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Metabolic dysfunction-associated steatotic liver disease affects millions of people worldwide. Progress towards a definitive cure has been incremental and treatment is currently limited to lifestyle modification. Hepatocyte-specific lipid accumulation is the main trigger of lipotoxic events, driving inflammation and fibrosis. The underlying pathology is extraordinarily heterogenous, and the manifestations of steatohepatitis are markedly influenced by metabolic communications across non-hepatic organs. Synthetic human tissue models have emerged as powerful platforms to better capture the mechanistic diversity in disease progression, while preserving person-specific genetic traits. In this review, we will outline current research efforts focused on integrating multiple synthetic tissue models of key metabolic organs, with an emphasis on organoid-based systems. By combining functional genomics and population-scale en masse profiling methodologies, human tissues derived from patients can provide insights into personalised genetic, transcriptional, biochemical, and metabolic states. These collective efforts will advance our understanding of steatohepatitis and guide the development of rational solutions for mechanism-directed diagnostic and therapeutic investigation.
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Doenças do Sistema Digestório , Fígado Gorduroso , Gastroenterologia , Hepatopatias , Doenças Metabólicas , Humanos , Hepatopatias/genética , Hepatopatias/terapia , OrganoidesRESUMO
INTRODUCTION: Small fibre neuropathy (SFN) is an early manifestation of diabetic polyneuropathy. Although oxidative stress, inflammation and change of intestinal bacterial population are assumed to be their pathogenesis, the effects of dietary nutrition have not been evaluated. The relationship between dietary nutrition intake and pain sensation was evaluated in the Japanese population. METHODS: We conducted the Iwaki project, a population-based study recruiting 1,028 individuals, in 2018. The relationships between the pain threshold from intraepidermal electrical stimulation (PINT) and the amount of dietary nutrition evaluated by a brief-type self-administered diet history questionnaire were examined. The odds ratio was further explored after categorizing subjects based on low (< 63.7 µg/day), intermediate (63.7-159.2 µg/day), and high cryptoxanthin levels (> 159.2 µg/day). RESULTS: Univariate linear regression analyses showed significant correlations between PINT and cryptoxanthin intake even after adjustments for other nutritional intakes (ß = 0.107, p < 0.01). Multivariate logistic regression analysis revealed low and high cryptoxanthin intake as significant risk factors for abnormal PINT (≥ 0.20 mA). Multivariate linear regression analyses showed significant correlations between PINT and cryptoxanthin intake levels after adjustment for other clinically PINT-related factors (ß = 0.09, p < 0.01). CONCLUSIONS: Adequate intake of cryptoxanthin is recommended to maintain the pain threshold in the Japanese population.
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Small fibre neuropathy (SFN) is an initial pathology of diabetic polyneuropathy (DPN). Serum lipopolysaccharide binding protein levels are positively correlated with the pain threshold in the foot, suggesting that the abundance of gut Gram-negative bacilli, which are a source of lipopolysaccharides, may be involved in the development of DPN. Furthermore, the abundance of the gut and oral microbiota is assumed to be involved in the pathogenesis of diabetes. Nevertheless, the association between SFN and the microbiota has not been clarified. A total of 1056 individuals were recruited in the 2018 Iwaki Health Promotion Project. Pain sensation was evaluated based on the pain threshold from intraepidermal electrical stimulation (PINT). Patients with PINT scores <0.15 mA were categorized into the low-PINT group (n = 718); otherwise, they were categorized into the high-PINT group (n = 283). Furthermore, each group was divided into the subjects with or without glucose tolerance based on HbA1c levels, fasting blood glucose levels and diabetic history. Principal coordinate analysis and α- and ß-diversity of the microbiota were evaluated. The correlation between clinical and microbiota data was examined. Oral microbiota diversity showed no structural differences according to PINT scores, whereas principal coordinate analysis and α- and ß-diversity revealed significant structural differences in gut microbiota (p < 0.01, p < 0.05 and p < 0.05, respectively), even after the participants with glucose intolerance were excluded (p < 0.01, p < 0.05 and p < 0.05, respectively). The relative abundance of the genus Bacteroides was significantly lower in high-PINT participants compared with low-PINT participants (10 ± 6.7% vs. 11.3 ± 7.0%, p < 0.01), even after the exclusion of subjects with diabetes and impaired fasting glucose (10.0 ± 6.5% vs. 11.2 ± 6.9%, p < 0.05). In univariate linear regression analyses, PINT was significantly correlated with metabolic syndrome parameters, eGFR, uric acid level and the abundance of Bacteroides. The correlation between Bacteroides and PINT scores remained significant after adjustment for multiple factors (ß = -0.07181, p < 0.05). Changes of bacterial diversity and a low abundance of gut Bacteroides were correlated with elevated PINT scores in the Japanese population. This correlation may represent a new therapeutic option for SFN.
