Leucine Facilitates Insulin Signaling through a Gαi Protein-dependent Signaling Pathway in Hepatocytes

Yang, Xuefeng; Mei, Shuang; Wang, Xiaolei; Li, Xiang; Li, Rui; Ma, Yan; Hao, Liping; Yao, Ping; Liu, Liegang; Sun, Xiufa; Gu, Haihua; Liu, Zhenqi; Cao, Wenhong

doi:10.1074/jbc.m112.409409

Cited by 10 publications

(6 citation statements)

References 46 publications

(38 reference statements)

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“…It is noted that, in parallel with arguments implicating plasma BCAA as negative regulator of glucose metabolism, there is evidence arguing about a positive role of BCAA in the regulation of glucose metabolism [ 36 – 42 ]. Increased plasma BCAA concentrations, secondary to disruption of genes implicated in BCAA catabolism in experimental animal models, results in significant improvements in insulin sensitivity [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Acute Exposure to Increased Plasma Branched-Chain Amino Acid Concentrations on Insulin-Mediated Plasma Glucose Turnover in Healthy Young Subjects

et al. 2015

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BackgroundPlasma branched-chain amino acids (BCAA) are inversely related to insulin sensitivity of glucose metabolism in humans. However, currently, it is not known whether there is a cause-and-effect relationship between increased plasma BCAA concentrations and decreased insulin sensitivity.ObjectiveTo determine the effects of acute exposure to increased plasma BCAA concentrations on insulin-mediated plasma glucose turnover in humans.MethodsTen healthy subjects were randomly assigned to an experiment where insulin was infused at 40 mU/m2/min (40U) during the second half of a 6-hour intravenous infusion of a BCAA mixture (i.e., BCAA; N = 5) to stimulate plasma glucose turnover or under the same conditions without BCAA infusion (Control; N = 5). In a separate experiment, seven healthy subjects were randomly assigned to receive insulin infusion at 80 mU/m2/min (80U) in association with the above BCAA infusion (N = 4) or under the same conditions without BCAA infusion (N = 3). Plasma glucose turnover was measured prior to and during insulin infusion.ResultsInsulin infusion completely suppressed the endogenous glucose production (EGP) across all groups. The percent suppression of EGP was not different between Control and BCAA in either the 40U or 80U experiments (P > 0.05). Insulin infusion stimulated whole-body glucose disposal rate (GDR) across all groups. However, the increase (%) in GDR was not different [median (1st quartile – 3rd quartile)] between Control and BCAA in either the 40U ([199 (167–278) vs. 186 (94–308)] or 80 U ([491 (414–548) vs. 478 (409–857)] experiments (P > 0.05). Likewise, insulin stimulated the glucose metabolic clearance in all experiments (P < 0.05) with no differences between Control and BCAA in either of the experiments (P > 0.05).ConclusionShort-term exposure of young healthy subjects to increased plasma BCAA concentrations does not alter the insulin sensitivity of glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Effects of Acute Exposure to Increased Plasma Branched-Chain Amino Acid Concentrations on Insulin-Mediated Plasma Glucose Turnover in Healthy Young Subjects

et al. 2015

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“…showed increased glucose uptake of L6 myotubes treated with leucine, which was observed both with and without insulin stimulation 21 . Other reports have also shown leucine increases insulin signaling in both liver and muscle 23,25 . A recent report also investigated the effect of whey protein or whey protein hydrolysate versus casein, and showed reduced body weight in high‐fat‐fed mice given whey protein hydrolysate versus casein controls 26 .…”

Section: Introductionmentioning

confidence: 90%

“…21 Other reports have also shown leucine increases insulin signaling in both liver and muscle. 23,25 A recent report also investigated the effect of whey protein or whey protein hydrolysate versus casein, and showed reduced body weight in highfat-fed mice given whey protein hydrolysate versus casein controls. 26 The report also demonstrated reduced serum glucose in high-fat-fed mice given either whey protein or whey protein hydrolysate versus casein controls, as well as reduced insulin and improved insulin sensitivity in high-fat-fed mice that received whey protein hydrolysate.…”

Section: Introductionmentioning

confidence: 99%

Branched‐chain amino acids at supraphysiological but not physiological levels reduce myotube insulin sensitivity

Rivera

Vaughan

2021

Diabetes Metabolism Res

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Aims Branched‐chain amino acids (BCAA) are often emphasized in the diets of avid exercisers, yet population data demonstrates a correlation between circulating BCAA and insulin resistance. However, it is unclear if BCAA independently promote insulin resistance in otherwise healthy cells. The purpose of this study is to examine the effect of a BCAA mixture on muscle insulin signaling in vitro in both insulin resistant and sensitive cells. Materials and Methods C2C12 myotubes were treated with a BCAA mixture containing leucine:isoleucine:valine at a ratio of 2:1:1 at 0.2, 2, or 20 mM (based on leucine content) for either 30 min, 1 day, or 6 days. Western blot was used to assess insulin sensitivity of cells treated with BCAA both with and without concurrent insulin resistance, and, with and without insulin stimulation. Results BCAA treatment for 1 day significantly reduced basal, but not insulin‐stimulated pAkt expression. BCAA treatment for 6 days resulted in significantly reduced basal insulin signaling in healthy cells and insulin‐stimulated insulin signaling in insulin resistant (but not insulin sensitive) cells. Conclusion Similar to previous observations demonstrating BCAA may correlate with insulin resistance during metabolically stressed conditions, we demonstrate excessively high BCAA exposure can negatively influence basal insulin signaling, as well as insulin sensitivity in insulin resistant myotubes. However, given the intentionally high concentrations of BCAA used in this study, the extent to which these observations translate to in vivo models is unclear and warrants further investigation.

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“…Gαq protein is involved in DMT-regulated AKT phosphorylation Given that Gαi protein inactivates adenylyl cyclase and reduces intracellular cAMP level (Li et al 2013), and it mediates insulin-regulated AKT phosphorylation to inhibit gluconeogenesis (Yang et al 2013), we wondered whether DMT exhibited capability in regulating Gαi signaling. As indicated in Fig.…”

Section: Figurementioning

confidence: 99%

DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway

Zhou

Shi

et al. 2017

Journal of Molecular Endocrinology

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Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including Gαs, Gαi and Gαq. Gαs-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Gαi-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Gαq-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7-(thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4()-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT-inhibited gluconeogenesis by regulating the Gαq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca)/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Gαq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM.

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Leucine Facilitates Insulin Signaling through a Gαi Protein-dependent Signaling Pathway in Hepatocytes

Cited by 10 publications

References 46 publications

Effects of Acute Exposure to Increased Plasma Branched-Chain Amino Acid Concentrations on Insulin-Mediated Plasma Glucose Turnover in Healthy Young Subjects

Effects of Acute Exposure to Increased Plasma Branched-Chain Amino Acid Concentrations on Insulin-Mediated Plasma Glucose Turnover in Healthy Young Subjects

Branched‐chain amino acids at supraphysiological but not physiological levels reduce myotube insulin sensitivity

DMT efficiently inhibits hepatic gluconeogenesis by regulating the Gαq signaling pathway

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