RESUMO
BACKGROUND: While the Sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) are widely used for the glycemic control in type 2 diabetes mellitus, the differences in the effects of SGLT2 inhibitors and DPP4 inhibitors on energy intake and diabetes-related indicators are unclear. METHODS: This was a subanalysis of the CANTABILE study which compared the effects of canagliflozin and teneligliptin on metabolic factors in Japanese patients with Type 2 diabetes. The changes at 24 weeks from the baseline of the diabetes-related indicators including Hemoglobin A1c (HbA1c), energy intake and body weight were compared between the canagliflozin and teneligliptin groups. RESULTS: Seventy-five patients in the canagliflozin group and 70 patients in the teneligliptin group were analyzed. A significant decrease in HbA1c was observed in both groups. In the teneligliptin group, although energy intake was significantly reduced, there was no significant change in body weight. Conversely, in the canagliflozin group, although energy intake tended to increase, body weight significantly decreased. CONCLUSION: Canagliflozin and teneligliptin have different effects on the dietary status of patients with Type 2 diabetes. Our result suggests that canagliflozin can manage blood glucose without weight gain, even with increased energy intake.
Assuntos
Peso Corporal , Canagliflozina , Diabetes Mellitus Tipo 2 , Ingestão de Energia , Pirazóis , Inibidores do Transportador 2 de Sódio-Glicose , Tiazolidinas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Canagliflozina/uso terapêutico , Masculino , Feminino , Tiazolidinas/uso terapêutico , Pessoa de Meia-Idade , Pirazóis/uso terapêutico , Peso Corporal/efeitos dos fármacos , Idoso , Japão/epidemiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Hipoglicemiantes/uso terapêutico , Glicemia/análise , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , População do Leste AsiáticoRESUMO
BACKGROUND: Visceral fat area (VFA) is a good surrogate marker of obesity-related disorders, such as hypertension, dyslipidemia and glucose intolerance. Although estimating the VFA by X-ray computed tomography (CT) is the primary index for visceral obesity, it is expensive and requires invasive radiation exposure. Dual bioelectrical impedance analysis (BIA) is a simple and reliable method to estimate VFA; however, the clinical usefulness of dual BIA remains unclear in patients with type 2 diabetes (T2D). METHODS: We estimated the VFAs by dual BIA and CT in 98 patients with T2D and assessed anthropometric parameters, blood test results, and the presence of comorbid hypertension and dyslipidemia. We compared the correlation between the VFAs examined by dual BIA and CT. Furthermore, we performed the receiver operating characteristic (ROC) analyses for the VFAs to detect the presence of comorbid hypertension and/or dyslipidemia with T2D, which are major comorbidities of visceral obesity, and estimated the area under the curve (AUC). RESULTS: The measurement error between the VFAs by dual BIA and CT was significantly higher among patients with brain natriuretic peptide (BNP) ≥ 100 pg/mL than those with BNP < 100 pg/mL (39.2% ± 31.1% vs. 24.1% ± 18.6%, P < 0.05). After excluding patients with BNP ≥ 100 pg/mL, the VFA by dual BIA significantly correlated with the VFA by CT (r = 0.917; P < 0.0001). The AUC in the ROC analysis for the VFA by dual BIA to detect the presence of comorbid hypertension and/or dyslipidemia with T2D was almost equivalent to that for the VFA by CT. CONCLUSIONS: In patients with T2D without elevated BNP > 100 pg/mL as indicator for fluid accumulation interfering with BIA, estimation of the VFA by dual BIA significantly correlated with that by CT and also detected comorbid hypertension and/or dyslipidemia with T2D equivalent to those detected by CT. Hence, dual BIA could be an alternative to CT as a standard method for estimating the VFA in patients with diabetes.
