Amino acid transporters as modulators of glucose homeostasis

Bröer, Stefan

doi:10.1016/j.tem.2021.11.004

Cited by 26 publications

(20 citation statements)

References 131 publications

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“…BCAA play a central role in insulin resistance and appear detrimental to insulin sensitivity in animals and humans ( 36 ). Amino acids may also affect a variety of other processes involved in glucose homeostasis ( 37 ). It has also been shown that amino acids influence the distribution of GLUT4-containing vesicles indicating that the insulin-dependent glucose influx mediated by an increase of GLUT4 density in the plasma membrane may already be compromised ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Plasma Metabolic Signatures of Healthy Overweight Subjects Challenged With an Oral Glucose Tolerance Test

et al. 2022

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Insulin secretion following ingestion of a carbohydrate load affects a multitude of metabolic pathways that simultaneously change direction and quantity of interorgan fluxes of sugars, lipids and amino acids. In the present study, we aimed at identifying markers associated with differential responses to an OGTT a population of healthy adults. By use of three metabolite profiling platforms, we assessed these postprandial responses of a total of 202 metabolites in plasma of 72 healthy volunteers undergoing comprehensive phenotyping and of which half enrolled into a weight-loss program over a three-month period. A standard oral glucose tolerance test (OGTT) served as dietary challenge test to identify changes in postprandial metabolite profiles. Despite classified as healthy according to WHO criteria, two discrete clusters (A and B) were identified based on the postprandial glucose profiles with a balanced distribution of volunteers based on gender and other measures. Cluster A individuals displayed 26% higher postprandial glucose levels, delayed glucose clearance and increased fasting plasma concentrations of more than 20 known biomarkers of insulin resistance and diabetes previously identified in large cohort studies. The volunteers identified by canonical postprandial responses that form cluster A may be called pre-pre-diabetics and defined as “at risk” for development of insulin resistance. Moreover, postprandial changes in selected fatty acids and complex lipids, bile acids, amino acids, acylcarnitines and sugars like mannose revealed marked differences in the responses seen in cluster A and cluster B individuals that sustained over the entire challenge test period of 240 min. Almost all metabolites, including glucose and insulin, returned to baseline values at the end of the test (at 240 min), except a variety of amino acids and here those that have been linked to diabetes development. Analysis of the corresponding metabolite profile in a fasting blood sample may therefore allow for early identification of these subjects at risk for insulin resistance without the need to undergo an OGTT.

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Section: Discussionmentioning

confidence: 99%

Plasma Metabolic Signatures of Healthy Overweight Subjects Challenged With an Oral Glucose Tolerance Test

et al. 2022

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“…Similar results have also been reported in obese mice [ 12 , 14 ]. Although GCN2 in other cells (e.g., skeletal muscle cells [ 19 ], adipocytes [ 20 ], and pancreatic β-cells [ 21 ]) may have the ability to affect glycemia and whole-body insulin sensitivity in mice. The finding that knockdown of hepatic GCN2 significantly alleviated hyperglycemia and insulin resistance in db/db mice suggested that hepatic GCN2 is an important glycemic regulator in T2D mice.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacological Inhibition of GCN2 Ameliorates Hyperglycemia and Insulin Resistance in Type 2 Diabetic Mice

Yuan

Shen

et al. 2022

Antioxidants

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It is well recognized that there is a strong and complex association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We previously demonstrated that genetic knockout or pharmacological inhibition of general control nondepressible kinase 2 (GCN2), a well-known amino acid sensor, alleviated hepatic steatosis and insulin resistance in obese mice. However, whether GCN2 affects the development of T2D remains unclear. After a high-fat diet (HFD) plus low-dose streptozotocin (STZ) treatments, Gcn2−/− mice developed less hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress than wild-type (WT) mice. Inhibition of GCN2 by intraperitoneal injection of 3 mg/kg GCN2iB (a specific inhibitor of GCN2) every other day for 6 weeks also ameliorated hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress in HFD/STZ- and leptin receptor deletion (db/db)-induced T2D mice. Moreover, depletion of hepatic GCN2 in db/db mice by tail vein injection of an AAV8-shGcn2 vector resulted in similar improvement in those metabolic disorders. The protective mechanism of GCN2 inhibition in T2D mice was associated with regulation of the glucose metabolic pathway, repression of lipogenesis genes, and activation of the Nrf2 pathway. Together, our data provide evidence that strategies to inhibit hepatic GCN2 activity may be novel approaches for T2D therapy.

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“…This is of particular importance when considering the initiating role of glutamine in the activation by leucine of the mechanistic Target Of Rapamycin (mTOR) Complex 1 (mTORC1), the main effector of postprandial protein synthesis [ 6 , 7 ]. Note that transport via LAT1 and SNAT2 is influenced by insulin via different mechanisms such as increased protein expression (LAT1, SNAT2) or membrane translocation to the plasma membrane of intracellular storage vesicles (SNAT2) from a subcellular localization similar to that of the glucose transporter GLUT4 [ 8 ].…”

Section: Bcaa Metabolismmentioning

confidence: 99%

“…In addition, they are very good substrates of energy metabolism, either at the muscular level or, when their muscular use reaches its limits, at the hepatic level, particularly for ketoneogenesis and gluconeogenesis in the post-absorptive period. Finally, the organism must take care to limit their plasma concentration, taking into account their potential central effects [ 24 ], namely their influence on the synthesis of neuromediators (via glutamate synthesis, or by competition with the cerebral transport of aromatic amino acids via LAT1/2 [ 8 ]) or because of their neurotoxicity, with the ultimate situation of maple syrup urine disease (MSUD, a BCKD deficiency) [ 25 ].…”

Section: Bcaa Metabolismmentioning

confidence: 99%

Branched-Chain Amino Acids and Insulin Resistance, from Protein Supply to Diet-Induced Obesity

2022

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For more than a decade, there has been a wide debate about the branched-chain amino acids (BCAA) leucine, valine, and isoleucine, with, on the one hand, the supporters of their anabolic effects and, on the other hand, those who suspect them of promoting insulin resistance. Indeed, the role of leucine in the postprandial activation of protein synthesis has been clearly established, even though supplementation studies aimed at taking advantage of this property are rather disappointing. Furthermore, there is ample evidence of an association between the elevation of their plasma concentrations and insulin resistance or the risk of developing type 2 diabetes, although there are many confounding factors, starting with the level of animal protein consumption. After a summary of their metabolism and anabolic properties, we analyze in this review the factors likely to increase the plasma concentrations of BCAAs, including insulin-resistance. After an analysis of supplementation or restriction studies in search of a direct role of BCAAs in insulin resistance, we discuss an indirect role through some of their metabolites: branched-chain keto acids, C3 and C5 acylcarnitines, and hydroxyisobutyrate. Overall, given the importance of insulin in the metabolism of these amino acids, it is very likely that small alterations in insulin sensitivity are responsible for a reduction in their catabolism long before the onset of impaired glucose tolerance.

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Amino acid transporters as modulators of glucose homeostasis

Cited by 26 publications

References 131 publications

Plasma Metabolic Signatures of Healthy Overweight Subjects Challenged With an Oral Glucose Tolerance Test

Plasma Metabolic Signatures of Healthy Overweight Subjects Challenged With an Oral Glucose Tolerance Test

Genetic and Pharmacological Inhibition of GCN2 Ameliorates Hyperglycemia and Insulin Resistance in Type 2 Diabetic Mice

Branched-Chain Amino Acids and Insulin Resistance, from Protein Supply to Diet-Induced Obesity

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