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Showing papers in "American Journal of Physiology-endocrinology and Metabolism in 2004"


Journal ArticleDOI
TL;DR: It is concluded that GLP-1 improves endothelial dysfunction but not insulin resistance in type 2 diabetic patients with coronary heart disease and adds yet another salutary property of the peptide useful in diabetes treatment.
Abstract: GLP-1 stimulates insulin secretion, suppresses glucagon secretion, delays gastric emptying, and inhibits small bowel motility, all actions contributing to the anti-diabetogenic peptide effect. Endo...

653 citations


Journal ArticleDOI
TL;DR: Strong support for the hypothesis that the incretin defect plays an important role in the insulin deficiency of patients is provided by the finding that administration of excess GLP-1 to patients may completely restore the glucose-induced insulin secretion as well as the beta-cells' sensitivity to glucose.
Abstract: The available evidence suggests that about two-thirds of the insulin response to an oral glucose load is due to the potentiating effect of gut-derived incretin hormones. The strongest candidates fo...

621 citations


Journal ArticleDOI
TL;DR: An important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins.
Abstract: Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to those of insulin-like growth factor I (IGF-I) and insulin, which promote growth. In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-I suppressed protein degradation and prevented the Dex-induced increase in proteolysis. IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly. IGF-I and insulin also blocked Dex induction of these E3s and several other atrophy-related genes ("atrogenes"). Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA. IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and inhibition of this pathway [but not the calcineurin-nuclear factor of activated T cell (NFAT) or the MEK-ERK pathway] increased proteolysis and atrogin-1 mRNA expression. Thus an important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins.

611 citations


Journal ArticleDOI
TL;DR: The preprandial increase of ghrelin levels that the authors observed among humans initiating meals voluntarily, without time- or food-related cues, and the overlap between these levels and hunger scores are consistent with a role for gh Relin in meal initiation.
Abstract: Ghrelin is an orexigenic hormone that is implicated in meal initiation, in part because circulating levels rise before meals. Because previous human studies have examined subjects fed on known schedules, the observed preprandial ghrelin increases could have been a secondary consequence of meal anticipation. A causal role for ghrelin in meal initiation would be better supported if preprandial increases occurred before spontaneously initiated meals not prompted by external cues. We measured plasma ghrelin levels among human subjects initiating meals voluntarily without cues related to time or food. Samples were drawn every 5 min between a scheduled lunch and a freely requested dinner, and hunger scores were obtained using visual analog scales. Insulin, glucose, fatty acids, leptin, and triglycerides were also measured. Ghrelin levels decreased shortly after the first meal in all subjects. A subsequent preprandial increase occurred over a wide range of intermeal intervals (IMI; 320-425 min) in all but one subject. Hunger scores and ghrelin levels showed similar temporal profiles and similar relative differences in magnitude between lunch and dinner. One subject displayed no preprandial ghrelin increase and was also the only individual whose insulin levels did not return to baseline between meals. This finding, along with a correlation between area-under-the-curve values of ghrelin and insulin, suggests a role for insulin in ghrelin regulation. The preprandial increase of ghrelin levels that we observed among humans initiating meals voluntarily, without time- or food-related cues, and the overlap between these levels and hunger scores are consistent with a role for ghrelin in meal initiation.

501 citations


Journal ArticleDOI
TL;DR: Despite differences in the time course of plasma phenylalanine kinetics and a greater residual IC phenylAlanine concentration, amino acid supplementation acutely stimulated muscle protein synthesis in both young and elderly individuals.
Abstract: We recently demonstrated that muscle protein synthesis was stimulated to a similar extent in young and elderly subjects during a 3-h amino acid infusion. We sought to determine if a more practical ...

471 citations


Journal ArticleDOI
TL;DR: It is concluded that rates of whole body and muscle protein metabolism decline with age in men and women, thus indicating that there is a progressive decline in the body's remodeling processes with aging.
Abstract: Aging in humans is associated with loss of lean body mass, but the causes are incompletely defined. Lean tissue mass and function depend on continuous rebuilding of proteins. We tested the hypothes...

418 citations


Journal ArticleDOI
TL;DR: A brief review recounts emerging themes in the pathobiology of vascular calcification and highlights some fundamental deficiencies in the understanding of vascular endocrinology and metabolism that are immediately relevant to human health and health care.
Abstract: Cardiovascular calcification is a common consequence of aging, diabetes, hypercholesterolemia, mechanically abnormal valve function, and chronic renal insufficiency. Although vascular calcification...

