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Hereditary hemorrhagic telangiectasia (HHT) causes arteriovenous malformations (AVMs) in several organs. This report is the first to document and image a thyroid AVM complication in HHT. A 72-year-old woman with HHT was referred for thyroid nodule evaluation. Ultrasonography showed a hypervascularized nodule in the right thyroid lobe which was initially suspected to be malignant. However, 3-dimensional computed tomography angiography demonstrated a thyroid AVM with abnormal anastomosis of the superior thyroid artery and the inferior thyroid vein. In the formation of thyroid AVM, here, chronic thyroiditis and hypothyroidism complications may have been a second hit, due to the predisposing first-hit germline mutation. This report sheds light on overlooked thyroid lesions in HHT and advocates a noninvasive imaging approach in diagnosing thyroid AVMs. Furthermore, this case suggests a potential mechanism of AVM formation in human HHT, possibly supporting the second-hit hypothesis.
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Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.
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Glucose lowering independently reduces liver fibrosis in human nonalcoholic fatty liver disease. This study investigated the impact of diabetes on steatohepatitis and established a novel mouse model for diabetic steatohepatitis. Male C57BL/6J mice were fed a 60% high-fat diet (HFD) and injected with carbon tetrachloride (CCl4) and streptozotocin (STZ) to induce diabetes. The HFD+CCl4+STZ group showed more severe liver steatosis, hepatocyte ballooning, and regenerative nodules compared with other groups. Diabetes up-regulated inflammatory cytokine-associated genes and increased the M1/M2 macrophage ratios in the liver. Single-cell RNA sequencing analysis of nonparenchymal cells in the liver showed that diabetes reduced Kupffer cells and increased bone marrow-derived recruited inflammatory macrophages, such as Ly6Chi-RM. Diabetes globally reduced liver sinusoidal endothelial cells (LSECs). Furthermore, genes related to the receptor for advanced glycation end products (RAGE)/Toll-like receptor 4 (TLR4) were up-regulated in Ly6Chi-RM and LSECs in mice with diabetes, suggesting a possible role of RAGE/TLR4 signaling in the interaction between inflammatory macrophages and LSECs. This study established a novel diabetic steatohepatitis model using a combination of HFD, CCl4, and STZ. Diabetes exacerbated steatosis, hepatocyte ballooning, fibrosis, regenerative nodule formation, and the macrophage M1/M2 ratios triggered by HFD and CCl4. Single-cell RNA sequencing analysis indicated that diabetes activated inflammatory macrophages and impairs LSECs through the RAGE/TLR4 signaling pathway. These findings open avenues for discovering novel therapeutic targets for diabetic steatohepatitis.
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Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Camundongos , Masculino , Humanos , Animais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Células Endoteliais/metabolismo , Transcriptoma , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Cirrose Hepática/patologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Dieta Hiperlipídica/efeitos adversosRESUMO
AIMS: Diabetes onset is difficult to predict. Since decreased insulinogenic index (IGI) is observed in prediabetes, and blood gene expression correlates with insulin secretion, candidate biomarkers can be identified. METHODS: We collected blood from 96 participants (54 males, 42 females) in 2008 (age: 52.5 years) and 2016 for clinical and gene expression analyses. IGI was derived from values of insulin and glucose at fasting and at 30 min post-OGTT. Two subgroups were identified based on IGI variation: "Minor change in IGI" group with absolute value variation between -0.05 and +0.05, and "Decrease in IGI" group with a variation between -20 and -0.05. RESULTS: Following the comparison of "Minor change in IGI" and "Decrease in IGI" groups at time 0 (2008), we identified 77 genes correlating with declining IGI, related to response to lipid, carbohydrate, and hormone metabolism, response to stress and DNA metabolic processes. Over the eight years, genes correlating to declining IGI were related to inflammation, metabolic and hormonal dysregulation. Individuals with minor change in IGI, instead, featured homeostatic and regenerative responses. CONCLUSIONS: By blood gene expression analysis of non-obese individuals, we identified potential gene biomarkers correlating to declining IGI, associated to a pathophysiology of inflammation and metabolic dysregulation.
