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1.  Glucose metabolism during leg exercise in man 
Journal of Clinical Investigation  1971;50(12):2715-2725.
Arterial concentrations and net substrate exchange across the leg and splanchnic vascular bed were determined for glucose, lactate, pyruvate, and glycerol in healthy postabsorptive subjects at rest and during 40 min of exercise on a bicycle ergometer at work intensities of 400, 800, and 1200 kg-m/min.
Rising arterial glucose levels and small decreases in plasma insulin concentrations were found during heavy exercise. Significant arterial-femoral venous differences for glucose were demonstrated both at rest and during exercise, their magnitude increasing with work intensity as well as duration of the exercise performed. Estimated glucose uptake by the leg increased 7-fold after 40 min of light exercise and 10- to 20-fold at moderate to heavy exercise. Blood glucose uptake could at this time account for 28-37% of total substrate oxidation by leg muscle and 75-89% of the estimated carbohydrate oxidation.
Splanchnic glucose production increased progressively during exercise reaching levels 3 to 5-fold above resting values at the heavy work loads. Close agreement was observed between estimates of total glucose turnover during exercise based on leg glucose uptake and splanchnic glucose production. Hepatic gluconeogenesis—estimated from splanchnic removal of lactate, pyruvate, glycerol, and glycogenic amino acids—could supply a maximum of 25% of the resting hepatic glucose production but could account for only 6-11% of splanchnic glucose production after 40 min of moderate to heavy exercise.
It is concluded that: (a) blood glucose becomes an increasingly important substrate for muscle oxidation during prolonged exercise of this type: (b) peripheral glucose utilization increases in exercise despite a reduction in circulating insulin levels: (c) increased hepatic output of glucose, primarily by means of augmented glycogenolysis, contributes to blood glucose homeostasis in exercise and provides an important source of substrate for exercising muscle.
PMCID: PMC292221  PMID: 5129319
1. The oxygen content of venous and of arterial blood from fifteen essentially normal individuals at rest in bed has been determined. 2. The percentage saturation of the arterial blood has varied between 100 and 94.3. The average is 95.5 per cent. 3. The oxygen consumption has varied between 2.6 and 8.3 volumes per cent. 4. The oxygen content and the percentage saturation of arterial blood taken at close intervals from three different peripheral arteries of a normal individual have shown values agreeing within the limits of error. Analyses of the blood gases of a normal individual, at rest and after exercise, have shown a lowering of the percentage oxygen saturation of the arterial blood and a diminished carbon dioxide content after exercise. 5. In three persons with severe anemia the saturation of the arterial blood has not differed from the normal. Very low absolute values were found for the oxygen content of the venous blood, but the normal oxygen consumption has been maintained. 6. The carbon dioxide content of the arterial blood from ten normal individuals has varied between 54.7 and 44.6 volumes per cent. That of the venous blood has varied between 60.4 and 48.3 volumes per cent. 7. No deviations from the normal values for oxygen and carbon dioxide were found in venous and arterial blood from cardiac patients without arrhytiunias, well compensated, and at rest in bed. 8. A series of determinations has been made upon nine cardiac patients with varying degrees of decompensation. The percentage oxygen saturation of the arterial blood on admission was abnormally low in seven of these cases. With the return to compensation and with the clearing up of pulmonary symptoms, the percentage saturation of the arterial blood returned to normal in four of them. 9. In a case of long standing mitral endocarditis with auricular fibrillation it remained low over a period of I month of observation. 10. In a case of chronic myocarditis secondary to emphysema and chronic bronchitis, it remained low over the period of observation. 11. Normal values for the percentage saturation of the arterial blood were found in two individuals with decompensated aortic disease but without physical signs of extensive pulmonary involvement. 12. The oxygen consumption tended to be high in individuals with cardiac disease during the periods of marked decompensation and to be lower as compensation was regained. 13. The data presented indicate that at least in many circulatory diseases during decompensation, particularly when there are physical signs of pulmonary congestion, there is a disturbance of the pulmonary exchange, as indicated by the lowering of the percentage saturation of the arterial blood with oxygen.
PMCID: PMC2126680  PMID: 19868356
3.  Ferumoxytol Enhanced resting state fMRI and Relative Cerebral Blood Volume mapping in Normal Human Brain 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.06.066.
The brain demonstrates spontaneous low-frequency (< 0.1 Hz) cerebral blood flow (CBF) fluctuations, measurable by resting-state functional MRI (rs-fMRI). Ultra small superparamagnetic iron oxide particles have been shown to enhance task-based fMRI signals (cerebral blood volume fMRI or CBV-fMRI), compared to the BOLD effect, by a factor of ≈ 2.5 at 3T in primates and humans. We evaluated the use of ferumoxytol for steady state,resting state FMRI (CBV-rs-fMRI) and relative cerebral blood volume (rCBV) mapping, at 3 Tesla, in healthy volunteers. All standard resting state networks (RSNs) were identified in all subjects.On average the RSN Z-statistics(Melodic independent components)and volumes of the Visual and default mode (DMN)networks were comparable rCBV values were averaged forthe visual (Vis) and DMN networks and correlated with the corresponding DMN and Visual network Z statistics. There was a negative correlation between the rCBV and the Z-statisticsforthe DMN, for both BOLD and CBVrs-fMRI contrast (R2= 0.63, 0.76).A similar correlation was not found for the visual network. Short repetition time rs-fMRI data were Fourier transformed to evaluate the effect of ferumoxytol on cardiac and respiratory fluctuations in the brain rs-BOLD, CBV signals. Cardiac and respiratory fluctuations decreased to baseline within large vessels post ferumoxytol.Robust rs-fMRI and CBV mapping is possible in normal human brain.
