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Gastric mucins serve as a protective barrier on the stomach's surface, protecting from external stimuli including gastric acid and gut microbiota. Their composition typically changes in response to the metaplastic sequence triggered by Helicobacter pylori infection. This alteration in gastric mucins is also observed in cases of gastric cancer, although the precise connection between mucin expressions and gastric carcinogenesis remains uncertain. This review first introduces the relationship between mucin expressions and gastric metaplasia or cancer observed in humans and mice. Additionally, we discuss potential pathogenic mechanisms of how aberrant mucins and their glycans affect gastric carcinogenesis. Finally, we summarize challenges to target tumor-specific glycans by utilizing lectin-drug conjugates that can bind to specific glycans. Understanding the correlation and mechanism between these mucin expressions and gastric carcinogenesis could pave the way for new strategies in gastric cancer treatment.
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BACKGROUND & AIMS: Potassium-competitive acid blockers (PCABs) have been increasingly used to treat upper gastrointestinal disorders, replacing proton pump inhibitors (PPIs). Whereas PPIs are associated with an increased risk of gastric cancer (GC) after Helicobacter pylori (Hp) eradication, it is uncertain whether PCABs carry the same risk. METHODS: Using a population-based claims database in Japan, we identified patients who were prescribed a clarithromycin-based first regimen of Hp eradication between 2015 and 2018. Patients who failed this regimen and those diagnosed with GC before or within 1 year after Hp eradication were excluded. We compared GC incidence between PCAB users and histamine type-2 receptor antagonist (H2RA) users, matching them on the basis of propensity scores calculated with considerations for age, sex, smoking, alcohol consumption, comorbidities, and co-administered medications. PCABs included only vonoprazan in this study. RESULTS: Among 54,055 patients, 568 (1.05%) developed GC during the follow-up period (mean, 3.65 years). The cumulative incidence of GC was 1.64% at 3 years, 2.02% at 4 years, and 2.36% at 5 years in PCAB users and 0.71% at 3 years, 1.04% at 4 years, and 1.22% at 5 years in H2RA users. The use of PCABs was associated with a higher GC risk (matched hazard ratio, 1.92; 95% confidence interval, 1.13-3.25; P = .016). Longer PCAB use and high-dose PCAB use were significantly associated with higher incidence of GC. Sensitivity analyses showed the risk of GC incidence among PCAB users was comparable with that of PPI users. CONCLUSIONS: The use of PCABs was associated with an increased risk of GC among Hp-eradicated patients, with duration/dose response effects.
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Infecções por Helicobacter , Inibidores da Bomba de Prótons , Pirróis , Neoplasias Gástricas , Sulfonamidas , Humanos , Masculino , Feminino , Neoplasias Gástricas/epidemiologia , Infecções por Helicobacter/complicações , Pessoa de Meia-Idade , Japão/epidemiologia , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Idoso , Incidência , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Helicobacter pylori , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Estudos Retrospectivos , Adulto , Medição de Risco , Fatores de Risco , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêuticoRESUMO
Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3'-phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B4 (LTB4) levels in plasma and in adipose tissue as well as the expression of 5-lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB4 receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4 production through down-regulation of 5-LO expression via the PDK1-FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB4 via the PDK1-FoxO1 pathway and thereby maintains systemic insulin sensitivity.
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Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Adipócitos/metabolismo , Araquidonato 5-Lipoxigenase/metabolismo , Proteína Forkhead Box O1 , Resistência à Insulina , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Animais , Células Cultivadas , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Leucotrieno B4/metabolismo , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/genéticaRESUMO
In addition to ligation of the T cell antigen receptor (TCR), activation of the CD28 coreceptor by the costimulatory molecule B7 is required for induction of the transcription factor NF-kappaB and robust T cell activation, although the contribution of CD28 to this process remains incompletely understood. We show here that phosphoinositide-dependent kinase 1 (PDK1) is essential for integrating the TCR and CD28 signals. After we deleted PDK1 from T cells, TCR-CD28 signals were unable to induce activation of NF-kappaB or phosphorylation of protein kinase C-theta, although T cell survival and pathways dependent on the kinases p38 and Jnk or the transcription factor NFAT were unaffected. CD28 facilitated NF-kappaB activation by regulating recruitment and phosphorylation of PDK1, which are necessary for efficient binding of PDK1 to protein kinase C-theta and the adaptor CARMA1 and thus for NF-kappaB induction.
