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Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Chemical inhibition of DVC GlyT1 regulates glucose homeostasis in healthy rats.(a) Schematic representation of working hypothesis: glycine transporter-1 (GlyT1) facilitates the cellular uptake of glycine in the dorsal vagal complex (DVC). Chemical (via DVC ALX infusion) or genetic (via DVC lentiviral injection of GlyT1 shRNA) inhibition of GlyT1 increases extracellular glycine levels in the DVC, which potentiates the activation of DVC N-methyl-D-aspartate receptors (NMDAr) to regulate glucose production and glucose tolerance, and food intake and body weight gain. MK-801, NMDAr ion channel blocker; 7-chlorokynurenic acid, 7CKNA-antagonist to the GluN1 subunit of NMDAr. (b) Plasma glucose levels (inset: integrated area under the curve (AUC)) and (c) plasma insulin levels during ivGTT with DVC infusion of ALX (n=8, black squares) or saline (n=7, white squares). †P<0.04, ††P<0.0008determined by Sidak's multiple comparisons test following repeated-measures ANOVA. *P<0.05 determined by t-test. (d) Glucose infusion rates and (e) glucose production during clamps with DVC infusion of saline (n=11), ALX (n=9), MK801 (n=9), ALX+MK801 (n=5), ALX+7CKNA (n=5), Ad-MM+ALX (n=5) or Ad-GluN1 shRNA+ALX (n=5). (d: *P<0.002 versus saline, MK801, ALX+MK801, and ALX+7CKNA determined by ANOVA and Dunnett's post hoc test; †P<0.002 versus Ad-GluN1 shRNA+ALX determined by t-test; (e) *P<0.02 versus saline, MK801, ALX+MK801 and ALX+7CKNA determined by ANOVA and Dunnett'spost hoc test; †P<0.0008 versus Ad-GluN1 shRNA+ALX determined by t-test.) (f) Glucose infusion rates and (g) glucose production during clamps with DVC ALX infusion in vagotomized (n=7) or sham-operated (n=5) rats or DVC saline infusion in vagotomized (n=7) or sham-operated rats (n=5) rats. (for f and g *P<0.01 compared with all the other groups determined by ANOVA and Dunnet's post hoc test). (h) Extracellular glycine levels within the DVC following DVC infusion of ALX (n=7) or saline (n=7) in microdialysis studies. *P<0.03 versus saline determined by t-test. Data are shown as the mean+s.e.m.
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f1: Chemical inhibition of DVC GlyT1 regulates glucose homeostasis in healthy rats.(a) Schematic representation of working hypothesis: glycine transporter-1 (GlyT1) facilitates the cellular uptake of glycine in the dorsal vagal complex (DVC). Chemical (via DVC ALX infusion) or genetic (via DVC lentiviral injection of GlyT1 shRNA) inhibition of GlyT1 increases extracellular glycine levels in the DVC, which potentiates the activation of DVC N-methyl-D-aspartate receptors (NMDAr) to regulate glucose production and glucose tolerance, and food intake and body weight gain. MK-801, NMDAr ion channel blocker; 7-chlorokynurenic acid, 7CKNA-antagonist to the GluN1 subunit of NMDAr. (b) Plasma glucose levels (inset: integrated area under the curve (AUC)) and (c) plasma insulin levels during ivGTT with DVC infusion of ALX (n=8, black squares) or saline (n=7, white squares). †P<0.04, ††P<0.0008determined by Sidak's multiple comparisons test following repeated-measures ANOVA. *P<0.05 determined by t-test. (d) Glucose infusion rates and (e) glucose production during clamps with DVC infusion of saline (n=11), ALX (n=9), MK801 (n=9), ALX+MK801 (n=5), ALX+7CKNA (n=5), Ad-MM+ALX (n=5) or Ad-GluN1 shRNA+ALX (n=5). (d: *P<0.002 versus saline, MK801, ALX+MK801, and ALX+7CKNA determined by ANOVA and Dunnett's post hoc test; †P<0.002 versus Ad-GluN1 shRNA+ALX determined by t-test; (e) *P<0.02 versus saline, MK801, ALX+MK801 and ALX+7CKNA determined by ANOVA and Dunnett'spost hoc test; †P<0.0008 versus Ad-GluN1 shRNA+ALX determined by t-test.) (f) Glucose infusion rates and (g) glucose production during clamps with DVC ALX infusion in vagotomized (n=7) or sham-operated (n=5) rats or DVC saline infusion in vagotomized (n=7) or sham-operated rats (n=5) rats. (for f and g *P<0.01 compared with all the other groups determined by ANOVA and Dunnet's post hoc test). (h) Extracellular glycine levels within the DVC following DVC infusion of ALX (n=7) or saline (n=7) in microdialysis studies. *P<0.03 versus saline determined by t-test. Data are shown as the mean+s.e.m.