PMCID: PMC3815982  PMID: 23831413
1. A simple method for arterial puncture is given which does no permanent injury to the artery. Arterial and venous punctures have been done on 33 cases of pneumonia and five normal subjects, and the blood thus obtained has been studied with reference to the oxygen capacity and arterial and venous unsaturation. 2. In five normal subjects the mean arterial unsaturation was 5 per cent of the total oxygen capacity; the mean venous unsaturation was 26.8 per cent. 3. In the pneumonia cases the arterial oxygen unsaturation varied over a wide range. The arterial unsaturation varied from 0.0 to 68.2 per cent, the venous from 14.4 to 85.5 per cent. In the fatal cases as opposed to the non-fatal cases of pneumonia, the mean arterial oxygen unsaturation was 32 per cent as against 13.9 per cent. As a rule, an arterial unsaturation of over 20 per cent was associated with a fatal outcome. Similarly, the mean venous oxygen unsaturation was 57 per cent in the fatal cases and 36.3 per cent in the non-fatal cases. 4. In five cases in which no cyanosis was observed at any time the mean arterial oxygen unsaturation was 5.4 per cent, the mean venous oxygen unsaturation 31.5 per cent. In cases which showed cyanosis of varying degree during the course of the illness, the mean arterial unsaturation was 24.7 per cent, and the mean venous unsaturation 44.5 per cent. Cases without cyanosis have an arterial unsaturation close to the normal. 5. There is a definite relation between the degree of cyanosis and the per cent of arterial unsaturation. With increasing cyanosis the arterial unsaturation becomes greater. The venous unsaturation varies similarly. 6. In individual cases with marked cyanosis associated with high arterial unsaturation, the clinical improvement of the patient and the diminution of the cyanosis are accompanied by a similar diminution in the arterial and venous unsaturation. Conversely, an increase of cyanosis is accompanied by an increase in arterial unsaturation. It is evident that the cyanosis of pneumonia patients is due to the incomplete saturation of venous blood with oxygen in the lungs, and that the various shades of blue observed in the distal parts are caused by an admixture of reduced hemoglobin and oxyhemoglobin in the superficial capillaries. 7. No unusually low total oxygen capacities were observed, even in fatal cases with intense cyanosis. On the contrary, in these cases the total oxygen capacity was unusually high, pointing toward a concentration of the blood. Again in only one case was there any marked fall in the oxygen capacity during the illness. Therefore, methemoglobin formation, in these cases, can hardly have occurred to such an extent as to be an important factor in the production of cyanosis. Of the 33 cases studied, however, only seven were lobar pneumonia, the rest being of types ordinarily unusual, which have accompanied the recent influenza epidemic; and of the seven, not all were in all respects typically lobar. The possibility still remains, therefore, that in typical lobar pneumonia caused by the pneumococcus methemoglobin may play a part in the cyanosis. 8. The oxygen consumption, i.e. difference between arterial and venous contents, was within normal limits, indicating that the cardiac output was not diminished in the cases (chiefly post influenza) of pneumonia studied.
PMCID: PMC2126679  PMID: 19868355
1. A procedure is devised whereby cutaneous blood (so called capillary blood) from a finger-tip can be obtained for gas analyses without coming in contact with the air. 2. Determination was made of the oxygen content of the arterial, cutaneous, and venous blood respectively from a normal resting individual, the arterial and cutaneous blood showing the same oxygen content (97.5 and 96.6 per cent of the total oxygen-combining power of the blood). Venous blood drawn simultaneously was 75 per cent saturated. 3. Using the fact that there is a maximum value for the oxygen-combining power of the blood, we have shown, without doing arterial puncture, that under different conditions (normal and pathological individuals, resting and after exercise) the cutaneous blood and the arterial blood are almost identical as far as the oxygen content is concerned. 4. We think that we are justified in extending the identity, found between the oxygen content of the arterial and cutaneous blood, to other substances in the blood, for instance sugar, salt, uric acid, etc., and also to the reaction of the blood. 5. We are unable to say whether this identity between cutaneous and arterial blood is always true; for example, in a patient with increased venous pressure. 6. In all the experiments we have discarded the first drop of blood, which in some instances was darker than the rest, and always used at least 2 cc. of cutaneous blood. Whether the same results would be obtained with a very small amount of blood, for instance 0.2 to 0.4 cc., we do not know. 7. The experiments show that unless the perfusion of the skin has been extremely great during the experiment, samples of blood obtained from an incision in the skin (of the finger) cannot represent the true capillary blood. The neutral expression cutaneous blood seems therefore for the present preferable to the term capillary blood for samples of blood obtained by cutaneous incisions.
PMCID: PMC2128380  PMID: 19868694
6.  Mechanisms of Epinephrine-induced Glucose Intolerance in Normal Humans 
Journal of Clinical Investigation  1982;69(2):284-293.
To evaluate the role of the splanchnic bed in epinephrine-induced glucose intolerance, we selectively assessed the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose production, and peripheral glucose uptake by combining infusion of [3-3H]glucose with hepatic vein catheterization. Normal humans received a 90-min infusion of either glucose alone (6.5 mg/kg−1 per min−1) or epinephrine plus glucose at two dose levels: (a) in amounts that simulated the hyperglycemia seen with glucose alone (3.0 mg/kg−1 per min−1); and (b) in amounts identical to the control study. During infusion of glucose alone, blood glucose rose twofold, insulin levels and net posthepatic insulin release increased three- to fourfold, and net splanchnic glucose output switched from a net output (1.65±0.12 mg/kg−1 per min−1) to a net uptake (1.56±0.18). This was due to a 90-95% fall (P < 0.001) in hepatic glucose production and a 100% rise (P < 0.001) in splanchnic glucose uptake (from 0.86±0.14 to 1.71±0.12 mg/kg−1 per min−1), which in the basal state amounted to 30-35% of total glucose uptake. Peripheral glucose uptake rose by 170-185% (P < 0.001). When epinephrine was combined with the lower glucose dose, blood glucose, insulin release, and hepatic blood flow were no different from values observed with glucose alone. However, hepatic glucose production fell only 40-45% (P < 0.05 vs. glucose alone) and, most importantly, the rise in splanchnic glucose uptake was totally blocked. As a result, splanchnic glucose clearance fell by 50% (P < 0.05), and net splanchnic glucose uptake did not occur. The rise in peripheral glucose uptake was also reduced by 50-60% (P < 0.001). When epinephrine was added to the same dose of glucose used in the control study, blood glucose rose twofold higher (P < 0.001). The initial rise in splanchnic glucose uptake was totally prevented; however, beyond 30 min, splanchnic glucose uptake increased, reaching levels seen in the control study when severe hyperglycemia occurred. Splanchnic glucose clearance, nevertheless, remained suppressed throughout the entire study (40%-50%, P < 0.01).
It is concluded that (a) the splanchnic bed accounts for one-third of total body glucose uptake in the basal state in normal humans; (b) epinephrine markedly inhibits the rise in splanchnic glucose uptake induced by infusion of glucose; and (c) this effect does not require a fall in insulin and is modulated by the level of hyperglycemia. Our data indicate that the splanchnic bed is an important site of glucose uptake in post-absorptive humans and that epinephrine impairs glucose tolerance by suppressing glucose uptake by both splanchnic and peripheral tissues, as well as by its well known stimulatory effect on endogenous glucose production.
PMCID: PMC370977  PMID: 7035494
7.  Cardiovascular function at rest and on exercise in patients with cryptogenic fibrosing alveolitis. 
Thorax  1988;43(4):276-283.