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Antígenos CD28/imunologia , Ativação Linfocitária/imunologia , NF-kappa B/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Antígenos CD28/metabolismo , Sobrevivência Celular , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunoprecipitação , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , NF-kappa B/metabolismo , Fosforilação , Proteína Quinase C-delta/imunologia , Proteína Quinase C-delta/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/metabolismoRESUMO
Immunoprecipitation with autoantibodies to the insulin receptor derived from patients with extreme insulin resistance and acanthosis nigricans revealed that the receptor is comprised of two subunits of 135 kDa (α subunit) and 95 kDa (ß subunit) and that insulin induces the rapid phosphorylation of the ß subunit in intact cells. Incubation of a highly purified insulin receptor preparation with [γ-32P]ATP also resulted in tyrosine phosphorylation of the ß subunit in an insulin-dependent manner, suggesting that the receptor itself is a tyrosine-specific protein kinase. Furthermore, a Japanese boy with insulin resistance and acanthosis nigricans was found to be heterozygous for a mutation of the insulin receptor gene that resulted in the replacement of glycine-996 with valine in the ATP binding site of the receptor. Expression of the mutant receptor in cultured cells revealed it to be deficient in tyrosine kinase activity and mediation of insulin action, suggesting that the tyrosine kinase activity of the insulin receptor is essential for insulin action in vivo.
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Receptor de Insulina/química , Receptor de Insulina/metabolismo , Trifosfato de Adenosina/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Humanos , Insulina/metabolismo , Resistência à Insulina , Mutação , Fosforilação , Ligação Proteica , Proteínas Tirosina Quinases/metabolismo , Receptor de Insulina/genética , Tirosina/químicaRESUMO
Genetic factors are important determinants of the onset and progression of diabetes mellitus. Numerous susceptibility genes for type 2 diabetes, including potassium voltage-gated channel, KQT-like subfamily Q, member1 (KCNQ1), have been identified in humans by genome-wide analyses and other studies. Experiments with genetically modified mice have also implicated various genes in the pathogenesis of diabetes. However, the possible effects of the parent of origin for diabetes susceptibility alleles on disease onset have remained unclear. Here, we show that a mutation at the Kcnq1 locus reduces pancreatic ß-cell mass in mice by epigenetic modulation only when it is inherited from the father. The noncoding RNA KCNQ1 overlapping transcript1 (Kcnq1ot1) is expressed from the Kcnq1 locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption of Kcnq1 results in reduced Kcnq1ot1 expression as well as the increased expression of cyclin-dependent kinase inhibitor 1C (Cdkn1c), an imprinted gene that encodes a cell cycle inhibitor, only when the mutation is on the paternal allele. Furthermore, histone modification at the Cdkn1c promoter region in pancreatic islets was found to contribute to this phenomenon. Our observations suggest that the Kcnq1 genomic region directly regulates pancreatic ß-cell mass and that genomic imprinting may be a determinant of the onset of diabetes mellitus.
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Inibidor de Quinase Dependente de Ciclina p57/genética , Epigênese Genética , Células Secretoras de Insulina/metabolismo , Canal de Potássio KCNQ1/genética , Mutação , Alelos , Animais , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Expressão Gênica , Impressão Genômica/genética , Glucose/farmacologia , Teste de Tolerância a Glucose , Immunoblotting , Padrões de Herança , Insulina/sangue , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Canal de Potássio KCNQ1/metabolismo , Masculino , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
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Diabetes Mellitus Tipo 2/genética , Canal de Potássio KCNQ1/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático/genética , Mapeamento Cromossômico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Células Secretoras de Insulina/fisiologia , População BrancaRESUMO
The Japan Diabetes Society/Japanese Cancer Association Joint Committee on Diabetes and Cancer published its first report in July 2013 on the epidemiological assessment of the associations of diabetes with cancer risk/prognosis, the common risk factors for diabetes and cancer, and cancer risk associated with diabetes treatment. The Joint Committee continued its work to assess the role of glycemic control in the development of cancer in patients with diabetes. This review shows that high-quality evidence examining the association between glycemic control and cancer risk is lacking.
