A model to measure insulin effects on glucose transport and phosphorylation in muscle: a three-tracer study

1996 ◽  
Vol 270 (1) ◽  
pp. E170-E185 ◽  
Author(s):  
M. P. Saccomani ◽  
R. C. Bonadonna ◽  
D. M. Bier ◽  
R. A. DeFronzo ◽  
C. Cobelli
Keyword(s):  
Glucose Transport ◽  
Nonlinear Least Squares ◽  
Distribution Volume ◽  
Human Muscle ◽  
Transmembrane Transport ◽  
Model Parameters ◽  
Identifiability Analysis ◽  
Glucose Phosphorylation ◽  
Intracellular Glucose

We studied five healthy subjects with perfused forearm and euglycemic clamp techniques in combination with a three-tracer (D-[12C]mannitol, not transportable; 3-O-[14C]methyl-D-glucose, transportable but not metabolizable; D-[3-3H]glucose, transportable and metabolizable) intra-arterial pulse injection to assess transmembrane transport and intracellular phosphorylation of glucose in vivo in human muscle. The washout curves of the three tracers were analyzed with a multicompartmental model. A priori identifiability analysis of the tracer model shows that the rate constants of glucose transport into and out of the cells and of glucose phosphorylation are uniquely identifiable. Tracer model parameters were estimated by a nonlinear least-squares parameter estimation technique. We then solved for the tracee model and estimated bidirectional transmembrane transport glucose fluxes, glucose intracellular phosphorylation, extracellular and intracellular volumes of glucose distribution, and extracellular and intracellular glucose concentrations. Physiological hyperinsulinemia (473 +/- 22 pM) caused 2.7-fold (63.1 +/- 7.2 vs. 23.4 +/- 6.1 mumol.min-1.kg-1, P < 0.01) and 5.1-fold (42.5 +/- 5.8 vs. 8.4 +/- 2.2 mumol.min-1.kg-1, P < 0.01) increases in transmembrane influx and intracellular phosphorylation of glucose, respectively. Extracellular distribution volume and concentration of glucose were unchanged, whereas intracellular distribution volume of glucose was increased (approximately 2-fold) and intracellular glucose concentration was almost halved by hyperinsulinemia. In summary, 1) a multicompartment model of three-tracer kinetic data can quantify transmembrane glucose fluxes and intracellular glucose phosphorylation in human muscle; and 2) physiological hyperinsulinemia stimulates both transport and phosphorylation of glucose and, in doing so, amplifies the role of glucose transport as a rate-determining step of muscle glucose uptake.

A compartmental model to quantitate in vivo glucose transport in the human forearm

1989 ◽  
Vol 257 (6) ◽  
pp. E943-E958 ◽  
Author(s):  
C. Cobelli ◽  
M. P. Saccomani ◽  
E. Ferrannini ◽  
R. A. Defronzo ◽  
R. Gelfand ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Compartmental Model ◽  
Nonlinear Least Squares ◽  
Normal Subjects ◽  
Glucose Disposal ◽  
Good Precision ◽  
Transport Parameters ◽  
Tracer Injection ◽  
Identifiability Analysis

Glucose transport is a critical step in the control of glucose disposal that, until presently, has not been quantitated in vivo in humans. We have employed the perfused forearm and euglycemic insulin-clamp techniques in combination with a dual-tracer injection to measure basal and insulin-mediated glucose transport in six normal subjects. L-[3H]glucose, which is not transported, was used to trace extracellular glucose kinetics; 3-O-[14C]-methyl-D-glucose, transportable but not metabolizable, was used to monitor glucose movement across the cell membrane. After bolus intra-arterial injection of the two tracers, plasma samples were obtained every 15-30 s for 10 min from a deep forearm vein to determine the washout curves. A linear compartmental model was developed that accounts for blood flow heterogeneity. It consists of three parallel, two-compartment chains merging into the sampling compartment to which cellular compartments are appended. A priori identifiability analysis was performed. The uniquely identifiable parameterization includes the transport rate constants of glucose into and out of the cell. The model was identified using nonlinear least-squares parameter estimation. Transport parameters are estimated with very good precision, and their reproducibility is satisfactory. The model also allows the estimation of the mean arteriovenous transit times of both the extracellular and the transported tracer. The compartmental model provides a novel approach to investigate glucose transport in vivo in humans.