Cardiovascular complications are common in fibrosing alveolitis, but there have been few physiological studies of the pulmonary circulation in this condition, and those that have been carried out have usually depended on right heart catheterisation. This paper reports non-invasive measurements of effective pulmonary blood flow, oxygen uptake, pulmonary arteriovenous oxygen content differences, and estimates of mixed venous oxygen saturation in 20 patients with histologically proved cryptogenic fibrosing alveolitis at rest and while exercising on a motorized treadmill. Results were compared with those of 20 age and sex matched normal subjects, at rest and at an arbitrarily chosen oxygen uptake of 0.75 l/min. The latter results were obtained by linear interpolation. Effective pulmonary blood flow was normal at rest, but oxygen dispatch to the tissues (blood flow x blood oxygen content) was significantly reduced at rest (mean reduction 190 (SD 68) ml/l/min; p less than 0.01) and at an oxygen uptake of 0.75 l/min (mean reduction 128 (50) ml/l/min; p less than 0.02), reflecting the presence of systemic arterial hypoxaemia. Pulmonary arteriovenous oxygen content differences were similar in patients and normal subjects, but mixed venous saturation was lower in the patients at rest (mean % reduction 6.8 (2.6); p less than 0.02) and at an oxygen uptake of 0.75 l/min (mean % reduction 9.6 (2.9); p less than 0.002). It is concluded that the supply of oxygen potentially available to the tissues is reduced at rest and during exercise in patients with fibrosing alveolitis and hence, by analogy with normal people exercising under hypoxic conditions, that pulmonary blood flow is inappropriately low in this condition. The low mixed venous oxygen saturation may contribute to the development of pulmonary hypertension in some patients. The rebreathing technique used in this study may be of use in monitoring treatment; it could be applied many times to the same patient, and might be a suitable way of following the response to pulmonary vasodilators.
PMCID: PMC461213  PMID: 3406914
8.  Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism 
PLoS Computational Biology  2012;8(6):e1002577.
Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.
Author Summary
Glucose is an indispensable fuel for all cells and organs, but at the same time leads to problems at high concentrations. As a consequence, blood glucose is controlled in a narrow range to guarantee constant supply and on the other hand avoid damages associated with elevated glucose levels. The liver is the main organ controlling blood glucose by (i) releasing newly synthesized or stored glucose in the blood stream when blood glucose is low (ii) using and storing glucose when blood glucose is elevated. These processes are regulated by hormones, in particular insulin, glucagon and epinephrine. We developed the first detailed kinetic model of this crucial metabolic system integrated with its hormonal control and validated the model based on a multitude of experimental data. Our model enables for the first time to simulate hepatic glucose metabolism in depth. Our results show how due to the hormonal control of key enzymes the liver metabolism can be switched between glucose production and utilization. We provide an essential model to analyze glucose regulation in the normal state and diseases associated with defects in glucose homeostasis like diabetes.
PMCID: PMC3383054  PMID: 22761565
9.  Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice 
PLoS ONE  2012;7(12):e52355.
Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK) activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at ∼115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart, and/or adipose tissue likely positively impact the liver.
PMCID: PMC3524103  PMID: 23285006
10.  Uncovering Intrinsic Modular Organization of Spontaneous Brain Activity in Humans 
PLoS ONE  2009;4(4):e5226.
The characterization of topological architecture of complex brain networks is one of the most challenging issues in neuroscience. Slow (<0.1 Hz), spontaneous fluctuations of the blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging are thought to be potentially important for the reflection of spontaneous neuronal activity. Many studies have shown that these fluctuations are highly coherent within anatomically or functionally linked areas of the brain. However, the underlying topological mechanisms responsible for these coherent intrinsic or spontaneous fluctuations are still poorly understood. Here, we apply modern network analysis techniques to investigate how spontaneous neuronal activities in the human brain derived from the resting-state BOLD signals are topologically organized at both the temporal and spatial scales. We first show that the spontaneous brain functional networks have an intrinsically cohesive modular structure in which the connections between regions are much denser within modules than between them. These identified modules are found to be closely associated with several well known functionally interconnected subsystems such as the somatosensory/motor, auditory, attention, visual, subcortical, and the “default” system. Specifically, we demonstrate that the module-specific topological features can not be captured by means of computing the corresponding global network parameters, suggesting a unique organization within each module. Finally, we identify several pivotal network connectors and paths (predominantly associated with the association and limbic/paralimbic cortex regions) that are vital for the global coordination of information flow over the whole network, and we find that their lesions (deletions) critically affect the stability and robustness of the brain functional system. Together, our results demonstrate the highly organized modular architecture and associated topological properties in the temporal and spatial brain functional networks of the human brain that underlie spontaneous neuronal dynamics, which provides important implications for our understanding of how intrinsically coherent spontaneous brain activity has evolved into an optimal neuronal architecture to support global computation and information integration in the absence of specific stimuli or behaviors.
PMCID: PMC2668183  PMID: 19381298
11.  Tissue oxygenation and muscular substrate turnover in two subjects with high hemoglobin oxygen affinity. 
Journal of Clinical Investigation  1983;72(4):1376-1384.
Oxygen transport to and substrate turnover in leg muscle were studied at rest and during light and heavy upright bicycle exercise in two brothers with a hereditary hemoglobinopathy associated with high oxygen affinity (P50 = 13 mmHg). Femoral venous oxygen tension was below normal and femoral venous oxygen saturation above normal at rest and during exercise. Thus, the arterial-femoral venous oxygen saturation difference was decreased. Despite a compensatory increase in hemoglobin concentration, the arterial-femoral venous oxygen content difference tended to be below normal at heavy exercise. Approximately 25% of the oxygen was delivered via the abnormal hemoglobin at relative heavy exercise. Arterial lactate levels, lactate release, and muscle lactate concentration were not increased at any level of exercise. Glucose, alanine, pyruvate, and glycerol turnover were essentially normal, but the glycogen and creatine phosphate stores were abnormally depleted at the termination of heavy exercise. The exercise electrocardiogram (ECG) was normal, indicating that myocardial oxygenation was adequate. Muscle-surface oxygen pressure fields were normal at rest (not investigated during exercise). It is concluded that the high oxygen affinity of the hemoglobin in our two subjects did not lead to heart or skeletal muscle hypoxia during heavy exercise, as judged from the ECG and from the leg lactate turnover. Despite the lack of evidence for muscle hypoxia, the subjects experienced leg muscle fatigue and the creatine phosphate and glycogen stores were depleted more than normally.
PMCID: PMC370422  PMID: 6630512
12.  Nutrient ingestion increased mTOR signaling, but not hVps34 activity in human skeletal muscle after sprint exercise 
Physiological Reports  2013;1(5):e00076.
Nutrient provision after sprint exercise enhances mammalian target of rapamycin (mTOR) signaling. One suggested that nutrient sensor is the class III phosphatidylinositol 3-kinase, vacuolar protein sorting 34 (Vps34), not previously studied in human skeletal muscle. It is hypothesized that oral ingestion of essential amino acids (EAA) and carbohydrates (Carb) increases Vps34 activity and mTOR signaling in human skeletal (hVps34) muscle after sprint exercise. Nine subjects were performed 3 × 30-sec all-out sprints with or without ingestion of EAA + Carb or placebo drinks in a randomized order with a month interval. Muscle biopsies were performed at rest and 140 min after last sprint and analyzed for p-mTOR, p-p70S6k, p-eEF2 and for hVps34 activity and hVps34 protein content. Venous blood samples were collected and analyzed for amino acids, glucose, lactate, and insulin. During the sprint exercise session, EAA, glucose, and insulin in blood increased significantly more in EAA + Carb than in placebo. P-mTOR and p-p70S6k were significantly increased above rest in EAA + Carb (P = 0.03, P = 0.007) 140 min after last sprint, but not in placebo. Activity and protein expression of hVps34 were not significantly changed from rest in EAA + Carb 140 min after the last sprint. However, hVps34 activity and protein expression tended to increase in placebo (both P = 0.08). In conclusion, on the contrary to the hypothesis, no increase in activation of hVps34 was found following sprint exercise in EAA + Carb condition. In spite of this, the results support an activation of mTOR during this condition. However, this does not exclude the permissive role of hVps34 in mediating the amino acid-induced activation of mTOR and muscle protein synthesis.
