RESUMEN
Kynurenic acid (KYNA) is an endogenous catabolite of tryptophan that has been found to demonstrate neuroprotective properties in psychiatric disorders. Recently, accumulating data have suggested that KYNA may also play a significant role in various metabolic diseases by stimulating energy metabolism in adipose tissue and muscle. However, whether KYNA can serves as an anti-diabetes agent has yet to be studied. In this study, we investigated the potential anti-diabetic effects of administering KYNA orally through drinking water in pre-diabetic Goto-Kakizaki rats and examined how this treatment may influence energy metabolism regulation within the liver. We found that hyperglycemic Goto-Kakizaki rats showed lower plasmatic KYNA levels compared to normal rats. Oral administration of KYNA significantly delayed the onset of diabetes in Goto-Kakizaki rats compared to untreated animals. Moreover, we found that KYNA treatment significantly increased respiration exchange ratio and promoted the energy expenditure by stimulating the expression of uncoupling protein (UCP). We confirmed that KYNA stimulated the UCP expression in HepG2 cells and mouse hepatocytes at mRNA and protein levels. Our study reveals that KYNA could potentially act as an anti-diabetic agent and KYNA-induced UCP upregulation is closely associated with the regulation of energy metabolism. These results provide further evidence for the therapeutic potential of KYNA in diabetes.
RESUMEN
Type 2 diabetes is associated with an inflammatory phenotype in the pancreatic islets. We previously demonstrated that proinflammatory cytokines potently activate the tryptophan/kynurenine pathway (TKP) in INS-1 cells and in normal rat islets. Here we examined: (1) the TKP enzymes expression in the diabetic GK islets; (2) the TKP enzymes expression profiles in the GK islets before and after the onset of diabetes; (3) The glucose-stimulated insulin secretion (GSIS) in vitro in GK islets after KMO knockdown using specific morpholino-oligonucleotides against KMO or KMO blockade using the specific inhibitor Ro618048; (4) The glucose tolerance and GSIS after acute in vivo exposure to Ro618048 in GK rats. We report a remarkable induction of the kmo gene in GK islets and in human islets exposed to proinflammatory conditions. It occurred prominently in beta cells. The increased expression and activity of KMO reflected an acquired adaptation. Both KMO knockdown and specific inhibitor Ro618048 enhanced GSIS in vitro in GK islets. Moreover, acute administration of Ro618048 in vivo improved glucose tolerance, GSIS and basal blood glucose levels in GK rats. These results demonstrate that targeting islet TKP is able to correct defective GSIS. KMO inhibition could represent a potential therapeutic strategy for type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animales , Glucemia/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Humanos , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Morfolinos , Ratas , Ratas Wistar , Triptófano/metabolismoRESUMEN
Kynurenic acid (KYNA) is an important bio-active product of tryptophan metabolism. In addition to its well-known neuroprotective effects on mental health disorders, it has been proposed as a bio-marker for such metabolic diseases as atherosclerosis and diabetes. Emerging evidence suggests that KYNA acts as a signaling molecule controlling the networks involved in the balance of energy store and expenditure through GPR35 and AMPK signaling pathway. KYNA plays an important role in the pathogenesis and development of several endocrine and metabolic diseases. Exercise training promotes KYNA production in skeletal muscles and increases thermogenesis in the long term and limits weight gain, insulin resistance and inflammation. Additionally, KYNA is also present in breast milk and may act as an anti-obesity agent in infants. Although we are far from fully understanding the role of KYNA in our body, administration of KYNA, enzyme inhibitors or metabolites may serve as a potential therapeutic strategy for treating metabolic diseases. The present review provides a perspective on the current knowledge regarding the biological effects of KYNA in metabolic diseases and perinatal nutrition.