Assuntos
Adiposidade , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Gordura Intra-Abdominal/fisiopatologia , Obesidade/diagnóstico , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Comorbidade , Diabetes Mellitus Tipo 2/diagnóstico , Dislipidemias/epidemiologia , Impedância Elétrica , Feminino , Humanos , Hipertensão/epidemiologia , Gordura Intra-Abdominal/diagnóstico por imagem , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Obesidade/epidemiologia , Obesidade/fisiopatologia , Valor Preditivo dos Testes , Prevalência , Reprodutibilidade dos Testes , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
Angiopoietin-like protein (ANGPTL)8 is a liver- and adipocyte-derived protein that controls plasma triglyceride (TG) levels. Most animal studies have used mouse models. Here, we generated an Angptl8 KO rat model using a clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) system to clarify the roles of ANGPTL8 in glucose and lipid metabolism. Compared with WT rats, Angptl8 KO rats had lower body weight and fat content, associated with impaired lipogenesis in adipocytes; no differences existed between the groups in food intake or rectal temperature. Plasma TG levels in both the fasted and refed states were significantly lower in KO than in WT rats, and an oral fat tolerance test showed decreased plasma TG excursion in Angptl8 KO rats. Higher levels of lipase activity in the heart and greater expression of genes related to ß-oxidation in heart and skeletal muscle were observed in Angptl8 KO rats. However, there were no significant differences between KO and WT rats in glucose metabolism or the histology of pancreatic ß-cells on both standard and high-fat diets. In conclusion, we demonstrated that Angptl8 KO in rats resulted in lower body weight and plasma TG levels without affecting glucose metabolism. ANGPTL8 might be an important therapeutic target for obesity and dyslipidemia.
Assuntos
Adiposidade/genética , Proteínas Semelhantes a Angiopoietina/genética , Sistemas CRISPR-Cas/genética , Técnicas de Inativação de Genes , Obesidade/genética , Triglicerídeos/sangue , Adipogenia/genética , Proteína 8 Semelhante a Angiopoietina , Animais , Sequência de Bases , Dieta/efeitos adversos , Feminino , Glucose/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Obesidade/induzido quimicamente , Oxirredução , RatosRESUMO
Rheumatoid arthritis (RA) patients often have altered body composition including reduced muscle mass and increased fat mass. Some RA patients are likely to increase visceral fat without obesity [Body Mass Index (BMI) ≥ 25]. The objective of the study was to determine the association between obesity and/or visceral adiposity and the risk for atherosclerosis in Japanese RA patients. Obesity was evaluated using the BMI, with visceral adiposity evaluated using the visceral fat area (VFA) and the visceral/subcutaneous fat ratio (V/S ratio), quantified using the dual bioelectrical impedance method. Atherosclerosis was evaluated based on the intima-media thickness (IMT) and Plaque score (PS) of the carotid artery, measured using ultrasonography. Multivariate analysis was performed to determine the factors associated with IMT and PS. IMT and PS were compared among groups of patients sub-classified according to BMI and VFA levels. The V/S ratio was higher in RA patients than healthy controls, after adjustment for age, BMI, and waist circumference. On multivariate analysis, the V/S ratio, but not the BMI, was independently associated with the IMT and PS. Among the sub-classifications for BMI and VFA, non-obese patients with a high visceral adiposity (18.5 ≤ BMI < 25 kg/m2 and VFA ≥ 100 cm2) had the highest IMT (mean IMT, 0.93 ± 0.29 mm; maximum IMT, 1.44 ± 0.71 mm) and PS (1.43 ± 0.61), compared to all other BMI and VFA subgroups. RA patients have increased visceral adiposity, which is associated with a high prevalence of atherosclerotic of plaques. Non-obese RA patients who have visceral adiposity have a specifically higher risk for atherosclerosis.
Assuntos
Adiposidade , Artrite Reumatoide/epidemiologia , Aterosclerose/epidemiologia , Gordura Intra-Abdominal/metabolismo , Obesidade/epidemiologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Distribuição da Gordura Corporal , Índice de Massa Corporal , Espessura Intima-Media Carotídea , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/patologia , Fatores de RiscoRESUMO
Seipin, encoded by BSCL2 gene, is a protein whose physiological functions remain unclear. Mutations of BSCL2 cause the most-severe form of congenital generalized lipodystrophy (CGL). BSCL2 mRNA is highly expressed in the brain and testis in addition to the adipose tissue in human, suggesting physiological roles of seipin in non-adipose tissues. Since we found BSCL2 mRNA expression pattern among organs in rat is similar to human while it is not highly expressed in mouse brain, we generated a Bscl2/seipin knockout (SKO) rat using the method with ENU (N-ethyl-N-nitrosourea) mutagenesis. SKO rats showed total lack of white adipose tissues including mechanical fat such as bone marrow and retro-orbital fats, while physiologically functional brown adipose tissue was preserved. Besides the lipodystrophic phenotypes, SKO rats showed impairment of spatial working memory with brain weight reduction and infertility with azoospermia. We confirmed reduction of brain volume and number of sperm in human patients with BSCL2 mutation. This is the first report demonstrating that seipin is necessary for normal brain development and spermatogenesis in addition to white adipose tissue development.
