, and 1.66 ± 0.96, respectively, all P<0.05 vs. baseline [1.47 ± 0.81]). Higher baseline HbA1c level, shorter diabetes duration, and greater CPR index increase after sitagliptin administration were associated with the response to sitagliptin. CONCLUSIONS: Our results suggest that sitagliptin improves glycaemic control via an improved intrinsic insulin response.