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Neuropatias Diabéticas , Microbioma Gastrointestinal , Humanos , Bacteroides , Glicemia , Hemoglobinas Glicadas , Japão , Lipopolissacarídeos , Limiar da Dor , Ácido ÚricoRESUMO
Autophagy is known to play a pivotal role in ß-cell function. While the lifelong inhibition of autophagy through Atg7 deletion in ß cells has been demonstrated to lead to impaired glucose tolerance together with ß-cell dysfunction, the temporal association between autophagy inhibition and ß-cell dysfunction remains unclear. To address such questions, inducible ß-cell-specific Atg7-knockout (ißAtg7KO) mice were generated, and autophagy inhibition was induced for two different time durations. Whereas 2 weeks of Atg7 ablation was sufficient to induce autophagy deficiency, confirmed by the accumulation of p62, ißAtg7KO mice exhibited normal glucose tolerance. In contrast, prolonged autophagy deficiency for 6 weeks resulted in glucose intolerance together with impaired insulin secretion. Direct mRNA sequencing and pathway analysis revealed that the gene set associated with insulin secretion was downregulated only after the 6-week prolonged autophagy inhibition. Furthermore, we identified a novel gene, Sprr1a, which was expressed at more than 50-fold higher levels during both the 2-week and 6-week autophagy inhibition. These findings suggest that autophagy insufficiency cumulatively leads to ß-cell failure after a certain interval, accompanied by stepwise alterations of gene expression patterns.
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Intolerância à Glucose , Células Secretoras de Insulina , Animais , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos KnockoutRESUMO
Inflammation and oxidative stress contribute to the pathophysiology of diabetic neuropathy. According to recent evidence, the modulation of macrophage polarization in peripheral nerves represents a potential therapeutic target for diabetic neuropathy. Xanthine oxidase, which is a form of xanthin oxidoreductase, is the rate-limiting enzyme that catalyzes the degradation of hypoxanthine and xanthine into uric acid. Activation of xanthine oxidase promotes oxidative stress and macrophage activation. A preclinical study reported the beneficial effects of xanthine oxidase inhibitors on peripheral nerve dysfunction in experimental models of diabetes. However, the detailed mechanisms remain unknown. In this study, we examined the effect of the xanthine oxidase inhibitor topiroxostat on macrophage polarization and peripheral neuropathy in an obese diabetic model, db/db mice. First, the effects of xanthine oxidase inhibitors on cultured macrophages and dorsal root ganglion neurons exposed to xanthine oxidase were assessed. Furthermore, five-week-old db/db mice were administered the xanthine oxidase inhibitors topiroxostat [1 mg/kg/day (dbT1) or 2 mg/kg/day (dbT2)] or febuxostat [1 mg/kg (dbF)]. Glucose metabolism and body weight were evaluated during the experimental period. At 4 and 8 weeks of treatment, peripheral nerve functions such as nerve conduction velocities, thermal thresholds and pathology of skin and sciatic nerves were evaluated. The mRNA expression of molecules related to inflammation and oxidative stress was also measured in sciatic nerves. Untreated db/db mice and the nondiabetic db strain (db/m) were studied for comparison. An in vitro study showed that topiroxostat suppressed macrophage activation and proinflammatory but not anti-inflammatory polarization, and prevented the reduction in neurite outgrowth from neurons exposed to xanthine oxidase. Neuropathic changes exemplified by delayed nerve conduction and reduced intraepidermal nerve fiber density developed in db/db mice. These deficits were significantly prevented in the treated group, most potently in dbT2. Protective effects were associated with the suppression of macrophage infiltration, cytokine expression, and oxidative stress in the sciatic nerve and decreased plasma xanthine oxidoreductase activity. Our results revealed the beneficial effects of the xanthine oxidase inhibitor topiroxostat on neuropathy development in a mouse model of type 2 diabetes. The suppression of proinflammatory macrophage activation and oxidative stress-induced damage were suggested to be involved in this process.