scholarly journals A computational bio-chemo-mechanical model of in vivo tissue-engineered vascular graft development

2020 ◽  
Vol 12 (3) ◽  
pp. 47-63
Author(s):  
Ramak Khosravi ◽  
Abhay B Ramachandra ◽  
Jason M Szafron ◽  
Daniele E Schiavazzi ◽  
Christopher K Breuer ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Optimal Parameter ◽  
Mechanistic Model ◽  
Vena Cava ◽  
Model Parameters ◽  
Identifiability Analysis ◽  
Macrophage Activity ◽  
Cost Efficient

Abstract Stenosis is the primary complication of current tissue-engineered vascular grafts used in pediatric congenital cardiac surgery. Murine models provide considerable insight into the possible mechanisms underlying this situation, but they are not efficient for identifying optimal changes in scaffold design or therapeutic strategies to prevent narrowing. In contrast, computational modeling promises to enable time- and cost-efficient examinations of factors leading to narrowing. Whereas past models have been limited by their phenomenological basis, we present a new mechanistic model that integrates molecular- and cellular-driven immuno- and mechano-mediated contributions to in vivo neotissue development within implanted polymeric scaffolds. Model parameters are inferred directly from in vivo measurements for an inferior vena cava interposition graft model in the mouse that are augmented by data from the literature. By complementing Bayesian estimation with identifiability analysis and simplex optimization, we found optimal parameter values that match model outputs with experimental targets and quantify variability due to measurement uncertainty. Utility is illustrated by parametrically exploring possible graft narrowing as a function of scaffold pore size, macrophage activity, and the immunomodulatory cytokine transforming growth factor beta 1 (TGF-β1). The model captures salient temporal profiles of infiltrating immune and synthetic cells and associated secretion of cytokines, proteases, and matrix constituents throughout neovessel evolution, and parametric studies suggest that modulating scaffold immunogenicity with early immunomodulatory therapies may reduce graft narrowing without compromising compliance.

scholarly journals Control of glucose phosphorylation in L6 myotubes by compartmentalization, hexokinase, and glucose transport

2003 ◽  
Vol 370 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Richard R. WHITESELL ◽  
Hossein ARDEHALI ◽  
Richard L. PRINTZ ◽  
Joseph M. BEECHEM ◽  
Susan M. KNOBEL ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Insulin Action ◽  
Cytochalasin B ◽  
L6 Myotubes ◽  
Test Models ◽  
Different Types ◽  
Extracellular Glucose ◽  
Low Glucose ◽  
Glucose Phosphorylation ◽  
Intracellular Glucose

In muscle, insulin enhances influx of glucose and its conversion to glucose 6-phosphate (G6P) by hexokinase (HK). While effects of insulin on glucose transport have been demonstrated, its effect on the activity of HK of cells has not. In L6 myotubes treated for 24h with insulin there was increased expression of the HK isoform, HKII, and increased glucose phosphorylation without a concomitant increase in glucose transport, indirectly suggesting that phosphorylation of glucose was a target of insulin action [Osawa, Printz, Whitesell and Granner (1995) Diabetes 44, 1426—1432]. In the present work the same treatment led to a 2-fold rise in G6P, suggesting that transport and/or HK were important targets of insulin action. We used a method to identify the site of rate control involving the specificity of phosphorylation towards 2-deoxy-[1-14C]glucose and d-[2-3H]glucose. Glucose transport does not greatly discriminate between these two tracers while HK shows increased specificity for glucose. Specificity of the glucose phosphorylation of the cells increased with addition of insulin and when extracellular glucose was raised. Specificity was reduced at low glucose concentrations or when the inhibitor of transport, cytochalasin B, was added. We conclude that transport and HK share nearly equal control over glucose phosphorylation in these cells. A computer program was used to test models for compatibility with the different types of experiments. The predicted intracellular glucose and transport rates associated with phosphorylation activity were lower than their measured values for the whole cell. In the most likely model, 15±4% of the glucose transporters serve a proportionate volume of the cytoplasm. Insulin activation of glucose phosphorylation might then result from stimulation of these transporters together with HK recruitment or relief from inhibition by G6P.