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Glicemia , Resistência à Insulina , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Glicemia/metabolismo , Teste de Tolerância a Glucose , Insulina , Inflamação/genética , Biomarcadores , Expressão GênicaRESUMO
INTRODUCTION: Hyperinsulinemia and hyperglycemia are associated with exaggerated systemic sympathetic nerve activity (SNA) in patients with type 2 diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels, whereas sulfonylureas increase insulin levels. We will test whether these two classes of antidiabetic agents have different effects on SNA. METHODS: The present study is an ongoing, 24-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial (jRCTs 041200035). Participants with type 2 diabetes with multiple atherosclerosis risk factors are randomly assigned in a 1:1 manner to receive 2.5 mg luseogliflozin or 0.5 mg glimepiride once daily. The sample size was calculated to be 14 in each group, with a significance level of 0.05 and a power of 0.80. The design required 40 evaluable study participants. Our primary endpoint will be the change in muscle SNA (MSNA). The secondary endpoints included organ-specific insulin sensitivity measured by a hyperinsulinemic-euglycemic clamp study using an artificial pancreas combined with a stable isotope-labeled glucose infusion, bioelectrical impedance analysis, and organ-specific (cardiac, renal, and hepatic) 123I-meta-iodobenzylguanidine (MIBG) innervation imaging. PLANNED OUTCOMES: Study recruitment started in April 2020 and will end in June 2024, with 40 participants randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by March 2025. TRIAL REGISTRATION: The study protocol has been approved by the Certified Review Board, Kanazawa University, Ishikawa, Japan, in accordance with the guidelines stipulated in the Declaration of Helsinki (CRB4180005, 2019-001). This trial is registered with the Japan Registry of Clinical Trials, jRCTs 041200035.
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PURPOSE: To clarify the relationships between the changes in hepatokines and weight loss, and between these changes and the metabolic effects, and the roles played by these changes, after laparoscopic sleeve gastrectomy (LSG). METHODS: We recruited 25 Japanese patients with severe obesity, who underwent LSG. We measured two hepatokines: selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2), at the baseline, and then 6 months and 1 year after LSG. Finally, we compared the changes in the hepatokines with the parameters of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). RESULTS: Changes in LECT2 were correlated with the percentage of total weight loss (ρ = - 0.499, P = 0.024) and the decrease in total fat area (ρ = 0.559, P = 0.003). The changes in SeP were correlated with those in hemoglobin A1c (ρ = 0.526, P = 0.043) and the insulinogenic index (ρ = 0.638, P = 0.010) in T2D patients. In patients with NASH, the LECT2 levels were correlated with liver steatosis (ρ = 0.601). CONCLUSIONS: SeP levels decrease in association with HbA1c reduction, whereas LECT2 levels are associated with reductions in fat mass and NASH scores after LSG. Hepatokines may be involved in the pathology of obesity and its complications.