PMCID: PMC3841023  PMID: 24303161
Amino acids; hormones; human; skeletal muscle; Western blot; Wingate test
13.  Neural Origin of Spontaneous Hemodynamic Fluctuations in Rats under Burst–Suppression Anesthesia Condition 
Cerebral Cortex (New York, NY)  2010;21(2):374-384.
Spontaneous hemodynamic signals fluctuate coherently within many resting-brain functional networks not only in awake humans and lightly anesthetized primates but also in animals under deep anesthesia characterized by burst–suppression electroencephalogram (EEG) activity and unconsciousness. To understand the neural origin of spontaneous hemodynamic fluctuations under such a deep anesthesia state, epidural EEG and cerebral blood flow (CBF) were simultaneously recorded from the bilateral somatosensory cortical regions of rats with isoflurane-induced burst–suppression EEG activity. Strong neurovascular coupling was observed between spontaneous EEG “bursts” and CBF “bumps,” both of which were also highly synchronized across the 2 hemispheres. Functional magnetic resonance imaging (fMRI) was used to image spontaneous blood oxygen level–dependent (BOLD) signals under the same anesthesia conditions and showed similar BOLD “bumps” and dependence on anesthesia depth as the CBF signals. The spatiotemporal BOLD correlations indicate a strong but less-specific coherent network covering a wide range of cortical regions. The overall findings reveal that the spontaneous CBF/BOLD fluctuations under unconscious burst–suppression anesthesia conditions originate mainly from underlying neural activity. They provide insights into the neurophysiological basis for the use of BOLD- and CBF-based fMRI signals for noninvasively imaging spontaneous and synchronous brain activity under various brain states.
PMCID: PMC3020581  PMID: 20530220
burst–suppression anesthesia; functional MRI; hemodynamic fluctuation; neurovascular coupling; spontaneous brain activity
14.  Mechanism of exercise-induced hypoglycemia in depancreatized dogs maintained on long-acting insulin. 
Journal of Clinical Investigation  1977;59(2):331-337.
Human diabetics on intermediate and long-acting insulin occasionaly become hypoglycemic during exercise. We have shown previously that during exercise, hypoglycemia did not occur in depancreatized insulin-infused dogs because the increments in glucose production and utilization were proportional and of the same magnitude as in normal dogs. Therefore, to elucidate the mechanism of the glucose-lowering effect of strenuous exercise, we measured glucose production and utilization, metabolic clearance of glucose, and serum immunoreactive insulin in postabsorptive depancreatized dogs 8 h after a subcutaneous injection of protamine zinc and crystalline insulin. During rest, plasma glucose was stable, but ranged between hypoglycemia and hyperglycemia. Hyperglycemia was associated with overproduction of glucose, indicating insulin deficiency despite normal or elevated serum immunoreactive insulin. Glucose clearance, as in normal dogs, increased threefold but glucose production increased only marginally (50%) and, consequently, glucose decreased in plasma. The decrease of plasma glucose was directly proportional to the preexercise concentration and production of glucose. The magnitude of inhibition glucose production was not correlated with the serum immunoreactive insulin indicating either that some released insluin was not active or that a moderate immunoreactive insulin increment induced a near-maximal inhibition. It is concluded that in depancreatized dogs injected with protamine zinc insulin, exercise accelerates mobilization of insulin from its injection site presumably because of increased blood and lymph flow. Glucose utilization did not exceed that in normal dogs, but hepatic glucose production failed to increase sufficiently to meet the needs of muscle in exercise.
PMCID: PMC333364  PMID: 833280
15.  Ongoing physiological processes in the cerebral cortex 
NeuroImage  2011;62(4):2190-2200.
Functional magnetic resonance imaging (fMRI) has revealed that the human brain undergoes prominent, regional hemodynamic fluctuations when a subject is at rest. These ongoing fluctuations exhibit distinct patterns of spatiotemporal synchronization that have been dubbed “resting state functional connectivity”, and which currently serve as a principal tool to investigate neural networks in the normal and pathological human brain. Despite the wide application of this approach in human neuroscience, the neural mechanisms that give rise to spontaneous fMRI correlations are largely unknown. Here we review results of recent electrophysiological studies in the cerebral cortex of humans and nonhuman primates that link neural activity to ongoing fMRI fluctuations. We begin by describing results obtained with simultaneous fMRI and electrophysiological measurements that allow for the identification of direct neural correlates of resting state functional connectivity. We next highlight experiments that investigate the correlational structure of spontaneous neural signals, including the spatial variation of signal coherence over the cortical surface, across cortical laminae, and between the two hemispheres. In the final section we speculate on the origins and potential consequences of ongoing signals for normal brain function, and point out inherent limitations of the fMRI correlation approach.
PMCID: PMC3288739  PMID: 22040739
16.  Differential Effects of Insulin on Splanchnic and Peripheral Glucose Disposal after an Intravenous Glucose Load in Man 
Journal of Clinical Investigation  1982;70(1):117-126.
The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg−1 min−1) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg−1 min−1; (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg−1 min−1); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg−1 min−1). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls (≃170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 μU/ml at 90 min. NSGB switched from a net output of 1.71±0.13 to a net uptake of 1.5-1.6 mg kg−1 min−1 due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78±0.13 to 1.6-1.8 mg kg−1 min−1; P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 μU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 μU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 μU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg−1 min−1). Peripheral glucose uptake rose to the same extent as in controls.
It is concluded that: (a) the suppressive effect of hyperglycemia on hepatic glucose output is strictly dependent on the degree of hepatic insulinization; (b) insulin plays an essential role in promoting splanchnic glucose uptake after an intravenous glucose load whereas hyperglycemia per se is totally unable to activate this process; (c) peripheral glucose uptake is markedly stimulated by hyperglycemia even in the face of insulin deficiency. Direct evidence also demonstrates that the skeletal muscle is involved in this response. Our data, thus, indicate that insulin rather than hyperglycemia regulates splanchnic glucose disposal in man. On the other hand, hyperglycemia per se appears to be an important regulator of glucose disposal by peripheral tissues.
