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1.
Endocrinology ; 165(7)2024 May 27.
Article in English | MEDLINE | ID: mdl-38781447

ABSTRACT

Leukocyte cell-derived chemotaxin 2 (LECT2) is a protein initially isolated as a neutrophil chemotactic factor. We previously found that LECT2 is an obesity-associated hepatokine that senses liver fat and induces skeletal muscle insulin resistance. In addition, hepatocyte-derived LECT2 activates macrophage proinflammatory activity by reinforcing the lipopolysaccharide (LPS)-induced c-Jun N-terminal kinase signaling. Based on these findings, we examined the effect of LECT2 deletion on nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) caused by bacterial translocation. We created the bacterial translocation-mediated NAFLD/NASH model using LECT2 knockout mice (LECT2 KO) with 28 times a low-dose LPS injection under high-fat diet feeding conditions. LECT2 deletion exacerbated steatosis and significantly reduced p38 phosphorylation in the liver. In addition, LECT2 deletion increased macrophage infiltration with decreased M1/M2 ratios. LECT2 might contribute to protecting against lipid accumulation and macrophage activation in the liver under pathological conditions, which might be accomplished via p38 phosphorylation. This study provides novel aspects of LECT2 in the bacterial translocation-mediated NAFLD/NASH model.


Subject(s)
Disease Models, Animal , Intercellular Signaling Peptides and Proteins , Lipopolysaccharides , Macrophages , Mice, Knockout , Non-alcoholic Fatty Liver Disease , Animals , Male , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/pathology , Mice , Lipopolysaccharides/toxicity , Macrophages/metabolism , Liver/metabolism , Liver/pathology , Mice, Inbred C57BL , Fatty Liver/genetics , Fatty Liver/metabolism , Fatty Liver/pathology , Diet, High-Fat/adverse effects , Gene Deletion , p38 Mitogen-Activated Protein Kinases/metabolism
2.
Am J Pathol ; 194(5): 693-707, 2024 May.
Article in English | MEDLINE | ID: mdl-38309428

ABSTRACT

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.


Subject(s)
Diabetes Mellitus , Non-alcoholic Fatty Liver Disease , Mice , Male , Humans , Animals , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Endothelial Cells/metabolism , Transcriptome , Mice, Inbred C57BL , Liver/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Liver Cirrhosis/pathology , Diabetes Mellitus/metabolism , Diabetes Mellitus/pathology , Diet, High-Fat/adverse effects
3.
Diabetes Res Clin Pract ; 208: 111090, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38216088

ABSTRACT

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.


Subject(s)
Blood Glucose , Insulin Resistance , Male , Female , Humans , Middle Aged , Blood Glucose/metabolism , Glucose Tolerance Test , Insulin , Inflammation/genetics , Biomarkers , Gene Expression
4.
Diabetes Ther ; 15(1): 269-280, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37883004

ABSTRACT

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.

5.
Diabetes ; 72(9): 1297-1306, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37343270

ABSTRACT

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.


Subject(s)
Diabetes Mellitus , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/complications , Transcriptome , Endothelial Cells , Glycated Hemoglobin , Liver Cirrhosis/genetics , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Liver/pathology , Diabetes Mellitus/pathology , Inflammation/pathology
6.
Curr Dev Nutr ; 7(4): 100051, 2023 Apr.
Article in English | MEDLINE | ID: mdl-37304843

ABSTRACT

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.

7.
Endocrinology ; 164(6)2023 04 17.
Article in English | MEDLINE | ID: mdl-37103220

ABSTRACT

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 ∼8-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.


Subject(s)
Muscular Atrophy , Proteasome Endopeptidase Complex , Mice , Male , Animals , Proteasome Endopeptidase Complex/metabolism , Mice, Obese , Muscular Atrophy/metabolism , Muscle, Skeletal/metabolism , Obesity/metabolism
8.
Am J Physiol Endocrinol Metab ; 324(6): E542-E552, 2023 06 01.
Article in English | MEDLINE | ID: mdl-36947851