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Background: Recent genome-wide association studies have revealed that nonalcoholic fatty liver disease (NAFLD) is correlated with genetic polymorphisms. However, the effects of genetic variation on nutritional metabolism and NAFLD are complex and further studies are still needed. Objectives: This study aimed to assess the nutritional characteristics interacting with the correlation between genetic predisposition and NAFLD. Methods: We assessed the 2013-2017 health examination data of 1191 adults aged ≥40 y living in Shika town, Ishikawa Prefecture, Japan. Adults with moderate or heavy alcohol consumption and hepatitis were excluded, and 464 participants who underwent genetic analyses were included in the study. Abdominal echography was performed to diagnose fatty liver condition, and dietary intake and nutritional balance were evaluated using the brief self-administered diet history questionnaire. NAFLD-related gene polymorphisms were identified using Japonica Array v2 (Toshiba). Results: Among the 31 single nucleotide polymorphisms, only the polymorphism T-455C in the apolipoprotein C3 (APOC3) gene (rs2854116) was significantly associated with fatty liver condition. The condition was more common in participants with heterozygotes of the APOC3 gene (rs2854116) than in those with the TT and CC genotypes. Significant interactions were observed between NAFLD and the intake of fat, vegetable fat, MUFAs, PUFAs, cholesterol, n-3 FAs, and n-6 FAs. Moreover, participants with NAFLD who presented with the TT genotype had a significantly higher fat intake than those without NAFLD. Conclusions: The polymorphism T-455C in the APOC3 gene (rs2854116) and fat intake are associated with the NAFLD risk in Japanese adults. Participants with a fatty liver who presented with the TT genotype of rs2854116 had a higher fat intake. Such nutrigenetic interaction can deepen our understanding of the NAFLD pathology. Moreover, in clinical settings, the correlation between genetic factors and nutrition intake should be considered in personalized nutritional interventions against NAFLD. Curr Dev Nutr 2023;xx:xx.The study was registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN 000024915.
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Understanding the mechanisms linking steatosis to fibrosis is needed to establish a promising therapy against nonalcoholic fatty liver disease (NAFLD). The aim of this study was to clarify clinical features and hepatic gene expression signatures that predict and contribute to liver fibrosis development during the long-term real-world histological course of NAFLD in subjects with and without diabetes. A pathologist scored 342 serial liver biopsy samples from 118 subjects clinically diagnosed with NAFLD during a 3.8-year (SD 3.45 years, maximum 15 years) course of clinical treatment. At the initial biopsy, 26 subjects had simple fatty liver, and 92 had nonalcoholic steatohepatitis (NASH). In the trend analysis, the fibrosis-4 index (P < 0.001) and its components at baseline predicted the future fibrosis progression. In the generalized linear mixed model, an increase in HbA1c, but not BMI, was significantly associated with fibrosis progression (standardized coefficient 0.17 [95% CI 0.009-0.326]; P = 0.038) for subjects with NAFLD and diabetes. In gene set enrichment analyses, the pathways involved in zone 3 hepatocytes, central liver sinusoidal endothelial cells (LSECs), stellate cells, and plasma cells were coordinately altered in association with fibrosis progression and HbA1c elevation. Therefore, in subjects with NAFLD and diabetes, HbA1c elevation was significantly associated with liver fibrosis progression, independent of weight gain, which may be a valuable therapeutic target to prevent the pathological progression of NASH. Gene expression profiles suggest that diabetes-induced hypoxia and oxidative stress injure LSECs in zone 3 hepatocytes, which may mediate inflammation and stellate cell activation, leading to liver fibrosis. ARTICLE HIGHLIGHTS: It remains uncertain how diabetes and obesity contribute to histological courses of nonalcoholic fatty liver disease (NAFLD). Clinical features and gene expression signatures that predict or are associated with future liver fibrosis development were assessed in a serial liver biopsy study of subjects with NAFLD. An increase in HbA1c, but not BMI, was associated with liver fibrosis progression in the generalized linear mixed model. Considering hepatic gene set enrichment analyses, diabetes may enhance liver fibrosis via injuring central liver sinusoidal endothelial cells that mediate inflammation and stellate cell activation during NAFLD development.