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Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Nitrilas/uso terapêutico , Obesidade/tratamento farmacológico , Piridinas/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Diabetes Mellitus Experimental/enzimologia , Inibidores Enzimáticos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Nitrilas/farmacologia , Obesidade/enzimologia , Piridinas/farmacologia , Células RAW 264.7 , Resultado do Tratamento , Xantina Oxidase/metabolismoRESUMO
Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activation in PDAC. The activation of cultured mouse PSCs was evaluated by qPCR. The induction of epithelial mesenchymal transition (EMT) in PDAC cell lines was assessed under stimulation with culture supernatant from activated PSCs. A total of 155 surgically resected PDAC subjects (83 nondiabetic, 18 with â¦3-years and 54 with >3-years history of diabetes) were clinicopathologically evaluated. A high-fat diet increased the expression of activated markers in cultured PSCs, which was abrogated by RAGE deletion. Culture supernatant from activated PSCs facilitated EMT of PDAC cells with elevation of TGF-ß and IL-6, but not from RAGE-deleted PSCs. Diabetic subjects complicated with metabolic syndrome, divided by cluster analysis, showed higher PSC activation and RAGE expression. In such groups, PDAC cells exhibited an EMT nature. The complication of metabolic syndrome with diabetes significantly worsened disease-free survival of PDAC subjects. Thus, RAGE in PSCs can be viewed as a new promoter and a future therapeutic target of PDAC in diabetic subjects with metabolic syndrome.
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Carcinoma Ductal Pancreático/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Actinas/metabolismo , Animais , Carcinoma Ductal Pancreático/complicações , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica/efeitos adversos , Transição Epitelial-Mesenquimal , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Neoplasias Intraductais Pancreáticas/metabolismo , Neoplasias Pancreáticas/complicações , Cultura Primária de CélulasRESUMO
Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.
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Nefropatias Diabéticas , Neuropatias Diabéticas , Glucose/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Humanos , JapãoRESUMO
Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation in a rural Japanese population. A population-based study of 894 individuals (average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold induced by intraepidermal electrical stimulation (PINT) and clinico-hematological parameters associated with OS were evaluated. Univariate linear regression analyses revealed age, BMI, HbA1c, the OS biomarker urine 8-hydroxy-2'-deoxyguanosine (8-OHdG), systolic blood pressure, and decreased Achilles tendon reflex on the PINT scores. Adjustments for age, gender, and multiple clinical measures confirmed a positive correlation between PINT scores and urine 8-OHdG (ß = 0.09, p < 0.01). Urine 8-OHdG correlated positively with higher HbA1c levels and age in the normoglycemic population. Unlike in the normoglycemic population, both inflammation and OS were correlated with elevated PINT scores in IFG subjects. OS may be a major contributing factor to elevated PINT scores in a healthy Japanese population.
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Hemoglobinas Glicadas/metabolismo , Estresse Oxidativo/fisiologia , Limiar da Dor/fisiologia , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Pressão Sanguínea , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Hemoglobinas Glicadas/fisiologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Limiar da Dor/etnologia , Estado Pré-Diabético/sangue , Estado Pré-Diabético/metabolismo , Fatores de RiscoRESUMO
Small nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20â mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group (n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-high group (n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants (P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors (ß = -0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy.
