bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced oxygen extraction and reduced flow heterogeneity in exercising muscle in endurance-trained men
Authors: Kalliokoski Kari K. , Oikonen Vesa , Takala Teemu O. , Sipilä Hannu , Knuuti Juhani , Nuutila Pirjo
Published: December 2017

The aim of this study was to investigate the effects of endurance training on skeletal muscle hemodynamics and oxygen consumption. Seven healthy endurance-trained and seven untrained subjects were studied. Oxygen uptake, blood flow, and blood volume were measured in the quadriceps femoris muscle group by use of positron emission tomography and [15O]O2, [15O]H2O, and [15O]CO during rest and one-legged submaximal intermittent isometric exercise. The oxygen extraction fraction was higher (0.49 ± 0.14 vs. 0.29 ± 0.12; P = 0.017) and blood transit time longer (0.6 ± 0.1 vs. 0.4 ± 0.1 min; P = 0.04) in the exercising muscle of the trained compared with the untrained subjects. The flow heterogeneity by means of relative dispersion was lower for the exercising muscle in the trained (50 ± 9%) compared with the untrained subjects (65 ± 13%, P = 0.025). In conclusion, oxygen extraction is higher, blood transit time longer, and perfusion more homogeneous in endurance-trained subjects compared with untrained subjects at the same workload. These changes may be associated with improved exercise efficiency in the endurance-trained subjects.
Immunization against IGF-I prevents increases in protein synthesis in diabetic rats after resistance exercise
Authors: Fedele Mark J. , Lang Charles H. , Farrell Peter A.
Published: December 2017

These studies examined whether passive immunization against insulin-like growth factor I (IGF-I) would prevent increases in rates of protein synthesis in skeletal muscle of diabetic rats after resistance exercise. Male Sprague-Dawley rats were pancreatectomized and randomly assigned to either an exercise or a sedentary group. Animals in each of these groups received either an IGF-I antibody or a nonspecific IgG from a subcutaneous osmotic pump. Exercise did not change plasma or gastrocnemius IGF-I concentrations in nondiabetic rats. However, plasma and muscle IGF-I concentrations were higher in IgG-treated diabetic rats that exercised compared with respective sedentary groups ( P < 0.05). Passively immunized diabetic rats did not exhibit the same exercise-induced increase in IGF-I concentrations. In nondiabetic rats, protein synthesis rates were higher after exercise in both control and immunized groups. In diabetic rats, exercise increased protein synthesis in the IgG-treated animals but not in those treated with IGF-I antibody. There was also a significant positive correlation between both plasma and gastrocnemius IGF-I concentrations and rates of protein synthesis in diabetic ( P < 0.01), but not nondiabetic, rats. These results suggest that IGF-I is compensatory for insulin in hypoinsulinemic rats by facilitating an anabolic response after acute resistance exercise.
Substrate utilization during endurance exercise in men and women after endurance training
Authors: Carter S. L. , Rennie C. , Tarnopolsky M. A.
Published: December 2017

We investigated the effect of endurance training on whole body substrate, glucose, and glycerol utilization during 90 min of exercise at 60% peak O2 consumption (V˙o 2 peak) in males and females. Substrate oxidation was determined before and after 7 wk of endurance training on a cycle ergometer, with posttesting performed at the same absolute (ABS, W) and relative (REL, %V˙o 2 peak) intensities. [6,6-2H]glucose and [1,1,2,3,3-2H]glycerol tracers were used to calculate the respective substrate tracee flux. Endurance training resulted in an increase inV˙o 2 peak for both males and females of 17 and 22%, respectively ( P < 0.001). Females demonstrated a lower respiratory exchange ratio (RER) both pretraining and posttraining compared with males during exercise ( P< 0.001). Glucose rate of appearance (Ra) and rate of disappearance (Rd) were not different between males and females. Glucose metabolic clearance rate (MCR) was lower at 75 and 90 min of exercise for females compared with males ( P < 0.05). Glucose Ra and Rd were lower during exercise at both ABS and REL posttraining exercise intensities compared with pretraining ( P < 0.001). Females had a higher exercise glycerol Ra and Rd compared with males both pre- and posttraining ( P < 0.001). Glycerol Ra was not different at either the ABS or REL posttraining exercise intensities compared with pretraining. We concluded that females oxidize proportionately more lipid and less carbohydrate during exercise compared with males both pre- and posttraining, which was cotemporal with a higher glycerol Ra in females. Furthermore, endurance training resulted in a decrease in glucose flux at both ABS and REL exercise intensities after endurance exercise training.
Determinants of insulin-stimulated glucose disposal in middle-aged, premenopausal women
Authors: Toth Michael J. , Sites Cynthia K. , Cefalu William T. , Matthews Dwight E. , Poehlman Eric T.
Published: December 2017

