The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts
Santina BruzzonePietro AmeriL. BriatoreElena ManninoGiovanna BasileGabriella AndraghettiAlessia GrozioMirko MagnoneLucrezia GuidaSonia Scarfı̀Annalisa SalisGianluca DamonteLaura SturlaAlessio NencioniDaniela FenoglioFrancesca FioryClaudia MieleFrancesco BèguinotVittorio RuvoloMariano BormioliG. ColomboDavide MaggiGiovanni MurialdoRenzo CorderaAntonio De FloraElena Zocchi
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Abstract:
The plant hormone abscisic acid (ABA) is released from glucose-challenged human pancreatic β cells and stimulates insulin secretion. We investigated whether plasma ABA increased during oral and intravenous glucose tolerance tests (OGTTs and IVGTTs) in healthy human subjects. In all subjects undergoing OGTTs (n=8), plasma ABA increased over basal values (in a range from 2- to 9-fold). A positive correlation was found between the ABA area under the curve (AUC) and the glucose AUC. In 4 out of 6 IVGTTs, little or no increase of ABA levels was observed. In the remaining subjects, the ABA increase was similar to that recorded during OGTTs. GLP-1 stimulated ABA release from an insulinoma cell line and from human islets, by ∼10- and 2-fold in low and high glucose, respectively. Human adipose tissue also released ABA in response to high glucose. Nanomolar ABA stimulated glucose uptake, similarly to insulin, in rat L6 myoblasts and in murine 3T3-L1 cells differentiated to adipocytes, by increasing GLUT-4 translocation to the plasma membrane. Demonstration that a glucose load in humans is followed by a physiological rise of plasma ABA, which can enhance glucose uptake by adipose tissues and muscle cells, identifies ABA as a new mammalian hormone involved in glucose metabolism.Keywords:
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The ongoing worldwide epidemic of diabetes increases the demand for the identification of environmental, nutritional, endocrine, genetic, and epigenetic factors affecting glucose uptake. The measurement of intracellular fluorescence is a widely used method to test the uptake of fluorescently-labeled glucose (FD-glucose) in cells in vitro, or for imaging glucose-consuming tissues in vivo. This assay assesses glucose uptake at a chosen time point. The intracellular analysis assumes that the metabolism of FD-glucose is slower than that of endogenous glucose, which participates in catabolic and anabolic reactions and signaling. However, dynamic glucose metabolism also alters uptake mechanisms, which would require kinetic measurements of glucose uptake in response to different factors. This article describes a method for measuring extracellular FD-glucose depletion and validates its correlation with intracellular FD-glucose uptake in cells and tissues ex vivo. Extracellular glucose depletion may be potentially applicable for high-throughput kinetic and dose-dependent studies, as well as identifying compounds with glycemic activity and their tissue-specific effects.
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Objectives The aim of this study was to evaluate the effects of Hwanggi-tang on glucose digestion, uptake, and metabolism in murine C2C12 myotubes. Methods Hwanggi-tang was prepared according to the Dong-ui-bo-gam (âªæ±é«å¯¶éâ«) prescription by 70% ethanol extraction. The effect on glucose digestion was examined by determining the inhibitory effect of Hwanggi-tang on α-glucosidase activity. We also compared and verified the gene and protein expression of genes related to glucose uptake in C2C12 myotubes treated with Hwanggi-tang or insulin. Glucose metabolism was assessed by the expression levels of associated enzymes. Results Hwanggi-tang caused a dose-dependent inhibition of α-glucosidase activity, induced glucose uptake by activation of the PI3K/Akt/mTOR pathway in the insulin signaling pathway, and promoted glucose oxidation and β-oxidation. Conclusions Hwanggi-tang exerts an anti-diabetic effect on murine myotubes by inhibiting glucose digestion and inducing glucose uptake and consumption. Keywords: carbohydrate metabolism, diabetes mellitus, herbal medicine, skeletal muscle fiber
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Glucose absorption promoters perform insulin mimic functions to enhance blood glucose transport to skeletal muscle cells and accelerate glucose consumption, thereby reducing blood glucose levels. In our screening exploration of food ingredients for improving glucose transportation and metabolism, we found that the saponins in American ginseng (Panaxquinquefolius L.) showed potential activity to promote glucose uptake, which can be used for stabilizing levels of postprandial blood glucose. The aim of this study was to identify key components of American ginseng with glucose uptake-promoting activity and to elucidate their metabolic regulatory mechanisms. Bio-guided isolation using zebrafish larvae and 2-NBDG indicator identified ginsenoside Rb1 (GRb1) as the most potential promotor of glucose uptake. Using UPLC-QTOF-MS/MS combined with RT-qPCR and phenotypic verification, we found that riboflavin metabolism is the hinge for GRb1-mediated facilitation of glucose transport. GRb1-induced restoration of redox homeostasis was mediated by targeting riboflavin transporters (SLC52A1 and SLC52A3) and riboflavin kinase (RFK).