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Diabetes Mellitus Tipo 2/epidemiologia , Neoplasias/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Incidência , Japão/epidemiologia , Neoplasias/etiologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
UNLABELLED: The liver has robust regenerative potential in response to damage, but hepatic steatosis (HS) weakens this potential. We found that the enhanced integrated stress response (ISR) mediated by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α) impairs regeneration in HS and that growth arrest and DNA damage-inducible 34 (Gadd34)-dependent suppression of ISR plays a crucial role in fatty liver regeneration. Although mice fed a high-fat diet for 2 weeks developed moderate fatty liver with no increase in eIF2α phosphorylation before 70% hepatectomy, they showed impaired liver regeneration as a result of reduced proliferation and increased death of hepatocytes with increased phosphorylation of eIF2α and ISR. An increased ISR through Gadd34 knockdown induced C/EBP homologous protein (CHOP)-dependent apoptosis and receptor-interacting protein kinase 3-dependent necrosis, resulting in increased hepatocyte death during fatty liver regeneration. Furthermore, Gadd34 knockdown and increased phosphorylation of eIF2α decreased cyclin D1 protein and reduced hepatocyte proliferation. In contrast, enhancement of Gadd34 suppressed phosphorylation of eIF2α and reduced CHOP expression and hepatocyte apoptosis without affecting hepatocyte proliferation, clearly improving fatty liver regeneration. In more severe fatty liver of leptin receptor-deficient db/db mice, forced expression of hepatic Gadd34 also promoted hepatic regeneration after hepatectomy. CONCLUSION: Gadd34-mediated regulation of ISR acts as a physiological defense mechanism against impaired liver regeneration resulting from steatosis and is thus a possible therapeutic target for impaired regeneration in HS.
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Fígado Gorduroso , Regeneração Hepática/fisiologia , Proteína Fosfatase 1/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The total mass of islets of Langerhans is reduced in individuals with type 2 diabetes, possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 receptors, insulin receptor substrate and phosphatidylinositol (PI) 3-kinase. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. Here we show that mice that lack PDK1 specifically in pancreatic beta cells (betaPdk1-/- mice) develop progressive hyperglycemia as a result of a loss of islet mass. The mice show reductions in islet density as well as in the number and size of cells. Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not the size, of cells and resulted in the restoration of glucose homeostasis in betaPdk1-/- mice. These results suggest that PDK1 is important in maintenance of pancreatic cell mass and glucose homeostasis.
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Diabetes Mellitus Experimental/genética , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Camundongos , Camundongos Knockout , Transdução de SinaisRESUMO
To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.
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Anquirinas/genética , Povo Asiático/genética , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Células Cultivadas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , JapãoRESUMO
PURPOSE: Although the rate of diabetic retinopathy (DR)-related blindness has decreased in developed countries in recent years, the reasons for this decrease have remained unclear. The prevalence/severity trends of DR at the first visit in patients with untreated type 2 diabetes mellitus (T2DM) patients seen between the1986s and 2018s were assessed. METHODS: A total of 1979 Japanese T2DM patients diagnosed between 1986 and 2018 were divided into four groups by the decade of their first visit: the 1986 years (1986-1987), the 1996 years (1996-1997), the 2006 years (2006-2008), the 2016 years (2016-2018). The DR prevalence/severity trends were assessed. RESULTS: A significant decrease in the rate of prevalence of DR from the 1986s to 2016s was observed among previously untreated T2DM patients visiting our hospital for the first time (1986s: 25.5%; 1996s: 26.2%; 2006s: 22.2%; and 2016s: 15.6%). The prevalence was significantly higher in females (30.2%) than in males (21.3%). Although the severity trend of DR did not differ significantly among the four measurement years, the rate of simple DR was the highest in the 2016s. CONCLUSION: We found, for the first time, a significant decrease in the rate of prevalence of DR from the 1986s to 2016s in patients with untreated T2DM visiting our hospital for the first time. A decrease in the rate of DR prevalence could explain, at least in part, the observed reduction in the rate of blindness in patients with T2DM.
