RESUMEN
Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases1-3. Here we show that centenarians have a distinct gut microbiome that is enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.
Asunto(s)
Bacterias/metabolismo , Vías Biosintéticas , Centenarios , Microbioma Gastrointestinal , Ácido Litocólico/análogos & derivados , Ácido Litocólico/biosíntesis , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Anciano de 80 o más Años , Animales , Antibacterianos/biosíntesis , Antibacterianos/metabolismo , Bacterias/clasificación , Bacterias/enzimología , Bacterias/aislamiento & purificación , Colestenona 5 alfa-Reductasa/metabolismo , Heces/química , Heces/microbiología , Femenino , Bacterias Grampositivas/metabolismo , Humanos , Ácido Litocólico/metabolismo , Masculino , Ratones , SimbiosisRESUMEN
AIM: The ingestion of Lactiplantibacillus plantarum OLL2712 (OLL2712) cells has been shown to improve glucose metabolism by suppressing chronic inflammation in murine models and clinical studies. This study aimed to clarify the effect of OLL2712 on glycaemic control in healthy adults with prediabetes. MATERIALS AND METHODS: The study was a randomized, double-blind, placebo-controlled, parallel-group design. Adult participants with prediabetes [n = 148, glycated haemoglobin (HbA1c) range: 5.6%-6.4%, age range: 20-64 years] were assigned randomly to placebo or OLL2712 groups (n = 74/group) and administered daily for 12 weeks either conventional yogurt or yogurt containing >5 × 109 heat-treated OLL2712 cells, respectively. In addition, the participants were followed for 8 weeks after the discontinuation of either yogurt. The primary outcome was the changes in HbA1c levels at weeks 12 and 16 by analysis of covariance. RESULTS: The levels of HbA1c and glycoalbumin decreased significantly in both groups at week 12 in comparison with those at week 0, but only in the OLL2712 group at week 16. HbA1c levels decreased significantly at weeks 12 and 16 in the OLL2712 group in comparison with the placebo group (p = .014 and p = .006, respectively). No significant inter- and intragroup differences in HbA1c levels were observed at week 20. CONCLUSIONS: The ingestion of OLL2712 prevents the deterioration of glycaemic control and maintains the HbA1c levels within the normal range in adults with prediabetes; yogurt probably exhibits similar effects, which may contribute to reducing the risk of developing type 2 diabetes.
Asunto(s)
Hemoglobina Glucada , Control Glucémico , Estado Prediabético , Probióticos , Yogur , Humanos , Método Doble Ciego , Probióticos/uso terapéutico , Probióticos/administración & dosificación , Estado Prediabético/dietoterapia , Estado Prediabético/sangre , Estado Prediabético/terapia , Adulto , Masculino , Persona de Mediana Edad , Femenino , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Control Glucémico/métodos , Glucemia/metabolismo , Adulto Joven , Lactobacillus plantarumRESUMEN
Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD+), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD+ intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD+ levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD+ content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD+ levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD+ biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.
Asunto(s)
Hiperinsulinismo , NAD , Masculino , Persona de Mediana Edad , Animales , Humanos , NAD/metabolismo , Mononucleótido de Nicotinamida/metabolismo , Leucocitos Mononucleares/metabolismo , Japón , Obesidad , Sueño , Suplementos DietéticosRESUMEN
BACKGROUND: The gut produces toxins that contribute to the cardiovascular complications of chronic kidney disease. Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor that is used as an anti-diabetic drug, has a weak inhibitory effect against SGLT1 and may affect the gut glucose concentration and environment. METHODS: Here, we determined the effect of canagliflozin on the gut microbiota and the serum gut-derived uremic toxin concentrations in 5/6th nephrectomized (Nx) rats. RESULTS: Canagliflozin increased the colonic glucose concentration and restored the number of Lactobacillus bacteria, which was low in Nx rats. In addition, the expression of tight junction proteins in the ascending colon was low in Nx rats, and this was partially restored by canagliflozin. Furthermore, the serum concentrations of gut-derived uremic toxins were significantly increased by Nx and reduced by canagliflozin. Finally, the wall of the thoracic aorta was thicker and there was more cardiac interstitial fibrosis in Nx rats, and these defects were ameliorated by canagliflozin. CONCLUSIONS: The increases in colonic glucose concentration, Lactobacillus numbers and tight junction protein expression, and the decreases in serum uremic toxin concentrations and cardiac interstitial fibrosis may have been caused by the inhibition of SGLT1 by canagliflozin because similar effects were not identified in tofogliflozin-treated rats.