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It is suggested that activation of receptor for advanced glycation end products (RAGE) induces proinflammatory response in diabetic nerve tissues. Macrophage infiltration is invoked in the pathogenesis of diabetic polyneuropathy (DPN), while the association between macrophage and RAGE activation and the downstream effects of macrophages remain to be fully clarified in DPN. This study explored the role of RAGE in the pathogenesis of DPN through the modified macrophages. Infiltrating proinflammatory macrophages impaired insulin sensitivity, atrophied the neurons in dorsal root ganglion, and slowed retrograde axonal transport (RAT) in the sciatic nerve of type 1 diabetic mice. RAGE-null mice showed an increase in the population of antiinflammatory macrophages, accompanied by intact insulin sensitivity, normalized ganglion cells, and RAT. BM transplantation from RAGE-null mice to diabetic mice protected the peripheral nerve deficits, suggesting that RAGE is a major determinant for the polarity of macrophages in DPN. In vitro coculture analyses revealed proinflammatory macrophage-elicited insulin resistance in the primary neuronal cells isolated from dorsal root ganglia. Applying time-lapse recording disclosed a direct impact of proinflammatory macrophage and insulin resistance on the RAT deficits in primary neuronal cultures. These results provide a potentially novel insight into the development of RAGE-related DPN.
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Diabetes Mellitus Experimental , Neuropatias Diabéticas , Resistência à Insulina , Camundongos , Animais , Receptor para Produtos Finais de Glicação Avançada/genética , Diabetes Mellitus Experimental/complicações , MacrófagosRESUMO
AIMS/INTRODUCTION: Islets have microvessels that might develop pathological alterations similar to microangiopathy in type 2 diabetes patients. It remains unclear, however, whether the changes correlate with endocrine cell deficits or whether the presence of macroangiopathy influences the islet microvasculature in Japanese type 2 diabetes patients. In this study, we characterized changes of the islet microvessels and endocrine cells in Japanese non-obese patients with type 2 diabetes who died of acute myocardial infarction (AMI). MATERIALS AND METHODS: Clinical profiles and islet pathology were examined for 35 diabetes patients who died of AMI (DM + AMI) and 13 diabetes patients who were free from AMI (DM). A total of 13 age-matched, individuals without diabetes who died of AMI and 16 individuals without diabetes who were free from AMI were also studied. Pancreata were subjected to morphometric evaluation of islets, including microvascular alterations of immunostained sections. RESULTS: Body mass index in DM + AMI was comparable to those in DM. Compared with DM, DM + AMI showed greater glycated hemoglobin levels, higher prevalence of renal failure, hypertension, smaller ß-cell volume density and greater amyloid area. DM + AMI showed an increased microvascular area and density compared with other groups. There was a significant increase in vascular basement membrane thickness and loss of pericytes in DM and DM + AMI compared with individuals without diabetes in each group, and the extent of thickening was correlated with the amyloid area and occurrence of ß-cell loss in DM + AMI. CONCLUSIONS: Islet microangiopathy was associated with augmented ß-cell loss and amyloid deposition in non-obese Japanese type 2 diabetes patients who died of AMI.
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Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/patologia , Células Secretoras de Insulina/patologia , Infarto do Miocárdio/patologia , Pâncreas/irrigação sanguínea , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Humanos , Japão , Microvasos/patologia , Infarto do Miocárdio/etiologia , Placa Amiloide/etiologia , Placa Amiloide/patologiaRESUMO
In diabetic pathology, insufficiency in ß-cell mass, unable to meet peripheral insulin demand, and functional defects of individual ß-cells in production of insulin are often concurrently observed, collectively causing hyperglycemia. Here we show that the phosphorylation of ERK1/2 is significantly decreased in the islets of db/db mice as well as in those of a cohort of subjects with type 2 diabetes. In mice with abrogation of ERK signaling in pancreatic ß-cells through deletion of Mek1 and Mek2, glucose intolerance aggravates under high-fat diet-feeding conditions due to insufficient insulin production with lower ß-cell proliferation and reduced ß-cell mass, while in individual ß-cells dampening of the number of insulin exocytosis events is observed, with the molecules involved in insulin exocytosis being less phosphorylated. These data reveal bifunctional roles for MEK/ERK signaling in ß-cells for glucose homeostasis, i.e., in regulating ß-cell mass as well as in controlling insulin exocytosis in individual ß-cells, thus providing not only a novel perspective for the understanding of diabetes pathophysiology but also a potential clue for new drug development for diabetes treatment.
