13C/31P NMR studies on the mechanism of insulin resistance in obesity.

Petersen, Kitt Falk; Hendler, Rosa; Price, Thomas B.; Perseghin, Gianluca; Rothman, Douglas L.; Held, Ntsiki M.; Amatruda, John M.; Shulman, Gerald I.

doi:10.2337/diabetes.47.3.381

Cited by 107 publications

(76 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Phosphorous NMR has been used to study effects of insulin (and of IR) on levels of glucose-6-phosphat e in skeletal muscle. By magnifying the subtraction (insulin¡basal) NMR spectrum of muscle phosphorous, it has been found that in healthy volunteers insulin causes increased G-6-P and this is blunted in IR (11,13,14). This supports the concept that IR derives from defects at glucose transport and/or phosphorylation.…”

Section: Non-pet Methods For Investigation Of Skeletal Muscle Glucosesupporting

confidence: 65%

“…NMR spectroscopy has been shown to be a very powerful tool for investigating glucose metabolism in vivo (9). It is very useful for the study of the synthesis and degradation of glycogen in muscle (9)(10)(11)(12)(13). Phosphorous NMR has been used to study effects of insulin (and of IR) on levels of glucose-6-phosphat e in skeletal muscle.…”

Section: Non-pet Methods For Investigation Of Skeletal Muscle Glucosementioning

confidence: 99%

See 1 more Smart Citation

Assessing Skeletal Muscle Glucose Metabolism With Positron Emission Tomography

Kelley¹,

Price²,

Cobelli³

2001

IUBMB Life

View full text Add to dashboard Cite

SummaryInsulin has a marked effect to stimulate the transport and metabolism of glucose in skeletal muscle in healthy individuals, whereas an impaired response, termed insulin resistance, is a major risk factor for diabetes mellitus and other metabolic diseases. Studies of the molecular physiology of insulin action in skeletal muscle indicate that a principal loci of control resides within the proximal steps of glucose transport and phosphorylation. Deoxyglucose, the metabolism of which is limited to these proximal steps, is widely used for in vitro studies of insulin action on glucose transport. The technologies of PET imaging provide a unique opportunity to carry out similar studies in vivo in human skeletal muscle. In this instance, a short-lived positron labeled tracer, [18F] FDG, can be given at suf ciently high speci c activity to image not only glucose uptake, but by dynamic PET imaging, by monitoring the time course of [18F] FDG tissue activity, data can be generated to examine the kinetics of glucose transport and phosphorylation. The experimental procedures of this approach, including an overview of the mathematical modeling, are described in this review, along with some of the key ndings of the initial applications of PET for the study of glucose metabolism in human skeletal muscle.

show abstract

Section: Non-pet Methods For Investigation Of Skeletal Muscle Glucosesupporting

confidence: 65%

Section: Non-pet Methods For Investigation Of Skeletal Muscle Glucosementioning

confidence: 99%

Assessing Skeletal Muscle Glucose Metabolism With Positron Emission Tomography

Kelley¹,

Price²,

Cobelli³

2001

IUBMB Life

View full text Add to dashboard Cite

show abstract

“…In contrast to the results from the model of Randle and co-workers, which predicted that fat-induced insulin resistance would result in an increase in intramuscular glucose-6-phosphate, we found that the drop in muscle glycogen synthesis was preceded by a fall in intramuscular glucose-6-phosphate, suggesting that increases in plasma fatty acid concentrations initially induce insulin resistance by inhibiting glucose transport or phosphorylation activity, and that the reduction in muscle glycogen synthesis and glucose oxidation follows. The reduction in insulin-activated glucose transport and phosphorylation activity in normal subjects maintained at high plasma fatty acid levels is similar to that seen in obese individuals, 16 patients with type 2 diabetes, 5,6 and lean, normoglycemic insulin-resistant offspring of type 2 diabetic individuals. 7,8 Hence, accumulation of intramuscular fatty acids (or fatty acid metabolites) appears to play an important role in the pathogenesis of insulin resistance seen in obese patients and patients with type 2 diabetes.…”