Controversy exists regarding the relative importance of adiposity, physical fitness, and physical activity in the regulation of insulin-stimulated glucose disposal. To address this issue, we measured insulin-stimulated glucose disposal [mg · kg fat-free mass (FFM)−1 · min−1; oxidative and nonoxidative components] in 45 nondiabetic, nonobese, premenopausal women (mean ± SD; 47 ± 3 yr) by use of hyperinsulinemic euglycemic clamp (40 mU · m−2 · min−1) and [6,6-2H2]glucose dilution techniques. We also measured body composition, abdominal fat distribution, thigh muscle fat content, maximal oxygen consumption (V˙o 2 max), and physical activity energy expenditure (2H2 18O kinetics) as possible correlates of glucose disposal.V˙o 2 max was the strongest correlate of glucose disposal ( r = 0.63, P < 0.01), whereas whole body and abdominal adiposity showed modest associations (range of r values from −0.32 to −0.46, P< 0.05 to P < 0.01). A similar pattern of correlations was observed for nonoxidative glucose disposal. None of the variables measured correlated with oxidative glucose disposal. The relationship of V˙o 2 max to glucose disposal persisted after statistical control for FFM, percent body fat, and intra-abdominal fat ( r = 0.40, P < 0.01). In contrast, correlations of total and regional adiposity measures to insulin sensitivity were no longer significant after statistical adjustment for V˙o 2 max.V˙o 2 max was the only variable to enter stepwise regression models as a significant predictor of total and nonoxidative glucose disposal. Our results highlight the importance ofV˙o 2 max as a determinant of glucose disposal and suggest that it may be a stronger determinant of variation in glucose disposal than total and regional adiposity in nonobese, nondiabetic, premenopausal women.
Mathematical model of FSH-induced cAMP production in ovarian follicles
Authors: Clément F. , Monniaux D. , Stark J. , Hardy K. , Thalabard J. C. , Franks S. , Claude D.
Published: December 2017

During the terminal part of their development, ovarian follicles become totally dependent on gonadotropin supply to pursue their growth and maturation. Both gonadotropins, follicle-stimulating hormone (FSH) and luteining hormone (LH), operate mainly through stimulatory G protein-coupled receptors, their signal being transduced by the activation of the enzyme adenylyl cyclase and the production of second-messenger cAMP. In this paper, we develop a mathematical model of the dynamics of the coupling between FSH receptor stimulation and cAMP synthesis. This model takes the form of a set of nonlinear, ordinary differential equations that describe the changes in the different states of FSH receptors (free, bound, phosphorylated, and internalized), coupling efficiency (activated adenylyl cyclase), and cAMP response. Classical analysis shows that, in the case of constant FSH signal input, the system converges to a unique, stable equilibrium state, whose properties are here investigated. The system also appears to be robust to nonconstant input. Particular attention is given to the influence of biologically relevant parameters on cAMP dynamics.
Inhibition of insulin signaling and glycogen synthesis by phorbol dibutyrate in rat skeletal muscle
Authors: Lin Yenshou , Itani Samar I. , Kurowski Theodore G. , Dean David J. , Luo Zhijun , Yaney Gordon C. , Ruderman Neil B.
Published: December 2017

Numerous studies have shown a correlation between changes in protein kinase C (PKC) distribution and/or activity and insulin resistance in skeletal muscle. To investigate which PKC isoforms might be involved and how they affect insulin action and signaling, studies were carried out in rat soleus muscle incubated with phorbol esters. Muscles preincubated for 1 h with 1 μM phorbol 12,13-dibutyrate (PDBu) showed an impaired ability of insulin to stimulate glucose incorporation into glycogen and a translocation of PKC-α, -βI, -θ, and -ε, and probably -βII, from the cytosol to membranes. Preincubation with 1 μM PDBu decreased activation of the insulin receptor tyrosine kinase by insulin and to an even greater extent the phosphorylation of Akt/protein kinase B and glycogen synthase kinase-3. However, it failed to diminish the activation of phosphatidylinositol 3′-kinase by insulin. Despite these changes in signaling, the stimulation by insulin of glucose transport (2-deoxyglucose uptake) and glucose incorporation into lipid and oxidation to CO2was unaffected. The results indicate that preincubation of skeletal muscle with phorbol ester leads to a translocation of multiple conventional and novel PKC isoforms and to an impairment of several, but not all, events in the insulin-signaling cascade. They also demonstrate that these changes are associated with an inhibition of insulin-stimulated glycogen synthesis but that, at the concentration of PDBu used here, glucose transport, its incorporation into lipid, and its oxidation to CO2are unaffected.
Assessment of islet β-cell mass in isolated rat pancreases perfused with d-[3H]mannoheptulose
Authors: Ladrière Laurence , Leclercq-Meyer Viviane , Malaisse Willy J.
Published: December 2017

d-mannoheptulose is apparently transported into cells mainly at the intervention of GLUT-2 and hence was recently proposed as a tool to label preferentially insulin-producing β-cells in the pancreatic gland. The validity of such a proposal was investigated in the present study conducted in isolated perfused pancreatic glands from control and streptozotocin-induced diabetic rats. After a 30-min equilibration period,d-[3H]mannoheptulose (0.1 mM) and [U-14C]sucrose (0.5 mM) were infused for 15 min in the presence of 30 mM d-glucose. The pancreatic glands were then perfused for 10 min with a nonradioactive medium during and after administration of cytochalasin B (0.02 mM). Under these experimental conditions, the intracellular distribution space ofd-[3H]mannoheptulose averaged 5.42 ± 0.75 nl/mg in control animals, whereas it failed to be significantly different from zero in the streptozotocin rats. The present procedure may thus allow the assessment of the relative contribution of islet β-cells to the total mass of the pancreatic gland.
Novel gastroinsular axis involving a gastric transmural glucose flux and vagal mediation
Authors: Nakagawa Atsushi , Azuma Shigeru , Nakabayashi Hajime
Published: December 2017