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Glicemia/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Homeostase , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , Animais , Linhagem Celular , Dieta Hiperlipídica , Exocitose , Humanos , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Transdução de SinaisRESUMO
Long-term metabolic aberrations contribute to the development of diabetic neuropathy but the precise mechanism or mechanisms remains elusive. We have previously shown that aldose reductase-deficient mice exhibit delayed onset and progression of neuropathy following induction of diabetes, suggesting a role both for downstream metabolites of this enzyme and also for other unrelated pathways. In this study, we have utilized comprehensive metabolomics analyses to identify potential neurotoxic metabolites in nerve of diabetic mice and explored the mechanism of peripheral nerve injury. Aldose reductase knockout and control C57Bl/6J mice were made diabetic by injection of streptozotocin and followed for 8-16 weeks. Diabetic aldose reductase knockout mice exhibited delayed onset of nerve conduction slowing compared to diabetic wild-type mice. The sciatic nerves from aldose reductase knockout mice exposed to 12 weeks of diabetes were used for metabolomics analysis and compared with analyses of nerves from age-matched diabetic wild-type mice as well as non-diabetic aldose reductase knockout and wild-type mice. Neurotoxicity of candidate metabolites was evaluated using cultured Schwann cells and dorsal root ganglion neurons, and further confirmed in vivo. Metabolomics analysis identified elevated glucosamine levels in both diabetic aldose reductase knockout and diabetic wild mice. Exposure to glucosamine reduced survival of cultured Schwann cells and neurons accompanied by increased expression of cleaved caspase 3, CCAT-enhancer-binding homologous protein and mitochondrial hexokinase-I, along with ATP depletion. These changes were suppressed by siRNA to hexokinase-I or the ATP donor, inosine, but not by the antioxidant N-acetylcysteine or the endoplasmic reticulum-stress inhibitor 4-phenylbutyrate. The O-GlcNAcylation enhancer, O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino N-phenylcarbamate, did not augment glucosamine neurotoxicity. Single dose glucosamine injection into mice caused a reduction of sciatic nerve Na, K-ATPase activity, ATP content and augmented expression of hexokinase-I, which were suppressed by pretreatment with inosine but not with 4-phenylbutyrate. Mice implanted with a subcutaneous pump to infuse glucosamine for 12 weeks developed nerve conduction slowing and intraepidermal nerve fibre loss, recapitulating prominent indices of diabetic neuropathy. While acute glucosamine neurotoxicity is unlikely to contribute substantially to the slowly developing neuropathy phenotype in humans, sustained energy deprivation induced by glucosamine may well contribute to the pathogenesis of diabetic neuropathy. Our data thus identifies a novel pathway for diabetic neuropathy that may offer a potential new therapeutic target.
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AIMS: Parasympathetic nerve (PN) signaling plays a crucial role in the maintenance of pancreatic ß-cell volume density (Vß). PN may be pathologically affected in diabetic polyneuropathy (DPN). However, the association between the reduction of PNs in islets and Vß and the therapeutic effects of a DPP4 inhibitor (DPP4i) and an SGLT2 inhibitor (SGLT2i) in nonobese type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats (GK) have not been investigated. MATERIALS AND METHODS: We divided 5-week old male GK and Wistar rats (W) into a DPP4i-treated group (GKTe), SGLT2i-treated group (GKCa), and combination-treated group (GKCaTe). After 25â¯weeks, the pancreata was pathologically evaluated. RESULTS: Vß in GK was significantly decreased (p < 0.01 vs. W), whereas Vß was the most well preserved in GKCaTe (p < 0.05 vs. GKTe), followed by GKTe (p < 0.05 vs. GK). The decreased amount of PNs in the islets and intraepidermal nerve fiber density (IENFD) in GK was significantly improved in the treated groups compared with GK (p < 0.05 vs. GKCa and GKTe and p < 0.01 vs. GKCaTe). PN density and IENFD were significantly correlated with Vß (râ¯=â¯0.55, p < 0.01 and râ¯=â¯0.54, p < 0.01, respectively). IENFD was identified as a surrogate marker for the prediction of Vß (cutoff value, 16.39). CONCLUSIONS: The combination therapy of DPP4i and SGLT2i improved Vß accompanied by PNs density and IENFD. IENFD was proportionally correlated with Vß. Therefore, the prevention of DPN development may be concurrently beneficial for the preservation of Vß in nonobese T2DM.