PMCID: PMC370233  PMID: 6123524
1. Determinations of the oxygen content and the oxygen unsaturation of the venous blood have been performed on patients with varying amounts of hemoglobin. 2. The oxygen unsaturation of the venous blood is independent of the oxygen capacity, unless the latter is reduced below the normal value for oxygen unsaturation (about 5 volumes per cent). In a polycythemic patient, for example, with 33.4 volumes per cent oxygen capacity (181 per cent hemoglobin), the venous oxygen content was. 28 volumes per cent, giving an unsaturation of 5.4 volumes per cent. Similarly, in an anemic patient with only 6.7 volumes per cent oxygen capacity (36 per cent hemoglobin), the venous oxygen was 1.5, giving an unsaturation of 5.2 volumes per cent. This means that the tissues extract from the blood all the oxygen they need with apparently equal readiness, regardless of whether the extraction leaves a great oxygen reserve in the blood as in polycythemia, or practically no reserve as in anemia. 3. The results seem to show that the resting organism does not increase its circulation until all the reserve oxygen is used. This means that the resting anemic organism does not need or use any compensation for its anemia until the hemoglobin has sunk below 30 per cent. Below that value the organism increases the blood flow in order to secure to the tissues the normal amount of oxygen.
PMCID: PMC2126492  PMID: 19868350
18.  Spontaneous Low-Frequency Fluctuations in the BOLD Signal in Schizophrenic Patients: Anomalies in the Default Network 
Schizophrenia Bulletin  2007;33(4):1004-1012.
Spontaneous low-frequency fluctuations in the blood oxygen level–dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. A “default network” of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulus-independent thought. Negatively correlated with this network are regions activated during attention-demanding tasks. Both these networks involve brain regions and functions that have been linked with schizophrenia in previous research. The present study examined spontaneous slow fluctuations in the BOLD signal at rest, as measured by correlation with low-frequency oscillations in the posterior cingulate, in 17 schizophrenic patients, and 17 comparable healthy volunteers. Healthy volunteers demonstrated correlation between spontaneous low-frequency fluctuations of the BOLD signal in the posterior cingulate and fluctuations in the lateral parietal, medial prefrontal, and cerebellar regions, similar to previous reports. Schizophrenic patients had significantly less correlation between spontaneous slow activity in the posterior cingulate and that in the lateral parietal, medial prefrontal, and cerebellar regions. Connectivity of the posterior cingulate was found to vary with both positive and negative symptoms in schizophrenic patients. Because these data suggest significant abnormalities in resting-state neural networks in schizophrenia, further investigations of spontaneous slow fluctuations of the BOLD signal seem warranted in this population.
PMCID: PMC2632312  PMID: 17556752
anticorrelated networksdefault network; schizophrenia; functional MRI; spontaneous slow fluctuations; posterior cingulate; medial prefrontal cortex
19.  Resting state functional connectivity in the human spinal cord 
eLife  2014;3:e02812.
Functional magnetic resonance imaging using blood oxygenation level dependent (BOLD) contrast is well established as one of the most powerful methods for mapping human brain function. Numerous studies have measured how low-frequency BOLD signal fluctuations from the brain are correlated between voxels in a resting state, and have exploited these signals to infer functional connectivity within specific neural circuits. However, to date there have been no previous substantiated reports of resting state correlations in the spinal cord. In a cohort of healthy volunteers, we observed robust functional connectivity between left and right ventral (motor) horns, and between left and right dorsal (sensory) horns. Our results demonstrate that low-frequency BOLD fluctuations are inherent in the spinal cord as well as the brain, and by analogy to cortical circuits, we hypothesize that these correlations may offer insight into the execution and maintenance of sensory and motor functions both locally and within the cerebrum.
eLife digest
Brain imaging methods such as functional magnetic resonance imaging (fMRI) can provide us with a picture of what the brain is doing when a person is carrying out a specific task. For example, an fMRI scan recorded whilst someone is reading is likely to show activity in regions in the left hemisphere of the brain that are known to be involved in language comprehension. fMRI can also be used to measure patterns of neuronal activity when someone is awake but not engaged in a specific task. This approach, known as resting state fMRI, can be used to examine which regions of the resting brain are active at the same time. Researchers are interested in these patterns of brain activity because they reflect neural circuits that work together to produce different functions and behaviors.
Over 4000 papers have used resting state fMRI to study the human brain. However, to date there has been no conclusive investigation of resting state activity in the spinal cord. This is largely because the spinal cord is much smaller than the brain, and most fMRI scanners are not sensitive enough to study it in detail. Consequently, little is known about intrinsic neural circuits in the resting spinal cord.
Now Barry et al. have used advances in fMRI technology to show that resting state functional connectivity does indeed exist in the spinal cord. Correlations were found in the resting levels of activity between spatially distinct areas of the cord, specifically between the ventral horns and between the dorsal horns. The ventral horns relay motor signals to the body, whilst the dorsal horns receive sensory signals from the body.
These findings also have clinical applications. Some patients with incomplete spinal cord injuries can recover near normal function, but the mechanisms responsible for this recovery are unclear because clinicians have not been able to probe neuronal connections in the spinal cord in a non-invasive manner. The work of Barry et al. should help with efforts to understand the neuronal changes that support recovery from spinal cord injury.
PMCID: PMC4120419  PMID: 25097248
fMRI; spinal cord; 7 Tesla; resting state; functional connectivity; human
20.  Quasi-periodic patterns (QPP): large-scale dynamics in resting state fMRI that correlate with local infraslow electrical activity 
NeuroImage  2013;84:10.1016/j.neuroimage.2013.09.029.
Functional connectivity measurements from resting state blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) are proving a powerful tool to probe both normal brain function and neuropsychiatric disorders. However, the neural mechanisms that coordinate these large networks are poorly understood, particularly in the context of the growing interest in network dynamics. Recent work in anesthetized rats has shown that the spontaneous BOLD fluctuations are tightly linked to infraslow local field potentials (LFPs) that are seldom recorded but comparable in frequency to the slow BOLD fluctuations. These findings support the hypothesis that long-range coordination involves low frequency neural oscillations and establishes infraslow LFPs as an excellent candidate for probing the neural underpinnings of the BOLD spatiotemporal patterns observed in both rats and humans. To further examine the link between large-scale network dynamics and infraslow LFPs, simultaneous fMRI and microelectrode recording were performed in anesthetized rats. Using an optimized filter to isolate shared components of the signals, we found that time-lagged correlation between infraslow LFPs and BOLD is comparable in spatial extent and timing to a quasi-periodic pattern (QPP) found from BOLD alone, suggesting that fMRI-measured QPPs and the infraslow LFPs share a common mechanism. As fMRI allows spatial resolution and whole brain coverage not available with electroencephalography, QPPs can be used to better understand the role of infraslow oscillations in normal brain function and neurological or psychiatric disorders.
PMCID: PMC3869452  PMID: 24071524
functional magnetic resonance imaging; blood oxygen level dependent; local field potential; spatiotemporal dynamics; infraslow oscillation; slow wave; quasi-periodic
21.  Effect of Statins on Venous Thromboembolic Events: A Meta-analysis of Published and Unpublished Evidence from Randomised Controlled Trials 
PLoS Medicine  2012;9(9):e1001310.