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2 , Sarcopenia , Mice , Animals , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Selenoprotein P/genetics , Selenoprotein P/metabolism , Sarcopenia/metabolism , Diabetes Mellitus, Type 2/metabolism , Muscular Atrophy/genetics , Muscular Atrophy/prevention & control , Muscular Atrophy/metabolism , Muscle, Skeletal/metabolism , Tripartite Motif Proteins
9.
Mod Rheumatol ; 33(2): 422-427, 2023 Mar 02.
Article in English | MEDLINE | ID: mdl-35107137

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2 , Osteoarthritis, Knee , Osteoarthritis, Spine , Spondylosis , Male , Female , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Prevalence , Spine , Spondylosis/epidemiology
10.
J Diabetes Investig ; 14(2): 230-235, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36479595

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Humans , Blood Glucose/analysis , Drug Therapy, Combination , Glucose , Hypoglycemic Agents/therapeutic use , Metformin/pharmacology , Selenoprotein P/metabolism , Selenoprotein P/therapeutic use , Uracil/therapeutic use
11.
Clin Endocrinol (Oxf) ; 98(3): 323-331, 2023 03.
Article in English | MEDLINE | ID: mdl-36367014

ABSTRACT

OBJECTIVE: Primary aldosteronism (PA) is a major cause of secondary hypertension and is associated with chronic renal injury. The glomerular filtration rate (GFR) in PA rapidly decreases after the removal of glomerular hyperfiltration due to aldosterone excess by adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment and is stable in the long term. However, the effects of these treatments on the long-term renal function of PA patients with chronic kidney disease (CKD) is not well understood. DESIGN AND PATIENTS: In this single-center, retrospective study, acute and chronic changes in the estimated GFR (eGFR) were examined in 107 patients with PA, including 49 patients with post-treatment CKD defined as eGFR < 60 ml/min/1.73 m2 . RESULTS: The reduction in eGFR observed 1 month after ADX in the CKD group (N = 31) was -20.1 ± 8.2 ml/min/1.73 m2 . Multivariate analysis showed that pre-treatment eGFR and plasma aldosterone concentration were independent predictive factors of the acute reduction in eGFR after ADX. The reduction of eGFR observed 1 month after MRA administration in the post-treatment CKD group (N = 18) was -9.2 ± 5.9 ml/min/1.73 m2 . Multivariate analysis showed that the duration of hypertension and pre-treatment eGFR were independent predictive factors of the acute reduction in eGFR after ADX administration. In 20 patients with CKD (N = 12 ADX and N = 8 MRA) followed for more than 5 years post-treatment, there was no further significant decline in eGFR over a follow-up period of 7 (6, 8) years nor any difference between the two treatment modalities. CONCLUSIONS: Our study suggests that treatment of PA in stage 3 CKD is safe and useful in preventing renal injury.


Subject(s)
Hyperaldosteronism , Hypertension , Renal Insufficiency, Chronic , Humans , Aldosterone , Retrospective Studies , Hyperaldosteronism/complications , Hyperaldosteronism/drug therapy , Hyperaldosteronism/surgery , Glomerular Filtration Rate/physiology , Mineralocorticoid Receptor Antagonists/therapeutic use , Mineralocorticoid Receptor Antagonists/pharmacology , Hypertension/drug therapy , Hypertension/complications
12.
Diabetes Care ; 45(9): 2064-2075, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35894933

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2 , Non-alcoholic Fatty Liver Disease , Benzhydryl Compounds , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Fibrosis , Glucosides , Humans , Inflammation/complications , Liver/metabolism , Non-alcoholic Fatty Liver Disease/complications , Sulfonylurea Compounds
13.
Intern Med ; 61(24): 3693-3698, 2022 Dec 15.
Article in English | MEDLINE | ID: mdl-35650126

ABSTRACT

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.


Subject(s)
ACTH Syndrome, Ectopic , Carcinoid Tumor , Carcinoma, Neuroendocrine , Cushing Syndrome , Lung Neoplasms , Neuroendocrine Tumors , Female , Humans , Aged , Cushing Syndrome/etiology , Cushing Syndrome/complications , Receptors, Somatostatin , ACTH Syndrome, Ectopic/complications , Neuroendocrine Tumors/complications , Neuroendocrine Tumors/diagnostic imaging , Neuroendocrine Tumors/surgery , Fluorodeoxyglucose F18 , Carcinoid Tumor/surgery , Positron-Emission Tomography , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/complications , Carcinoma, Neuroendocrine/complications , Somatostatin , Lung/pathology
14.
Cell Rep ; 38(13): 110566, 2022 03 29.
Article in English | MEDLINE | ID: mdl-35354056

ABSTRACT

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.