Roles of glucose transport and glucose phosphorylation in muscle insulin resistance of NIDDM

Diabetes ◽  
1996 ◽  
Vol 45 (7) ◽  
pp. 915-925 ◽  
Author(s):  
R. C. Bonadonna ◽  
S. Del Prato ◽  
E. Bonora ◽  
M. P. Saccomani ◽  
G. Gulli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Transport ◽  
Muscle Insulin Resistance ◽  
Glucose Phosphorylation

scholarly journals Functional expression, quantification and cellular localization of the Hxt2 hexose transporter of Saccharomyces cerevisiae tagged with the green fluorescent protein

1999 ◽  
Vol 339 (2) ◽  
pp. 299-307 ◽  
Author(s):  
Arthur L. KRUCKEBERG ◽  
Ling YE ◽  
Jan A. BERDEN ◽  
Karel van DAM
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Plasma Membrane ◽  
Green Fluorescent Protein ◽  
Glucose Transport ◽  
Cellular Localization ◽  
Fluorescent Protein ◽  
Hexose Transporter ◽  
High Concentrations ◽  
Green Fluorescent

The Hxt2 glucose transport protein of Saccharomyces cerevisiae was genetically fused at its C-terminus with the green fluorescent protein (GFP). The Hxt2-GFP fusion protein is a functional hexose transporter: it restored growth on glucose to a strain bearing null mutations in the hexose transporter genes GAL2 and HXT1 to HXT7. Furthermore, its glucose transport activity in this null strain was not markedly different from that of the wild-type Hxt2 protein. We calculated from the fluorescence level and transport kinetics that induced cells had 1.4×105 Hxt2-GFP molecules per cell, and that the catalytic-centre activity of the Hxt2-GFP molecule in vivo is 53 s-1 at 30 °C. Expression of Hxt2-GFP was induced by growth at low concentrations of glucose. Under inducing conditions the Hxt2-GFP fluorescence was localized to the plasma membrane. In a strain impaired in the fusion of secretory vesicles with the plasma membrane, the fluorescence accumulated in the cytoplasm. When induced cells were treated with high concentrations of glucose, the fluorescence was redistributed to the vacuole within 4 h. When endocytosis was genetically blocked, the fluorescence remained in the plasma membrane after treatment with high concentrations of glucose.

scholarly journals The Topical Nanodelivery of Vismodegib Enhances Its Skin Penetration and Performance In Vitro While Reducing Its Toxicity In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 186
Author(s):  
Maria Natalia Calienni ◽  
Daniela Maza Vega ◽  
C. Facundo Temprana ◽  
María Cecilia Izquierdo ◽  
David E. Ybarra ◽  
...  
Keyword(s):  
Side Effects ◽  
Water Solubility ◽  
Polymeric Micelles ◽  
Skin Penetration ◽  
Distribution Volume ◽  
And Performance ◽  
Oral Doses ◽  
Advanced Basal Cell Carcinoma

Vismodegib is a first-in-class inhibitor for advanced basal cell carcinoma treatment. Its daily oral doses present a high distribution volume and several side effects. We evaluated its skin penetration loaded in diverse nanosystems as potential strategies to reduce side effects and drug quantities. Ultradeformable liposomes, ethosomes, colloidal liquid crystals, and dendrimers were able to transport Vismodegib to deep skin layers, while polymeric micelles failed at this. As lipidic systems were the most effective, we assessed the in vitro and in vivo toxicity of Vismodegib-loaded ultradeformable liposomes, apoptosis, and cellular uptake. Vismodegib emerges as a versatile drug that can be loaded in several delivery systems for topical application. These findings may be also useful for the consideration of topical delivery of other drugs with a low water solubility.