A systematic review and meta-analysis conducted by Kazem Rahimi and colleagues re-evaluates the hypothesis, generated in previous studies, that statins may reduce the risk of venous thromboembolic events. Their meta-analysis does not support the previous findings.
It has been suggested that statins substantially reduce the risk of venous thromboembolic events. We sought to test this hypothesis by performing a meta-analysis of both published and unpublished results from randomised trials of statins.
Methods and Findings
We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to March 2012 for randomised controlled trials comparing statin with no statin, or comparing high dose versus standard dose statin, with 100 or more randomised participants and at least 6 months' follow-up. Investigators were contacted for unpublished information about venous thromboembolic events during follow-up. Twenty-two trials of statin versus control (105,759 participants) and seven trials of an intensive versus a standard dose statin regimen (40,594 participants) were included. In trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events (465 [0.9%] statin versus 521 [1.0%] control, odds ratio [OR] = 0.89, 95% CI 0.78–1.01, p = 0.08) with no evidence of heterogeneity between effects on deep vein thrombosis (266 versus 311, OR 0.85, 95% CI 0.72–1.01) and effects on pulmonary embolism (205 versus 222, OR 0.92, 95% CI 0.76–1.12). Exclusion of the trial result that provided the motivation for our meta-analysis (JUPITER) had little impact on the findings for venous thromboembolic events (431 [0.9%] versus 461 [1.0%], OR = 0.93 [95% CI 0.82–1.07], p = 0.32 among the other 21 trials). There was no evidence that higher dose statin therapy reduced the risk of venous thromboembolic events compared with standard dose statin therapy (198 [1.0%] versus 202 [1.0%], OR = 0.98, 95% CI 0.80–1.20, p = 0.87). Risk of bias overall was small but a certain degree of effect underestimation due to random error cannot be ruled out.
Please see later in the article for the Editors' Summary.
The findings from this meta-analysis do not support the previous suggestion of a large protective effect of statins (or higher dose statins) on venous thromboembolic events. However, a more moderate reduction in risk up to about one-fifth cannot be ruled out.
Editors' Summary
Blood normally flows smoothly throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant blood clot (thrombus) plugs the wound and prevents blood loss. Occasionally, however, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. A clot inside one of the veins (vessels that take blood towards the heart) deep within the body is called a deep vein thrombosis (DVT). Symptoms of DVT (which usually occurs in the leg) include pain, swelling, and redness in the affected limb. DVT is treated with heparin and warfarin, two anticoagulant drugs that stop the blood clot growing. If left untreated, part of the clot (an embolus) can break off and travel to the lungs, where it can cause a pulmonary embolism (PE), a life-threatening condition characterized by chest pain, breathlessness, coughing, and dizziness. Little is known about how to prevent DVTs and PEs but risk factors for these venous thromboembolic events include having an inherited blood clotting disorder, oral contraceptive use, having surgery, and prolonged inactivity (on long-haul plane flights, for example).
Why Was This Study Done?
In 2009, a secondary (add-on) analysis of data from a randomized controlled trial (RCT, a study that randomly assigns individuals to receive different treatments and compares the outcomes associated with each treatment) called the JUPITER trial reported that rosuvastatin—a cholesterol-lowering drug (statin)—halved the risk of venous thromboembolic events among apparently healthy adults. The JUPITER trial was initiated to test whether statins reduce the risk of strokes, heart attacks, and other cardiovascular diseases (conditions that involve the heart and the blood vessels) among adults with raised levels of a predictor for these diseases called C-reactive protein; statins reduce the levels of this protein as well as those of cholesterol. Because fewer than 100 of the participants in the JUPITER trial developed a DVT or PE, the reduction in the risk of a venous thromboembolic event among the participants who took rosuvastatin could have happened by chance. In this systematic review and meta-analysis of 29 RCTs of statins that collected information on many more venous thromboembolic events, the researchers test the hypothesis that statins substantially reduce the risk of such events. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 RCTs (105,759 participants) that compared the effects of statins with control (dummy) tablets and seven (40,594 participants) that compared an intensive statin regimen with a standard regimen. They then obtained largely unpublished information about the venous thromboembolic events that occurred during these trials (about 1,000 DVTs and PEs) from the original investigators. In the trials of statin versus control, allocation to statin therapy did not significantly reduce the risk of venous thromboembolic events. Thus, although events occurred in 465 participants who were given statins (0.9% of the participants) and in 521 participants who were given control tablets (1% of the participants), this difference in outcomes was not statistically significant—it could have happened by chance. Exclusion of the JUPITER trial results from the meta-analysis did not alter this finding. The researchers also found no evidence that intensive statin therapy reduced the risk of venous thromboembolic events compared to standard therapy.
What Do These Findings Mean?
The findings of this meta-analysis do not support the suggestion that statins, either at the standard dose or at higher doses, reduce the risk of venous thromboembolic events substantially among healthy adults. It is possible that the effect of statins has been underestimated in this meta-analysis because of missing data or because of some other source of bias. Furthermore, because the total number of events in this meta-analysis is still relatively modest, these findings do not rule out the possibility that statins may reduce the risk of venous thromboembolic events by up to about one-fifth in some or all individuals. Additional large RCTs are now needed to investigate whether statin treatment does in fact reduce the risk of venous thromboembolic events in adults and, if it does, whether all statins have a similar effect and whether statin treatment is beneficial in everyone or only in specific subgroups of people.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Frits Rosendaal
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolisms), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, on pulmonary embolism, and on statins; a Behind the Headlines article describes the JUPITER trial and its implications
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and statins (in English and Spanish)
PMCID: PMC3445446  PMID: 23028261
22.  ATP Depletion, a Possible Role in the Pathogenesis of Hyperuricemia in Glycogen Storage Disease Type I 
Journal of Clinical Investigation  1978;62(2):321-328.
Other investigators have shown that fructose infusion in normal man and rats acutely depletes hepatic ATP and Pi and increases the rate of uric acid formation by the degradation of preformed nucleotides. We postulated that a similar mechanism of ATP depletion might be present in patients with glucose-6-phosphatase deficiency (GSD-I) as a result of ATP consumption during glycogenolysis and resulting excess glycolysis. The postulate was tested by measurement of: (a) hepatic content of ATP, glycogen, phosphorylated sugars, and phosphorylase activities before and after increasing glycolysis by glucagon infusion and (b) plasma urate levels and urate excretion before and after therapy designed to maintain blood glucose levels above 70 mg/dl and thus prevent excess glycogenolysis and glycolysis.