Subject(s)
Adipose Tissue, Brown , Selenoprotein P , Adipocytes, Brown , Adipose Tissue, Brown/metabolism , Animals , Diet, High-Fat , Mice , Selenoprotein P/metabolism , Thermogenesis/physiology
15.
J Diabetes Investig ; 13(6): 965-974, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35034428

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2 , Glucagon-Like Peptide-1 Receptor , Blood Glucose , Diabetes Mellitus, Type 2/drug therapy , Glucagon-Like Peptide 1/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Glycated Hemoglobin/analysis , Humans , Hyperglycemia/prevention & control , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Liraglutide/therapeutic use
16.
J Diabetes Investig ; 13(3): 532-542, 2022 Mar.
Article in English | MEDLINE | ID: mdl-34670012

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 2 , Dyslipidemias , Insulin Resistance , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dyslipidemias/complications , Dyslipidemias/metabolism , Eicosapentaenoic Acid , Humans , Insulin/metabolism , Insulin Resistance/physiology , Liver/metabolism , Selenoprotein P/metabolism
17.
Endocr J ; 67(11): 1099-1105, 2020 Nov 28.
Article in English | MEDLINE | ID: mdl-32641618

ABSTRACT

Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200-300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor. We noticed that her serum sitosterol and campesterol levels were relatively high. Targeted analysis sequencing identified a novel heterozygous ABCG5 variant (c.203A>T; p.Ile68Asn) in the patient, whereas no mutations were found in low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), or Niemann-Pick C1-like intracellular cholesterol transporter 1 (NPC1L1). While sitosterolemia is a rare disease, a recent study has reported that the incidence of loss-of-function mutation in the ABCG5 or ABCG8 gene is higher than we thought at 1 in 220 individuals. The present case suggests that serum plant sterol levels should be examined and ezetimibe treatment should be considered in patients with hypercholesterolemia who are resistant to HMG-CoA reductase inhibitors.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , Anticholesteremic Agents/therapeutic use , Ezetimibe/therapeutic use , Hypercholesterolemia/drug therapy , Intestinal Diseases/drug therapy , Lipid Metabolism, Inborn Errors/drug therapy , Lipoproteins/genetics , Phytosterols/adverse effects , Cholesterol/analogs & derivatives , Cholesterol/blood , Cholesterol, LDL/blood , Diagnostic Errors , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/diagnosis , Hypercholesterolemia/genetics , Hyperlipoproteinemia Type II/diagnosis , Intestinal Diseases/diagnosis , Intestinal Diseases/genetics , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Loss of Function Mutation , Middle Aged , Phytosterols/blood , Phytosterols/genetics , Sitosterols/blood , Treatment Failure
18.
Eur J Endocrinol ; 181(1): 69-78, 2019 Jul 01.
Article in English | MEDLINE | ID: mdl-31096184

ABSTRACT

OBJECTIVE: The pathophysiology of aldosterone-producing adenomas (APAs) has been intensively investigated using genetic and epigenetic approaches. However, the role of miRNAs in APA is not fully understood. The present study profiled miRNAs in APAs as an exploratory approach to elucidate their pathophysiological roles in APAs. DESIGN: Tissues of APAs and other adrenocortical adenomas were obtained from patients who underwent adrenalectomy. METHODS: Candidate miRNAs differentially detected from samples were examined by whole miRNA sequencing. The expression of candidate miRNAs in APA tissues were further validated by real-time quantitative polymerase chain reaction (qPCR). Further, differential miRNA expression between APAs with and without KCNJ5 somatic mutations was examined. Prediction of miRNA target genes was performed by bioinformatics analysis. For specific miRNAs, correlation analysis between the levels of their target genes and CYP11B2 was analyzed in APA tissues. RESULTS: Our study determined differential expression of six miRNAs in APA or APA with KCNJ5 mutations. We further demonstrated that miR299 levels were negatively correlated with mRNA levels of CACNB2, which encodes the beta-subunit of the L-type calcium channel. Additionally, we found significant correlations among miR299, CACNB2, and CYP11B2 levels in APA tissues. CONCLUSIONS: Our study suggests the possible pathophysiological involvement of specific miRNAs in calcium signaling and aldosterone hypersecretion in APAs. Further studies, including in vitro analyses, are required to clarify these findings.