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Diabetes Mellitus , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Transcriptoma , Células Endoteliais , Hemoglobinas Glicadas , Cirrose Hepática/genética , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Fígado/patologia , Diabetes Mellitus/patologia , Inflamação/patologiaRESUMO
Muscle atrophy is the cause and consequence of obesity. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum (ER) stress and insulin resistance in the liver and adipose tissues. However, obesity-associated regulation of proteasome function and its role in the skeletal muscles remains underinvestigated. Here, we established skeletal muscle-specific 20S proteasome assembly chaperone-1 (PAC1) knockout (mPAC1KO) mice. A high-fat diet (HFD) activated proteasome function by â¼8-fold in the skeletal muscles, which was reduced by 50% in mPAC1KO mice. mPAC1KO induced unfolded protein responses in the skeletal muscles, which were reduced by HFD. Although the skeletal muscle mass and functions were not different between the genotypes, genes involved in the ubiquitin proteasome complex, immune response, endoplasmic stress, and myogenesis were coordinately upregulated in the skeletal muscles of mPAC1KO mice. Therefore, we introduced an immobilization-induced muscle atrophy model in obesity by combining HFD and immobilization. mPAC1KO downregulated atrogin-1 and MuRF1, together with their upstream Foxo1 and Klf15, and protected against disused skeletal muscle mass reduction. In conclusion, obesity elevates proteasome functions in the skeletal muscles. PAC1 deficiency protects mice from immobilization-induced muscle atrophy in obesity. These findings suggest obesity-induced proteasome activation as a possible therapeutic target for immobilization-induced muscle atrophy.
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Atrofia Muscular , Complexo de Endopeptidases do Proteassoma , Camundongos , Masculino , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Camundongos Obesos , Atrofia Muscular/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismoRESUMO
The quality of skeletal muscle is maintained by a balance between protein biosynthesis and degradation. Disruption in this balance results in sarcopenia. However, its underlying mechanisms remain underinvestigated. Selenoprotein P (SeP; encoded by Selenop in mice) is a hepatokine that is upregulated in type 2 diabetes and aging and causes signal resistances via reductive stress. We created immobilized muscle atrophy model in Selenop knockout (KO) mice. Immobilization (IMM) significantly reduced cross-sectional areas and the size of skeletal muscle fibers, which were ameliorated in KO mice. IMM upregulated the genes encoding E3 ubiquitin ligases and their upstream FoxO1, FoxO3, and KLF15 transcription factors in the skeletal muscle, which were suppressed in KO mice. These findings suggest a possible involvement of SeP-mediated reductive stress in physical inactivity-mediated sarcopenia, which may be a therapeutic target against sarcopenia.NEW & NOTEWORTHY Selenoprotein P (SeP) is a hepatokine that is upregulated in type 2 diabetes and aging and causes signal resistances via reductive stress. Immobilization (IMM) significantly reduced skeletal muscle mass in mice, which was prevented in SeP knockout (KO) mice. IMM-induced Foxos/KLF15-atrogene upregulation was suppressed in the skeletal muscle of KO mice. These findings suggest that SeP-mediated reductive stress is involved in and may be a therapeutic target for physical inactivity-mediated muscle atrophy.
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Diabetes Mellitus Tipo 2 , Sarcopenia , Camundongos , Animais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Selenoproteína P/genética , Selenoproteína P/metabolismo , Sarcopenia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/prevenção & controle , Atrofia Muscular/metabolismo , Músculo Esquelético/metabolismo , Proteínas com Motivo TripartidoRESUMO
AIMS/INTRODUCTION: Selenoprotein P (SeP; encoded by SEPP1 in humans) is a hepatokine that causes impaired insulin secretion and insulin resistance. Metformin downregulates SELENOP promoter activity through an adenosine monophosphate-activated kinase-forkhead box protein O3a pathway in hepatocytes. This study aimed to test our hypothesis that circulating SeP levels are associated with the glucose-lowering effect of metformin in humans. MATERIALS AND METHODS: A total of 84 participants with poorly controlled type 2 diabetes were randomly assigned to receive metformin (1,000 mg, twice daily) or a dipeptidyl peptidase-4 inhibitor, alogliptin (25 mg, once daily) for 12 weeks. We tested metformin and alogliptin on SeP levels and factors associated therewith as a post-hoc analysis. RESULTS: Both metformin and aloglipitin did not change the SeP levels. Although metformin significantly increased the insulin secretory index secretory units of islets in transplantation only in participants with higher baseline SeP (>3.87), both agents similarly reduced fasting plasma glucose and glycated hemoglobin. SeP levels at baseline were correlated negatively with changes in SeP (r = -0.484, P = 0.004) and fasting plasma glucose (r = -0.433, P = 0.011), and positively with changes in C-peptide immunoreactivity (r = 0.420, P = 0.017) and secretory units of islets in transplantation (r = 0.388, P = 0.028) in the metformin, but not alogliptin, group. CONCLUSIONS: Higher baseline levels of SeP significantly predicted metformin-mediated, but not alogliptin-mediated, glucose-lowering and insulinotropic effects. Serum SeP levels might be a novel biomarker for predicting the outcomes of metformin therapy, which might be helpful in tailoring diabetes medication.