Glucagon infusion in seven patients with GSD-I caused a decrease in hepatic ATP from 2.25 ± 0.09 to 0.73 ± 0.06 μmol/g liver (P <0.01), within 5 min, persisting in one patient to 20 min (1.3 μmol/g). Three patients with GSD other than GSD-I (controls), and 10 normal rats, showed no change in ATP levels after glucagon infusion. Glucagon caused an increase in hepatic phosphorylase activity from 163 ± 21 to 311 ± 17 μmol/min per g protein (P <0.01), and a decrease in glycogen content from 8.96 ± 0.51 to 6.68 ± 0.38% weight (P <0.01). Hepatic content of phosphorylated hexoses measured in two patients, showed the following mean increases in response to glucagon; glucose-6-phosphate (from 0.25 to 0.98 μmol/g liver), fructose-6-phosphate (from 0.17 to 0.45 μmol/g liver), and fructose-1,6-diphosphate (from 0.09 to 1.28 μmol/g) within 5 min. These changes, except for glucose-6-phosphate, returned toward preinfusion levels within 20 min.
Treatment consisted of continuous intragastric feedings of a high glucose dietary mixture. Such treatment increased blood glucose from a mean level of 62 (range 28-96) to 86 (range 71-143) mg/dl (P <0.02), decreased plasma glucagon from a mean of 190 (range 171-208) to 56 (range 30-70) pg/ml (P <0.01), but caused no significant change in insulin levels. Urate output measured in three patients showed an initial increase, coinciding with a decrease in plasma lactate and triglyceride levels, then decreased to normal within 3 days after treatment. Normalization of urate excretion was associated with normalization of serum uric acid.
We suggest that the maintenance of blood glucose levels above 70 mg/dl is effective in reducing serum urate levels and that transient and recurrent depletion of hepatic ATP due to glycogenolysis is contributory in the genesis of hyperuricemia in untreated patients with GSD-I.
PMCID: PMC371769  PMID: 276529
23.  Loss of resting interhemispheric functional connectivity after complete section of the corpus callosum 
Slow (<0.1Hz), spontaneous fluctuations in the fMRI blood oxygen level-dependent (BOLD) signal have been shown to exhibit phase coherence within functionally related areas of the brain. Surprisingly, this phenomenon appears to transcend levels of consciousness. The genesis of coherent BOLD fluctuations remains to be fully explained. We present a resting state functional connectivity study of a six-year old child with radiologically normal brain imaged both before and after complete section of the corpus callosum for the treatment of intractable epilepsy. Post-operatively, there was a striking loss of interhemispheric BOLD correlations with preserved intrahemispheric correlations. These unique data provide important insights into the relationship between connectional anatomy and functional organization of the human brain. Such observations have the potential to increase our understanding of large-scale brain systems in health and disease as well as improve the treatment of neurologic disorders.
PMCID: PMC2738991  PMID: 18562616
synchrony; functional connectivity; corpus callosotomy; epilepsy; fMRI; resting state
24.  Chronic Antidiabetic Sulfonylureas In Vivo: Reversible Effects on Mouse Pancreatic β-Cells 
PLoS Medicine  2008;5(10):e206.
Pancreatic β-cell ATP-sensitive potassium (KATP) channels are critical links between nutrient metabolism and insulin secretion. In humans, reduced or absent β-cell KATP channel activity resulting from loss-of-function KATP mutations induces insulin hypersecretion. Mice with reduced KATP channel activity also demonstrate hyperinsulinism, but mice with complete loss of KATP channels (KATP knockout mice) show an unexpected insulin undersecretory phenotype. Therefore we have proposed an “inverse U” hypothesis to explain the response to enhanced excitability, in which excessive hyperexcitability drives β-cells to insulin secretory failure without cell death. Many patients with type 2 diabetes treated with antidiabetic sulfonylureas (which inhibit KATP activity and thereby enhance insulin secretion) show long-term insulin secretory failure, which we further suggest might reflect a similar progression.
Methods and Findings
To test the above hypotheses, and to mechanistically investigate the consequences of prolonged hyperexcitability in vivo, we used a novel approach of implanting mice with slow-release sulfonylurea (glibenclamide) pellets, to chronically inhibit β-cell KATP channels. Glibenclamide-implanted wild-type mice became progressively and consistently diabetic, with significantly (p < 0.05) reduced insulin secretion in response to glucose. After 1 wk of treatment, these mice were as glucose intolerant as adult KATP knockout mice, and reduction of secretory capacity in freshly isolated islets from implanted animals was as significant (p < 0.05) as those from KATP knockout animals. However, secretory capacity was fully restored in islets from sulfonylurea-treated mice within hours of drug washout and in vivo within 1 mo after glibenclamide treatment was terminated. Pancreatic immunostaining showed normal islet size and α-/β-cell distribution within the islet, and TUNEL staining showed no evidence of apoptosis.
These results demonstrate that chronic glibenclamide treatment in vivo causes loss of insulin secretory capacity due to β-cell hyperexcitability, but also reveal rapid reversibility of this secretory failure, arguing against β-cell apoptosis or other cell death induced by sulfonylureas. These in vivo studies may help to explain why patients with type 2 diabetes can show long-term secondary failure to secrete insulin in response to sulfonylureas, but experience restoration of insulin secretion after a drug resting period, without permanent damage to β-cells. This finding suggests that novel treatment regimens may succeed in prolonging pharmacological therapies in susceptible individuals.
In a mouse study aiming to understand why long-term treatment for type 2 diabetes with sulfonylureas eventually fails, Colin Nichols and Maria Remedi suggest that slow restoration of insulin secretion may be possible after a drug-resting period.
Editors' Summary
Diabetes is an increasingly common chronic disease characterized by high blood sugar (glucose) levels. In normal people, blood sugar levels are controlled by the hormone insulin. Insulin is released by β-cells in the pancreas when blood glucose levels rise after eating (glucose is produced by the digestion of food). In fasting people, membrane proteins called ATP-sensitive potassium (KATP) channels keep the β-cell in a “hyperpolarized” state in which they do not secrete insulin. After a meal, glucose enters the β-cell where its chemical breakdown converts ADP into ATP (the molecule that provides the energy that drives cellular processes). The increased ratio of ATP to ADP closes the KATP channels, “depolarizes” the β-cells, and allows the entry of calcium ions, which trigger insulin release. The released insulin then “instructs” insulin-responsive muscle and fat cells to take up glucose from the bloodstream. In type 2 diabetes, the commonest type of diabetes, the muscle and fat cells gradually become nonresponsive to insulin and consequently blood glucose levels rise. Over time, this hyperglycemia increases the risk of heart attacks, kidney failure, and other life-threatening complications. On average, people with diabetes die 5–10 y younger than people without diabetes.
Why Was This Study Done?
People with type 2 diabetes are often initially treated with drugs called sulfonylureas (for example, glibenclamide). Sulfonylureas help to reduce blood glucose levels by inhibiting (in effect, closing) the KATP channels, which enhances insulin secretion. Unfortunately, after patients have been treated for several years with sulfonylureas, their β-cells often stop secreting insulin and the patients then have to inject insulin to control their blood sugar levels. The mechanism by which chronic sulfonylurea treatment affects β-cell behavior is poorly understood, which means that it is hard to improve this antidiabetes treatment. Mice that have been genetically altered so that they have no KATP channels (KATP knockout mice) also rapidly lose their ability to secrete insulin, although they secrete unusually large amounts at birth. This suggests that permanent membrane depolarization (β-cell hyperexcitability) may cause insulin secretory failure. In this study, the researchers investigate whether this mechanism might be responsible for sulfonylurea-induced loss of insulin secretion.