Assuntos
Adipogenia/genética , Encéfalo/crescimento & desenvolvimento , Subunidades gama da Proteína de Ligação ao GTP/genética , Espermatogênese/genética , Animais , Encéfalo/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , RNA Mensageiro/biossíntese , Ratos , Espermatozoides/crescimento & desenvolvimento , Espermatozoides/metabolismo , Testículo/crescimento & desenvolvimento , Testículo/metabolismoRESUMO
BACKGROUND: Difficulty in detecting and measuring Achilles tendon (AT) xanthomas may be responsible for underdiagnosis of familial hypercholesterolemia (FH). We aimed to determine a cutoff value for AT thickness (AT-T) using ultrasonography to diagnose FH, and to investigate the relationship between AT-T and atherosclerosis.MethodsâandâResults:Ultrasonographic AT-T and carotid intima-media thickness (IMT) were evaluated in 130 genetically diagnosed FH patients and 155 non-FH patients. The outline and internal properties of the AT could be clearly determined using ultrasonography, and a good correlation in AT-T was observed between ultrasonography and the conventional method of X-ray radiography (r=0.924, P<0.001). Cutoff values for the diagnosis of FH derived from receiver-operating curves were 5.8 mm (sensitivity 71%, specificity 78%) in men, and 5.5 mm (sensitivity 80%, specificity 81%) in women. Importantly, increased AT-T was positively associated with carotid IMT only in the FH group. Additionally, increased AT-T was associated with the presence of coronary artery disease in a logistic regression analysis adjusted for traditional cardiovascular risk factors. CONCLUSIONS: This is the first study to determine a cutoff value for AT-T based on ultrasonography for the diagnosis of FH in Japanese subjects. Clearer detection and easier measurement of AT-T using ultrasonography would encourage clinicians to diagnose FH more actively, and could solve the problem of underdiagnosis of FH.
Assuntos
Tendão do Calcâneo/diagnóstico por imagem , Hiperlipoproteinemia Tipo II/diagnóstico , Ultrassonografia/métodos , Adulto , Idoso , Povo Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos-induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse transcription-PCR revealed that adipocytes respond directly to asbestos exposure with an increased production of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y-MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.
Assuntos
Adipócitos/patologia , Amianto/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Mesotelioma/induzido quimicamente , Mesotelioma/patologia , Células 3T3-L1 , Adipócitos/metabolismo , Adipocinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Amianto/farmacocinética , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mesotelioma Maligno , Camundongos , Camundongos EndogâmicosRESUMO
Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair ß-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired ß-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 µg·kg⻹·day⻹) and/or exenatide (20 µg·kg⻹·day⻹) for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hipoglicemiantes/uso terapêutico , Leptina/uso terapêutico , Sobrepeso/complicações , Pâncreas/efeitos dos fármacos , Peptídeos/uso terapêutico , Peçonhas/uso terapêutico , Adiposidade/efeitos dos fármacos , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Implantes de Medicamento , Sinergismo Farmacológico , Quimioterapia Combinada , Exenatida , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Insulina/metabolismo , Secreção de Insulina , Leptina/administração & dosagem , Leptina/genética , Masculino , Camundongos Endogâmicos C57BL , Sobrepeso/tratamento farmacológico , Sobrepeso/etiologia , Sobrepeso/metabolismo , Pâncreas/metabolismo , Peptídeos/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêutico , Estreptozocina , Triglicerídeos/metabolismo , Peçonhas/administração & dosagemRESUMO
INTRODUCTION: In patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors has been shown to reduce hospital admission rates for heart failure (HF). However, the multiple mechanisms hypothesized and investigated to explain the cardioprotection of SGLT2 inhibitors are not fully understood. OBJECTIVES: The effect of luseogliflozin on myocardial flow reserve (MFR) in patients with T2D (LUCENT-J) study aims to examine the effects of SGLT2 inhibitors on myocardial perfusion. METHODS: The LUCENT-J study is a prospective, single-center, randomized, two-arm, parallel-group, open-label (i.e., the radiology readers are blinded), active-controlled study. A cohort of 40 patients with T2D with no or stable (with no history of myocardial infarction and with or without previous percutaneous coronary intervention) coronary artery disease will be included. Patients will be randomized in a 1:1 ratio to luseogliflozin or control and treated for 24 weeks. The primary outcome is the change in MFR, as measured by 13N-ammonia positron emission tomography/computed tomography, from baseline to 24 weeks after treatment initiation. PLANNED OUTCOMES: The LUCENT-J study will elucidate the mechanisms of cardioprotection by SGLT2 inhibitors in patients with T2D. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCTs051220016).