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BACKGROUND: Previous studies demonstrate an association between metabolic factors and Helicobacter pylori-related gastric cancer. However, the association of gastric atrophy or intestinal metaplasia (IM) with these factors remains unknown. METHODS: Data on 1603 Helicobacter pylori-positive patients who underwent esophagogastroduodenoscopy between 2001 and 2021 were evaluated. The outcome measures were endoscopic atrophy, IM grade, and the incidence of endoscopically diagnosed and pathologically confirmed gastric neoplasms. Clinical factors associated with these findings were also determined. RESULTS: Advanced age; successful Helicobacter pylori eradication; and comorbidities including diabetes mellitus (DM), hypertension, dyslipidemia, and fib4 index were significantly associated with endoscopic gastric atrophy grade. Male sex; advanced age; and comorbidities including DM, hypertension, dyslipidemia, hyperuricemia, fatty liver, aortic calcification, and fib4 index were also significantly associated with endoscopic IM grade, whereas advanced age, successful Helicobacter pylori eradication, DM, fatty liver, and fib4 index were significantly associated with the incidence of gastric neoplasms. CONCLUSION: Several metabolic disorders, including DM, hypertension, dyslipidemia, hyperuricemia, and fatty liver disease, are risk factors for advanced-grade gastric atrophy, intestinal metaplasia, and gastric neoplasms. Risk stratification according to these factors, particularly those with metabolic disorders, would affect EGD surveillance for Helicobacter pylori-positive patients.
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BACKGROUND AND AIM: The diagnostic accuracy for cholangiocarcinoma (CCA) is inadequate, necessitating the exploration of novel diagnostic approaches. Protoporphyrin IX (Pp IX), a metabolic product of 5-aminolevulinic acid (5-ALA), emits red fluorescence upon blue light exposure. Because it accumulates selectively in cancer cells, photodynamic diagnosis using 5-ALA (5-ALA-PDD) has been integrated into clinical practice for diverse cancer types. Nevertheless, there is currently no device capable of capturing Pp IX-derived fluorescence for real-time 5-ALA-PDD within the biliary tract, largely due to challenges in device miniaturization. METHODS: To investigate the feasibility of real-time 5ALA-PDD in CCA, we developed two essential components of the cholangioscopy system: a small-diameter flexible camera and a light guide for emitting blue light. We evaluated the detectability of Pp IX fluorescence using these devices in experimental gels and animal models. RESULTS: Our camera and light guide were smoothly inserted into the lumen of existing cholangioscopes. Incorporating a long-pass filter at the camera tip enabled efficient detection of red fluorescence without significantly impacting white-light observation. The integration of these devices facilitated clear visualization of red fluorescence from gels containing Pp IX at concentrations of 5 µM or higher. Additionally, when observing subcutaneous human CCA tumor models in nude mice treated with 5-ALA, we successfully demonstrated distinct red fluorescence from Pp IX accumulation in tumors compared to peritumoral subcutaneous areas. CONCLUSION: The integration of our device combination holds promise for real-time 5-ALA-PDD in human CCA, potentially enhancing the diagnostic accuracy for this complex condition.