To determine whether the appearance of nutrients into the gastric lumen per se provokes insulin secretion, glucose solution was instilled into the pylorus-cannulated stomach via an orogastric tube in anesthetized dogs. When 200 ml of 0, 5, 10, and 20% glucose solution were sequentially instilled, transgastric gradients (TGG) of plasma glucose concentration across the fundus [short gastric vein (SGV) − femoral artery, TGG(SGV)] and insulin levels in the superior pancreaticoduodenal vein (SPDV) increased stepwise. Upon instillation of 300 ml of 10% glucose, but not 1.8% saline, for 12 min followed by 48-min spontaneous drainage via the cannula ( n = 5 each), TGG(SGV) and insulin levels in the SPDV increased concomitantly and significantly by 0.95 mM and 1,334 pM (mean), respectively, regardless of unaltered arterial glucose levels. The amount of secreted insulin (area under the curve) significantly correlated with the maximum TGG(SGV) ( r = 0.693). In selectively gastric-vagotomized dogs ( n = 5), insulin levels in the SPDV did not increase upon instillation despite a TGG(SGV) rise comparable to that in normal dogs. These results indicate that intragastric glucose appearance provokes vagus-mediated insulin secretion probably related to the transfundic glucose flux, suggesting the presence of a novel neurogenic gastroinsular axis.
Type 1 diabetes leads to cytoskeleton changes that are reflected in insulin action on rat cardiac K+currents
Authors: Shimoni Y. , Rattner J. B.
Published: December 2017

A sustained K+current ( Iss) is attenuated in ventricular cells from streptozotocin (STZ)-induced diabetic rats. The in vitro addition of insulin to isolated cells augments Issin a process that is blocked by disrupting either actin microfilaments (with cytochalasin D) or microtubules (with colchicine). When these agents are added at progressively later times, the effect of insulin becomes evident in a time-dependent manner. Issis also augmented by insulin in control cells in a cytoskeleton-dependent manner. However, in contrast to diabetic cells, cytoskeleton-dependent augmentation of Issby insulin occurs at a considerably faster rate in control cells. Immunofluorescent labeling shows a reduced density of β-tubulin in diabetic cells, particularly in perinuclear regions. In vitro insulin replacement or in vivo insulin injections given to STZ-treated rats enhances β-tubulin density. These results suggest an impairment of cytoskeleton function and structure under insulin-deficient conditions, which may have implications for cardiac function.
Glucocorticoids impair fetal β-cell development in rats
Authors: Blondeau B. , Lesage J. , Czernichow P. , Dupouy J. P. , Bréant B.
Published: December 2017

In rats, poor fetal growth due to maternal food restriction during pregnancy is associated with decreased β-cell mass at birth and glucose intolerance in adulthood. Overexposure to glucocorticoids in utero can induce intrauterine growth retardation in humans and animals and subsequent glucose intolerance in rodents. The aims of this study were to investigate whether glucocorticoid overexposure mediates the effect of undernutrition on β-cell mass and to study their potential role in normally nourished rats. Undernutrition significantly increased maternal and fetal corticosterone levels. Twenty-one-day-old fetuses with undernutrition showed growth retardation and decreased pancreatic insulin content; adrenalectomy and subcutaneous corticosterone implants in their dams prevented the maternal corticosterone increase and restored fetal β-cell mass. In fetuses with normal nutrition, fetal corticosterone levels were negatively correlated to fetal weight and insulin content; fetal β-cell mass increased from 355 ± 48 μg in sham to 516 ± 160 μg after maternal adrenalectomy; inhibition of steroid production by metyrapone induced a further increase to 757 ± 125 μg. Our data support the new concept of a negative role of glucocorticoids in fetal β-cell development.
Insulin increases FA uptake and esterification but reduces lipid utilization in isolated contracting muscle
Authors: Dyck D. J. , Steinberg G. , Bonen A.
Published: December 2017

We examined the effect of insulin on the synthesis and degradation of muscle lipid pools [phospholipid (PL), diacylglycerol (DG), triacylglycerol (TG)] and palmitate oxidation in isolated resting and contracting (20 tetani/min) soleus muscles. Lipid metabolism was monitored using the previously defined pulse-chase procedure. At rest, insulin significantly increased total palmitate uptake into soleus muscle (+49%, P < 0.05), corresponding to enhanced DG (+60%, P < 0.05) and TG (+61%, P < 0.05) esterification, but blunted palmitate oxidation (−38%, P < 0.05) and TG hydrolysis (−34%, P< 0.05). During muscle contraction, when total palmitate uptake was increased, insulin further enhanced uptake (+21%, P < 0.05) and esterification of fatty acids (FA) to PL (+73%, P < 0.05), DG (+19%, P < 0.05), and TG (+161%, P < 0.01). Despite a profound shift in the relative partitioning of FA away from esterification and toward oxidation during contraction, the increase in palmitate oxidation and TG hydrolysis was significantly blunted by insulin [oxidation, −24% ( P = 0.05); hydrolysis, −83% ( P < 0.01)]. The effects of insulin on FA esterification (stimulation) and oxidation (inhibition) during contraction were reduced in the presence of the phosphatidylinositol 3-kinase inhibitor LY-294002. In summary, the effects of insulin and contraction on palmitate uptake and esterification are additive, while insulin opposes the stimulatory effect of contraction on FA oxidation and TG hydrolysis. Insulin's modulatory effects on muscle FA metabolism during contraction are mediated at least in part through phosphatidylinositol 3-kinase.
Postprandial dyslipidemia in men with visceral obesity: an effect of reduced LDL receptor expression?
Authors: Mamo John C. L. , Watts Gerald F. , Barrett P. Hugh R. , Smith Darrin , James Anthony P. , Pal Sebely
Published: December 2017

