Biomedical subjects

Alessandra Bertoldo

Publications and source records attributed to Alessandra Bertoldo.

7 recordsLinked to original sources

PubMed2006

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals.

Our objectives were to quantitate insulin-stimulated inward glucose transport and glucose phosphorylation in forearm muscle in lean and obese nondiabetic subjects, in lean and obese type 2 diabetic (T2DM) subjects, and in normal glucose-tolerant, insulin-resistant offspring of two T2DM parents. Subjects received a euglycemic insulin (40 mU.m(-2).min(-1)) clamp with brachial artery/deep forearm vein catheterization. After 120 min of hyperinsulinemia, a bolus of d-mannitol/3-O-methyl-d-[(14)C]glucose/d-[3-(3)H]glucose (triple-tracer technique) was given into brachial artery and deep vein samples obtained every 12-30 s for 15 min. Insulin-stimulated forearm glucose uptake (FGU) and whole body glucose metabolism (M) were reduced by 40-50% in obese nondiabetic, lean T2DM, and obese T2DM subjects (all P < 0.01); in offspring, the reduction in FGU and M was approximately 30% (P < 0.05). Inward glucose transport and glucose phosphorylation were decreased by approximately 40-50% (P < 0.01) in obese nondiabetic and T2DM groups and closely paralleled the decrease in FGU. The intracellular glucose concentration in the space accessible to glucose was significantly greater in obese nondiabetic, lean T2DM, obese T2DM, and offspring compared with lean controls. We conclude that 1) obese nondiabetic, lean T2DM, and offspring manifest moderate-to-severe muscle insulin resistance (FGU and M) and decreased insulin-stimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus T2DM; and 2) the increase in intracelullar glucose concentration under hyperinsulinemic euglycemic conditions in obese and T2DM groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport.

Adult↗

PubMed2006

Dose-responsive insulin regulation of glucose transport in human skeletal muscle.

Glucose transport is regarded as the principal rate control step governing insulin-stimulated glucose utilization by skeletal muscle. To assess this step in human skeletal muscle, quantitative PET imaging of skeletal muscle was performed using 3-O-methyl-[11C]glucose (3-[11C]OMG) in healthy volunteers during a two-step insulin infusion [n = 8; 30 and 120 mU.min(-1).m(-2), low (LO) and high (HI)] and during basal conditions (n = 8). Positron emission tomography images were coregistered with MRI to assess 3-[11C]OMG activity in regions of interest placed on oxidative (soleus) compared with glycolytic (tibialis anterior) muscle. Insulin dose-responsive increases of 3-[11C]OMG activity in muscle were observed (P < 0.01). Tissue activity was greater in soleus than in tibialis anterior (P < 0.05). Spectral analysis identified that two mathematical components interacted to shape tissue activity curves. These two components were interpreted physiologically as likely representing the kinetics of 3-[11C]OMG delivery from plasma to tissue and the kinetics of bidirectional glucose transport. During low compared with basal, there was a sixfold increase in k3, the rate constant attributed to inward glucose transport, and another threefold increase during HI (0.012 +/- 0.003, 0.070 +/- 0.014, 0.272 +/- 0.059 min(-1), P < 0.001). Values for k3 were similar in soleus and tibialis anterior, suggesting similar kinetics for transport, but compartmental modeling indicated a higher value in soleus for k1, denoting higher rates of 3-[11C]OMG delivery to soleus than to tibialis anterior. In summary, in healthy volunteers there is robust dose-responsive insulin stimulation of glucose transport in skeletal muscle.

Biological Transport↗

PubMed2006

Interactions between delivery, transport, and phosphorylation of glucose in governing uptake into human skeletal muscle.