Section: Fatty Acid-induced Muscle Insulin Resistancementioning

confidence: 49%

Cellular mechanism of insulin resistance: potential links with inflammation

Perseghin¹,

2003

Self Cite

View full text Add to dashboard Cite

Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential ratecontrolling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using 13 C/ 31 P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar 13 C/ 31 P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase Cy and IKK-b, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.

show abstract

“…Whereas this study evaluated data from rodents, we have some reason to believe that it may be applicable to human subjects as well. Specifically, even under experimentally induced conditions of hyperglycemia and hyperinsulinemia, healthy human subjects never displayed a Ͼ2-fold increase in [G6P] (12,33,34,36,37), suggesting the importance of G6P homeostasis in human skeletal muscle. Given the delicacy of the system's homeostatic balance, it is surprising that it does not seem to be substantially disrupted in patients with non-insulin-dependent diabetes (NIDDM) or genetic, obesity, and lipid-induced insulin resistance (IR) (12,33,34,37).…”

Section: Role Of Insulin-stimulated Proportional Activation In Maintamentioning

confidence: 99%

Protein phosphorylation can regulate metabolite concentrations rather than control flux: The example of glycogen synthase

Schafer

Fell

Rothman

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Despite dramatic increases in glucose influx during the transition from fasting to fed states, plasma glucose concentration remains tightly controlled. This constancy is in large part due to the capacity of skeletal muscle to absorb excess glucose and store it as glycogen. The magnitude of this capacity is controlled by insulin by way of regulated insertion of glucose transporters into the muscle cell membrane. Here, we examine the mechanism by which muscle cells are able to tolerate large flux increases across their transporters without significantly changing their own metabolite pools. MCA was used to probe data sets that measured the effects of changing plasma glucose and͞or insulin concentrations on the rates of glycogen synthesis and the concentrations of metabolites, particularly glucose-6-phosphate. We find that homeostasis is achieved by insulin-dependent phosphorylation changes in GSase sensitivity to the upstream metabolite glucose-6-phosphate. The centrality of GSase to homeostasis resolves the paradox of its sensitivity to allosteric and covalent regulation despite its minimal role in flux control. The importance of this role for enzymatic phosphorylation to diabetes pathology is discussed, and its general applicability is suggested.M etabolic control analysis (MCA) has revolutionized our understanding of flux control through theoretical and experimental studies (1-4). One of its key precepts is the flux control coefficient, a quantitative characterization of the influence of any enzyme over the flux of a metabolic pathway. As MCA has matured, it has expanded into associated areas. One of particular interest has been the mechanism of metabolite control, in which the central question is how metabolite homeostasis, the constancy of metabolite concentrations, is maintained during changes in flux (5-9). One well known example of such metabolite homeostasis comes from the study of fluxes through the energetic pathway of glucose oxidation. There, the flux can change by more than an order of magnitude whereas metabolites remain constant within small experimental error (10, 11). Although theoretical analyses of such homeostatic phenomena have been available since the first description of MCA, physical exploration of this important physiological area has been scarce due to experimental limitations. The primary hurdle has been the difficulties in simultaneously obtaining in vivo values of metabolite concentrations and of fluxes through the pathway.These limitations have been somewhat eased by the development of in vivo NMR methods. Valuable information about energetics has been obtained by 31 P NMR of high-energy metabolites (e.g., ATP, PO 4 , and creatine phosphate) and about metabolic regulation from phosphorylated pathway intermediates such as glucose-6-phosphate (G6P) (12). In complementary experiments, the weak natural abundance (1.1%) of the 13 C isotope allows direct 13 C NMR of labeled 13 C substrates to measure flux, by following the time course of label flow into metabolic pools (13). Comprehensive a...

show abstract

13C/31P NMR studies on the mechanism of insulin resistance in obesity.

Cited by 107 publications

References 0 publications

Assessing Skeletal Muscle Glucose Metabolism With Positron Emission Tomography

Assessing Skeletal Muscle Glucose Metabolism With Positron Emission Tomography

Cellular mechanism of insulin resistance: potential links with inflammation

Protein phosphorylation can regulate metabolite concentrations rather than control flux: The example of glycogen synthase

Contact Info

Product

Resources

About