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

Yue, Jessica T.Y.; Abraham, Mona A.; Bauer, Paige V.; LaPierre, Mary P.; Wang, Peili; Duca, Frank A.; Filippi, B; Chan, Owen; Lam, Tony K.T.

doi:10.1038/ncomms13501

Cited by 24 publications

(13 citation statements)

References 56 publications

(85 reference statements)

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“…5a ), which has previously been shown to reverse the ability of upper small intestinal lipid-sensing mechanisms to regulate glucose homeostasis 39 . Consistent with previous studies 41 , 3-day HFD-fed rats were hyperphagic (Supplementary Fig. 4a ) compared to animals that received regular chow (RC) and exhibited hyperinsulinemia (RC: 1.1 ± 0.4 ng mL −1 versus HFD: 1.7 ± 0.6 ng mL −1 , p < 0.05 (two-tailed, unpaired t -test)) (i.e., evidence of insulin resistance) despite no difference in post-surgical body weight (Supplementary Fig.…”

Section: Resultssupporting

confidence: 93%

Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing

et al. 2018

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High protein feeding improves glucose homeostasis in rodents and humans with diabetes, but the mechanisms that underlie this improvement remain elusive. Here we show that acute administration of casein hydrolysate directly into the upper small intestine increases glucose tolerance and inhibits glucose production in rats, independently of changes in plasma amino acids, insulin levels, and food intake. Inhibition of upper small intestinal peptide transporter 1 (PepT1), the primary oligopeptide transporter in the small intestine, reverses the preabsorptive ability of upper small intestinal casein infusion to increase glucose tolerance and suppress glucose production. The glucoregulatory role of PepT1 in the upper small intestine of healthy rats is further demonstrated by glucose homeostasis disruption following high protein feeding when PepT1 is inhibited. PepT1-mediated protein-sensing mechanisms also improve glucose homeostasis in models of early-onset insulin resistance and obesity. We demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by PepT1 have beneficial effects on whole-body glucose homeostasis.

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Section: Resultssupporting

confidence: 93%

Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing

et al. 2018

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“…Other neurotransmitters, including glutamate and GABA (-aminobutyric acid) (64)(65)(66), are also affected by DBS of the NAc area and may be involved in its glucoregulatory effects. In light of this, facilitation of glutamatergic NMDA (N-methyld-aspartate) receptor-mediated neurotransmission by pharmacological increase of extracellular glycine, an essential co-agonist, has recently been shown to improve glucose tolerance and energy homeostasis (9). Here, (i) striatal dopamine release and peripheral insulin sensitivity were differentially regulated by DBS in lean and obese patients, whereas the DBS effect on hepatic insulin sensitivity was similar in lean and obese patients; (ii) pharmacological dopamine reduction with AMPT acutely reduced peripheral, but not hepatic, insulin sensitivity; and (iii) D 1 R + neuronal activation in mice enhanced glucose clearance, but did not lower fasting blood glucose, which is primarily determined by EGP.…”

Section: Discussionmentioning

confidence: 99%

Striatal dopamine regulates systemic glucose metabolism in humans and mice

et al. 2018

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The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. We present a series of experiments supporting the regulation of peripheral glucose metabolism by striatal dopamine signaling. First, we present the case of a diabetes patient who displayed strongly reduced insulin requirements after treatment with bilateral deep brain stimulation (DBS) targeting the anterior limb of the internal capsule. Next, we show that DBS in this striatal area, which induced dopamine release, increased hepatic and peripheral insulin sensitivity in 14 nondiabetic patients with obsessive-compulsive disorder. Conversely, systemic dopamine depletion reduced peripheral insulin sensitivity in healthy subjects. Supporting these human data, we demonstrate that optogenetic activation of dopamine D receptor-expressing neurons in the nucleus accumbens increased glucose tolerance and insulin sensitivity in mice. Together, these findings support the hypothesis that striatal neuronal activity regulates systemic glucose metabolism.

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“…Selective GlyT-1 inhibitors increase extracellular glycine levels and potentiate N-methyl-D-aspartate (NMDA) receptor activity [55]. Hence, GLYT1 inhibition in the dorsal vagal complex suppressed hepatic glucose production, increased glucose tolerance, and reduced food intake and body weight gain in healthy, obese, and diabetic rats [56]. GLYT1 is also found throughout the intestine, where it is responsible for 30–50% of glycine uptake into intestinal epithelial cells across the basolateral membrane.…”

Section: Glycine Dietary Intake and Metabolismmentioning

confidence: 99%

Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases

et al. 2019

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Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation. The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency—especially in obesity and associated metabolic disorders—and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances. This study focuses on the importance of diet, gut microbiota, and liver metabolism in determining glycine availability in obesity and associated metabolic disorders.

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

Cited by 24 publications

References 56 publications

Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing

Physiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing

Striatal dopamine regulates systemic glucose metabolism in humans and mice

Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases

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