Postprandial lipemia after an oral fat challenge was studied in middle-aged men with visceral obesity. The two groups had similar plasma cholesterol levels, but obese subjects had higher levels of plasma triglyceride and reduced amounts of high-density cholesterol. Fasting plasma insulin was fourfold greater in obese subjects because of concomitant insulin resistance, with a calculated HOMA score of 3.1 ± 0.6 vs. 0.8 ± 0.2, respectively. Plasma apolipoprotein B48(apoB48) and retinyl palmitate (RP) after an oral fat challenge were used to monitor chylomicron metabolism. Compared with lean subjects, the fasting concentration of apoB48was more than twofold greater in obese individuals, suggestive of an accumulation of posthydrolyzed particles. After the oral lipid load, the incremental areas under the apoB48and RP curves (IAUC) were both significantly greater in obese subjects (apoB48: 97 ± 17 vs. 44 ± 12 μg · ml−1· h; RP: 3,120 ± 511 vs. 1,308 ± 177 U · ml−1· h, respectively). A delay in the conversion of chylomicrons to remnants probably contributed to postprandial dyslipidemia in viscerally obese subjects. The triglyceride IAUC was 68% greater in obese subjects (4.7 ± 0.6 vs. 2.8 ± 0.8 mM · h, P< 0.06). Moreover, peak postprandial triglyceride was delayed by ∼2 h in obese subjects. The reduction in triglyceride lipolysis in vivo did not appear to reflect changes in hydrolytic enzyme activities. Postheparin plasma lipase rates were found to be similar for lean and obese subjects. In this study, low-density lipoprotein (LDL) receptor expression on monunuclear cells was used as a surrogate marker of hepatic activity. We found that, in obese subjects, the binding of LDL was reduced by one-half compared with lean controls (70.9 ± 15.07 vs. 38.9 ± 4.6 ng LDL bound/μg cell protein, P = 0.02). Because the LDL receptor is involved in the removal of proatherogenic chylomicron remnants, we suggest that the hepatic clearance of these particles might be compromised in insulin-resistant obese subjects. Premature and accelerated atherogenesis in viscerally obese, insulin-resistant subjects may in part reflect delayed clearance of postprandial lipoprotein remnants.
Programming into adulthood of islet adaptations induced by early nutritional intervention in the rat
Authors: Aalinkeel Ravikumar , Srinivasan Malathi , Song Fei , Patel Mulchand S.
Published: December 2017

To investigate the influence of a high carbohydrate (HC) intake during the suckling period on pancreatic function in adult life, neonatal rats were artificially reared on a HC milk formula during the preweaning period and then weaned onto lab chow. In the adult HC rat, hyperinsulinemia is sustained by a variety of biochemical and molecular adaptations induced in the HC islets during the suckling period. The adult HC islets showed a distinct left shift in the glucose-stimulated insulin-secretory pattern. HC islets were also able to secrete moderate levels of insulin in the absence of glucose and in the presence of Ca2+channel inhibitors. In addition, the mRNA levels of preproinsulin, somatostatin transcription factor-1, upstream stimulatory factor-1, stress-activated protein kinase-2, phosphatidylinositol kinase, and GLUT-2 genes were significantly increased in HC islets. These results show that consumption of a HC formula during the suckling period programs pancreatic islet function in adult rats, resulting in the maintenance of hyperinsulinemia in the postweaning period and eventually leading to the development of obesity in adult life.
Contribution to glucose tolerance of insulin-independent vs. insulin-dependent mechanisms in mice
Authors: Pacini Giovanni , Thomaseth Karl , Ahrén Bo
Published: December 2017

To study the contributions of insulin-dependent vs. insulin-independent mechanisms to intravenous glucose tolerance (KG), 475 experiments in mice were performed. An intravenous glucose bolus was given either alone or with exogenous insulin or with substances modulating insulin secretion and sensitivity. Seven samples were taken over 50 min. Insulin [suprabasal area under the curve (ΔAUCins)] ranged from 0 to 100 mU · ml−1 · 50 min. After validation against the euglycemic hyperinsulinemic clamp, the minimal model of net glucose disappearance was exploited to analyze glucose and insulin concentrations to measure the action of glucose per se independent of dynamic insulin (SG) and the combined effect of insulin sensitivity (SI) and secretion. Sensitivity analysis showed that insulin [through disposition index (DI)] contributed to glucose tolerance by 29 ± 4% in normal conditions. In conditions of elevated hyperinsulinemia, contribution by insulin increased on average to 69%. KG correlated with DI but was saturated for ΔAUCins above 15 mU · ml−1 · 50 min. Insulin sensitivity related to ΔAUCins in a hyperbolic manner, whereas SG did not correlate with the insulin peak in the physiological range. Thus glucose tolerance in vivo is largely mediated by mechanisms unrelated to dynamic insulin and saturates with high insulin.
Insulin infusion increases levels of free IGF-I and IGFBP-3 proteolytic activity in patients after surgery
Authors: Nygren J. , Carlsson-Skwirut C. , Brismar K. , Thorell A. , Ljungqvist O. , Bang P.
Published: December 2017