Asunto(s)
Sistema Cardiovascular , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Ratas , Animales , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Glucosa , FibrosisRESUMEN
Ketone bodies, including ß-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. ß-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.
Asunto(s)
Dieta Cetogénica , Cuerpos Cetónicos/metabolismo , Metabolismo de los Lípidos/fisiología , Receptores Acoplados a Proteínas G/fisiología , Animales , Ayuno , Células HEK293 , Humanos , Ligandos , Lipoproteína Lipasa/sangre , Ratones , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G/genética , Transducción de SeñalRESUMEN
AIMS/HYPOTHESIS: Accumulation of adipose tissue macrophages is considered pivotal in the development of obesity-associated inflammation and insulin resistance. In addition, recent studies suggest an involvement of the intestine as the primary organ in inducing hyperglycaemia and insulin resistance. We have reported that the C-C motif chemokine receptor (CCR) CCR9 is associated with intestinal immunity and has a pathogenic role in various liver diseases. However, its contribution to type 2 diabetes is unknown. In the current study, we aimed to clarify the involvement of CCR9 in the pathology of type 2 diabetes and the potential underlying mechanisms. METHODS: To elucidate how CCR9 affects the development of metabolic phenotypes, we examined the impact of CCR9 deficiency on the pathogenesis of type 2 diabetes using male C57BL/6J (wild-type [WT]) and CCR9-deficient (CCR9 knockout [KO]) mice fed a 60% high-fat diet (HFD) for 12 weeks. RESULTS: WT and Ccr9KO mice fed an HFD exhibited a comparable weight gain; however, glucose tolerance and insulin resistance were significantly improved in Ccr9KO mice. Moreover, visceral adipose tissue (VAT) and the liver of Ccr9KO mice presented with less inflammation and increased expression of glucose metabolism-related genes than WT mice. Ccr9 and Ccl25 expression were specifically higher in the small intestine but was not altered by HFD feeding and type 2 diabetes development. Accumulation of IFN-γ-producing CD4+ T lymphocytes and increased intestinal permeability in the small intestine was observed in WT mice following HFD feeding, but these changes were suppressed in HFD-fed Ccr9KO mice. Adoptive transfer of gut-tropic CCR9-expressing T lymphocytes partially reversed the favourable glucose tolerance found in Ccr9KO mice via exacerbated inflammation in the small intestine and VAT. CONCLUSIONS/INTERPRETATION: CCR9 plays a central role in the pathogenesis of type 2 diabetes by inducing an inflammatory shift in the small intestine. Our findings support CCR9 as a new therapeutic target for type 2 diabetes via the gut-VAT-liver axis.
Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Enteritis/etiología , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina , Intestino Delgado/metabolismo , Obesidad/complicaciones , Receptores CCR/metabolismo , Animales , Glucemia/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Quimiotaxis de Leucocito , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Enteritis/inmunología , Enteritis/metabolismo , Insulina/sangre , Interferón gamma/metabolismo , Intestino Delgado/inmunología , Grasa Intraabdominal/inmunología , Grasa Intraabdominal/metabolismo , Hígado/inmunología , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/inmunología , Obesidad/metabolismo , Receptores CCR/genética , Transducción de SeñalRESUMEN
BACKGROUND: Chronic kidney disease (CKD) leads to insulin resistance (IR) and sarcopenia, which are associated with a high mortality risk in CKD patients; however, their pathophysiologies remain unclear. Recently, alterations in gut microbiota have been reported to be associated with CKD. We aimed to determine whether uremic dysbiosis contributes to CKD-associated IR and sarcopenia. METHODS: CKD was induced in specific pathogen-free mice via an adenine-containing diet; control animals were fed a normal diet. Fecal microbiota transplantation (FMT) was performed by oral gavage in healthy germ-free mice using cecal bacterial samples obtained from either control mice (control-FMT) or CKD mice (CKD-FMT). Vehicle mice were gavaged with sterile phosphate-buffered saline. Two weeks after inoculation, mice phenotypes, including IR and sarcopenia, were evaluated. RESULTS: IR and sarcopenia were evident in CKD mice compared with control mice. These features were reproduced in CKD-FMT mice compared with control-FMT and vehicle mice with attenuated insulin-induced signal transduction and mitochondrial dysfunction in skeletal muscles. Intestinal tight junction protein expression and adipocyte sizes were lower in CKD-FMT mice than in control-FMT mice. Furthermore, CKD-FMT mice showed systemic microinflammation, increased concentrations of serum uremic solutes, fecal bacterial fermentation products and elevated lipid content in skeletal muscle. The differences in gut microbiota between CKD and control mice were mostly consistent between CKD-FMT and control-FMT mice. CONCLUSIONS: Uremic dysbiosis induces IR and sarcopenia, leaky gut and lipodystrophy.