375 citations


Journal ArticleDOI
TL;DR: Long-term (2)H(2)O administration to human subjects allows measurement of the dynamics of adipose tissue components, and turnover of all elements is slow, and DNL contributes approximately 20% of new TG.
Abstract: The turnover of adipose tissue components (lipids and cells) and the pathways of adipose lipid deposition have been difficult to measure in humans. We apply here a 2H2O long-term labeling technique...

332 citations


Journal ArticleDOI
TL;DR: The results of this study suggest that muscle contraction, phenformin, or AICAR activates AMPK by a mechanism that does not involve direct activation of LKB1, and suggest that the effects of excercise, phen formin, and AICar on metabolic processes in muscle may be mediated through activation of AMPK rather than activation ofLKB1 or the AMPK-related kinases.
Abstract: Activation of AMP-activated protein kinase (AMPK) by exercise and metformin is beneficial for the treatment of type 2 diabetes. We recently found that, in cultured cells, the LKB1 tumor suppressor ...

316 citations


Journal ArticleDOI
TL;DR: Western blots show that this protein, which is termed "mitoNEET," is located in the mitochondrial fraction of rodent brain, liver, and skeletal muscle, showing the identical subcellular location and migration on SDS-PAGE as the protein cross-linked specifically by the thiazolidinedione photoprobe.
Abstract: Thiazolidinediones address underlying causes of type 2 diabetes, although their mechanism of action is not clearly understood. The compounds are thought to function as direct activators of the nucl...

301 citations


Journal ArticleDOI
TL;DR: BCAA, ingested during and after resistance exercise, mediate signal transduction through p70(S6k) in skeletal muscle during exercise and throughout recovery after exercise (2 h postexercise), whereas no change was noted after the placebo trial.
Abstract: The aim of the study was to investigate the effect of resistance exercise alone or in combination with oral intake of branched-chain amino acids (BCAA) on phosphorylation of the 70-kDa S6 protein kinase (p70(S6k)) and mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK1/2), and p38 MAPK in skeletal muscle. Seven male subjects performed one session of quadriceps muscle resistance training (4 x 10 repetitions at 80% of one repetition maximum) on two occasions. In a randomized order, double-blind, crossover test, subjects ingested a solution of BCAA or placebo during and after exercise. Ingestion of BCAA increased plasma concentrations of isoleucine, leucine, and valine during exercise and throughout recovery after exercise (2 h postexercise), whereas no change was noted after the placebo trial. Resistance exercise led to a robust increase in p70(S6k) phosphorylation at Ser(424) and/or Thr(421), which persisted 1 and 2 h after exercise. BCAA ingestion further enhanced p70(S6k) phosphorylation 3.5-fold during recovery. p70(S6k) phosphorylation at Thr(389) was unaltered directly after resistance exercise. However, during recovery, Thr(389) phosphorylation was profoundly increased, but only during the BCAA trial. Furthermore, phosphorylation of the ribosomal protein S6 was also increased in the recovery period only during the BCAA trial. Exercise led to a marked increase in ERK1/2 and p38 MAPK phosphorylation, which was completely suppressed upon recovery and unaltered by BCAA. In conclusion, BCAA, ingested during and after resistance exercise, mediate signal transduction through p70(S6k) in skeletal muscle.