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Diabetes Mellitus Tipo 2 , Metformina , Humanos , Glicemia/análise , Quimioterapia Combinada , Glucose , Hipoglicemiantes/uso terapêutico , Metformina/farmacologia , Selenoproteína P/metabolismo , Selenoproteína P/uso terapêutico , Uracila/uso terapêuticoRESUMO
OBJECTIVES: We investigated the prevalence of locomotive syndrome (LS) and related musculoskeletal diseases [osteoarthritis (OA), lumbar spondylosis, and spinal alignment] in Type 2 diabetes mellitus (DM) patients. METHODS: Clinical data were collected from 101 patients (55 males; 46 females) admitted to our hospital for diabetes education from October 2018 to April 2021. Patients underwent full-spine and whole-legs standing radiography and physical measurements (10-m walking and grip strength tests and three LS risk tests). RESULTS: The estimated prevalence of LS was 86.1% (Stage 1: 44.5%, Stage 2: 41.6%), lumbar spondylosis was 11.9%, and hip, knee, and ankle OA were 16.9%, 51.5%, and 12.9%, respectively. Multiple logistic regression analysis identified grip strength [odds ratio (OR) = 0.89, confidence interval (CI) = 0.83-0.94], diabetic retinopathy (OR = 5.85, CI = 1.64-20.78), knee OA (OR = 3.34, CI = 1.11-10.02), and a sagittal vertical axis >40 mm (OR = 3.42, CI = 1.13-10.39) as significantly associated risk factors for worsening LS in Type 2 DM patients. CONCLUSIONS: This study clarified the epidemiological indicators of LS and associated factors in DM patients. Exercise therapy and DM management are effective strategies to reduce the occurrence and progression of LS.
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Diabetes Mellitus Tipo 2 , Osteoartrite do Joelho , Osteoartrite da Coluna Vertebral , Espondilose , Masculino , Feminino , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Prevalência , Coluna Vertebral , Espondilose/epidemiologiaRESUMO
OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS: We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS: Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS: Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Compostos Benzidrílicos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Fibrose , Glucosídeos , Humanos , Inflamação/complicações , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Compostos de SulfonilureiaRESUMO
Localization of ectopic cyclic Cushing's syndrome, which causes life-threatening complications, is challenging. A 70-year-old woman showed cyclic hypokalemia and hyperglycemia and was diagnosed with cyclic ectopic Cushing's syndrome. Although somatostatin-receptor scintigraphy failed to localize the responsible tumor, fluorodeoxyglucose-positron emission tomography (FDG-PET) showed the uptake of tracer in a lung tumor. Lobectomy resulted in remission. The resected adrenocorticotropic hormone (ACTH)-producing neuroendocrine tumor had Ki-67<2% and negative staining for somatostatin receptors. This is the first case assessed both radiological findings and pathological findings in cyclic ectopic Cushing's syndrome. Subsequent FDG-PET is recommended if somatostatin-receptor scintigraphy is negative.