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Obesity is among the risk factors for male infertility. Although several mechanisms underlying obesity-induced male subfertility have been reported, the entire mechanism of obesity-induced male infertility still remains unclear. Here, we show that sperm count, sperm motility and sperm fertilizing ability were decreased in male mice fed a high-fat diet and that the expression of the AdipoR1 gene and protein was decreased, and the expression of pro-apoptotic genes and protein increased, in the testis from mice fed a high-fat diet. Moreover, we demonstrate that testes weight, sperm count, sperm motility and sperm fertilizing ability were significantly decreased in AdipoR1 knockout mice compared to those in wild-type mice; furthermore, the phosphorylation of AMPK was decreased, and the expression of pro-apoptotic genes and proteins, caspase-6 activity and pathologically apoptotic seminiferous tubules were increased, in the testis from AdipoR1 knockout mice. Furthermore, study findings show that orally administrated AdipoRon decreased caspase-6 activity and apoptotic seminiferous tubules in the testis, thus ameliorating sperm motility in male mice fed a high-fat diet. This was the first study to demonstrate that decreased AdipoR1/AMPK signaling led to increased caspase-6 activity/increased apoptosis in the testis thus likely accounting for male infertility.
Assuntos
Proteínas Quinases Ativadas por AMP , Infertilidade Masculina , Animais , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Caspase 6/metabolismo , Infertilidade Masculina/etiologia , Infertilidade Masculina/metabolismo , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Sêmen , Motilidade dos Espermatozoides , Espermatozoides/metabolismo , Testículo/metabolismoRESUMO
BACKGROUND AND AIMS: There is a lack of biliary epithelial molecular markers for primary sclerosing cholangitis (PSC). We analyzed candidates from disease susceptibility genes identified in recent genome-wide association studies (GWAS). METHODS: Expression levels of GWAS genes were analyzed in archival liver tissues of patients with PSC and controls. Immunohistochemical analysis was performed to evaluate expression levels in the biliary epithelia of PSC (N = 45) and controls (N = 12). Samples from patients with primary biliary cholangitis (PBC) were used as disease controls (N = 20). RESULTS: Hepatic expression levels of ATXN2, HHEX, PRDX5, MST1, and TNFRSF14 were significantly altered in the PSC group. We focused on the immune-related receptor, TNFRSF14. Immunohistochemistry revealed that high expression of TNFRSF14 in biliary epithelial cells was observed only in the PSC group. In addition, the expression of LIGHT, which encodes a TNFRSF14-activating ligand, was increased in PSC liver. Immunohistochemistry showed that high expression of LIGHT was more common in PSC biliary epithelia (53%) than in the PBC (15%) or control (0%) groups; moreover, it was positively associated with fibrotic progression, although it was not an independent prognostic factor. CONCLUSIONS: TNFRSF14 and LIGHT are promising candidate markers for PSC.
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Sistema Biliar , Colangite Esclerosante , Cirrose Hepática Biliar , Humanos , Colangite Esclerosante/genética , Colangite Esclerosante/patologia , Células Epiteliais , Estudo de Associação Genômica Ampla , Fígado/patologia , Cirrose Hepática Biliar/patologia , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismoRESUMO
The transcriptional coactivator PGC-1α has been implicated in the regulation of multiple metabolic processes. However, the previously reported metabolic phenotypes of mice deficient in PGC-1α have been inconsistent. PGC-1α exists as multiple isoforms, including variants transcribed from an alternative first exon. We show here that alternative PGC-1α variants are the main entity that increases PGC-1α during exercise. These variants, unlike the canonical isoform of PGC-1α, are robustly upregulated in human skeletal muscle after exercise. Furthermore, the extent of this upregulation correlates with oxygen consumption. Mice lacking these variants manifest impaired energy expenditure during exercise, leading to the development of obesity and hyperinsulinemia. The alternative variants are also upregulated in brown adipose tissue in response to cold exposure, and mice lacking these variants are intolerant of a cold environment. Our findings thus indicate that an increase in PGC-1α expression, attributable mostly to upregulation of alternative variants, is pivotal for adaptive enhancement of energy expenditure and heat production and thereby essential for the regulation of whole-body energy metabolism.
