Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes

Cline, Gary W.; Petersen, Kitt Falk; Krššák, Martin; Sakata, Jun; Hundal, Ripudaman S.; Trajanoski, Zlatko; Inzucchi, Silvio E.; Dresner, Alan; Rothman, Douglas L.; Shulman, Gerald I.

doi:10.1056/nejm199907223410404

Cited by 573 publications

(397 citation statements)

References 30 publications

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“…A combination of 13 C-and 31 P-MRS opens multiple views on the carbohydrate metabolism (131)(132)(133)(134), which is particularly promising in the different forms of insulinand non-insulin-dependent diabetes patients. While glucose-6-phosphate can observed in the 31 P-MR spectrum, 13 C-MRS gives access to glycogen and glucose, especially in connection with an infusion of 13 C-enriched [1-13 C]glucose.…”

Section: Combination Of 1 H-mrs Of Imcl and Other Mrs Techniquesmentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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1 H-MR spectroscopy (MRS) of intramyocellular lipids (IMCL) became particularly important when it was recognized that IMCL levels are related to insulin sensitivity. While this relation is rather complex and depends on the training status of the subjects, various other influences such as exercise and diet also influence IMCL concentrations. This may open insight into many metabolic interactions; however, it also requires careful planning of studies in order to control all these confounding influences. This review summarizes various historical, methodological, and practical aspects of 1 H-MR spectroscopy (MRS) of muscular lipids. That includes a differentiation of bulk magnetic susceptibility effects and residual dipolar coupling that can both be observed in MRS of skeletal muscle, yet affecting different metabolites in a specific way. Fitting of the intra-(IMCL) and extramyocellular (EMCL) signals with complex line shapes and the transformation into absolute concentrations is discussed. Since the determination of IMCL in muscle groups with oblique fiber orientation or in obese subjects is still difficult, potential improvement with high-resolution spectroscopic imaging or at higher field strength is considered. Fat selective imaging is presented as a possible alternative to MRS and the potential of multinuclear MRS is discussed. 1 H-MRS of muscle lipids allows non-invasive and repeated studies of muscle metabolism that lead to highly relevant findings in clinics and patho-physiology.

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Section: Combination Of 1 H-mrs Of Imcl and Other Mrs Techniquesmentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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“…Since the phosphorylation of glucose in the muscle cell can be followed by 31 P-MR spectroscopy and the formation of intra-myocellular glycogen by 13 C-MRS, a combination of both methods allows the stepwise observation of glucose metabolism in muscle cells. Using these techniques 68 in human muscle during a hyperglycemic-hyperinsulinemic clamp in non-insulindependent diabetes patients, it was possible to show a reduced glucose transport since the phosphorylated glucose-6-phosphate did not accumulate while glycogen synthesis was reduced compared to healthy controls.…”

Section: Cellular and Subcellular Compart-mentation Transport Phenomenamentioning

confidence: 99%

Dipolar coupling and ordering effects observed in magnetic resonance spectra of skeletal muscle

Boesch

Kreis

2001

NMR in Biomedicine

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Skeletal muscle is a biological structure with a high degree of organization at different spatial levels. This order influences magnetic resonance (MR) in vivo-in particular 1 H-spectra-by a series of effects that have very distinct physical sources and biomedical applications: (a) bulk fat (extramyocellular lipids, EMCL) along fasciae forms macroscopic plates, changing the susceptibility within these structures compared to the spherical droplets that contain intra-myocellular lipids (IMCL); this effect leads to a separation of the signals from EMCL and IMCL; (b) dipolar coupling effects due to anisotropic motional averaging have been shown for 1 H-resonances of creatine, taurine, and lactate; (c) aromatic protons of carnosine show orientation-dependent effects that can be explained by dipolar coupling, chemical shift anisotropy or by relaxation anisotropy; (d) limited rotational freedom and/or compartmentation may explain differences of 1 H-MR-visibility of the creatine/phosphocreatine resonances; (e) lactate 1 H-MR resonances are reported to reveal information on tissue compartmentation; (f) transverse relaxation of water and metabolites show multiple components, indicative of intra-, extracellular and/or macromolecular-bound pools, and in addition dipolar or J-coupling lead to a modulation of the signal decay, hindering straightforward interpretation; (g) diffusion weighted 31 P-MRS has shown restricted diffusion of phosphocreatine; (h) magnetization transfer (MT) indicates that there is a motionally restricted proton pool in spin-exchange with free creatine; reduced availability or restricted motion of creatine is particularly important for an estimation of ADP from 31 P-MR spectra, and in addition MT effects may alter the signal intensity of creatine 1 H-resonances following water-suppression pulses; (i) transcytolemmal water-exchange can be studied in 1 H-MRS by contrast-agents applied to the extracellular space; (k) transport of glucose across the cell membrane has been studied in diabetes patients using a combination of 13 C-and 31 P-MRS; and (l) residual quadrupolar interaction in 23 Na MR spectra from human skeletal muscle suggest that sodium ions are bound to ordered muscular structures.

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“…At these low concentrations the glucose transporter is nearly unidirectional, which in combination with the previous results from 13 C/ 31 P MRS indicate it is the primary rate controlling step. Cline and coworkers 59,60 have developed a direct method for measuring the extracellular and blood contribution to the MRS glucose signal by co-infusing 1-13 C mannitol, which is not transported into the muscle cell. Figure 8 shows the 13 C NMR spectra of intracellular and extracellular glucose and extracellular mannitol obtained from the muscle of a healthy volunteer.…”

Section: Mrs Studies Of Insulin-stimulated Mus-cle Glucose Transport mentioning

confidence: 99%

Studies of metabolic compartmentation and glucose transport using in vivo MRS

Rothman

2001

NMR in Biomedicine

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Organs consist of several types of cells with specialized functions. This cellular localization of function is often referred to as compartmentation. Due to the intrinsic low sensitivity of MR methods it is generally not possible in vivo to obtain images or spectra of single cells. Instead the MRS signal is the sum of the signal from millions of cells and multiple cell types. A major challenge in using MRS to study biological processes such as metabolism and transport is to devise measurements that provide cell-specific information from this mix. Fortunately nature has helped the MR scientist by in several cases nearly completely localizing metabolic pathways and their associated metabolites in specific cell types. The chemical specificity of MRS allows the concentrations and synthesis rates of these metabolites to be measured, providing information about the compartmentation of metabolism and function. In this review examples are presented from MRS studies of metabolic trafficking between neurons and astrocytes in the brain, brain glucose transport, and the role of muscle glucose transport in insulin resistance and diabetes. The concepts and approaches used in these studies are generally applicable for studying cellular metabolic compartmentation in a wide range of systems.

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Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes

Abstract: Impaired insulin-stimulated glucose transport is responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes mellitus.

Cited by 573 publications

References 30 publications

Role of proton MR for the study of muscle lipid metabolism

Role of proton MR for the study of muscle lipid metabolism

Dipolar coupling and ordering effects observed in magnetic resonance spectra of skeletal muscle

Studies of metabolic compartmentation and glucose transport using in vivo MRS

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