RESUMO
Introduction: This study aimed to investigate the association between scan frequency and intermittently scanned continuous glucose monitoring (isCGM) metrics and to clarify the factors affecting scan frequency in adults with type 1 diabetes mellitus (T1D). Methods: We enrolled adults with T1D who used FreeStyle® Libre. Scan and self-monitoring of blood glucose (SMBG) frequency and CGM metrics from the past 90-day glucose data were collected. The receiver operating characteristic curve was plotted to obtain the optimal cutoff values of scan frequency for the target values of time in range (TIR), time above range (TAR), and time below range (TBR). Results: The study was conducted on 211 adults with T1D (mean age, 50.9 ± 15.2 years; male, 40.8%; diabetes duration, 16.4 ± 11.9 years; duration of CGM use, 2.1 ± 1.0 years; and mean HbA1c, 7.6 ± 0.9%). The average scan frequency was 10.5 ± 3.3 scan/day. Scan frequency was positively correlated with TIR and negatively correlated with TAR, although it was not significantly correlated with TBR. Scan frequency was positively correlated with the hypoglycemia fear survey-behavior score, while it was negatively correlated with some glycemic variability metrics. Adult patients with T1D and good exercise habits had a higher scan frequency than those without exercise habits. The AUC for > 70% of the TIR was 0.653, with an optimal cutoff of 11 scan/day. Conclusions: In real-world conditions, frequent scans were linked to improved CGM metrics, including increased TIR, reduced TAR, and some glycemic variability metrics. Exercise habits and hypoglycemia fear-related behavior might affect scan frequency. Our findings could help healthcare professionals use isCGM to support adults with T1D.Clinical Trial Registry No. UMIN000039376.
RESUMO
Aim: The Effect of Intermittent-Scanning Continuous Glucose Monitoring to Glycemic Control Including Hypoglycemia and Quality of Life of Patients with Type 1 Diabetes Mellitus (ISCHIA) study was a randomized, crossover trial that reported the decrease in time below range (TBR) by the use of intermittent-scanning continuous glucose monitoring (isCGM) combined with structured education in adults with type 1 diabetes (T1D) treated by multiple daily injections. The participants were instructed to perform frequent scanning of the isCGM sensor (10 times a day or more) and ingest sugar when impending hypoglycemia is suspected by tracking the sensor glucose levels and the trend arrow. We conducted post-hoc analysis to identify factors affecting difference in TBR (∆TBR), in time in range (∆TIR), and in time above range (∆TAR). Participants and methods: Data from 93 participants who completed the ISCHIA study were used. Multiple regression analyses were performed to identify factors affecting CGM metrics. Results: Pearson's correlation analysis showed the negative association between log-transformed scan frequency and with ∆TBR (r = - 0.255, P = 0.015), while there was no significant association of log-transformed scan frequency with ∆TIR (r = 0.172, P = 0.102) and ∆TAR (r = 0.032, P = 0.761), respectively. The log-transformed scan frequency was an independent predictor of ∆TBR (Beta = - 7.712, P = 0.022), but not of ∆TIR(Beta = 7.203, P = 0.091) and of ∆TAR (Beta = 0.514, P = 0.925). Conclusions: Our findings suggest that more frequent scanning of isCGM may be beneficial to reduce TBR in T1D adults.
RESUMO
Background and aims: Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. Methods: The OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). Results: All patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to -0.5) vs. -0.4 (-0.6 to -0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to -0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to -1.3) vs. -0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (-0.9 ± 0.25 vs. -0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19-16.30, p = 0.02). Conclusions: In statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.