We have studied the effects of insulin on the bioavailability of insulin-like growth factor (IGF) I in insulin-resistant patients after surgery. Serum levels of total IGF-I (tIGF-I), free IGF (fIGF)-I, fIGF-II, and IGF-binding protein (IGFBP) 1 and IGFBP-3 proteolytic activity (IGFBP-3-PA), determined on the day before surgery and on the 1st postoperative day, were related to insulin sensitivity measured by a hyperinsulinemic, normoglycemic clamp. Before surgery, the decreased tIGF-I ( P < 0.05) in response to insulin infusion was accompanied by an 18% reduction of IGFBP-1 ( P < 0.001), while IGFBP-3-PA remained unchanged. Levels of fIGF-I and fIGF-II were not changed by insulin infusions. After surgery, IGFBP-3-PA increased ( P < 0.05) during insulin infusion, and this was associated with an increase in tIGF-I ( P < 0.001) and fIGF-I ( P < 0.01), while no significant change was found in fIGF-II. The reduction in IGFBP-1 in response to insulin infusion was not affected by surgery. The change in IGFBP-3-PA during insulin infusion after surgery was related to the corresponding change in fIGF-I ( r 2 = 0.26, P < 0.05) and postoperative insulin sensitivity ( r 2 = −0.22, P < 0.05). These data suggest that increased IGFBP-3-PA during insulin infusion after surgery governs the increased levels of fIGF-I, while insulin-induced suppression of IGFBP-1 was not affected by surgery. We propose that, in catabolic, postoperative patients, increased levels of insulin from exogenous or, possibly, endogenous sources (nutritionally induced) may be a signal to increase IGF-I bioavailability by increased expression of IGFBP-3-PA to counteract further deterioration in glucose metabolism.
Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr
Authors: Gresl Theresa A. , Colman Ricki J. , Roecker Ellen B. , Havighurst Thomas C. , Huang Ze , Allison David B. , Bergman Richard N. , Kemnitz Joseph W.
Published: December 2017

In a longitudinal study of the effects of moderate (70%) dietary restriction (DR) on aging, plasma glucose and insulin concentrations were measured from semiannual, frequently sampled intravenous glucose tolerance tests (FSIGTT) in 30 adult male rhesus monkeys. FSIGTT data were analyzed with Bergman's minimal model, and analysis of covariance revealed that restricted (R) monkeys exhibited increased insulin sensitivity (SI, P < 0.001) and plasma glucose disappearance rate (KG, P = 0.015), and reduced fasting plasma insulin (Ib, P < 0.001) and insulin response to glucose (AIRG, P = 0.023) compared with control (C; ad libitum-fed) monkeys. DR reduced the baseline fasting hyperinsulinemia of two R monkeys, whereas four C monkeys have maintained from baseline, or subsequently developed, fasting hyperinsulinemia; one has progressed to diabetes. Compared with only the normoinsulinemic C monkeys, R monkeys exhibited similarly improved FSIGTT and minimal-model parameters. Thus chronic DR not only has protected against the development of insulin resistance in aging rhesus monkeys, but has also improved glucoregulatory parameters compared with those of otherwise normoinsulinemic monkeys.
The vagus is inhibitory of insulin secretion under fasting conditions
Authors: Blat S. , Malbert C. H.
Published: December 2017

The involvement of the vagus in the insulin response during the early phase of absorption of a meal has been demonstrated recently. The extent of this vagal influence was investigated during fasting in an anesthetized porcine model. Portal and systemic insulin were evaluated together with glycemia during cooling and sectioning of both cervical vagal trunks in 12 splanchnicotomized or sham-operated pigs. In sham-operated animals, portal and systemic insulin were significantly and reversibly increased by cooling (173 and 123%, respectively). Portal insulin peaked 20 min after the onset of cooling but declined slowly while cooling was still activated. In contrast, systemic insulin was increased evenly along cooling. Section of the vagus was also associated with a portal and systemic insulin increase (144 and 117%) but to a lesser extent than cooling. In both treatments, portal and systemic insulin increases were either reduced (vagal cooling) or eliminated (vagal section) in splanchnicotomized animals. We conclude that the vagus exerts an inhibitory activity on interdigestive insulin secretion that is partly mediated by the splanchnic nerves.
Chronic exposure to high leucine impairs glucose-induced insulin release by lowering the ATP-to-ADP ratio
Authors: Anello M. , Ucciardello V. , Piro S. , Patané G. , Frittitta L. , Calabrese V. , Giuffrida Stella A. M. , Vigneri R. , Purrello F. , Rabuazzo A. M.
Published: December 2017

Exposure of rat pancreatic islets to 20 mM leucine for 24 h reduced insulin release in response to glucose (16.7 and 22.2 mM). Insulin release was normal when the same islets were stimulated with leucine (40 mM) or glyburide (1 μM). To investigate the mechanisms responsible for the different effect of these secretagogues, we studied several steps of glucose-induced insulin secretion. Glucose utilization and oxidation rates in leucine-precultured islets were similar to those of control islets. Also, the ATP-sensitive K+channel-independent pathway of glucose-stimulated insulin release, studied in the presence of 30 mM K+and 250 μM diazoxide, was normal. In contrast, the ATP-to-ADP ratio after stimulation with 22.2 mM glucose was reduced in leucine-exposed islets with respect to control islets. The decrease of the ATP-to-ADP ratio was due to an increase of ADP levels. In conclusion, prolonged exposure of pancreatic islets to high leucine levels selectively impairs glusoce-induced insulin release. This secretory abnormality is associated with (and might be due to) a reduced ATP-to-ADP ratio. The abnormal plasma amino acid levels often present in obesity and diabetes may, therefore, affect pancreatic islet insulin secretion in these patients.
Reduced body fat and increased hepatic lipid synthesis in mice bearing interleukin-6-secreting tumor
Authors: Metzger S. , Hassin T. , Barash V. , Pappo O. , Chajek-Shaul T.
Published: December 2017

Chronic secretion of interleukin-6 (IL-6) in mice causes metabolic alteration in the liver, leading to increased synthesis of hepatic cholesterol and fatty acids (FA). Mice were injected with allogeneic tumor cells transduced with the murine IL-6 gene. During the 3 wk after tumor inoculation, elevated serum IL-6 levels were associated with increased spleen and liver weight. Histological examination of sections from the liver showed increased hepatocyte proliferation, resulting in liver enlargement. Body composition analysis revealed that IL-6 caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic de novo synthesis of FA and cholesterol, as measured by3H2O incorporation, was three to five times as high in mice secreting IL-6 (IL-6 mice) as in pair-fed mice bearing nonsecreting tumors. This increase in FA and cholesterol synthesis is sufficient to maintain hepatic triglyceride secretion at levels comparable with those of pair-fed mice bearing nonsecreting tumors and, presumably, is the main source of cholesterol and FA-phospholipids necessary for hepatocyte proliferation.
Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in Ucp3(−/−) and wild-type mice
Authors: Bézaire Véronic , Hofmann Wolfgang , Kramer John K. G. , Kozak Leslie P. , Harper Mary-Ellen
Published: December 2017