Subject(s)
Adrenocortical Adenoma/genetics , Aldosterone/biosynthesis , Cytochrome P-450 CYP11B2/genetics , Gene Expression Profiling , MicroRNAs/physiology , Adrenalectomy , Adrenocortical Adenoma/metabolism , Aged , Calcium Channels, L-Type/genetics , Female , G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics , Gene Expression/physiology , Humans , Male , MicroRNAs/analysis , Middle Aged , Mutation , RNA, Messenger/analysis , Real-Time Polymerase Chain Reaction
19.
Case Rep Endocrinol ; 2019: 5986014, 2019.
Article in English | MEDLINE | ID: mdl-30867970

ABSTRACT

Refractory hypothyroidism is caused by decreased gut absorption, increased metabolism, and poor compliance. Previous studies suggested that the weekly oral, suppository, or intramuscular administration of levothyroxine (LT4) is an effective treatment for refractory hypothyroidism. However, limited information is currently available on treatment involving the weekly intravenous administration of LT4. We managed a case of refractory hypothyroidism due to poor compliance, for which, by weekly intravenous LT4 administration, LT4 was intravenously administered weekly at a dose of 300 µg without any adverse effects such as acute ischemic heart diseases or liver dysfunction and effectively maintained the euthyroid status for 14 months. The weekly oral administration of LT4 (700 µg) was also safely performed and was as effective as its intravenous administration. We herein present precise clinical course of the present case including pharmacokinetic data during the weekly intravenous and oral administration of LT4 and discuss the safety and efficacy of the treatments.

20.
Int J Urol ; 26(2): 273-277, 2019 02.
Article in English | MEDLINE | ID: mdl-30467902

ABSTRACT

OBJECTIVES: To determine the incidence and preoperative risk factors of post-excisional hypoglycemia in patients undergoing pheochromocytoma resection. METHODS: Patients who underwent surgical resection of pheochromocytoma at a single institution were retrospectively enrolled in the present study. The primary end-point was the development of post-excisional hypoglycemia; that is, a serum glucose level <70 mg/dL. The serum levels of immunoreactive insulin and glucose levels during the preoperative oral glucose-tolerance test and surgery were analyzed to elucidate the mechanism of hypoglycemia. RESULTS: A total of 49 patients underwent surgical resection of pheochromocytoma, of which 21 patients (43%) developed post-excisional hypoglycemia. The incidence of hypoglycemia was not statistically different between patients with adrenal tumors and those with extra-adrenal tumors (18/41 [44%] vs 3/8 [38%], respectively, P = 0.73). There was no difference in the immunoreactive insulin/glucose ratio during the preoperative oral glucose-tolerance test between patients with and those without post-excisional hypoglycemia. The intraoperative immunoreactive insulin/glucose ratio was significantly higher in patients with hypoglycemia than in those without hypoglycemia. A higher 24-h urinary epinephrine level, but not norepinephrine level, was a predictive factor for post-excisional hypoglycemia. CONCLUSIONS: Post-excisional hypoglycemia is a frequent complication of pheochromocytoma resection, irrespective of the tumor location, and might be common in patients with epinephrine-predominant tumors. All patients undergoing resection of adrenal and extra-adrenal pheochromocytoma require intensive monitoring of serum glucose levels during and after surgery.


Subject(s)
Adrenal Gland Neoplasms/surgery , Adrenalectomy/adverse effects , Hypoglycemia/epidemiology , Pheochromocytoma/surgery , Postoperative Complications/epidemiology , Adolescent , Adrenal Gland Neoplasms/urine , Adult , Aged , Blood Glucose , Epinephrine/urine , Female , Humans , Hypoglycemia/blood , Hypoglycemia/diagnosis , Hypoglycemia/etiology , Incidence , Male , Middle Aged , Norepinephrine/urine , Perioperative Period , Pheochromocytoma/urine , Postoperative Complications/blood , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Prognosis , Retrospective Studies , Risk Factors , Treatment Outcome , Young Adult
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