Asunto(s)
Bacterias/aislamiento & purificación , Disbiosis/complicaciones , Microbioma Gastrointestinal , Resistencia a la Insulina , Insuficiencia Renal Crónica/fisiopatología , Sarcopenia/etiología , Uremia/complicaciones , Animales , Disbiosis/microbiología , Trasplante de Microbiota Fecal , Lípidos/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Sarcopenia/patología , Sarcopenia/terapiaRESUMEN
Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention. The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.
Asunto(s)
Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Presión Intraocular/efectos de los fármacos , Mononucleótido de Nicotinamida/farmacología , Sueño/efectos de los fármacos , Administración Oral , Adulto , Bilirrubina/sangre , Glucemia/metabolismo , Cloruros/sangre , Cromatografía Liquida , Creatinina/sangre , Técnicas de Diagnóstico Oftalmológico , Relación Dosis-Respuesta a Droga , Electrocardiografía , Voluntarios Sanos , Humanos , Japón , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Mononucleótido de Nicotinamida/análogos & derivados , Mononucleótido de Nicotinamida/metabolismo , Oxígeno/metabolismo , Piridonas/metabolismo , Espectrometría de Masas en Tándem , Agudeza VisualRESUMEN
BACKGROUND: Oral charcoal adsorbent AST-120 (AST) is reported to ameliorate renal dysfunction by the absorption of toxic substance in the gut. Recent study revealed that, in CKD, gut environment is disturbed including the decrease in tight junctions and Lactobacillus (Lact). In this study, we examined whether AST improves the renal dysfunction through gut environment. METHOD: Six-week-old spontaneously hypertensive rats (SHR) were rendered CKD by 5/6th nephrectomy (Nx). SHRs were divided into SHR (Sham), SHR with Nx (Nx), and Nx given AST (Nx + AST) (n = 10, each). After 12 weeks, rats were killed and biochemical parameters were explored. The gut flora was analyzed. Furthermore, gut molecular changes in tight junctions and toll-like receptors were examined. We also investigated the effects of the combination therapy with AST and Lact. RESULTS: The increase in serum urea nitrogen and urinary protein excretion in Nx was restored in Nx + AST. The increased renal glomerulosclerosis in Nx was ameliorated in Nx + AST. Increases in serum uremic toxins and IL-6 in Nx were ameliorated in Nx + AST. The gut flora analysis revealed that the decrease in Lact in Nx was restored in Nx + AST. The downregulation in the tight junction and TLR2 in Nx was mitigated by AST. However, combination therapy failed to exhibit additional effects. CONCLUSION: AST ameliorated renal function with the restoration of Lact and tight junction through TLR pathway, which would mitigate systemic inflammation and contributed to their renoprotective effects. Our study provides a novel mechanism of the renoprotective effects by AST.
Asunto(s)
Carbono/farmacología , Absorción Intestinal/efectos de los fármacos , Óxidos/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Animales , Nefrectomía , Ratas , Ratas Endogámicas SHR , TokioRESUMEN
Sirtuins are NAD+-dependent deacetylase and have drawn much attention as important regulators of aging and longevity. Because NAD+ decline during the aging process, the approach to regulating aging using NAD+ precursor such as nicotinamide mononucleotide (NMN) to replenish cellular NAD+ through the activation of sirtuins have been investigated. In various animal models, NMN has been shown to mitigate age-associated physiological changes in liver, adipose tissue, muscle, pancreas, kidney, retina, and central nerve system. In animal models of metabolic diseases, NMN has been demonstrated to improve obesity, insulin resistance, and muscle mitochondrial dysfunction. In this review, recent findings in the NMN research will be summarized, and the potential of NMN on the regulation of age-associated diseases in humans will be discussed.