Mentions: On the other hand, regulating glycine concentration by manipulating glycine transporters (GlyT) has demonstrated clinical feasibility. Since glycine uptake into cells is regulated by glycine transporters, of which GlyT1 is the primary regulator of glycine levels in the vicinity of NMDA receptors24, GlyT1 inhibition therefore increases extracellular glycine levels to potentiate the activation of NMDA receptors25. Modulation of NMDA receptor neurotransmission is currently used as a therapy for schizophrenia, a disease that displays reduced NMDA receptor function. In fact, the clinical trials have shown that augmentation of NMDA receptor function via GlyT1 inhibitors improve symptoms of schizophrenia2627. However, no studies to date have investigated the therapeutic potential of GlyT1 inhibition for the treatment of diabetes and obesity. Here, we examined whether GlyT1 inhibition regulates glucose and energy homeostasis in healthy,obese and diabetic rodents (Fig. 1a). We demonstrate that direct inhibition of GlyT1 in the DVC confers metabolic benefits including improved glucose tolerance, lowered glucose production, reduced feeding and lowered body weight gain in diabetic and obese rodents. We also report that systemic infusion of GlyT1 inhibitor recapitulates the metabolic effects of DVC GlyT1 inhibition. Thus, inhibiting GlyT1 in the brain represents a potential novel therapeutic strategy to lower plasma glucose levels and body weight in diabetes and obesity.


Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity
Chemical inhibition of DVC GlyT1 regulates glucose homeostasis in healthy rats.(a) Schematic representation of working hypothesis: glycine transporter-1 (GlyT1) facilitates the cellular uptake of glycine in the dorsal vagal complex (DVC). Chemical (via DVC ALX infusion) or genetic (via DVC lentiviral injection of GlyT1 shRNA) inhibition of GlyT1 increases extracellular glycine levels in the DVC, which potentiates the activation of DVC N-methyl-D-aspartate receptors (NMDAr) to regulate glucose production and glucose tolerance, and food intake and body weight gain. MK-801, NMDAr ion channel blocker; 7-chlorokynurenic acid, 7CKNA-antagonist to the GluN1 subunit of NMDAr. (b) Plasma glucose levels (inset: integrated area under the curve (AUC)) and (c) plasma insulin levels during ivGTT with DVC infusion of ALX (n=8, black squares) or saline (n=7, white squares). †P<0.04, ††P<0.0008determined by Sidak's multiple comparisons test following repeated-measures ANOVA. *P<0.05 determined by t-test. (d) Glucose infusion rates and (e) glucose production during clamps with DVC infusion of saline (n=11), ALX (n=9), MK801 (n=9), ALX+MK801 (n=5), ALX+7CKNA (n=5), Ad-MM+ALX (n=5) or Ad-GluN1 shRNA+ALX (n=5). (d: *P<0.002 versus saline, MK801, ALX+MK801, and ALX+7CKNA determined by ANOVA and Dunnett's post hoc test; †P<0.002 versus Ad-GluN1 shRNA+ALX determined by t-test; (e) *P<0.02 versus saline, MK801, ALX+MK801 and ALX+7CKNA determined by ANOVA and Dunnett'spost hoc test; †P<0.0008 versus Ad-GluN1 shRNA+ALX determined by t-test.) (f) Glucose infusion rates and (g) glucose production during clamps with DVC ALX infusion in vagotomized (n=7) or sham-operated (n=5) rats or DVC saline infusion in vagotomized (n=7) or sham-operated rats (n=5) rats. (for f and g *P<0.01 compared with all the other groups determined by ANOVA and Dunnet's post hoc test). (h) Extracellular glycine levels within the DVC following DVC infusion of ALX (n=7) or saline (n=7) in microdialysis studies. *P<0.03 versus saline determined by t-test. Data are shown as the mean+s.e.m.
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f1: Chemical inhibition of DVC GlyT1 regulates glucose homeostasis in healthy rats.(a) Schematic representation of working hypothesis: glycine transporter-1 (GlyT1) facilitates the cellular uptake of glycine in the dorsal vagal complex (DVC). Chemical (via DVC ALX infusion) or genetic (via DVC lentiviral injection of GlyT1 shRNA) inhibition of GlyT1 increases extracellular glycine levels in the DVC, which potentiates the activation of DVC N-methyl-D-aspartate receptors (NMDAr) to regulate glucose production and glucose tolerance, and food intake and body weight gain. MK-801, NMDAr ion channel blocker; 7-chlorokynurenic acid, 7CKNA-antagonist to the GluN1 subunit of NMDAr. (b) Plasma glucose levels (inset: integrated area under the curve (AUC)) and (c) plasma insulin levels during ivGTT with DVC infusion of ALX (n=8, black squares) or saline (n=7, white squares). †P<0.04, ††P<0.0008determined by Sidak's multiple comparisons test following repeated-measures ANOVA. *P<0.05 determined by t-test. (d) Glucose infusion rates and (e) glucose production during clamps with DVC infusion of saline (n=11), ALX (n=9), MK801 (n=9), ALX+MK801 (n=5), ALX+7CKNA (n=5), Ad-MM+ALX (n=5) or Ad-GluN1 shRNA+ALX (n=5). (d: *P<0.002 versus saline, MK801, ALX+MK801, and ALX+7CKNA determined by ANOVA and Dunnett's post hoc test; †P<0.002 versus Ad-GluN1 shRNA+ALX determined by t-test; (e) *P<0.02 versus saline, MK801, ALX+MK801 and ALX+7CKNA determined by ANOVA and Dunnett'spost hoc test; †P<0.0008 versus Ad-GluN1 shRNA+ALX determined by t-test.) (f) Glucose infusion rates and (g) glucose production during clamps with DVC ALX infusion in vagotomized (n=7) or sham-operated (n=5) rats or DVC saline infusion in vagotomized (n=7) or sham-operated rats (n=5) rats. (for f and g *P<0.01 compared with all the other groups determined by ANOVA and Dunnet's post hoc test). (h) Extracellular glycine levels within the DVC following DVC infusion of ALX (n=7) or saline (n=7) in microdialysis studies. *P<0.03 versus saline determined by t-test. Data are shown as the mean+s.e.m.
Mentions: On the other hand, regulating glycine concentration by manipulating glycine transporters (GlyT) has demonstrated clinical feasibility. Since glycine uptake into cells is regulated by glycine transporters, of which GlyT1 is the primary regulator of glycine levels in the vicinity of NMDA receptors24, GlyT1 inhibition therefore increases extracellular glycine levels to potentiate the activation of NMDA receptors25. Modulation of NMDA receptor neurotransmission is currently used as a therapy for schizophrenia, a disease that displays reduced NMDA receptor function. In fact, the clinical trials have shown that augmentation of NMDA receptor function via GlyT1 inhibitors improve symptoms of schizophrenia2627. However, no studies to date have investigated the therapeutic potential of GlyT1 inhibition for the treatment of diabetes and obesity. Here, we examined whether GlyT1 inhibition regulates glucose and energy homeostasis in healthy,obese and diabetic rodents (Fig. 1a). We demonstrate that direct inhibition of GlyT1 in the DVC confers metabolic benefits including improved glucose tolerance, lowered glucose production, reduced feeding and lowered body weight gain in diabetic and obese rodents. We also report that systemic infusion of GlyT1 inhibitor recapitulates the metabolic effects of DVC GlyT1 inhibition. Thus, inhibiting GlyT1 in the brain represents a potential novel therapeutic strategy to lower plasma glucose levels and body weight in diabetes and obesity.

View Article: PubMed Central - PubMed

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.

No MeSH data available.