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

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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.


DVC and intravenous infusion of ALX regulates glucose homeostasis in 3d-HFD rats.(a) Experimental protocol for b–c. (b) Glucose infusion rates and (c) glucose production during clamps with DVC infusion of saline (n=5), glycine (n=6), ALX (n=5), glycine+7CKNA (n=5) and ALX+7CKNA (n=5). (b: *P<0.0003 versus saline and glycine+7CKNA; †P<0.001 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test; c: *P<0.006 versus saline and glycine+7CKNA; †P<0.002 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test.) (d) Glucose infusion rates and (e) glucose production during clamps with intravenous infusion of 6% DMSO(n=7) or ALX (n=7) in 3-d HFD rats. (d,e: *P<0.001 versus intravenous DMSO determined by t-test). Data are shown as the mean + s.e.m.
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f3: DVC and intravenous infusion of ALX regulates glucose homeostasis in 3d-HFD rats.(a) Experimental protocol for b–c. (b) Glucose infusion rates and (c) glucose production during clamps with DVC infusion of saline (n=5), glycine (n=6), ALX (n=5), glycine+7CKNA (n=5) and ALX+7CKNA (n=5). (b: *P<0.0003 versus saline and glycine+7CKNA; †P<0.001 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test; c: *P<0.006 versus saline and glycine+7CKNA; †P<0.002 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test.) (d) Glucose infusion rates and (e) glucose production during clamps with intravenous infusion of 6% DMSO(n=7) or ALX (n=7) in 3-d HFD rats. (d,e: *P<0.001 versus intravenous DMSO determined by t-test). Data are shown as the mean + s.e.m.

Mentions: We next sought to ascertain a therapeutic relevance for the glucose-lowering capacity of DVC GlyT1 inhibition first in 3-day high-fat-diet (3-d HFD)-fed rats (Fig. 3a). The rats placed on a 3-d HFD were first confirmed to be hyperphagic (cumulative food intake: 258±10 versus 178±11 kcal, P<0.01 3-d HFD (n=26) versus 3-d RC (n=11), t-tests) and hyperinsulinemic (3-d HFD (1.7±0.2, n=5) versus 3d RC rats (0.9±0.1, n=8), P<0.05, t-tests), consistent with the fact that 3d HFD rats were validated in parallel under hyperinsulinemic–euglycaemic clamp conditions in our research facility to exhibit hepatic insulin resistance20. We here evaluated whether antagonism of DVC GlyT1 modulates glucose homeostasis in these 3-d HFD rats to the same extent as direct DVC glycineinfusion during the pancreatic (basal insulin)–euglycaemic clamp conditions, given that DVC GlyT1 inhibition increases extracellular DVC glycine levels (Fig. 1h). Indeed, DVC GlyT1 inhibition with ALX increases the requirement of glucose (Fig. 3b) and suppresses the rate of glucose production (Fig. 3c) independent of alterations in glucose uptake (Supplementary Fig. 5a) and plasma glucose levels (Supplementary Fig. 5b) during the pancreatic clamp in HFD rats to the same extent as DVC glycine infusion (Fig. 3b,c). Further, this glucose production-lowering effect of DVC ALX or glycine in 3-d HFD rats requires the activation of the NMDA receptor GluN1 subunits as co-infusion of 7CKNA with ALX or glycine abates the glucose-suppressive ability of ALX and glycine (Fig.3b,c).


Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity
DVC and intravenous infusion of ALX regulates glucose homeostasis in 3d-HFD rats.(a) Experimental protocol for b–c. (b) Glucose infusion rates and (c) glucose production during clamps with DVC infusion of saline (n=5), glycine (n=6), ALX (n=5), glycine+7CKNA (n=5) and ALX+7CKNA (n=5). (b: *P<0.0003 versus saline and glycine+7CKNA; †P<0.001 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test; c: *P<0.006 versus saline and glycine+7CKNA; †P<0.002 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test.) (d) Glucose infusion rates and (e) glucose production during clamps with intravenous infusion of 6% DMSO(n=7) or ALX (n=7) in 3-d HFD rats. (d,e: *P<0.001 versus intravenous DMSO determined by t-test). Data are shown as the mean + s.e.m.
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f3: DVC and intravenous infusion of ALX regulates glucose homeostasis in 3d-HFD rats.(a) Experimental protocol for b–c. (b) Glucose infusion rates and (c) glucose production during clamps with DVC infusion of saline (n=5), glycine (n=6), ALX (n=5), glycine+7CKNA (n=5) and ALX+7CKNA (n=5). (b: *P<0.0003 versus saline and glycine+7CKNA; †P<0.001 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test; c: *P<0.006 versus saline and glycine+7CKNA; †P<0.002 versus saline and ALX+7CKNA; determined by ANOVA and Dunnett's post hoc test.) (d) Glucose infusion rates and (e) glucose production during clamps with intravenous infusion of 6% DMSO(n=7) or ALX (n=7) in 3-d HFD rats. (d,e: *P<0.001 versus intravenous DMSO determined by t-test). Data are shown as the mean + s.e.m.
Mentions: We next sought to ascertain a therapeutic relevance for the glucose-lowering capacity of DVC GlyT1 inhibition first in 3-day high-fat-diet (3-d HFD)-fed rats (Fig. 3a). The rats placed on a 3-d HFD were first confirmed to be hyperphagic (cumulative food intake: 258±10 versus 178±11 kcal, P<0.01 3-d HFD (n=26) versus 3-d RC (n=11), t-tests) and hyperinsulinemic (3-d HFD (1.7±0.2, n=5) versus 3d RC rats (0.9±0.1, n=8), P<0.05, t-tests), consistent with the fact that 3d HFD rats were validated in parallel under hyperinsulinemic–euglycaemic clamp conditions in our research facility to exhibit hepatic insulin resistance20. We here evaluated whether antagonism of DVC GlyT1 modulates glucose homeostasis in these 3-d HFD rats to the same extent as direct DVC glycineinfusion during the pancreatic (basal insulin)–euglycaemic clamp conditions, given that DVC GlyT1 inhibition increases extracellular DVC glycine levels (Fig. 1h). Indeed, DVC GlyT1 inhibition with ALX increases the requirement of glucose (Fig. 3b) and suppresses the rate of glucose production (Fig. 3c) independent of alterations in glucose uptake (Supplementary Fig. 5a) and plasma glucose levels (Supplementary Fig. 5b) during the pancreatic clamp in HFD rats to the same extent as DVC glycine infusion (Fig. 3b,c). Further, this glucose production-lowering effect of DVC ALX or glycine in 3-d HFD rats requires the activation of the NMDA receptor GluN1 subunits as co-infusion of 7CKNA with ALX or glycine abates the glucose-suppressive ability of ALX and glycine (Fig.3b,c).

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.