Asunto(s)
Envejecimiento , Homeostasis , Mononucleótido de Nicotinamida/metabolismo , Animales , Nefropatías Diabéticas/metabolismo , Humanos , Mononucleótido de Nicotinamida/uso terapéutico , Sirtuina 1/metabolismoRESUMEN
PURPOSE OF REVIEW: The gut microbiota and its metabolites have been implicated in the regulation of host physiological functions such as inflammatory and metabolic responses. The short-chain fatty acid (SCFA) receptor is expressed in the kidney and blood vessels as well, and has been reported to function as a regulator of blood pressure (BP). This review highlights the role of SCFAs derived from gut microbial fermentation in the regulation of BP. RECENT FINDINGS: Olfactory receptor 78 (Olfr78) is a member of the G-protein-coupled receptor family, and it plays a key role as a chemosensor in various tissues. Both Olfr78 and G protein-coupled receptor 41 (GPR41) are expressed in smooth muscle cells of blood vessels and they recognize SCFAs. Oral administration of SCFAs was found to change BP in vivo, an effect that was altered in Olfr78 and GPR41-deficient mice. SUMMARY: The regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. We summarize these interactions and describe their contributions to a novel pathway involved in BP regulation. These recent findings could open new avenues for the development of therapeutic strategies for the treatment of cardiovascular diseases.
Asunto(s)
Presión Sanguínea , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal/fisiología , Músculo Liso Vascular/metabolismo , Animales , Fermentación , Humanos , Riñón/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Odorantes/metabolismoRESUMEN
BACKGROUND: The role of gut microbiota in the progression of chronic kidney disease (CKD) has not been fully elucidated. METHODS: Renal failure was induced in 6-week-old spontaneously hypertensive rats by 5/6 nephrectomy (Nx). We analyzed the gut microbiota population to identify the relevant species potentially involved in inducing renal damage. Human colon Caco-2 cells were used to delineate the mechanism involved in the molecular changes in the gut of Nx rats. RESULTS: Nx rats showed an increase in Bacteroides (Bact) and a decrease in Lactobacillus (Lact) species compared with sham-operated rats. Lact, but not Bact, populations were significantly associated with urinary protein excretion. Treatment of Nx rats with 1 × 10(10) CFU/kg/day Lact ameliorated increased urinary protein excretion and higher serum levels of the uremic toxins, indoxyl sulfate and p-cresyl sulfate, and serum urea nitrogen levels. Lact also attenuated systemic inflammation in Nx rats, as evaluated by serum lipopolysaccharide, interleukin-6 and C-reactive protein levels. Histologically, renal sclerosis in Nx rats was restored by Lact treatment. A reduction in the expression of tight junction proteins and the Toll-like receptor 2 (TLR2), a putative Lact receptor, in the colons of Nx rats were mitigated by Lact. Treatment of Caco-2 cells with indole downregulated tight junction protein expression, which was abolished by exposure to Lact. The effects of Lact were reversed by treatment with OxPAPC, a TLR inhibitor. Similarly, the increase in the permeability of the Caco-2 cell monolayer was reversed by the administration of Lact. Lact upregulated TLR2 expression in Caco-2 cells. Lact also attenuated the increase in serum indoxyl sulfate and urea levels and urinary protein excretion in Nx rats even in the pseudogerm-free environment. CONCLUSIONS: Lact supplementation mitigated the systemic inflammation and proteinuria associated with renal failure, suggesting that in the gut microbiota, Lact plays a protective role against the progression of CKD.
Asunto(s)
Intestinos/microbiología , Lactobacillus/fisiología , Insuficiencia Renal Crónica/prevención & control , Animales , Nitrógeno de la Urea Sanguínea , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Masculino , Ratas , Insuficiencia Renal Crónica/sangreRESUMEN
There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 ± 0.80% vs. -0.80 ± 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes , Liraglutida/uso terapéutico , Metformina/uso terapéutico , Obesidad/complicaciones , Sobrepeso/complicaciones , Adulto , Anciano , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Japón , Liraglutida/efectos adversos , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , Aumento de PesoRESUMEN
Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 × 10(-20)). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.