RESUMO
Leptin is one of the key molecules in maintaining energy homeostasis. Although genetically leptin-deficient Lep(ob)/Lep(ob) mice have greatly contributed to elucidating leptin physiology, the use of more than one species can improve the accuracy of analysis results. Using the N-ethyl-N-nitrosourea mutagenesis method, we generated a leptin-deficient Lep(mkyo)/Lep(mkyo) rat that had a nonsense mutation (Q92X) in leptin gene. Lep(mkyo)/Lep(mkyo) rats showed obese phenotypes including severe fatty liver, which were comparable to Lep(ob)/Lep(ob) mice. To identify genes that respond to leptin in the liver, we performed microarray analysis with Lep(mkyo)/Lep(mkyo) rats and Lep(ob)/Lep(ob) mice. We sorted out genes whose expression levels in the liver of Lep(mkyo)/Lep(mkyo) rats were changed from wild-type (WT) rats and were reversed toward WT rats by leptin administration. In this analysis, livers were sampled for 6 h, a relatively short time after leptin administration to avoid the secondary effect of metabolic changes such as improvement of fatty liver. We did the same procedure in Lep(ob)/Lep(ob) mice and selected genes whose expression patterns were common in rat and mouse. We verified their gene expressions by real-time quantitative PCR. Finally, we identified eight genes that primarily respond to leptin in the liver commonly in rat and mouse. These genes might be important for the effect of leptin in the liver.
Assuntos
Expressão Gênica , Leptina/genética , Fígado/fisiologia , Obesidade/genética , Ratos Mutantes/genética , Animais , Códon sem Sentido , Modelos Animais de Doenças , Etilnitrosoureia/toxicidade , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Leptina/sangue , Leptina/deficiência , Leptina/farmacologia , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Masculino , Camundongos Mutantes , Mutagênese , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: AMPK activation promotes glucose and lipid metabolism. RESULTS: Hepatic AMPK activities were decreased in fatty liver from lipodystrophic mice, and leptin activated the hepatic AMPK via the α-adrenergic effect. CONCLUSION: Leptin improved the fatty liver possibly by activating hepatic AMPK through the central and sympathetic nervous systems. SIGNIFICANCE: Hepatic AMPK plays significant roles in the pathophysiology of lipodystrophy and metabolic action of leptin. Leptin is an adipocyte-derived hormone that regulates energy homeostasis. Leptin treatment strikingly ameliorates metabolic disorders of lipodystrophy, which exhibits ectopic fat accumulation and severe insulin-resistant diabetes due to a paucity of adipose tissue. Although leptin is shown to activate 5'-AMP-activated protein kinase (AMPK) in the skeletal muscle, the effect of leptin in the liver is still unclear. We investigated the effect of leptin on hepatic AMPK and its pathophysiological relevance in A-ZIP/F-1 mice, a model of generalized lipodystrophy. Here, we demonstrated that leptin activates hepatic AMPK through the central nervous system and α-adrenergic sympathetic nerves. AMPK activities were decreased in the fatty liver of A-ZIP/F-1 mice, and leptin administration increased AMPK activities in the liver as well as in skeletal muscle with significant reduction in triglyceride content. Activation of hepatic AMPK with A769662 also led to a decrease in hepatic triglyceride content and blood glucose levels in A-ZIP/F-1 mice. These results indicate that the down-regulation of hepatic AMPK activities plays a pathophysiological role in the metabolic disturbances of lipodystrophy, and the hepatic AMPK activation is involved in the therapeutic effects of leptin.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fígado Gorduroso/enzimologia , Leptina/metabolismo , Lipodistrofia/enzimologia , Receptores Adrenérgicos alfa 1/metabolismo , Sistema Nervoso Simpático/enzimologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Células Cultivadas , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Leptina/uso terapêutico , Lipodistrofia/tratamento farmacológico , Lipodistrofia/genética , Lipodistrofia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/genética , Sistema Nervoso Simpático/metabolismoRESUMO
Previously, we reported that exogenous administration of ghrelin ameliorates glucose metabolism in a neonate streptozotocin (STZ)-induced diabetic rat model through enhancement of ß-cell proliferation. However, it was not clear whether the observed ß-cell proliferation was a direct or indirect effect (e.g., via orexigenic or growth hormone-stimulated pathways) of ghrelin activity. Here, we aimed to investigate whether ghrelin directly impacts ß-cell proliferation after STZ-induced injury in mice. Seven-week-old male rat insulin II promoter-ghrelin internal ribosomal sequence ghrelin O-acyltransferase transgenic (RIP-GG Tg) mice, which have elevated pancreatic ghrelin levels, but only minor changes in plasma ghrelin levels when fed a medium-chain triglyceride-rich diet, were treated with STZ. Then, serum insulin, pancreatic insulin mRNA expression, and islet histology were evaluated. We found that the serum insulin levels, but not blood glucose levels, of RIP-GG Tg mice were significantly ameliorated 14 days post-STZ treatment. Pancreatic insulin mRNA expression was significantly elevated in RIP-GG Tg mice, and ß-cell numbers in islets were increased. Furthermore, the number of phospho-histone H3⺠or Ki67⺠proliferating ß-cells was significantly elevated in RIP-GG Tg mice, whereas the apoptotic indexes within the islets, as determined by TUNEL assay, were not changed. These results indicate that ghrelin can directly stimulate ß-cell proliferation in vivo after ß-cell injury even without its orexigenic or GH-stimulating activities, although it did not have enough impact to normalize the glucose tolerance in adult mice.