Determination of cerebral glucose transport and metabolic kinetics by dynamic MR spectroscopy

1997 ◽  
Vol 273 (6) ◽  
pp. E1216-E1227 ◽  
Author(s):  
P. C. M. Van Zijl ◽  
D. Davis ◽  
S. M. Eleff ◽  
C. T. W. Moonen ◽  
R. J. Parker ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Kinetic Equations ◽  
Direct Determination ◽  
Life Time ◽  
Compartment Model ◽  
Brain Extract ◽  
Influx Rate ◽  
Positron Emission

A new in vivo nuclear magnetic resonance (NMR) spectroscopy method is introduced that dynamically measures cerebral utilization of magnetically labeled [1-13C]glucose from the change in total brain glucose signals on infusion. Kinetic equations are derived using a four-compartment model incorporating glucose transport and phosphorylation. Brain extract data show that the glucose 6-phosphate concentration is negligible relative to glucose, simplifying the kinetics to three compartments and allowing direct determination of the glucose-utilization half-life time [ t ½ = ln2/( k 2 + k 3)] from the time dependence of the NMR signal. Results on isofluorane ( n = 5)- and halothane ( n = 7)- anesthetized cats give a hyperglycemic t ½ = 5.10 ± 0.11 min−1 (SE). Using Michaelis-Menten kinetics and an assumed half-saturation constant Kt = 5 ± 1 mM, we determined a maximal transport rate T max = 0.83 ± 0.19 μmol ⋅ g−1 ⋅ min−1, a cerebral metabolic rate of glucose CMRGlc = 0.22 ± 0.03 μmol ⋅ g−1 ⋅ min−1, and a normoglycemic cerebral influx rate CIRGlc = 0.37 ± 0.05 μmol ⋅ g−1 ⋅ min−1. Possible extension of this approach to positron emission tomography and proton NMR is discussed.

FULL-WAVEFORM INVERSION WITH SOURCE AND RECEIVER COUPLING EFFECTS CORRECTION

Geophysics ◽  
2021 ◽  
pp. 1-37
Author(s):  
Xinhai Hu ◽  
Wei Guoqi ◽  
Jianyong Song ◽  
Zhifang Yang ◽  
Minghui Lu ◽  
...  
Keyword(s):  
Waveform Inversion ◽  
Nonlinear Least Squares ◽  
Real Data ◽  
Model Parameters ◽  
Full Waveform Inversion ◽  
Linear Inversion ◽  
Near Surface ◽  
Model Parameter ◽  
Full Waveform ◽  
Coupling Factors

Coupling factors of sources and receivers vary dramatically due to the strong heterogeneity of near surface, which are as important as the model parameters for the inversion success. We propose a full waveform inversion (FWI) scheme that corrects for variable coupling factors while updating the model parameter. A linear inversion is embedded into the scheme to estimate the source and receiver factors and compute the amplitude weights according to the acquisition geometry. After the weights are introduced in the objective function, the inversion falls into the category of separable nonlinear least-squares problems. Hence, we could use the variable projection technique widely used in source estimation problem to invert the model parameter without the knowledge of source and receiver factors. The efficacy of the inversion scheme is demonstrated with two synthetic examples and one real data test.

Simulation of calcium homeostasis: modeling and parameter estimation

1983 ◽  
Vol 245 (5) ◽  
pp. R664-R672 ◽  
Author(s):  
S. Hurwitz ◽  
S. Fishman ◽  
A. Bar ◽  
M. Pines ◽  
G. Riesenfeld ◽  
...  
Keyword(s):  
Simulation Model ◽  
Plasma Calcium ◽  
Model Parameters ◽  
Estimation Of Parameters ◽  
Designed Experiments ◽  
Calcium Loading ◽  
Infusion Experiment ◽  
Dose Model ◽  
Edta Infusion

The system that regulates plasma calcium in the bird has been formalized into a model based on a series of differential equations and solved by computer simulation. Bone, kidney, and intestine have been considered as the control subsystems, with parathyroid hormone and 1,25-dihydroxycholecalciferol as the regulating hormones. The parameters used in the simulation model have been computed either from published results or by specifically designed experiments described here. For the estimation of parameters, an iterative procedure has been developed that was designed to minimize the sum of square errors between observed and system-simulated values. Parameters of 1,25-dihydroxycholecalciferol metabolism were experimentally obtained from the kinetic behavior of the 3H-labeled hormone in rachitic birds after a single dose. Model parameters have been adjusted using the results of in vivo calcium loading and validated by an EDTA infusion experiment. The simulation model has been used to study the hierarchy of the activities of the three control subsystems and of the regulating hormones, at different calcium intakes. Positive or negative errors in plasma calcium resulted in an asymmetry in the activities of the controlling systems, bone and kidney, whereas the intestine is characterized by its relatively long response time.

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