What Did the Researchers Do and Find?
The researchers implanted slowly releasing pellets of glibenclamide into wild-type mice and then monitored their blood glucose levels and glucose tolerance (the speed of glucose removal from the blood after a glucose “meal”) for up to 128 d; the pellets released drug for 90 d. The glibenclamide-implanted mice progressively developed diabetes, lost the ability to secrete insulin in response to glucose and, after 1 wk of treatment, were as glucose intolerant as adult KATP knockout mice. Compared to freshly isolated β-cells from untreated wild-type mice, glucose-stimulated insulin secretion by β-cells isolated from glibenclamide-treated wild-type mice and from KATP knockout mice was reduced to a similar degree. However, the secretory capacity of β-cells isolated from the glibenclamide-treated wild-type mice was restored to normal within hours of drug washout and was normal in β-cells isolated from treated mice 1 mo after exhaustion of the slow-release pellets. Consistent with this result, there was no obvious β-cell death in the glibenclamide-treated mice.
What Do These Findings Mean?
Although findings from animal studies do not always reflect what happens in people, these findings suggest that insulin secretion might sometimes fail in people who take sulfonylureas for a long time, because these drugs cause β-cell hyperexcitability. The finding that the secretory failure caused by sulfonylurea treatment is reversible is important because it suggests that short-acting sulfonylureas might be re-evaluated to see whether they could delay sulfonylurea-induced failure of the insulin secretory response by providing the pancreatic β-cells with periods when they are not depolarized. This finding (and the absence of β-cells death in the glibenclamide-treated mice) also suggests that there may be a way to reverse the loss of the insulin secretory response in patients who have taken sulfonylureas for a long time. Both approaches could help patients with diabetes delay or even avoid the need for insulin injections.
Additional Information.
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Renstrom and colleagues
The MedlinePlus encyclopedia provides information for patients about diabetes (in English and Spanish)
The US National Diabetes Information Clearinghouse provides information on all aspects of diabetes (in English and Spanish)
The International Diabetes Federation also provides comprehensive information about diabetes
Wikipedia has pages on KATP channels and on sulfonylurea drugs (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2573909  PMID: 18959471
25.  Muscle Mitochondrial ATP Synthesis and Glucose Transport/Phosphorylation in Type 2 Diabetes 
PLoS Medicine  2007;4(5):e154.
Muscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM).
Methods and Findings
We measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with 31P/1H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%–99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%–42%; older: 11%, 95% CI 2%–25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux.
Patients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients.
Michael Roden and colleagues report that even patients with well-controlled insulin-resistant type 2 diabetes have altered mitochondrial function.
Editors' Summary
Diabetes mellitus is an increasingly common chronic disease characterized by high blood sugar (glucose) levels. In normal individuals, blood sugar levels are maintained by the hormone insulin. Insulin is released by the pancreas when blood glucose levels rise after eating (glucose is produced by the digestion of food) and “instructs” insulin-responsive muscle and fat cells to take up glucose from the bloodstream. The cells then use glucose as a fuel or convert it into glycogen, a storage form of glucose. In type 2 diabetes, the commonest type of diabetes, the muscle and fat cells become nonresponsive to insulin (a condition called insulin resistance) and consequently blood glucose levels rise. Over time, this hyperglycemia increases the risk of heart attacks, kidney failure, and other life-threatening complications.
Why Was This Study Done?
Insulin resistance is often an early sign of type 2 diabetes, sometimes predating its development by many years, so understanding its causes might provide clues about how to stop the global diabetes epidemic. One theory is that mitochondria—cellular structures that produce the energy (in the form of a molecule called ATP) needed to keep cells functioning—do not work properly in people with insulin resistance. Mitochondria change (metabolize) fatty acids into energy, and recent studies have revealed that fat accumulation caused by poorly regulated fatty acid metabolism blocks insulin signaling, thus causing insulin resistance. Other studies using magnetic resonance spectroscopy (MRS) to study mitochondrial function noninvasively in human muscle indicate that mitochondria are dysfunctional in people with insulin resistance by showing that ATP synthesis is impaired in such individuals. In this study, the researchers have examined both baseline and insulin-stimulated mitochondrial function in nonobese patients with well-controlled type 2 diabetes and in normal controls to discover more about the relationship between mitochondrial dysfunction and insulin resistance.
What Did the Researchers Do and Find?
The researchers determined the insulin sensitivity of people with type 2 diabetes and two sets of people (the “controls”) who did not have diabetes: one in which the volunteers were age-matched to the people with diabetes, and the other containing younger individuals (insulin resistance increases with age). To study insulin sensitivity in all three groups, the researchers used a “hyperinsulinemic–euglycemic clamp.” For this, after an overnight fast, the participants' insulin levels were kept high with a continuous insulin infusion while blood glucose levels were kept normal using a variable glucose infusion. In this situation, the glucose infusion rate equals glucose uptake by the body and therefore measures tissue sensitivity to insulin. Before and during the clamp, the researchers used MRS to measure glucose-6-phosphate (an indicator of how effectively glucose is taken into cells and phosphorylated), ATP synthesis, and the fat content of the participants' muscle cells. Insulin sensitivity was lower in the patients with diabetes than in the controls, but muscle lipid content was comparable and hyperinsulinemia increased glucose-6-phosphate levels similarly in all the groups. Patients with diabetes and the older controls had lower fasting ATP synthesis rates than the young controls and, whereas insulin stimulation increased ATP synthesis in all the controls, it had no effect in the patients with diabetes. In addition, fasting blood fatty acid levels were inversely related to basal ATP synthesis, whereas insulin sensitivity was directly related to insulin-stimulated ATP synthesis.
What Do These Findings Mean?
These findings indicate that the impairment of muscle mitochondrial ATP synthesis in fasting conditions and after insulin stimulation in people with diabetes is not due to impaired glucose transport/phosphorylation or fat deposition in the muscles. Instead, it seems to be determined by lipid availability and insulin sensitivity. These results add to the evidence suggesting that mitochondrial function is disrupted in type 2 diabetes and in insulin resistance, but also suggest that there may be abnormalities in glycogen synthesis. More work is needed to determine the exact nature of these abnormalities and to discover whether they can be modulated to prevent the development of insulin resistance and type 2 diabetes. For now, though, these findings re-emphasize the need for people with type 2 diabetes or insulin resistance to reduce their food intake to compensate for the reduced energy needs of their muscles and to exercise to increase the ATP-generating capacity of their muscles. Both lifestyle changes could improve their overall health and life expectancy.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia has pages on diabetes
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information for patients on diabetes and insulin resistance
The US Centers for Disease Control and Prevention has information on diabetes for patients and professionals
American Diabetes Association provides information for patients on diabetes and insulin resistance
Diabetes UK has information for patients and professionals on diabetes
PMCID: PMC1858707  PMID: 17472434

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