Uncoupling protein-3 (UCP3) is a mitochondrial carrier protein of as yet undefined physiological function. To elucidate characteristics of its function, we studied the effects of fasting on resting metabolic rate, respiratory quotient, muscle Ucp3expression, and mitochondrial proton leak in wild-type and Ucp3(−/−) mice. Also analyzed were the fatty acid compositions of skeletal muscle mitochondria in fed and fasted Ucp3(−/−) and wild-type mice. In wild-type mice, fasting caused significant increases in Ucp3 (4-fold) and Ucp2 (2-fold) mRNA but did not significantly affect mitochondrial proton leak. State 4 oxygen consumption was not affected by fasting in either of the two groups. However, protonmotive force was consistently higher in mitochondria of Ucp3(−/−) animals ( P = 0.03), and fasting further augmented protonmotive force in Ucp3(−/−) mice; there was no effect in wild-type mitochondria. Resting metabolic rates decreased with fasting in both groups. Ucp3(−/−) mice had higher respiratory quotients than wild-type mice in fed resting states, indicating impaired fatty acid oxidation. Altogether, results show that the fasting-induced increases in Ucp2 and Ucp3 do not correlate with increased mitochondrial proton leak but support a role for UCP3 in fatty acid metabolism.
Triidothyronine and epinephrine rapidly modify myocardial substrate selection: a13C isotopomer analysis
Authors: Krueger Julia J. , Ning Xue-Han , Argo Barisa M. , Hyyti Outi , Portman Michael A.
Published: December 2017

Triiodothyronine (T3) exerts direct action on myocardial oxygen consumption (MV˙o2), although its immediate effects on substrate metabolism have not been elucidated. The hypothesis, that T3regulates substrate selection and flux, was tested in isovolumic rat hearts under four conditions: control, T3(10 nM), epinephrine (Epi), and T3and Epi (TE). Hearts were perfused with [1,3-13C]acetoacetic acid (AA, 0.17 mM),l-[3-13C]lactic acid (LAC, 1.2 mM), U-13C-labeled long-chain free fatty acids (FFA, 0.35 mM), and unlabeled d-glucose (5.5 mM) for 30 min. Fractional acetyl-CoA contribution to the tricarboxylic acid cycle (Fc) per substrate was determined using13C NMR and isotopomer analysis. Oxidative fluxes were calculated using Fc, the respiratory quotient, and MV˙o2. T3increased ( P < 0.05) FcFFA, decreased FcLAC, and increased absolute FFA oxidation from 0.58 ± 0.03 to 0.68 ± 0.03 μmol · min−1· g dry wt−1( P < 0.05). Epi decreased FcFFAand FcAA, although FFA flux increased from 0.58 ± 0.03 to 0.75 ± 0.09 μmol · min−1· g dry wt−1. T3moderated the change in FcFFAinduced by Epi. In summary, T3exerts direct action on substrate pathways and enhances FFA selection and oxidation, although the Epi effect dominates at a high work state.
Estimation of gluconeogenesis in newborn infants
Authors: Kalhan Satish C. , Parimi Prabhu , Van Beek Ron , Gilfillan Carol , Saker Firas , Gruca Lourdes , Sauer Pieter J. J.
Published: December 2017

The rate of glucose turnover (Ra) and gluconeogenesis (GNG) via pyruvate were quantified in seven full-term healthy babies between 24 and 48 h after birth and in twelve low-birth-weight infants on days 3 and 4 by use of [13C6]glucose and2H2O. The preterm babies were receiving parenteral alimentation of either glucose or glucose plus amino acid with or without lipids. The contribution of GNG to glucose production was measured by the appearance of 2H on C-6 of glucose. Glucose Ra in full-term babies was 30 ± 1.7 (SD) μmol · kg−1 · min−1. GNG via pyruvate contributed ∼31% to glucose Ra. In preterm babies, the contribution of GNG to endogenous glucose Rawas variable (range 6–60%). The highest contribution was in infants receiving low rates of exogenous glucose infusion. In an additional group of infants of normal and diabetic mothers, lactate turnover and its incorporation into glucose were measured within 4–24 h of birth by use of [13C3]lactate tracer. The rate of lactate turnover was 38 μmol · kg−1 · min−1, and lactate C, not corrected for loss of tracer in the tricarboxylic acid cycle, contributed ∼18% to glucose C. Lactate and glucose kinetics were similar in infants that were small for their gestational age and in normal infants or infants of diabetic mothers. These data show that gluconeogenesis is evident soon after birth in the newborn infant and that, even after a brief fast (5 h), GNG via pyruvate makes a significant contribution to glucose production in healthy full-term infants. These data may have important implications for the nutritional support of the healthy and sick newborn infant.
Sources of blood glycerol during fasting
Authors: Jensen Michael D. , Chandramouli Visvanathan , Schumann William C. , Ekberg Karin , Previs Stephen F. , Gupta Sameer , Landau Bernard R.
Published: December 2017