Assuntos
Proliferação de Células , Diabetes Mellitus Experimental/fisiopatologia , Grelina/genética , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Animais , Apoptose/fisiologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Grelina/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Intolerância à Glucose/fisiopatologia , Histonas/metabolismo , Insulina/sangue , Insulina/genética , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Distribuição Aleatória , RatosRESUMO
Experimental transplantation of endocrine tissues has led to significant advances in our understanding of endocrinology and metabolism. Endocrine cell transplantation therapy is expected to be applied to the treatment of metabolic endocriopathies. Restoration of functional pancreatic beta-cell mass or of functional adipose mass are reasonable treatment approaches for patients with diabetes or lipodystrophy, respectively. Human induced pluripotent stem (iPS) cell research is having a great impact on life sciences. Doctors Takahashi and Yamanaka discovered that the forced expression of a set of genes can convert mouse and human somatic cells into a pluripotent state [1, 2]. These iPS cells can differentiate into a variety of cell types. Therefore, iPS cells from patients may be a potential cell source for autologous cell replacement therapy. This review briefly summarizes the current knowledge about transplantation therapy for diabetes mellitus, the development of the endocrine pancreas and adipocytes, and endocrine-metabolic disease-specific iPS cells.
Assuntos
Adipócitos/fisiologia , Diabetes Mellitus/terapia , Células-Tronco Pluripotentes Induzidas/transplante , Células Secretoras de Insulina/transplante , Ilhotas Pancreáticas/fisiologia , Adipócitos/transplante , Animais , Humanos , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/embriologia , Transplante das Ilhotas Pancreáticas/fisiologia , CamundongosRESUMO
Alpha-Klotho (alpha-Kl) and its homolog, beta-Klotho (beta-Kl) are key regulators of mineral homeostasis and bile acid/cholesterol metabolism, respectively. FGF15/ humanFGF19, FGF21, and FGF23, members of the FGF19 subfamily, are believed to act as circulating metabolic regulators. Analyses of functional interactions between alpha- and beta-Kl and FGF19 factors in wild-type, alpha-kl(-/-), and beta-kl(-/-) mice revealed a comprehensive regulatory scheme of mineral homeostasis involving the mutually regulated positive/negative feedback actions of alpha-Kl, FGF23, and 1,25(OH)(2)D and an analogous regulatory network composed of beta-Kl, FGF15/humanFGF19, and bile acids that regulate bile acid/cholesterol metabolism. Contrary to in vitro data, beta-Kl is not essential for FGF21 signaling in adipose tissues in vivo, because (i) FGF21 signals are transduced in the absence of beta-Kl, (ii) FGF21 could not be precipitated by beta-Kl, and (iii) essential phenotypes in Fgf21(-/-) mice (decreased expressions of Hsl and Atgl in WAT) were not replicated in beta-kl(-/-) mice. These findings suggest the existence of Klotho-independent FGF21 signaling pathway(s) where undefined cofactors are involved. One-to-one functional interactions such as alpha-Klotho/FGF23, beta-Klotho/FGF15 (humanFGF19), and undefined cofactor/FGF21 would result in tissue-specific signal transduction of the FGF19 subfamily.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Transdução de Sinais , Tecido Adiposo/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica , Glucuronidase/deficiência , Proteínas Klotho , Fígado/metabolismo , Camundongos , Camundongos Knockout , Ligação Proteica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Vitamina D/metabolismoRESUMO
Two novel bioelectrical impedance analysis (BIA) methods have been developed recently for evaluation of intra-abdominal fat accumulation. Both methods use electrodes that are placed on abdominal wall and allow evaluation of intra-abdominal fat area (IAFA) easily without radiation exposure. Of these, "abdominal BIA" method measures impedance distribution along abdominal anterior-posterior axis, and IAFA by BIA method(BIA-IAFA) is calculated from waist circumference and the voltage occurring at the flank. Dual BIA method measures impedance of trunk and body surface at the abdominal level and calculates BIA-IAFA from transverse and antero-posterior diameters of the abdomen and the impedance of trunk and abdominal surface. BIA-IAFA by these two BIA methods correlated well with IAFA measured by abdominal CT (CT-IAFA) with correlatipn coefficient of 0.88 (n = 91, p < 0.0001) for the former, and 0.861 (n = 469, p < 0.01) for the latter. These new BIA methods are useful for evaluating abdominal adiposity in clinical study and routine clinical practice of metabolic syndrome and obesity.