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Tecido Adiposo Marrom , Processamento Alternativo , Metabolismo Energético , Músculo Esquelético , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Metabolismo Energético/genética , Animais , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Humanos , Camundongos , Processamento Alternativo/genética , Masculino , Músculo Esquelético/metabolismo , Tecido Adiposo Marrom/metabolismo , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Obesidade/metabolismo , Obesidade/genética , Termogênese/genética , Consumo de Oxigênio , Exercício Físico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Adulto , Camundongos KnockoutRESUMO
In recent years, diabetes has been shown to be associated with cancer risk, and this has led to a joint committee being formed, enlisting experts from the Japan Diabetes Society and the Japanese Cancer Association to address this issue. Epidemiological data in Japan provides evidence to demonstrate that diabetes is associated with increased risk for cancers, especially colorectal, liver, and pancreatic cancers. The mechanisms through which diabetes is assumed to promote oncogenesis include insulin resistance and associated hyperinsulinemia, hyperglycemia, and inflammation. Common risk factors for type 2 diabetes and cancer include aging, male sex, obesity, physical inactivity, inappropriate diet (excessive red/processed meat intake, inadequate vegetable/fruit/dietary fiber intake), excessive alcohol drinking, and smoking. Given that inappropriate diet/exercise, smoking and excessive alcohol drinking are common risk factors for diabetes and cancer, diet/exercise therapy, smoking cessation and alcohol moderation may be associated with decreased risk for cancer in diabetic patients. There is as yet limited evidence as to whether any particular antidiabetic agents may influence cancer risk.
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Diabetes Mellitus Tipo 2/epidemiologia , Neoplasias/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Metanálise como Assunto , Fatores de RiscoRESUMO
Recent advances in genome research have enabled the identification of new genomic variations that are associated with type 2 diabetes mellitus (T2DM). Via fine mapping of SNPs in a candidate region of chromosome 21q, the current study identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the beta cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals in three independent Japanese sample sets (p = 2.5 x 10(-7), odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76-3.67) and with unstratified T2DM (p = 6.7 x 10(-6), OR = 1.76, 95% CI = 1.37-2.25). The diabetes risk allele frequency was, however, very low among Europeans in whom no association between this variant and T2DM could be shown. Functional analysis in human embryonic kidney 293 cells demonstrated that the risk allele of the synonymous SNP in exon 4 increased KCNJ15 expression via increased mRNA stability, which resulted in the higher expression of protein as compared to that of the nonrisk allele. We also showed that KCNJ15 is expressed in human pancreatic beta cells. In conclusion, we demonstrated a significant association between a synonymous variant in KCNJ15 and T2DM in lean Japanese patients with T2DM, suggesting that KCNJ15 is a previously unreported susceptibility gene for T2DM among Asians.
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Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Adulto , Idoso , Povo Asiático , Estudos de Casos e Controles , Cromossomos Humanos Par 21 , Feminino , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Chemerin, a recently discovered adipocytokine plays an important role in obesity and obesity-associated metabolic complications. However, the role of chemerin in the pathogenesis of type 2 diabetes mellitus (T2DM) has not fully been elucidated. We compared the serum chemerin levels and metabolic parameters between 88 control subjects, 86 patients with metabolic syndrome (MS), and 147 patients with T2DM in a Japanese population and further analyzed their correlation. Enzyme-linked immunosorbent assay was used to measure the serum chemerin levels. The chemerin levels were significantly higher in male than in female control subjects (p < 0.005), with significant decreases in patients with T2DM compared with those with MS and control subjects (164.9 ± 6.3 ng/mL vs. 209.8 ± 7.7 and 218.7 ± 7.3 ng/mL; p < 0.0001 vs. p < 0.0001, respectively) but no significant differences in female subjects. The multiple regression analysis revealed that the chemerin levels negatively correlated with the fasting glucose and HbA1c levels in total and male subjects. In the patients with T2DM, the chemerin levels negatively correlated with fasting glucose and high-density lipoprotein cholesterol but positively correlated with body mass index (BMI), and total cholesterol and triglyceride levels. The negative correlation between the chemerin and fasting glucose levels remained significant after adjustment for age, sex, and BMI in the total and male subjects and those with T2DM. These results suggest the role of chemerin in sex dimorphism and a potential link between chemerin levels and T2DM pathogenesis in a Japanese population.