Journal ArticleDOI
TL;DR: Results show that mitochondria are a primary target in the diabetic heart, probably due to oxidative stress, and that this damage coincides with and may stimulate mitochondrial biogenesis.
Abstract: Diabetic cardiomyopathy is a common complication leading to heightened risk of heart failure and death. In the present report, we performed proteomic analysis on total cardiac proteins from the OVE26 mouse model of type 1 diabetes to identify protein changes that may contribute to diabetic cardiomyopathy. This analysis revealed that a surprising high proportion (12 of 20) of the altered proteins that could be identified by mass spectrometry were of mitochondrial origin. All but one of these proteins were upregulated by diabetes. Quantitative RT-PCR, performed for two of these proteins, indicated that part of the upregulation was attributed to increased messenger RNA levels. Morphological study of diabetic hearts showed significantly increased mitochondrial area and number as well as focal regions with severe damage to mitochondria. Diabetic mitochondria also showed reduced respiratory control ratio (9.63 +/- 0.20 vs. 6.13 +/- 0.41, P < 0.0001), apparently due to reduced state 3 rate, and diminished GSH level (5.5 +/- 0.9 vs. 8.2 +/- 2.5 micromol/mg protein, P < 0.05), indicating impaired mitochondrial function and increased oxidative stress. Further examination revealed increased mitochondrial DNA (1.03 +/- 0.18 vs. 0.69 +/- 0.13 relative copy number, P < 0.001) and a tendency to higher protein yield in OVE26 cardiac mitochondria, as well as increased mRNA level for mitochondrial transcription factor A and two mitochondrial encoded proteins. Taken together, these results show that mitochondria are a primary target in the diabetic heart, probably due to oxidative stress, and that this damage coincides with and may stimulate mitochondrial biogenesis.

Journal ArticleDOI
TL;DR: The reason for the training-induced increase in peak lactate and H+ release during exercise is a combination of an increased density of the lactateand H+ transporting systems, an improved blood flow and blood flow distribution, and an increased systemic lactate & H+ clearance.
Abstract: The study investigated the effect of training on lactate and H+ release from human skeletal muscle during one-legged knee-extensor exercise. Six subjects were tested after 7–8 wk of training (fifte...

Journal ArticleDOI
TL;DR: This paper observed that estrogen treatment increased the transcript levels of several mitochondrial DNA (mtDNA)-encoded genes for mitochondrial respiratory chain (MRC) proteins and MRC activity, and showed that MRC protein activity increased with estrogen treatment.
Abstract: We observed previously that estrogen treatment increased the transcript levels of several mitochondrial DNA (mtDNA)-encoded genes for mitochondrial respiratory chain (MRC) proteins and MRC activity...

Journal ArticleDOI
TL;DR: It is concluded that elevated IMCL deposits are unlikely to be directly responsible for inducing insulin resistance, and IMCL contents can be substantially greater in trained endurance athletes compared with overweight and/or type 2 diabetes patients.
Abstract: Recent evidence suggests that intramyocellular lipid (IMCL) accretion is associated with obesity and the development of insulin resistance and/or type 2 diabetes. However, trained endurance athletes are markedly insulin sensitive, despite an elevated mixed muscle lipid content. In an effort to explain this metabolic paradox, we compared muscle fiber type-specific IMCL storage between populations known to have elevated IMCL deposits. Immunofluorescence microscopy was performed on muscle biopsies obtained from eight highly trained endurance athletes, eight type 2 diabetes patients, and eight overweight, sedentary men after an overnight fast. Mixed muscle lipid content was substantially greater in the endurance athletes (4.0 +/- 0.4% area lipid stained) compared with the diabetes patients and the overweight men (2.3 +/- 0.4 and 2.2 +/- 0.5%, respectively). More than 40% of the greater mixed muscle lipid content was attributed to a higher proportion type I muscle fibers (62 +/- 8 vs. 38 +/- 3 and 33 +/- 7%, respectively), which contained 2.8 +/- 0.3-fold more lipid than the type II fibers. The remaining difference was explained by a significantly greater IMCL content in the type I muscle fibers of the trained athletes. Differences in IMCL content between groups or fiber types were accounted for by differences in lipid droplet density, not lipid droplet size. IMCL distribution showed an exponential increase in lipid content from the central region toward the sarcolemma, which was similar between groups and fiber types. In conclusion, IMCL contents can be substantially greater in trained endurance athletes compared with overweight and/or type 2 diabetes patients. Because structural characteristics and intramyocellular distribution of lipid aggregates seem to be similar between groups, we conclude that elevated IMCL deposits are unlikely to be directly responsible for inducing insulin resistance.

Journal ArticleDOI
TL;DR: It is demonstrated that prenatal glucocorticoids program adulthood cardiovascular and metabolic physiology in a gender-specific pattern, and that an activated RAS may in part underlie the hypertension associated with prenatal DEX programming.
Abstract: Glucocorticoid overexposure in utero may underlie the association between low birth weight and subsequent development of common cardiovascular and metabolic pathologies. Previously, we have shown t...

Journal ArticleDOI
TL;DR: It is concluded that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis.
Abstract: Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR−/−) mice exhibit severe growth retar...