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Blood sugar regulation
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To investigate the role of skeletal muscle tissue expression of the glucose transporter protein GLUT1 in mediating glucose disposal in the basal (fasting) state, skeletal muscle biopsies (vastus lateralis) were obtained from lean and obese nondiabetics and type 2 diabetic subjects. Basal and insulin-stimulated glucose uptakes were measured. Basal whole body glucose uptake was measured using isotope dilution, and arteriovenous catheterization limb balance was used to determine leg muscle glucose uptake. Basal (noninsulin-stimulated) whole body glucose uptake was higher in the type 2 group compared with the controls (2.26 ± 0.17 vs. 1.83 ± 0.15 mg/kg·min; P < 0.05). However, basal leg muscle glucose uptake was reduced in diabetic subjects (1.53 ± 0.56 vs. 3.89 ± 0.83 mg/100 ml·min; P < 0.025) despite basal hyperglycemia (230 ± 13 vs. 94 ± 2 mg/dl; P < 0.0005). Skeletal muscle GLUT1 protein expression was lower in the type 2 subjects (57 ± 12 vs. 91 ± 11 arbitrary units/10 μg protein; P < 0.05), although GLUT1 mRNA levels did not differ. In summary, 1) skeletal muscle tissue GLUT1 protein expression is reduced in type 2 diabetes and could contribute to impaired basal leg glucose uptake; and 2) elevated rates of basal whole body glucose uptake in type 2 diabetes are due to uptake in tissues other than skeletal muscle.
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GLUT4
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Metabolic pathway
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Skeletal muscle glucose uptake is regulated by insulin and contractile activity. The diaphragm is constantly active and may rely on higher basal glucose uptake rates. We tested the hypothesis that glucose uptake by the rat diaphragm is not regulated by contractile activity. We used diaphragm bundles from adult Sprague-Dawley rats to measure 3H-glucose uptake under basal conditions, insulin (100 nM), or under the following activity protocols: (1) 0.1 train/s @ 40 Hz, 500 ms train duration for 20 min (parameters to increase glucose uptake in other muscles); (2) 40 Hz for 10 min; (3) 20 Hz for 10 min; and (4) 10 Hz for 10 min. Protocols 2–4 were done at 0.5 train/s and 500 ms train duration. We found that insulin increased glucose uptake 4-fold over basal rates: 0.6±0.1 vs. 2.8±0.7 μmol/g/h basal and insulin respectively (p=0.01). Activity protocol #1 did not change glucose uptake: 1.1±0.12 vs. 1.1±0.15 μmol/g/h basal and activity respectively (p=0.5). Activity protocols #2–4 increased glucose significantly over the basal rates: #2: 1.6±0.2 vs. 2.1±0.2; #3: 2.2±0.11 vs. 3.4±0.3; #4: 1.9±0.3 vs. 2.7±0.2 μmol/g/h basal and activity respectively, (p≤0.01 for each comparison). In summary, glucose uptake in the rat diaphragm does not increase in response to an activity protocol used in other muscles. Most strenuous activity protocols increase glucose uptake, but not to the same extent as insulin. Supported by R01 EY012998 to FHA.
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Diaphragm (acoustics)
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Diaphragm muscle
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Purpose: To examine noninsulin- (basal) and insulin-mediated glucose uptake in human skeletal muscle cells from endurance-trained and sedentary individuals. Methods: Muscle biopsies (vastus lateralis) were obtained from competitive, endurance-trained athletes (N = 12; V̇O2peak 64.9 ± 2.3 mL·kg−1·min−1) and their sedentary counterparts (N = 8; O2peak 51.8 ± 2.2 mL·kg−1·min−1), and isolated satellite cells allowed to proceed to myotubes. Results: The myotubes exhibited a dose response for glucose uptake with increasing insulin concentrations; maximal glucose uptake was ≈1.5-fold over basal. In relation to exercise training status, basal glucose uptake was significantly (P < 0.05) elevated by ≈75% in the endurance-trained versus sedentary men (20.1 ± 2.1 vs 11.9 ± 1.9 pmol·mg protein−1·min−1, respectively). This difference persisted at insulin concentrations of 10 and 1000 ηM, although the relative increase in insulin-mediated glucose uptake (fold increase over basal) did not differ between the sedentary and endurance-trained cells. Conclusions: These data suggest that cultured skeletal muscle cells from endurance-trained athletes may differ in respect to basal glucose uptake.