Assuntos
Gordura Abdominal/química , Gordura Abdominal/anatomia & histologia , Adiposidade , Composição Corporal/fisiologia , Índice de Massa Corporal , Impedância Elétrica , Humanos , Obesidade/diagnósticoRESUMO
CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is caused by a rare pathogenic variant in the LDLR, APOB, and PCSK9 genes. However, the causative variants in these genes have not been identified in approximately 40% of HeFH patients. OBJECTIVE: Our aim was to identify novel (or additional) genes/variants that contribute to HeFH. METHODS: Whole-exome sequencing was performed for 215 family members from 122 families with HeFH without pathogenic variants in the LDLR or PCSK9 genes. RESULTS: We could not find novel causative familial hypercholesterolemia (FH) genes/variants by family analysis. Next, we examined all APOB variants. Twenty-four nonsynonymous APOB variants were identified. The allele frequencies of the c.2863C > T:p.(Pro955Ser) variant in the HeFH probands and the general Japanese population were 0.15 and 0.034, respectively [odds ratio 4.9 (95% CI 3.4-7.1); P = 6.9 × 10-13]. The patients harboring the c.2863C > T:p.(Pro955Ser) variant accounted for 9.8% (n = 63) of unrelated patients with HeFH (n = 645). The penetrance of the c.2863C > T:p.(Pro955Ser) variant was low in the pedigree-based genetic analysis. In an in vitro assay, low-density lipoprotein (LDL) uptake from patients with the homozygous c.2863C > T:p.(Pro955Ser) variant was 44% of the LDL uptake from control subjects, and it was similar to that of the LDL uptake from patients with the known pathogenic heterozygous p.(Arg3527Gln) variant. CONCLUSIONS: The low-frequency APOB c.2863C > T:p.(Pro955Ser) variant is not an FH-causative variant, but it has a moderate effect size in HeFH. These findings suggest that the combination of the APOB c.2863C > T:p.(Pro955Ser) variant and age, environmental factors, or other genetic factors contributes to the severity of or variability in the HeFH phenotype.
Assuntos
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Hiperlipoproteinemia Tipo II/genética , Fenótipo , Apolipoproteínas B/genética , MutaçãoRESUMO
AIMS/INTRODUCTION: The discrepancy between HbA1c and glucose exposure may have significant clinical implications; however, the association between the hemoglobin glycation index (HGI) and clinical parameters in type 1 diabetes remains controversial. This study aimed to find the factors associated with HGI (laboratory HbA1c - predicted HbA1c derived from the continuous glucose monitoring [CGM]). MATERIALS AND METHODS: We conducted a cross-sectional study of adults with type 1 diabetes (n = 211, age 50.9 ± 15.2 years old, female sex = 59.2%, duration of CGM use = 2.1 ± 1.0 years). All subjects wore the CGM for 90 days before HbA1c measurement. Data derived from the FreeStyle Libre sensor were used to calculate the glucose management indicator (GMI) and glycemic variability (GV) parameters. HGI was defined as the difference between the GMI and the laboratory HbA1c levels. The participants were divided into three groups according to the HGI tertile (low, moderate, and high). Multivariate regression analyses were performed. RESULTS: The female sex ratio, HbA1c, and % coefficient of variation (%CV) significantly increased over the HGI tertile, while eGFR and Hb decreased over the HGI tertile. In multivariate analysis, the factors associated with HGI were %CV and eGFR, after adjusting for HbA1c level and sex (R2 = 0.44). CONCLUSIONS: This study demonstrated that HGI is associated with female sex, eGFR, and some glycemic variability indices, independently of HbA1c. Minimizing glycemic fluctuations might reduce HGI. This information provides diabetic health professionals and patients with personalized diabetes management for adults with type 1 diabetes.