Otto Muzik1, Paul Burghardt2, Zhengping Yi3, Ajay Kumar4, Berhane Seyoum5. 1. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; Department of Radiology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: otto@pet.wayne.edu. 2. Department of Food and Nutrition Science, Wayne State University School of Medicine, Detroit, MI, USA. 3. Department of Pharmacological Sciences, College of Pharmacy and Health Sciences, Wayne State University School of Medicine, Detroit, MI, USA. 4. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA. 5. Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Wayne State University School of Medicine, Detroit, MI, USA.
Abstract
CONTEXT: 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. CASE DESCRIPTION: 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). CONCLUSION: 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. Published by Elsevier Inc.
CONTEXT: 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. CASE DESCRIPTION: 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). CONCLUSION: 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. Published by Elsevier Inc.
Entities:
Keywords:
AMT PET imaging; Insulin resistance; Kynurenine pathway; Tryptophan metabolism
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