Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway

• Published in: Biochemical and biophysical research communications Vol. 488; no. 1; pp. 29 - 32
• Main Authors: Muzik, Otto, Burghardt, Paul, Yi, Zhengping, Kumar, Ajay, Seyoum, Berhane
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.06.2017
• Subjects: 60 APPLIED LIFE SCIENCES; Adult; AMT PET imaging; BIOLOGICAL PATHWAYS; BIOMEDICAL RADIOGRAPHY; brain; correlation; Down-Regulation - drug effects; Humans; HYDROXY COMPOUNDS; hyperglycemia; image analysis; INSULIN; Insulin Resistance; KYNURENINE; Kynurenine - metabolism; Kynurenine pathway; metabolism; METABOLITES; metformin; Metformin - administration & dosage; Metformin - pharmacology; pancreas; patients; POSITRON COMPUTED TOMOGRAPHY; RADIOLOGY AND NUCLEAR MEDICINE; TRYPTOPHAN; Tryptophan metabolism; Insulin resistance; Tryptophan metabolism; AMT PET imaging; Kynurenine pathway
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2017.04.155

An extensive body of literature indicates a relationship between insulin resistance and the up-regulation of the kynurenine pathway, i.e. the preferential conversion of tryptophan to kynurenine, with subsequent overproduction of diabetogenic downstream metabolites, such as kynurenic acid. We have measured the concentration of kynurenine pathway metabolites (kynurenines) in the brain and pancreas of two young (27 and 28 yrs) insulin resistant, normoglycemic subjects (M-values 2 and 4 mg/kg/min, respectively) using quantitative C-11-alpha-methyl-tryptophan PET/CT imaging. Both subjects underwent a preventive 12-week metformin treatment regimen (500 mg daily) prior to the PET/CT study. Whereas treatment was successful in one of the subject (M-value increased from 2 to 12 mg/kg/min), response was poor in the other subjects (M-value changed from 4 to 5 mg/kg/min). Brain and pancreas concentrations of kynurenines observed in the responder were similar to that in a healthy control subject, whereas kynurenines determined in the non-responder were about 25% higher and similar to those found in a severely insulin resistant patient. Consistent with this outcome, M-values were negatively correlated with both kynurenic acid levels (R2 = 0.68, p = 0.09) as well as with the kynurenine to tryptophan ratio (R2 = 0.63, p = 0.11). The data indicates that kynurenine pathway metabolites are increased in subjects with insulin resistance prior to overt manifestation of hyperglycemia. Moreover, successful metformin treatment leads to a normalization of tryptophan metabolism, most likely as a result of decreased contribution from the kynurenine metabolic pathway.