Skeletal muscle accounts for a large proportion of insulin-stimulated glucose utilization. It is generally regarded that much of the control over rates of uptake is posited within the proximal steps of delivery, transport, and phosphorylation of glucose, with glucose transport as the main locus of control. Whether insulin modulates the distribution of control across these steps and in what manner remains uncertain. The current study addressed this in vivo using dynamic positron emission tomography (PET) imaging of human muscle with sequential injections of three tracers ([(15)O]H(2)O, [(11)C]3-O-methyl glucose [3-OMG], and [(18)F]fluoro-deoxy glucose [FDG]) that enabled quantitative determinations of glucose delivery, transport, and its phosphorylation, respectively. Lean, healthy, research volunteers were studied during fasting conditions (n = 8) or during a euglycemic insulin infusion at 30 mU/min per m(2) (n = 8). PET images were coregistered with magnetic resonance imaging to contrast glucose kinetics in soleus, a highly oxidative muscle, with tibialis anterior, a less oxidative muscle. During fasting conditions, uptake of [(11)C]3-OMG was similar in soleus and tibialis anterior muscles, despite higher delivery to soleus (by 35%; P < 0.01). Uptake of [(18)F]FDG was also similar between muscle during fasting, and glucose transport was found to be the dominant locus of control (90%) for glucose uptake under this condition. Insulin increased uptake of [(11)C]3-OMG substantially and strongly stimulated the kinetics of bidirectional glucose transport. Uptake of [(11)C]3-OMG was higher in soleus than tibialis anterior muscle (by 22%; P < 0.01), a difference partially due to higher delivery, which was again found to be 35% higher to soleus (P < 0.01). The uptake of [(18)F]FDG was 65% greater in soleus compared with tibialis anterior muscle, a larger difference than for [(11)C]3-OMG (P < 0.01), indicating an added importance of glucose phosphorylation in defining insulin sensitivity. Analysis of the distribution of control during insulin-stimulated conditions revealed that most of the control was posited at delivery and transport and was equally divided between these steps. Thus, insulin evokes a broader distribution of control than during fasting conditions in governing glucose uptake into skeletal muscle. This redistribution of control is triggered by the robust stimulation of glucose transport, which in turn unmasks a greater dependence upon delivery and glucose phosphorylation.

Adult↗

PubMed2004

Quantitative assessment of glucose transport in human skeletal muscle: dynamic positron emission tomography imaging of [O-methyl-11C]3-O-methyl-D-glucose.

Insulin-stimulated glucose transport in skeletal muscle is regarded as a key determinant of insulin sensitivity, yet isolation of this step for quantification in human studies is a methodological challenge. One notable approach is physiological modeling of dynamic positron emission tomography (PET) imaging using 2-[18-fluoro]2-deoxyglucose ([(18)F]FDG); however, this has a potential limitation in that deoxyglucose undergoes phosphorylation subsequent to transport, complicating separate estimations of these steps. In the current study we explored the use of dynamic PET imaging of [(11)C]3-O-methylglucose ([(11)C]3-OMG), a glucose analog that is limited to bidirectional glucose transport. Seventeen lean healthy volunteers with normal insulin sensitivity participated; eight had imaging during basal conditions, and nine had imaging during euglycemic insulin infusion at 30 mU/min.m(2). Dynamic PET imaging of calf muscles was conducted for 90 min after the injection of [(11)C]3-OMG. Spectral analysis of tissue activity indicated that a model configuration of two reversible compartments gave the strongest statistical fit to the kinetic pattern. Accordingly, and consistent with the structure of a model previously used for [(18)F]FDG, a two-compartment model was applied. Consistent with prior [(18)F]FDG findings, insulin was found to have minimal effect on the rate constant for movement of [(11)C]3-OMG from plasma to tissue interstitium. However, during insulin infusion, a robust and highly significant increase was observed in the kinetics of inward glucose transport; this and the estimated tissue distribution volume for [(11)C]3-OMG increased 6-fold compared with basal conditions. We conclude that dynamic PET imaging of [(11)C]3-OMG offers a novel quantitative approach that is both chemically specific and tissue specific for in vivo assessment of glucose transport in human skeletal muscle.

Adult↗

PubMed2004

"Population" approach improves parameter estimation of kinetic models from dynamic PET data.