Asunto(s)
Tejido Adiposo/inmunología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/inmunología , Receptores de Hialuranos/genética , Tejido Adiposo/patología , Anciano , Animales , Glucemia/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/etiología , Grasas de la Dieta/administración & dosificación , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Receptores de Hialuranos/metabolismo , Resistencia a la Insulina/inmunología , Macrófagos/inmunología , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/genética , Obesidad/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Paniculitis/complicaciones , Paniculitis/genética , Paniculitis/inmunología , Paniculitis/patologíaRESUMEN
Glucagon-like peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b(+)Gr-1(low) macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b(+)/Gr-1(-) and CD11b(+)/Gr-1(high) cells, but not CD11b(+)/Gr-1(low) cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic cerulein-administered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b(+)-cell migration to the pancreas is critically involved in chronic pancreatitis-mediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion.
Asunto(s)
Hiperglucemia/genética , Hiperglucemia/metabolismo , Pancreatitis Crónica/genética , Pancreatitis Crónica/metabolismo , Receptores CCR2/genética , Receptores de Glucagón/genética , Enfermedad Aguda , Animales , Antígeno CD11b/metabolismo , Ceruletida/toxicidad , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Receptor del Péptido 1 Similar al Glucagón , Intolerancia a la Glucosa/inducido químicamente , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Hiperglucemia/inducido químicamente , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Pancreatitis Crónica/inducido químicamente , Receptores CCR2/metabolismo , Receptores de Glucagón/metabolismoRESUMEN
Human fulminant type 1 diabetes (FT1D) is an extremely aggressive disease. The delay of proper diagnosis results in high mortality. However, the pathophysiology of this disease remains unclear. We took advantage of CD28-deficient NOD (CD28(-/-) NOD) mice, which have limited numbers of regulatory T cells and develop aggressive autoimmune diabetes, to create a FT1D model that mimicked the disease in humans. Young CD28(-/-) NOD mice were injected with polyinosinic-polycytidylic acid to activate innate immunity in an effort to induce diabetes onset. In this model, innate immune cell activation precedes the onset of diabetes similar to â¼70% of FT1D patients. Eighty-three percent of CD28(-/-) NOD mice developed diabetes within 1-6 d after injection of polyinosinic-polycytidylic acid. Moreover, T cells infiltrated the pancreatic exocrine tissue and destroyed α cells, an observation characteristic of human FT1D. We conclude that an FT1D-like phenotype can be induced in the background of autoimmune diabetes by a mimic of viral dsRNA, and this model is useful for understanding human FT1D.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Linfopenia/inmunología , Imitación Molecular/inmunología , ARN Bicatenario/inmunología , ARN Viral/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Modelos Animales de Enfermedad , Enterovirus/genética , Enterovirus/inmunología , Femenino , Linfopenia/genética , Linfopenia/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Imitación Molecular/genética , Síndrome , Linfocitos T Reguladores/patologíaRESUMEN
BACKGROUND: There are limited data about the association between body mass index (BMI), glycemic variability (GV), and life-related factors in healthy nondiabetic adults. METHODS: This cross-sectional study was carried out within our ethics committee-approved study called "Exploring the impact of nutrition advice on blood sugar and psychological status using continuous glucose monitoring (CGM) and wearable devices". Prediabetes was defined by the HbA1c level of 5.7-6.4% and /or fasting glucose level of 100-125 mg/dL. Glucose levels and daily steps were measured for 40 participants using Free Style Libre and Fitbit Inspire 2 under normal conditions for 14 days. Dietary intakes and eating behaviors were assessed using a brief-type self-administered dietary history questionnaire and a modified questionnaire from the Obesity Guidelines. RESULTS: All indices of GV were higher in the prediabetes group than in the healthy group, but a significant difference was observed only in mean amplitude of glycemic excursions (MAGE). In the multivariate analysis, only the presence of prediabetes showed a significant association with the risk of higher than median MAGE (Odds, 6.786; 95% CI, 1.596-28.858; P = 0.010). Additionally, the underweight (BMI < 18.5) group had significantly higher value in standard deviation (23.7 ± 3.5 vs 19.8 ± 3.7 mg/dL, P = 0.038) and coefficient variability (22.6 ± 4.6 vs 18.4 ± 3.2%, P = 0.015), compared to the normal group. This GV can be partially attributed to irregularity of eating habits. On the contrary, the overweight (BMI ≥ 25) group had the longest time above the 140 or 180 mg/dL range, which may be due to eating style and taking fewer steps (6394 ± 2337 vs 9749 ± 2408 steps, P = 0.013). CONCLUSIONS: Concurrent CGM with diet and activity monitoring could reduce postprandial hyperglycemia through assessment of diet and daily activity, especially in non- normal weight individuals.
