Modulation of glucose metabolism by a natural compound from Chloranthus japonicus via activation of AMP-activated protein kinase

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

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Myostatin regulates glucose metabolism via the AMP-activated protein kinase pathway in skeletal muscle cells

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2010.09.017 ◽

2010 ◽

Vol 42 (12) ◽

pp. 2072-2081 ◽

Cited By ~ 53

Author(s):

Yuewen Chen ◽

Jianwei Ye ◽

Lingzhi Cao ◽

Yong Zhang ◽

Weibo Xia ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Glucose Metabolism ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Amp Activated Protein Kinase ◽

Kinase Pathway

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Glucose Metabolism and Energy Homeostasis in Mouse Hearts Overexpressing Dominant Negative α2 Subunit of AMP-activated Protein Kinase

Journal of Biological Chemistry ◽

10.1074/jbc.m303521200 ◽

2003 ◽

Vol 278 (31) ◽

pp. 28372-28377 ◽

Cited By ~ 168

Author(s):

Yanqiu Xing ◽

Nicolas Musi ◽

Nobuharu Fujii ◽

Liqun Zou ◽

Ivan Luptak ◽

...

Keyword(s):

Protein Kinase ◽

Glucose Metabolism ◽

Energy Homeostasis ◽

Dominant Negative ◽

Amp Activated Protein Kinase

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Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6616906 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Caiping Lu ◽

Hanying Xing ◽

Linquan Yang ◽

Kaiting Chen ◽

Linyi Shu ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Glucose Metabolism ◽

Glucose Uptake ◽

High Fat Diet ◽

Blood Glucose Concentration ◽

Glycogen Synthesis ◽

Liver Fat ◽

High Fat ◽

Amp Activated Protein Kinase

Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKβ inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKβ.

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Alanine alters carbohydrate metabolism of rainbow trout: Glucose fluxes and cell signaling

Journal of Experimental Biology ◽

10.1242/jeb.232918 ◽

2021 ◽

Author(s):

Mais Jubouri ◽

Giancarlo G.M. Talarico ◽

Jean-Michel Weber ◽

Jan A. Mennigen

Keyword(s):

Rainbow Trout ◽

Protein Kinase ◽

Glucose Metabolism ◽

Cell Signaling ◽

Glucose Levels ◽

Dietary Amino Acid ◽

Gluconeogenic Enzyme ◽

Mechanistic Basis ◽

Amp Activated Protein Kinase

In rainbow trout, dietary carbohydrates are poorly metabolized compared to other macronutrients. One prevalent hypothesis suggests that high dietary amino acid levels could contribute to the poor utilization of carbohydrates in trout. In mammals, alanine is considered an important gluconeogenic precursor, but has recently been found to stimulate AMP-activated protein kinase (AMPK) to reduce glucose levels. In trout, the effect of alanine on glucose fluxes is unknown. The goal of this study was to determine the effects of 4h exogenous alanine infusion on glucose metabolism in rainbow trout. Glucose fluxes, glucose appearance (Ra), and disposal (Rd) were measured in vivo. Key glycolytic and gluconeogenic enzyme expression and activity and cell signaling molecules relevant to glucose metabolism were assessed in liver and muscle. Results show that alanine inhibits Ra glucose (from 13.2+/-2.5 to 7.3+/-1.6 micromol / kg min) and Rd glucose (from 13.2+/-2.5 to 7.4+/-1.5 micromol / kg min) and the slight mismatch between Ra and Rd caused a reduction in glycemia, similar to the effects of insulin in trout. The reduction in Rd glucose can be partially explained by a reduction in glut4b expression in red muscle. In contrast to mammals, alanine-dependent glucose-lowering effects in trout did not involve hepatic AMPK activation, suggesting a different mechanistic basis. Interestingly, protein kinase B (AKT) activation increased only in muscle similar to effects observed in insulin-infused trout. We speculate that alanine-dependent effects were probably mediated through stimulation of insulin secretion which could indirectly promote alanine oxidation to provide the needed energy.

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Ganoderma lucidum Extract Reduces Insulin Resistance by Enhancing AMPK Activation in High-Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu12113338 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3338

Author(s):

Hyeon A Lee ◽

Jae-Han Cho ◽

Qonita Afinanisa ◽

Gi-Hong An ◽

Jae-Gu Han ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Glucose Metabolism ◽

High Fat Diet ◽

Ganoderma Lucidum ◽

Fatty Acid Synthase ◽

Metabolic Diseases ◽

Ampk Activation ◽

High Fat ◽

Amp Activated Protein Kinase

Ganoderma lucidum is used widely in oriental medicine to treat obesity and metabolic diseases. Bioactive substances extracted from G. lucidum have been shown to ameliorate dyslipidemia, insulin resistance, and type 2 diabetes in mice via multiple 5′ AMP-activated protein kinase (AMPK)-mediated mechanisms; however, further studies are required to elucidate the anti-obesity effects of G. lucidum in vivo. In this study, we demonstrated that 3% G. lucidum extract powder (GEP) can be used to prevent obesity and insulin resistance in a mouse model. C57BL/6 mice were provided with a normal diet (ND) or a high-fat diet (HFD) supplemented with 1, 3, or 5% GEP for 12 weeks and the effect of GEP on body weight, liver, adipose tissue, adipokines, insulin and glucose tolerance (ITT and GTT), glucose uptake, glucose-metabolism related proteins, and lipogenesis related genes was examined. GEP administration was found to reduce weight gain in the liver and fat tissues of the mice. In addition, serum parameters were significantly lower in the 3% and 5% GEP mice groups than in those fed a HFD alone, whereas adiponectin levels were significantly higher. We also observed that GEP improved glucose metabolism, reduced lipid accumulation in the liver, and reduced adipocyte size. These effects may have been mediated by enhanced AMPK activation, which attenuated the transcription and translation of lipogenic genes such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), and sterol regulatory element-binding protein-1c (SREBP1c). Moreover, AMP-activated protein kinase (AMPK) activation increased acetyl-CoA carboxylase (ACC), insulin receptor (IR), IR substrate 1 (IRS1), and Akt protein expression and activation, as well as glucose transporter type 1/4 (GLUT1/4) protein production, thereby improving insulin sensitivity and glucose metabolism. Together, these findings demonstrate that G. lucidum may effectively prevent obesity and suppress obesity-induced insulin resistance via AMPK activation.

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