RESUMEN
BACKGROUND AND AIMS: Insulin resistance and poor glycemic control are key drivers of the development of NAFLD and have recently been shown to be associated with fibrosis progression in NASH. However, the underlying mechanisms involving dysfunctional glucose metabolism and relationship with NAFLD/NASH progression remain poorly understood. We set out to determine whether protease-activated receptor 2 (PAR2), a sensor of extracellular inflammatory and coagulation proteases, links NAFLD and NASH with liver glucose metabolism. APPROACH AND RESULTS: Here, we demonstrate that hepatic expression of PAR2 increases in patients and mice with diabetes and NAFLD/NASH. Mechanistic studies using whole-body and liver-specific PAR2-knockout mice reveal that hepatic PAR2 plays an unexpected role in suppressing glucose internalization, glycogen storage, and insulin signaling through a bifurcating Gq -dependent mechanism. PAR2 activation downregulates the major glucose transporter of liver, GLUT2, through Gq -MAPK-FoxA3 and inhibits insulin-Akt signaling through Gq -calcium-CaMKK2 pathways. Therapeutic dosing with a liver-homing pepducin, PZ-235, blocked PAR2-Gq signaling and afforded significant improvements in glycemic indices and HbA1c levels in severely diabetic mice. CONCLUSIONS: This work provides evidence that PAR2 is a major regulator of liver glucose homeostasis and a potential target for the treatment of diabetes and NASH.
Asunto(s)
Diabetes Mellitus Experimental , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptor PAR-2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hígado/metabolismo , Insulina/metabolismo , Glucosa/metabolismo , Ratones NoqueadosRESUMEN
Pancreatic ß-cell failure in type 2 diabetes mellitus is a serious challenge that results in an inability of the pancreas to produce sufficient insulin to properly regulate blood glucose levels. Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor expressed by ß-cells that has recently been proposed as a potential target for improving glycemic control and suppressing binge eating behaviors. We discovered that TAAR1 is coupled to Gαs-signaling pathways in insulin-secreting ß-cells to cause protein kinase A (PKA)/exchange protein activated by cAMP (Epac)-dependent release of insulin, activation of RAF proto-oncogene, Ser/Thr kinase (Raf)-mitogen-activated protein kinase (MAPK) signaling, induction of cAMP response element-binding protein (CREB)-insulin receptor substrate 2 (Irs-2), and increased ß-cell proliferation. Interestingly, TAAR1 triggered cAMP-mediated calcium influx and release from internal stores, both of which were required for activation of a MAPK cascade utilizing calmodulin-dependent protein kinase II (CaMKII), Raf, and MAPK/ERK kinase 1/2 (MEK1/2). Together, these data identify TAAR1/Gαs-mediated signaling pathways that promote insulin secretion, improved ß-cell function and proliferation, and highlight TAAR1 as a promising new target for improving ß-cell health in type 2 diabetes mellitus.
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Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Transducción de Señal/fisiología , Adenilil Ciclasas/metabolismo , Animales , Calcio/metabolismo , Línea Celular , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Glucosa/farmacología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/enzimología , Ratones , Fosforilación , Ratas , Receptores Acoplados a Proteínas G/agonistasRESUMEN
The roles of monocytes/macrophages and their mechanisms of action in the regulation of pancreatitis are poorly understood. To address these issues, we have employed genetically altered mouse strains that either express the human diphtheria toxin receptor (DTR) coupled to the CD11b promoter or have global deletion of TNF-α. Targeted, conditional depletion of monocytes/macrophages was achieved by administration of diphtheria toxin (DT) to CD11b-DTR mice. We show that in the absence of DT administration, pancreatitis is associated with an increase in pancreatic content of Ly-6C(hi) monocytes/macrophages but that this response is prevented by prior administration of DT to CD11b-DTR mice. DT administration also reduces pancreatic edema and acinar cell injury/necrosis in two dissimilar experimental models of acute pancreatitis (a secretagogue-induced model and a model elicited by retrograde pancreatic duct infusion of sodium taurocholate). In the secretagogue-elicited model, the DT-induced decrease in pancreatitis severity is reversed by adoptive transfer of purified Ly-6C(hi) monocytes harvested from non-DT-treated CD11b-DTR mice or by the transfer of purified Ly-6C(hi) monocytes harvested from TNF-α(+/+) donor mice, but it is not reversed by the transfer of Ly-6C(hi) monocytes harvested from TNF-α(-/-) donors. Our studies indicate that the Ly-6C(hi) monocyte subset regulates the severity of pancreatitis by promoting pancreatic edema and acinar cell injury/necrosis and that this phenomenon is dependent upon the expression of TNF-α by those cells. They suggest that therapies targeting Ly-6C(hi) monocytes and/or TNF-α expression by Ly-6C(hi) monocytes might prove beneficial in the prevention or treatment of acute pancreatitis.
Asunto(s)
Antígenos Ly/metabolismo , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Monocitos/metabolismo , Páncreas Exocrino/metabolismo , Pancreatitis Aguda Necrotizante/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Traslado Adoptivo , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Antígeno CD11b/genética , Antígeno CD11b/inmunología , Antígeno CD11b/metabolismo , Toxina Diftérica/toxicidad , Modelos Animales de Enfermedad , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Transgénicos , Monocitos/inmunología , Monocitos/patología , Monocitos/trasplante , Páncreas Exocrino/inmunología , Páncreas Exocrino/patología , Pancreatitis Aguda Necrotizante/inducido químicamente , Pancreatitis Aguda Necrotizante/genética , Pancreatitis Aguda Necrotizante/inmunología , Pancreatitis Aguda Necrotizante/patología , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
INTRODUCTION: A significant number of children with bipolar disorder (BP) have co-morbid attention-deficit/hyperactivity disorder (ADHD). It is unknown if these children have neuroimaging findings unique to their co-morbid presentation, or if their brain findings are similar to children diagnosed with BP alone. METHOD: Fifty three children with Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) BP (23 with ADHD, 30 without), 29 healthy controls (HC), and 23 children with ADHD, similar in sex and age, had magnetic resonance imaging (MRI) scans on a 1.5T GE scanner. Volumetric assessments were performed for basal ganglia and limbic subcortical structures. RESULTS: Youths with ADHD had smaller caudate and putamen volumes compared to both BP groups and they had moderately smaller total amygdala volumes compared to the other three groups. Youths with BP + ADHD had moderately larger nucleus accumbens volumes than HC, and females in both BP groups had smaller hippocampal volumes compared to ADHD and HC. No differences were found between the BP and BP + ADHD groups. CONCLUSION: These data suggest that morphometric subcortical volumes in youths with BP + ADHD are more similar to those in youths with BP. They do not share subcortical neuroanatomic correlates with the ADHD group. These findings suggest that BP + ADHD is a subtype of pediatric BP rather than severe ADHD.