Asunto(s)
Diabetes Mellitus Tipo 2 , Estado Prediabético , Adulto , Humanos , Glucemia/análisis , Índice de Masa Corporal , Automonitorización de la Glucosa Sanguínea , Estudios Transversales , Hemoglobina Glucada , Estilo de VidaRESUMEN
Fermented foods demonstrate remarkable health benefits owing to probiotic bacteria or microproducts produced via bacterial fermentation. Fermented foods are produced by the fermentative action of several lactic acid bacteria, including Leuconostoc mesenteroides; however, the exact mechanism of action of these foods remains unclear. Here, we observed that prebiotics associated with L. mesenteroides-produced exopolysaccharides (EPS) demonstrate substantial host metabolic benefits. L. mesenteroides-produced EPS is an indigestible α-glucan, and intake of the purified form of EPS improved glucose metabolism and energy homeostasis through EPS-derived gut microbial short-chain fatty acids, and changed gut microbial composition. Our findings reveal an important mechanism that accounts for the effects of diet, prebiotics, and probiotics on energy homeostasis and suggests an approach for preventing lifestyle-related diseases by targeting bacterial EPS.
Asunto(s)
Microbioma Gastrointestinal , Lactobacillales , Leuconostoc mesenteroides , Probióticos , Prebióticos , Lactobacillales/metabolismo , Bacterias , FermentaciónRESUMEN
Primary biliary cirrhosis (PBC) is an autoimmune disease with a strong genetic component characterized by biliary ductular inflammation with eventual liver cirrhosis. The serologic hallmark of PBC is antimitochondrial antibodies that react with the pyruvate dehydrogenase complex, targeting the inner lipoyl domain of the E2 subunit (anti-PDC-E2). Herein we demonstrate that NOD.c3c4 mice congenically derived from the nonobese diabetic strain develop an autoimmune biliary disease (ABD) that models human PBC. NOD.c3c4 (at 9-10 wk, before significant biliary pathology) develop antibodies to PDC-E2 that are specific for the inner lipoyl domain. Affected areas of biliary epithelium are infiltrated with CD3+, CD4+, and CD8+ T cells, and treatment of NOD.c3c4 mice with monoclonal antibody to CD3 protects from ABD. Furthermore, NOD.c3c4-scid mice develop disease after adoptive transfer of splenocytes or CD4+ T cells, demonstrating a central role for T cells in pathogenesis. Histological analysis reveals destructive cholangitis, granuloma formation, and eosinophilic infiltration as seen in PBC, although, unlike PBC, the extrahepatic biliary ducts are also affected. Using a congenic mapping approach, we define the first ABD (Abd) locus, Abd1. These results identify the NOD.c3c4 mouse as the first spontaneous mouse model of PBC.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Acetiltransferasa de Residuos Dihidrolipoil-Lisina/inmunología , Cirrosis Hepática Biliar/inmunología , Proteínas Mitocondriales/inmunología , Traslado Adoptivo , Animales , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Complejo CD3/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Colangitis/genética , Colangitis/inmunología , Colangitis/patología , Mapeo Cromosómico , Acetiltransferasa de Residuos Dihidrolipoil-Lisina/genética , Modelos Animales de Enfermedad , Granuloma/genética , Granuloma/inmunología , Granuloma/patología , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/patología , Cirrosis Hepática Experimental/genética , Cirrosis Hepática Experimental/inmunología , Cirrosis Hepática Experimental/patología , Ratones , Ratones Congénicos , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Proteínas Mitocondriales/genética , Estructura Terciaria de Proteína/genética , Sitios de Carácter Cuantitativo/genética , Sitios de Carácter Cuantitativo/inmunologíaRESUMEN
Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.