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Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/patologia , Pirazóis/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Tiazolidinas/uso terapêutico , Animais , Glicemia/metabolismo , Contagem de Células , Diabetes Mellitus Tipo 2/patologia , Quimioterapia Combinada , Hemoglobinas Glicadas/análise , Ilhotas Pancreáticas/patologia , Masculino , Pâncreas/patologia , Sistema Nervoso Parassimpático/patologia , Ratos , Ratos WistarRESUMO
INTRODUCTION: Small fiber neuropathy (SFN) is an early manifestation in diabetic polyneuropathy (DPN); however, the mechanisms are not fully understood. In diabetes, SFN is presumed to be common in individuals with overt DPN, enhancing activation of polyol pathway, oxidative stress, advanced glycation end products (AGEs), and inflammation. We explored the relationship between clinicohematological factors related to DPN and pain sensation in the Japanese population. RESEARCH DESIGN AND METHODS: We conducted a population-based study, recruiting 1030 individuals (average age 54.4±0.5 years), in 2017, to participate in our Iwaki project. After initial screening by fasting blood glucose and glycohemoglobin A1c (HbA1c) measurements, the subjects were categorized into control (n=894), type 2 diabetes (n=81), and impaired fasting glucose (n=55) groups. Clinical data were gathered, and relationships between pain threshold from intraepidermal electrical stimulation (PINT) and DPN were examined by analysis of variance, post hoc test, and χ2 tests to study correlations among and between groups of the clinical data and DPN. RESULTS: Univariate linear regression analyses showed significant correlations between PINT and serum lipopolysaccharide-binding protein (LBP) level (ß=0.1025, p=0.001). Adjustments for the clinical measurements confirmed a positive correlation (ß=0.070, p=0.034). Logistic regression analysis revealed high LBP value (>6.7 mg/dL) as a significant risk factor toward abnormal PINT (≥0.35 mA). LBP significantly correlated with the high-sensitivity C reactive protein, inflammation marker, elevated similarly in both pre-diabetic and overt-diabetic groups, compared with controls, but it did not correlate with a decreased Achilles tendon reflex. In contrast, urine 8-hydroxy-2'-deoxyguanosine, oxidative stress marker, and pentosidine, AGEs, markedly increased in individuals with type 2 diabetes with high HbA1c. CONCLUSIONS: Individuals with high LBP exhibited an elevated PINT in the Japanese population. Low level of inflammation evoked by metabolic endotoxemia is possibly implicated in the pathophysiology of SFN from pre-diabetic stage.
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Diabetes Mellitus Tipo 2 , Proteínas de Fase Aguda , Biomarcadores , Proteínas de Transporte , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Japão/epidemiologia , Glicoproteínas de Membrana , Pessoa de Meia-Idade , Limiar da DorRESUMO
Pancreatic ß-cell mass is known to be considerably altered during pregnancy and after parturition in rodents and humans. While ß-cell mass increases during pregnancy and starts to return toward its original level after parturition, the cellular mechanisms by which ß-cell mass during this period is regulated remains unclear. To address this issue in mice, we quantified ß-cell mass and investigated the mechanisms underlying its regulation throughout the perinatal and postpartum period. The increased ß-cell size and proliferation during pregnancy were significantly reduced shortly after parturition, whereas there was no evidence of ß-cell reprogramming or increased apoptosis. Direct RNA sequencing of islets from pregnant and postpartum mice demonstrated dynamic changes in gene expression patterns, showing robust downregulation of cell cycle-related genes 1 day after parturition, and the reupregulation of serotonin metabolism-related genes at postpartum day 7. Serotonin synthesis was activated only in lactating females, accompanied by increased ß-cell mass. Taken together, these findings demonstrate that ß-cell mass is decreased shortly after parturition owing to reduced ß-cell size and proliferation, and is subsequently increased, in association with lactation and serotonin biosynthesis.