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Síndrome de ACTH Ectópico , Tumor Carcinoide , Carcinoma Neuroendócrino , Síndrome de Cushing , Neoplasias Pulmonares , Tumores Neuroendócrinos , Feminino , Humanos , Idoso , Síndrome de Cushing/etiologia , Síndrome de Cushing/complicações , Receptores de Somatostatina , Síndrome de ACTH Ectópico/complicações , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/cirurgia , Fluordesoxiglucose F18 , Tumor Carcinoide/cirurgia , Tomografia por Emissão de Pósitrons , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/complicações , Carcinoma Neuroendócrino/complicações , Somatostatina , Pulmão/patologiaRESUMO
Reactive oxygen species (ROS) activate uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, the endogenous regulator of ROS in activated BAT and its role in pathological conditions remain unclear. We show that serum levels of selenoprotein P (SeP; encoded by SELENOP) negatively correlate with BAT activity in humans. Physiological cold exposure downregulates Selenop in BAT. Selenop knockout mice show higher rectal temperatures and UCP1 sulfenylation during cold exposure. SeP treatment to brown adipocytes eliminated the NA-induced mitochondrial ROS by upregulating glutathione peroxidase 4 and impaired cellular thermogenesis. A high-fat/high-sucrose diet elevates serum SeP levels and diminishes the elevated NA-induced thermogenesis in BAT-Selenop KO mice. Therefore, SeP is the intrinsic factor inducing reductive stress that impairs thermogenesis in BAT and may be a potential therapeutic target for obesity and diabetes.
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Tecido Adiposo Marrom , Selenoproteína P , Adipócitos Marrons , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica , Camundongos , Selenoproteína P/metabolismo , Termogênese/fisiologiaRESUMO
BACKGROUND: Few epidemiological studies have been performed to clarify the association between glucose metabolism disorders in early adults (20 years old) and physiological and environmental factors, including body mass index (BMI) in junior high school days. Therefore, we examined the association between hemoglobin A1c (HbA1c) level and body size (BMI) in early adulthood and lifestyles, including sleep habits and BMI in junior high school days in Shika town, a small town in Japan, by conducting a retrospective cohort study. METHODS: We examined the HbA1c levels and body size (BMI) of 99 early adults who turned 20 years old between 2016 and 2020 and were residing in Shika town, Ishikawa Prefecture. We obtained the information on lifestyles and living environment factors, including BMI, from a questionnaire survey conducted among the subjects during their junior high school days (13-15 years old) from 2009 to 2013. RESULTS: No correlations were observed between the HbA1c levels and the BMI values of the early adults. A two-way analysis of covariance (with the HbA1c levels and BMI values of the early adults as main factors) of the body size and lifestyle habits of the junior high school students revealed that "sleep quality in junior high school" was significantly poorer in the high HbA1c group than in the low HbA1c group in the early adults with high BMI values only. This result was also supported by the logistic regression analysis result. CONCLUSIONS: The present results indicate that poor sleep quality in junior high school was associated with the high HbA1c levels of the early adults with higher BMI values, which suggests that good sleep quality in junior high school prevents the development of hyperglycemia. However, the present study did not find any relationship between early-adult BMI and HbA1c level.
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Índice de Massa Corporal , Hemoglobinas Glicadas/análise , Qualidade do Sono , Feminino , Humanos , Japão , Masculino , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
AIMS/INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) might be less effective in patients with severe hyperglycemia, because hyperglycemia downregulated the GLP-1 receptor in an animal study. To examine this hypothesis clinically, we compared the glucose-lowering effects of GLP-1 receptor agonist liraglutide with and without prior glycemic control. MATERIALS AND METHODS: In an open-label, parallel trial, participants with poorly controlled type 2 diabetes were recruited and randomized to receive once-daily insulin therapy, degludec (Insulin-GLP-1 RA relay group, mean 16.8 ± 11.4 IU/day), for 12 weeks and then liraglutide for 12 weeks or subcutaneous injections of GLP-1 RA, liraglutide (GLP-1 RA first group, 0.9 mg), for 24 weeks. The primary efficacy end-points consisted of changes in the levels of fasting plasma glucose and glycated hemoglobin (HbA1c). RESULTS: The median fasting plasma glucose and HbA1c before the study were 210.0 mg/dL and 9.8%, respectively. The levels of fasting plasma glucose and HbA1c significantly decreased in the Insulin-GLP-1 RA relay group (P < 0.001) and GLP-1 RA first group (P < 0.001) by week 24, although no intergroup differences were observed. The reduction of HbA1c in the Insulin-GLP-1 RA relay group tended to be larger than that in the GLP-1 RA first group in the lowest CPR (C-peptide immunoreactivity) quartile (P = 0.072). The adverse events consisted of gastrointestinal problems, followed by hypoglycemia. CONCLUSIONS: The GLP-1 receptor agonist is overall effective without prior glycemic control with insulin in participants with poorly controlled type 2 diabetes. However, in participants with insulinopenic type 2 diabetes, prior glycemic control with insulin might overcome glucose toxicity-induced GLP-1 resistance.