Journal ArticleDOI
James A. Levine1
TL;DR: A scheme is described in this review in which NEAT corresponds to a carefully regulated "tank" of physical activity that is crucial for weight control.
Abstract: Nonexercise activity thermogenesis (NEAT) is the energy expended for everything that is not sleeping, eating, or sports-like exercise. It includes the energy expended walking to work, typing, perfo...

Journal ArticleDOI
TL;DR: The data suggest that the observed elevation in circulating levels of IL-8 in obese subjects is due primarily to the release ofIL-8 from nonfat cells from adipose tissue.
Abstract: IL-8 is released from human adipose tissue. Circulating IL-8 is increased in obese compared with lean subjects and is associated with measures of insulin resistance, development of atherosclerosis,...

Journal ArticleDOI
TL;DR: A bout of moderate-intensity aerobic exercise induces short-term increases in muscle and plasma protein synthesis in both younger and older men.
Abstract: Regular aerobic exercise strongly influences muscle metabolism in elderly and young; however, the acute effects of aerobic exercise on protein metabolism are not fully understood. We investigated t...

Journal ArticleDOI
TL;DR: It is demonstrated that a single sequence of intermittent bright light pulses can phase delay the human circadian pacemaker and show that intermittent pulses have a greater resetting efficacy on a per minute basis than does continuous exposure.
Abstract: It has been shown in animal studies that exposure to brief pulses of bright light can phase shift the circadian pacemaker and that the resetting action of light is most efficient during the first minutes of light exposure. In humans, multiple consecutive days of exposure to brief bright light pulses have been shown to phase shift the circadian pacemaker. The aim of the present study was to determine whether a single sequence of brief bright light pulses administered during the early biological night would phase delay the human circadian pacemaker. Twenty-one healthy young subjects underwent a 6.5-h light exposure session in one of three randomly assigned conditions: 1) continuous bright light of approximately 9,500 lux, 2) intermittent bright light (six 15-min bright light pulses of approximately 9,500 lux separated by 60 min of very dim light of <1 lux), and 3) continuous very dim light of <1 lux. Twenty subjects were included in the analysis. Core body temperature (CBT) and melatonin were used as phase markers of the circadian pacemaker. Phase delays of CBT and melatonin rhythms in response to intermittent bright light pulses were comparable to those measured after continuous bright light exposure, even though the total exposure to the intermittent bright light represented only 23% of the 6.5-h continuous exposure. These results demonstrate that a single sequence of intermittent bright light pulses can phase delay the human circadian pacemaker and show that intermittent pulses have a greater resetting efficacy on a per minute basis than does continuous exposure.

Journal ArticleDOI
TL;DR: Results indicate that high-amplitude pulses of GH were nearly abolished and that concentrations of GH, IGF-I, PRL, and leptin all were suppressed by sleep deprivation, indicating failed negative feedback and point to hypothalamic mechanisms as containing the foci responsible for peripheral signs.
Abstract: The main systemic disorders resulting from prolonged sleep deprivation in laboratory animals are a negative energy balance, low circulating thyroid hormones, and host defense impairments. Low thyroid hormones previously have been found caused by altered regulation at the level of the hypothalamus with possible pituitary involvement. The present studies investigated the effects of sleep deprivation on other major anabolic hormonal systems. Plasma growth hormone (GH) concentrations and major secretory bursts were characterized. Insulin-like growth factor I (IGF-I) was evaluated as an integrative marker of peripheral GH effector activity. Prolactin (PRL) was assessed by basal concentrations and by stimulating the pituitary with exogenous thyrotropin-releasing hormone. Leptin was studied for its linkage to metabolic signs of sleep loss and its correspondence to altered neuroendocrine regulation in other disease states. Last, plasma corticosterone was measured to investigate the degree of hypothalamic-pituitary-adrenal activation. Sleep deprivation was produced by the disk-over-water method, a well-established means of selective deprivation of sleep and noninterference with normal waking behaviors. Hormone concentrations were determined in sham comparisons and at intervals during baseline and experimental periods lasting at least 15 days in partially and totally sleep-deprived rats. The results indicate that high-amplitude pulses of GH were nearly abolished and that concentrations of GH, IGF-I, PRL, and leptin all were suppressed by sleep deprivation. Corticosterone concentration was relatively unaffected. Features of these results, such as low GH and low IGF-I, indicate failed negative feedback and point to hypothalamic mechanisms as containing the foci responsible for peripheral signs.