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Glucose is important for energy; however, excessive daily intake of sugar may act as a toxin inducing the body to become overweight or obese. High blood glucose level reduces secretion of insulin, and glucose toxicity worsens insulin resistance. We investigated the metabolic fate of excess glucose by changing glucose levels in MRC-5 fibroblasts. Uptake of glucose into fibroblasts, the first stage of glucose metabolism, was measured. Treatment of fibroblasts under diabetic conditions led to rapid glucose incorporation. Glucose was absorbed into the cell almost constantly and reached excessive levels, and its metabolism was assessed by 14CO2 output from [U-14C] D-glucose, the glucose metabolism end product. When fibroblasts were cultured in the presence of high glucose levels, CO2 production decreased significantly in comparison with normal glucose conditions. Glucose metabolism in the diabetic setting was not accompanied by an increase in glucose uptake. Diabetic patients exercise tight glycemic control to avert disorders from such glucose toxicity. Pyruvate dehydrogenase (PDH) activity is reduced in diabetes; therefore, we investigated the influence of thiamine on PDH activity and intracellular glucose concentration in fibroblast cells exposed to diabetic conditions. Thiamine reversed high glucose-induced PDH inhibition and prevented glucose accumulation. These results, taken together with those of our previous report, suggest that thiamine partially plays a role in modifying the metabolic fate of glucose and reducing glucose toxicity.
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The purpose of this study was to attain a better understanding of how the adipocyte transports and metabolizes glucose with and without the influence of exercise training. Rates of 2-deoxyglucose and glucose oxidation, using [1-14C]-and [6-14C]glucose, were measured in adipocytes from exercise-trained and sedentary control female rats of the same age. The trained animals were exercised by swimming, 6 h/day, 5 days/wk for 10 wk. The fat cells of the sedentary rats were significantly larger (P less than 0.005) than the trained animals and had very low rates of glucose uptake and [1-14C]- and [6-14C]glucose oxidation. The adipocytes of the trained rats were very responsive to insulin with 2-deoxyglucose rates seven times higher than those of the control animals and [1-14C]- and [6-14C]-glucose oxidation rates 14- and 13-fold (respectively) larger than control values. Comparisons of the data from exercised animals to younger sedentary rats indicates that glucose oxidation remains normal in the adipocytes of the trained animals whereas glucose transport is greatly improved. If the older sedentary controls are compared to younger animals, it can be seen that as the cell enlarges it loses its ability to take up or metabolize glucose. The combination of a loss in glucose transporting capacity with cellular enlargement and an increase in glucose uptake with exercise training suggests that movement of glucose across the cell membrane may be a limiting factor in glucose utilization in fat cells.
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Deoxyglucose
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Successful embryo implantation requires receptive endometrium, which is conducive to the process of embryo recognition, adhesion, and invasion within a certain period of time and is inseparable from the dynamic interaction between 17β-estradiol (E2) and progesterone (P4). Proper glucose metabolism is critical for the profound physiological changes in the endometrium entering the receptive state. And glucose transporters (GLUTs) are responsible for intracellular uptake of glucose and are the first step in glucose metabolism. Prior literature has reported the presence of GLUTs in the endometrium. However, we still do not understand the specific mechanisms of this process. In this study, we identified the effect of P4 on glucose transporter 1 (GLUT1) using in vivo animal models and determined the regulation of glucose metabolism by P4 in cells. We highly suspect that this pregnancy failure may be due to reduced GLUT1-mediated glucose metabolism, resulting in a decrease in endometrial receptivity caused by an inadequate energy supply and synthesis of substrate. Here, we propose a possible mechanism to explain how embryo implantation is affected by P4 and glucose utilization under abnormal endometrial conditions.
Carbohydrate Metabolism
Snf3
GLUT4
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