To determine the source(s) of blood and very low density lipoprotein (VLDL)-triglyceride glycerol during fasting, four men ingested2H2O from 14 to 20 h into a 60-h fast to achieve ∼0.5% body water enrichment. At 60 h of fasting, glycerol flux was measured using [2-14C]glycerol. Blood was taken for measurement of2H enrichment at carbon 6 of glucose and at carbon 3 of free glycerol and VLDL-triglyceride glycerol.2H enrichment of the 2 hydrogens bound to carbon 3 of VLDL-triglyceride glycerol was 105 ± 2% of the2H enrichment of the 2 hydrogens bound to carbon 6 of glucose, indicating isotopic equilibrium between hepatic glyceraldehyde 3- P and glycerol 3- P. The2H enrichment of the 2 hydrogens bound to carbon 3 of free glycerol was 17 ± 3% of VLDL-triglyceride glycerol, indicating that a significant percentage of free glycerol in blood originated from the hydrolysis of circulating VLDL-triglyceride or a pool of glycerol with similar2H enrichment. Glycerol flux was 6.3 ± 1.1 μmol · kg−1· min−1. Glycerol appearing from nonadipose tissue sources was then ∼1.1 μmol · kg−1· min−1. Seven other subjects were fasted for 12, 42, and 60 h. A small percentage of glycerol in the circulation after 12 h of fasting was enriched with2H. The enrichment of the 2 hydrogens bound to carbon 3 of free glycerol in the longer periods of fasting was ∼16% of the enrichment of the 2 hydrogens bound to carbon 6 of glucose. Therefore, as much as 15–20% of systemic glycerol turnover during fasting is not from lipolysis of adipose tissue triglyceride.
Nontraditional aspects of aldosterone physiology
Authors: Ngarmukos Chardpraorn , Grekin Roger J.
Published: December 2017

Aldosterone is the most important circulating mineralocorticoid. It is secreted by the zona glomerulosa of the adrenal gland and plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct, promoting sodium resorption and potassium excretion. The action of aldosterone on its classic target epithelia has been extensively studied, and many of the signaling events that mediate its effects have been described. Recently, there has been increased interest in aldosterone actions on the cardiovascular system, which are mediated through nonclassical actions. These include local tissue production, nongenomic actions, and effects on nonepithelial targets. In this review article, we focus on the effects of aldosterone in nonepithelial tissues that are mediated through MR, especially cardiovascular effects.
Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet
Authors: Peters Sandra J. , Harris Robert A. , Wu Pengfei , Pehleman Tanya L. , Heigenhauser George J. F. , Spriet Lawrence L.
Published: December 2017

The increase in skeletal muscle pyruvate dehydrogenase kinase (PDK) activity was measured in skeletal muscle of six healthy males after a eucaloric high-fat/low-carbohydrate (HF/LC; 5% carbohydrate, 73% fat, and 22% protein of total energy intake) diet compared with a standardized prediet (50% carbohdyrate, 30% fat, and 21% protein). Biopsies were obtained from the vastus lateralis muscle after 3 days on the prediet ( day 0) and after 1, 2, and 3 days of the HF/LC diet. Intact mitchondria were extracted from fresh muscle and analyzed for PDK activity and Western blotting of PDK2 and PDK4 protein. A second biopsy was taken at each time point and frozen for Northern blot analysis of PDK2 and PDK4 mRNAs. PDK activity increased in a linear fashion over the 3-day HF/LC diet and was significantly higher than control by 1 day. PDK activity was 0.09 ± 0.03, 0.18 ± 0.05, 0.30 ± 0.07, and 0.37 ± 0.09 min−1 at 0, 1, 2, and 3 days, respectively. PDK4 protein and mRNA increased maximally by day 1, and PDK2 protein and mRNA were unaffected by the HF/LC diet. Resting respiratory exchange ratios decreased after 1 day of the HF/LC diet (from 0.79 ± 0.02 to 0.72 ± 0.02) and remained depressed throughout the 3-day dietary intervention (0.68 ± 0.01). The immediate shift to fat utilization was accompanied by increased blood glycerol, β-hydroxybutyrate, and plasma free fatty acid concentrations. These results suggest that the continuing increase in PDK activity over the 3-day HF/LC diet is not due to increasing PDK protein beyond 1 day. This could be due to the contribution of another isoform to the total PDK activity or to a continual increase in PDK4 or PDK2 specific activity.
Activation of mitogenic and antimitogenic pathways in cyclically stretched arterial smooth muscle
Authors: Standley Paul R. , Stanley Melinda A. , Senechal P.
Published: December 2017

Biophysical forces regulate vascular smooth muscle cell (VSMC) physiology and evoke vascular remodeling. Two VSMC autocrine molecules, insulin-like growth factor I (IGF-I) and nitric oxide (NO), are implicated in remodeling attributable to VSMC hyperplasia. We investigated the role of in vitro cyclic stretch on rat VSMC IGF-I, NO, and cellular growth. Cyclic stretch (1 Hz at 120% resting length for 48 h) stimulated VSMC proliferation 2.5-fold vs. unstretched cells and was accompanied by a 1.8-fold increase in VSMC IGF-I secretion. Despite activation of this proliferative pathway, cyclic stretch induced inducible (i) nitric oxide synthase (NOS) expression and a twofold increase in NO secretion, a molecule with documented antiproliferative effects. Cytokine treatment enhanced iNOS expression and NO secretion while inhibiting vascular growth by ≈50% in static cells. Cytokine treatment of stretched VSMC enhanced NO secretion 2.5-fold while inhibiting growth by ≈80%. Exogenous IGF-I increased NOS activity 1.5-fold and NO secretion 8.5-fold in static cells. In turn, iNOS inhibition increased IGF-I secretion 1.6-fold and enhanced VSMC growth 1.6-fold in stretched cells. An NO donor (sodium nitroprusside) similarly inhibited VSMC proliferation in static (24%) and stretched (50%) VSMC while also inhibiting IGF-I secretion from stretched cells by ≈35%. Thus cyclic stretch stimulates mitogenic (IGF-I) and antimitogenic (NO) pathways in VSMC. These two molecules regulate each other's secretory rates, providing tight regulation of VSMC proliferation. These data may have profound implications in understanding vascular growth alterations in vascular injury and hypertension.
High glucose-enhanced activation of mesangial cell p38 MAPK by ET-1, ANG II, and platelet-derived growth factor
Authors: Tsiani Evangelia , Lekas Poli , Fantus I. George , Dlugosz John , Whiteside Catharine
Published: December 2017

