Abstract
Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / metabolism
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Diabetes Mellitus, Experimental / chemically induced*
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Diet, High-Fat / adverse effects
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Energy Metabolism
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Gene Expression Regulation / drug effects
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Glycemic Index
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Glycine Plasma Membrane Transport Proteins / genetics
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Glycine Plasma Membrane Transport Proteins / metabolism*
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Homeostasis
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Kynurenic Acid / administration & dosage
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Kynurenic Acid / analogs & derivatives
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Kynurenic Acid / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Obesity / metabolism*
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Rats
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Rats, Sprague-Dawley
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Receptors, Lipoxin / administration & dosage*
Substances
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Glycine Plasma Membrane Transport Proteins
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Receptors, Lipoxin
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Slc6a9 protein, mouse
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Slc6a9 protein, rat
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Kynurenic Acid
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7-chlorokynurenic acid