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Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Lactação/fisiologia , Parto/fisiologia , Serotonina/metabolismo , Adulto , Animais , Feminino , Humanos , Camundongos , Período Pós-Parto , GravidezRESUMO
A concurrent increase in the prevalence of hepatocellular carcinoma (HCC) with that of type 2 diabetes (T2D) and obesity has been reported in the absence of hepatitis B virus surface antigen-negative/hepatitis C virus antibody-negative HCC (NBNC-HCC). However, the prognostic relevance of this association remains unclear. Promoter methylation (PM) of the dihydropyrimidinase-like 3 gene (DPYSL3) has been implicated in virus-related HCC. However, it remains unclear whether T2D influences PM in NBNC-HCC. We determined the influence of T2D on clinicopathological profile and PM of DPYSL3 and CDK2NA in patients with NBNC-HCC who were divided into two groups: non-diabetes (non-DM; n = 46) and diabetes (DM; n = 47). DM was associated with a higher Union for International Cancer Control grade, marginal vascular invasion and tumour cell proliferation irrespective of the duration of T2D as well as higher rates of PM of DPYSL3 than non-DM; however, PM of CDK2NA was similar between both groups. PM of DPYSL3 reduced its expression which inversely correlated with reduced patient survival. In conclusion, T2D is associated with poor prognosis of NBNC-HCC in which a high frequency of PM of DPYSL3 may play a pivotal role in its pathogenesis.
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Carcinoma Hepatocelular/genética , Metilação de DNA , Diabetes Mellitus Tipo 2/complicações , Neoplasias Hepáticas/genética , Proteínas Musculares/genética , Regiões Promotoras Genéticas , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Inibidor p16 de Quinase Dependente de Ciclina/análise , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobinas Glicadas/análise , Hepatite Viral Humana/complicações , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Obesidade/complicações , Prognóstico , RecidivaRESUMO
[This corrects the article DOI: 10.3389/fendo.2019.00651.].
RESUMO
A sufficient ß-cell mass is crucial for preventing diabetes, and perinatal ß-cell proliferation is important in determining the adult ß-cell mass. However, it is not yet known how perinatal ß-cell proliferation is regulated. Here, we report that serotonin regulates ß-cell proliferation through serotonin receptor 2B (HTR2B) in an autocrine/paracrine manner during the perinatal period. In ß-cell-specific Tph1 knockout (Tph1 ßKO) mice, perinatal ß-cell proliferation was reduced along with the loss of serotonin production in ß-cells. Adult Tph1 ßKO mice exhibited glucose intolerance with decreased ß-cell mass. Disruption of Htr2b in ß-cells also resulted in decreased perinatal ß-cell proliferation and glucose intolerance in adulthood. Growth hormone (GH) was found to induce serotonin production in ß-cells through activation of STAT5 during the perinatal period. Thus, our results indicate that GH-GH receptor-STAT5-serotonin-HTR2B signaling plays a critical role in determining the ß-cell mass by regulating perinatal ß-cell proliferation, and defects in this pathway affect metabolic phenotypes in adults.
Assuntos
Glucose/metabolismo , Células Secretoras de Insulina/fisiologia , Serotonina/metabolismo , Animais , Animais Recém-Nascidos , Proliferação de Células , Feminino , Hormônio do Crescimento/metabolismo , Humanos , Lactente , Camundongos , Camundongos Knockout , Gravidez , Propafenona/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismoRESUMO
Purpose: Small fiber dysfunction is common in subjects with diabetic polyneuropathy (DPN). It is unsettled, however, whether marginal glucose intolerance is implicated in the onset and progression of small fiber dysfunction. Herein, we explored the relationship between glycated hemoglobin levels (HbA1c) and pain sensation in the Japanese population. Methods: A population-based study of 894 individuals (352 men, 542 women; average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) in the 2017 Iwaki project were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold for intraepidermal electrical stimulation (P-IES) and parameters associated with metabolic syndrome were examined. Results: P-IES was elevated with increasing of age in women but not in men. Average P-IES (mA) was increased in IFG subjects (n = 55, 0.20 ± 0.03) compared with normoglycemic/non-IFG individuals (n = 894, 0.15 ± 0.11) (p < 0.01). It was comparable between IFG and a group of normal high HbA1c (5.9-6.4%). Univariate linear regression analyses showed no influence of sex, triglyceride, or cholesterol on the value of P-IES. In contrast, there were significant correlations between P-IES and serum HbA1c level (ß = 0.120, p < 0.001) Adjustments for the multiple clinical measurements confirmed positive correlation of P-IES with HbA1c (ß = 0.077, p = 0.046). Conclusion: Individuals with normal high HbA1c exhibited an elevated P-IES in a healthy Japanese population which may be useful for the screening of subclinical DPN.