Kinetic modeling is used to indirectly measure physiological parameters from dynamic positron emission tomography (PET) data. Usually, the unknown parameters of the model are estimated, in any given region of interest (ROI), by least squares (LS). However, when the signal-to-noise ratio (SNR) of PET data is too low, LS does not allow reliable parameter estimation. To overcome this problem, we study in this paper the applicability of approaches originally developed in the pharmacokinetic/pharmacodynamic literature and referred to as "population approaches." In particular, we consider the iterative two stage (ITS) method, which, given a set of M ROIs drawn on PET images of a given individual, estimates the unknown model parameters of each ROI by exploiting the information contained in all the M ROIs. After having revised the theory behind ITS, we assess its performance versus LS by using Monte Carlo simulations which allow us to evaluate the bias of the two methods in a variety of situations. Then, we compare the performance of LS and ITS in two case studies on [18F]FDG kinetics in human skeletal muscle. Both simulated and real case studies results show that a population approach is of potential in modeling PET images since it allows to reliably estimate model parameters also in those ROIs where either a bad SNR or a poor sampling (e.g., infrequent scanning and/or short experiment duration) make the use of LS unsuccessful.

Algorithms↗

PubMed2003

Glucose transport and phosphorylation in skeletal muscle in obesity: insight from a muscle-specific positron emission tomography model.

A controversial area in understanding the contribution of obesity to skeletal muscle insulin resistance is the distribution of control of glucose metabolism across proximal steps of glucose delivery, trans-membrane transport, and intracellular trapping via phosphorylation. Dynamic positron emission tomography (PET) imaging of skeletal muscle [(18)F]2-deoxy-2-D-glucose ((18)F-FDG) uptake provides an in vivo method for assessment of these steps in humans. In the current study we have examined the application of a four-compartment skeletal muscle-specific model for assessment of (18)F-FDG metabolism that takes interstitial (18)F-FDG kinetics into account and compared this to the classic three-compartment model in lean and obese volunteers. We assessed the effects of insulin infusions at three rates (0, 40, and 120 mU/m(2).min). In comparison with the classic model, the skeletal muscle-specific model reveals more clearly definable effects of insulin on transmembrane glucose transport and an impairment of this response in obesity. Compared with the classic model for assessment of (18)F-FDG metabolism, both the skeletal muscle-specific and the classic model indicate that, with respect to distribution of control, glucose phosphorylation has an important effect at low to moderate levels of insulin stimulation in both lean and obese subjects.

Biological Transport↗

PubMed2003

Weight loss-induced plasticity of glucose transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.

We tested the hypothesis that weight loss alleviates insulin resistance in skeletal muscle within the proximal steps of glucose metabolism, namely substrate delivery, glucose transport, and glucose phosphorylation. In obese subjects with and without type 2 diabetes, in vivo skeletal muscle assessments were obtained with dynamic positron emission tomography (PET) imaging performed during euglycemic clamps at moderate hyperinsulinemia (40 mU x min(-1) x m(-2)), using [(15)O]H(2)O and [(18)F]fluoro-deoxyglucose ([(18)F]FDG) to quantify tissue perfusion and glucose metabolism. Dynamic [(18)F]FDG PET data were analyzed using both a novel muscle-specific compartmental model and a compartmental model originally developed for the brain and often used for [(18)F]FDG muscle image quantification. Weight loss in obese subjects with (n = 9) and without (n = 9) type 2 diabetes over a 4-month intervention was substantial (14 +/- 2 kg, P < 0.05). Muscle insulin resistance, assessed by insulin-stimulated [(18)F]FDG uptake, decreased threefold in diabetic subjects and twofold in nondiabetic subjects (P < 0.001). Kinetic parameters for [(18)F]FDG transport and phosphorylation improved substantially in both groups, whereas tissue blood flow did not change. In particular, clinically significant weight loss fully corrected insulin resistance in type 2 diabetes at the step of glucose phosphorylation and largely, but incompletely, corrected insulin resistance at the glucose transport step.

Biological Transport↗