Journal ArticleDOI
TL;DR: Results indicate that activation of the NO-guanylate cyclase pathway contributes to, but is not the sole mediator of, AMPK stimulation of glucose uptake and GLUT4 translocation in heart muscle.
Abstract: AMP-activated protein kinase (AMPK) is a serine-threonine kinase that regulates cellular metabolism and has an essential role in activating glucose transport during hypoxia and ischemia. The mechan...

Journal ArticleDOI
TL;DR: Even though the classical first phase does not exist under physiological conditions, the oscillatory behavior identified at the portal level does serve the purpose of rapidly exposing the liver to elevated insulin levels that, in virtue of their up-and-down pattern, are particularly effective in restraining hepatic glucose production.
Abstract: To fulfill its preeminent function of regulating glucose metabolism, insulin secretion must not only be quantitatively appropriate but also have qualitative, dynamic properties that optimize insuli...

Journal ArticleDOI
TL;DR: The nocturnal increase in ghrelin levels is more likely to be caused by sleep-associated processes than by circadian influences, and secretion during the first hours of sleep correlated positively with peak hGH concentrations.
Abstract: Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been shown to promote slow-wave sleep (SWS, non-REM sleep stages 3 and 4). Plasma levels of ghrelin are dependent on food intake and increase in sleeping subjects during the early part of the night. It is unknown whether sleep itself affects ghrelin levels or whether circadian networks are involved. Therefore, we studied the effect of sleep deprivation on nocturnal ghrelin secretion. In healthy male volunteers, plasma levels of ghrelin, cortisol, and human growth hormone (hGH) were measured during two experimental sessions of 24 h each: once when the subjects were allowed to sleep between 2300 and 0700 and once when they were kept awake throughout the night. During sleep, ghrelin levels increased during the early part of the night and decreased in the morning. This nocturnal increase was blunted during sleep deprivation, and ghrelin levels increased only slightly until the early morning. Ghrelin secretion during the first hours of sleep correlated positively with peak hGH concentrations. We conclude that the nocturnal increase in ghrelin levels is more likely to be caused by sleep-associated processes than by circadian influences. During the first hours of sleep, ghrelin might promote sleep-associated hGH secretion and contribute to the promotion of SWS.

Journal ArticleDOI
TL;DR: IL-6 plays an important role in regulating fat metabolism in muscle, increasing rates of FA oxidation, and attenuating insulin's lipogenic effects, which may be involved in the development of TNF-alpha-induced insulin resistance in skeletal muscle.
Abstract: IL-6 and TNF-α have been associated with insulin resistance and type 2 diabetes. Furthermore, abnormalities in muscle fatty acid (FA) metabolism are strongly associated with the development of insu...

Journal ArticleDOI
TL;DR: Expression patterns of the three isoforms of the regulatory γ-subunit of AMP-activated protein kinase (AMPK) were determined in various tissues from adult humans, mice, and rats, as well as in huma...
Abstract: Expression patterns of the three isoforms of the regulatory γ-subunit of AMP-activated protein kinase (AMPK) were determined in various tissues from adult humans, mice, and rats, as well as in huma...

Journal ArticleDOI
TL;DR: In this article, the authors studied whether training changes β-cell function in type 2 diabetic patients, and they found that training increased insulin sensitivity but decreased the capacity to secrete insulin.
Abstract: In healthy young subjects, training increases insulin sensitivity but decreases the capacity to secrete insulin. We studied whether training changes β-cell function in type 2 diabetic patients. Pat...

Journal ArticleDOI
TL;DR: Exercise training increases IMCL in older persons in parallel with an enhanced capacity for fat oxidation and succinate dehydrogenase staining intensity.
Abstract: Intramyocellular lipid (IMCL) has been associated with insulin resistance. However, an association between IMCL and insulin resistance might be modulated by oxidative capacity in skeletal muscle. W...

Journal ArticleDOI
TL;DR: Exercise-induced PGC-1alpha expression in skeletal muscle may be mediated by at least two exercise-induced signaling factors: AMPK activation and Ca2+ elevation.
Abstract: The purpose of this study was to elucidate the mechanisms underlying low-intensity exercise-induced peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein expression in rat sk...