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Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Liraglutida/uso terapêuticoRESUMO
AIM: Selenoprotein P (SeP, encoded by SELENOP in humans) is a hepatokine that causes insulin resistance in the liver and skeletal muscle. It was found that polyunsaturated fatty acid eicosapentaenoic acid (EPA) downregulates Selenop expression by inactivating SREBP-1c. The present study aimed to examine the effect of EPA for 12 weeks on circulating SeP levels and insulin sensitivity in humans with type 2 diabetes. METHODS: A total of 20 participants with dyslipidemia and type 2 diabetes were randomly assigned to an EPA (900 mg, twice daily) group and a control group. The primary endpoint was a change in serum SeP levels. Organ-specific insulin sensitivity in the liver (HGP and %HGP), skeletal muscle (Rd), and adipose tissue (FFA and %FFA) were assessed using a hyperinsulinemic-euglycemic clamp study with stable isotope-labeled glucose infusion. RESULTS: Serum SeP levels were not changed in either group at the end of the study. In the EPA group, the changes in SeP levels were positively correlated with the change in serum EPA levels (r = 0.709, P = 0.022). Treatment with EPA significantly enhanced %FFA but not %HGP and Rd. The change in serum EPA levels was significantly positively correlated with the change in %HGP, and negatively correlated with changes in Rd. CONCLUSIONS: The change in serum EPA levels was positively correlated with serum SeP levels, hepatic insulin sensitivity, and negatively with skeletal muscle insulin sensitivity in humans with type 2 diabetes. The EPA-induced enhancement of hepatic insulin sensitivity might be associated with a mechanism independent of serum SeP levels.
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Diabetes Mellitus Tipo 2 , Dislipidemias , Resistência à Insulina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/complicações , Dislipidemias/metabolismo , Ácido Eicosapentaenoico , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Selenoproteína P/metabolismoRESUMO
BACKGROUND: Co-infection between hepatitis B virus (HBV) and hepatitis delta virus (HDV) causes the severest chronic hepatitis and is associated with a high risk of cirrhosis and hepatocellular carcinoma (HCC). The Global Health Sector Strategy on Viral Hepatitis called for the elimination of hepatitis (- 65% mortality and - 90% incidence) by 2030. Our aims were to summarize key points of knowledge and to identify the gaps that need to be addressed to mount a public health response to HDV. METHODS: We performed a current literature review in terms of epidemiology by WHO regions, genotypes distribution and their pathogenicity, factors associated with HDV infection, mortality due to HDV infection, testing strategies and treatment. RESULTS: Prevalence of infection and genotypes are heterogeneous distributed, with highest prevalence in foci around the Mediterranean, in the Middle East, and in Central, Northern Asia and Eastern Asia. Persons who inject drugs (PWID) and migrants from highly endemic areas are highly affected. While antibody detection tests are available, HDV RNA tests of current infection are not standardized nor widely available. The few therapeutic options, including lofartinib, are not widely available; however several new and promising agents have entered clinical trials. CONCLUSION: HDV infection is an poorly known cause of chronic liver disease. To mount a public health response, we need a better description of the HDV epidemic, standardized testing strategies and better treatment options.
RESUMO
[This corrects the article DOI: 10.3389/fnut.2021.633703.].