Mitogen-activated protein kinase (MAPK) p38 is activated in response to stress stimuli and growth factors relevant to the pathogenesis of diabetic nephropathy. We postulated that mesangial cells exposed to high glucose and to endothelin-1 (ET-1), angiotensin II (ANG II), and platelet-derived growth factor (PDGF) demonstrate enhanced p38 activity and subsequent activation of the cAMP responsive element binding (CREB) transcription factor. Primary rat mesangial cells exposed to 5.6 (NG) or 30 mM glucose (HG) or NG plus 24.4 mM sorbitol (osmotic control) for ≤4 days were acutely stimulated with ET-1, ANG II, or PDGF. After 3 days of HG, p38 phosphorylation and kinase activity increased twofold ( P < 0.05 vs. NG, n = 5). No change in p38 activity was observed with sorbitol. In HG, activation of p38 by ET-1, ANG II, or PDGF was enhanced compared with NG and was protein kinase C (PKC) independent. In HG, CREB phosphorylation in response to ET-1, ANG II, and PDGF stimulation was enhanced compared with NG and was abolished by p38 inhibition with SB202190. To conclude, in HG, mesangial cell p38 is activated, which in turn stimulates CREB phosphorylation. Furthermore, in HG, mesangial cell p38 responsiveness to ET-1, ANG II, and PDGF and consequent CREB phosphorylation are enhanced through a PKC-independent pathway, which may contribute to the pathogenesis of diabetic nephropathy.
Elevated basal PI 3-kinase activity and reduced insulin signaling in sucrose-induced hepatic insulin resistance
Authors: Pagliassotti Michael J. , Kang Jione , Thresher Jeffrey S. , Sung Chin K. , Bizeau Michael E.
Published: December 2017

Sucrose feeding reduces the ability of insulin to suppress glucose production and hepatic gluconeogenesis. The present study examined the effect of a high-sucrose diet on early insulin-signaling steps in the liver. Rats were provided a high-starch (STD, control diet) or high-sucrose diet (HSD) for 3 wk. On the day of study, overnight-fasted rats were anesthetized and injected with either saline ( n = 5/diet group) or insulin (2 mU/kg, n = 5/diet group) via the portal vein. Portal venous blood and liver tissue were harvested 2 min after injections. Portal vein plasma glucose levels were not significantly different among groups, pooled average 147 ± 12 mg/dl. Western blot analysis revealed no significant differences in the amount of insulin receptor (IR), insulin receptor substrates-1 and -2 (IRS-1, IRS-2), and the p85 subunit of phosphatidylinositol (PI) 3-kinase. In contrast, the amount of the p110β subunit of PI 3-kinase was increased ∼2-fold in HSD vs. STD ( P < 0.05). After saline injection, tyrosine phosphorylation (pY) of IR, IRS-1, and IRS-2 was not significantly different between groups. However, PI 3-kinase activity associated with phosphorylated proteins was increased ∼40% in HSD vs. STD ( P < 0.05). After insulin injection, pY of the IR was not different between groups, whereas pY of IRS-1 and IRS-2 was reduced ( P < 0.05) in HSD vs. STD. In addition, association of IRS-1 and IRS-2 with p85 was significantly reduced in HSD vs. STD. These data demonstrate that an HSD impairs insulin-stimulated early postreceptor signaling (pY of IRS proteins, IRS interaction with p85). Furthermore, the increased amount of p110β and increased basal PI 3-kinase activity suggest a diet-induced compensatory response.
Control of glycolysis in contracting skeletal muscle. II. Turning it off
Authors: Crowther Gregory J. , Kemper William F. , Carey Michael F. , Conley Kevin E.
Published: December 2017

Glycolytic flux in muscle declines rapidly after exercise stops, indicating that muscle activation is a key controller of glycolysis. The mechanism underlying this control could be 1) a Ca2+-mediated modulation of glycogenolysis, which supplies substrate (hexose phosphates, HP) to the glycolytic pathway, or 2) a direct effect on glycolytic enzymes. To distinguish between these possibilities, HP levels were raised by voluntary 1-Hz exercise, and glycolytic flux was measured after the exercise ceased. Glycolytic H+and ATP production were quantified from changes in muscle pH, phosphocreatine concentration, and Piconcentration as measured by31P magnetic resonance spectroscopy. Substrate (HP) and metabolite (Pi, ADP, and AMP) levels remained high when exercise stopped because of the occlusion of blood flow with a pressure cuff. Glycolytic flux declined to basal levels within ∼20 s of the end of exercise despite elevated levels of HP and metabolites. Therefore, this flux does not subside because of insufficient HP substrate; rather, glycolysis is controlled independently of glycogenolytic HP production. We conclude that the inactivation of glycolysis after exercise reflects the cessation of contractile activity and is mediated within the glycolytic pathway rather than via the control of glycogen breakdown.