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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.


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Chemical inhibition of DVC GlyT1 regulates glucose homeostasis in obese rats.(a) Experimental protocol for b–d. (b) Body weight gain in rats that were fed with HFD (white circles, n=18) or regular chow (RC, white squares, n=6). Inflections of the body weight curves at day 16 and day 24 represent DVC cannulation and vascular catheterization surgery days, respectively. *P<0.02 main effect of diet, F(1,22)=6.964 determined by repeated measures ANOVA. (c) Glucose infusion rates and (d) glucose production during clamps in 28d RC-fed rats with DVC infusion of saline (n=5) or ALX (n=5) and in 28-d HFD-fed rats with DVC infusion of saline (n=7) or ALX (n=7; c,d: *P<0.01 versus the respective DVC saline determined by ANOVA and Tukey's post hoc test). Data are shown as the mean + s.e.m.
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f5: Chemical inhibition of DVC GlyT1 regulates glucose homeostasis in obese rats.(a) Experimental protocol for b–d. (b) Body weight gain in rats that were fed with HFD (white circles, n=18) or regular chow (RC, white squares, n=6). Inflections of the body weight curves at day 16 and day 24 represent DVC cannulation and vascular catheterization surgery days, respectively. *P<0.02 main effect of diet, F(1,22)=6.964 determined by repeated measures ANOVA. (c) Glucose infusion rates and (d) glucose production during clamps in 28d RC-fed rats with DVC infusion of saline (n=5) or ALX (n=5) and in 28-d HFD-fed rats with DVC infusion of saline (n=7) or ALX (n=7; c,d: *P<0.01 versus the respective DVC saline determined by ANOVA and Tukey's post hoc test). Data are shown as the mean + s.e.m.

Mentions: We next assessed whether DVC GlyT1 inhibition improves glucose metabolism in 28-d HFD-induced obese rats (Fig. 5a). The rats fed a HFD for 28 days were first confirmed to be obese (Fig. 5b) and hyperinsulinemic (28d HFD rats (2.5±0.2, n=10) versus 28d RC rats (1.9±0.2, n=9), P<0.05, t-test), consistent with the fact that this obese model was validated in parallel under hyperinsulinemic–euglycaemic clamp conditions in our research facility to exhibit hepatic and peripheral insulin resistance20. Importantly, in both 28-day regular chow and HFD cohorts, we here report that acute inhibition of DVC GlyT1 with ALX infusion into the DVC increases glucose infusion rates (Fig. 5c) and lowers glucose production (Fig. 5d) independent of changes in the glucose uptake (Supplementary Fig. 6a) and plasma glucose levels (Supplementary Fig. 6b) during pancreatic (basal insulin)–euglycaemic clamp conditions. Notably, the glucose production-lowering effect of acute DVC GlyT1 antagonism is evident in spite of the weight gain incurred by chronic high-fat feeding (body weight on the morning of clamp experiments: 419±7 versus 390±10 g, P<0.05 28-d HFD versus 28-d RC, t-test).


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 obese rats.(a) Experimental protocol for b–d. (b) Body weight gain in rats that were fed with HFD (white circles, n=18) or regular chow (RC, white squares, n=6). Inflections of the body weight curves at day 16 and day 24 represent DVC cannulation and vascular catheterization surgery days, respectively. *P<0.02 main effect of diet, F(1,22)=6.964 determined by repeated measures ANOVA. (c) Glucose infusion rates and (d) glucose production during clamps in 28d RC-fed rats with DVC infusion of saline (n=5) or ALX (n=5) and in 28-d HFD-fed rats with DVC infusion of saline (n=7) or ALX (n=7; c,d: *P<0.01 versus the respective DVC saline determined by ANOVA and Tukey's post hoc test). Data are shown as the mean + s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121412&req=5

f5: Chemical inhibition of DVC GlyT1 regulates glucose homeostasis in obese rats.(a) Experimental protocol for b–d. (b) Body weight gain in rats that were fed with HFD (white circles, n=18) or regular chow (RC, white squares, n=6). Inflections of the body weight curves at day 16 and day 24 represent DVC cannulation and vascular catheterization surgery days, respectively. *P<0.02 main effect of diet, F(1,22)=6.964 determined by repeated measures ANOVA. (c) Glucose infusion rates and (d) glucose production during clamps in 28d RC-fed rats with DVC infusion of saline (n=5) or ALX (n=5) and in 28-d HFD-fed rats with DVC infusion of saline (n=7) or ALX (n=7; c,d: *P<0.01 versus the respective DVC saline determined by ANOVA and Tukey's post hoc test). Data are shown as the mean + s.e.m.
Mentions: We next assessed whether DVC GlyT1 inhibition improves glucose metabolism in 28-d HFD-induced obese rats (Fig. 5a). The rats fed a HFD for 28 days were first confirmed to be obese (Fig. 5b) and hyperinsulinemic (28d HFD rats (2.5±0.2, n=10) versus 28d RC rats (1.9±0.2, n=9), P<0.05, t-test), consistent with the fact that this obese model was validated in parallel under hyperinsulinemic–euglycaemic clamp conditions in our research facility to exhibit hepatic and peripheral insulin resistance20. Importantly, in both 28-day regular chow and HFD cohorts, we here report that acute inhibition of DVC GlyT1 with ALX infusion into the DVC increases glucose infusion rates (Fig. 5c) and lowers glucose production (Fig. 5d) independent of changes in the glucose uptake (Supplementary Fig. 6a) and plasma glucose levels (Supplementary Fig. 6b) during pancreatic (basal insulin)–euglycaemic clamp conditions. Notably, the glucose production-lowering effect of acute DVC GlyT1 antagonism is evident in spite of the weight gain incurred by chronic high-fat feeding (body weight on the morning of clamp experiments: 419±7 versus 390±10 g, P<0.05 28-d HFD versus 28-d RC, t-test).

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.


Related in: MedlinePlus