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Pharmacodynamics of Glucose Regulation by Methylprednisolone. II. Normal Rats
Jin, Jin Y.
Jusko, William J.
Biopharmaceutics & drug disposition
A physiologic pharmacodynamic model was developed to jointly describe the effects of methylprednisolone (MPL) on adrenal suppression and glycemic control in normal rats. Six groups of animals were given MPL intravenously at 0, 10 and 50 mg/kg, or by subcutaneous 7 day infusion at rates of 0, 0.1 and 0.3 mg/kg/h. Plasma concentrations of MPL, corticosterone (CST), glucose and insulin were determined at various times up to 72 h after injection and 336 h after infusion. The pharmacokinetics of MPL was described by a two-compartment model. A circadian rhythm for CST was found in untreated rats with a stress-altered baseline caused by handling, which was captured by a circadian harmonic secretion rate with an increasing mesor. All drug treatments caused CST suppression. Injection of MPL caused temporary increases in glucose over 4 h. Insulin secretion was thereby stimulated yielding a later peak around 6 h. In turn, insulin can normalize glucose. However, long-term dosing caused continuous hyperglycemia during and after infusion. Hyperinsulinemia was achieved during infusion, but diminished immediately after dosing despite the high glucose concentration. The effects of CST and MPL on glucose production were described with a competitive stimulation function. A disease progression model incorporating reduced endogenous glucose uptake/utilization was used to describe glucose metabolism under different treatments. The results exemplify the roles of endogenous and exogenous hormones in mediating glucose dynamics. The pharmacokinetic/pharmacodynamic model is valuable for quantitating diabetogenic effects of corticosteroid treatments and provides mechanistic insights into the hormonal control of the metabolic system.
corticosterone; methylprednisolone; pharmacodynamics; pharmacokinetics; glucose; insulin
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Meta-Modeling of Methylprednisolone Effects on Glucose Regulation in Rats
Fang, Jing
Sukumaran, Siddharth
DuBois, Debra C.
Almon, Richard R.
Jusko, William J.
PLoS ONE
A retrospective meta-modeling analysis was performed to integrate previously reported data of glucocorticoid (GC) effects on glucose regulation following a single intramuscular dose (50 mg/kg), single intravenous doses (10, 50 mg/kg), and intravenous infusions (0.1, 0.2, 0.3 and 0.4 mg/kg/h) of methylprednisolone (MPL) in normal and adrenalectomized (ADX) male Wistar rats. A mechanistic pharmacodynamic (PD) model was developed based on the receptor/gene/protein-mediated GC effects on glucose regulation. Three major target organs (liver, white adipose tissue and skeletal muscle) together with some selected intermediate controlling factors were designated as important regulators involved in the pathogenesis of GC-induced glucose dysregulation. Assessed were dynamic changes of food intake and systemic factors (plasma glucose, insulin, free fatty acids (FFA) and leptin) and tissue-specific biomarkers (cAMP, phosphoenolpyruvate carboxykinase (PEPCK) mRNA and enzyme activity, leptin mRNA, interleukin 6 receptor type 1 (IL6R1) mRNA and Insulin receptor substrate-1 (IRS-1) mRNA) after acute and chronic dosing with MPL along with the GC receptor (GR) dynamics in each target organ. Upon binding to GR in liver, MPL dosing caused increased glucose production by stimulating hepatic cAMP and PEPCK activity. In adipose tissue, the rise in leptin mRNA and plasma leptin caused reduction of food intake, the exogenous source of glucose input. Down-regulation of IRS-1 mRNA expression in skeletal muscle inhibited the stimulatory effect of insulin on glucose utilization further contributing to hyperglycemia. The nuclear drug-receptor complex served as the driving force for stimulation or inhibition of downstream target gene expression within different tissues. Incorporating information such as receptor dynamics, as well as the gene and protein induction, allowed us to describe the receptor-mediated effects of MPL on glucose regulation in each important tissue. This advanced mechanistic model provides unique insights into the contributions of major tissues and quantitative hypotheses for the multi-factor control of a complex metabolic system.
Related Articles
Pharmacodynamics of Glucose Regulation by Methylprednisolone. I. Adrenalectomized Rats
Jin, Jin Y.
Jusko, William J.
Biopharmaceutics & drug disposition
Mechanisms related to the adverse effects of corticosteroids on glucose homeostasis were studied. Five groups of adrenalectomized (ADX) rats were given methylprednisolone (MPL) intravenously at 10 and 50 mg/kg, or a continuous 7 day infusion at rates of 0, 0.1, 0.3 mg/kg/h via subcutaneously implanted Alzet mini-pumps. Plasma concentrations of MPL, glucose and insulin were determined at various time points up to 72 h after injection or 336 h after infusion. The pharmacokinetics of MPL was captured with a two-compartment model. The Adapt II software was used in modeling. Injection of MPL caused a temporary glucose increase over 6 h by stimulating gluconeogenesis. The glucose changes stimulated pancreatic β-cell secretion yielding a later insulin peak at around 10 h. In turn, insulin can stimulate glucose disposition. However, long-term MPL treatment caused continuous hyperglycemia during and after infusion. Insulin was increased during infusion, and immediately returned to baseline after the infusion was terminated, despite the almost doubled glucose concentration. A disease progression model incorporating the reduced endogenous glucose disposition was included to capture glucose homeostasis under different treatments. The results exemplify the importance of the steroid dosing regimen in mediating pharmacological and adverse metabolic effects. This mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model quantitatively describes the induction of hyperglycemia and provides additional insights into metabolic disorders such as diabetes.
corticosteroids; methylprednisolone; pharmacodynamics; pharmacokinetics; glucose; insulin
Related Articles
Effect of insulin and acute diabetes on plasma FFA and ketone bodies in the fasting rat
Bieberdorf, Frederick A.
Chernick, Sidney S.
Scow, Robert O.
Journal of Clinical Investigation
The metabolism of FFA and ketone bodies was studied in fasted rats by infusing at a constant rate tracer amounts of FFA-3H, β-hydroxybutyrate-14C or acetoacetate-14C for periods up to 2 hr. Blood that was removed for analyses was replaced by continuous transfusion. The rates of turnover of FFA, β-hydroxybutyrate, and acetoacetate in rats fasted for 2 days were, respectively, 3.2, 5.6, and 2.5 μmoles/100 g body weight per min.
Infusion of mannoheptulose with anti-insulin serum increased plasma glucose, FFA, and ketone body concentrations and decreased the specific activity of plasma FFA. Injection of insulin (20 mU i.v.) decreased almost simultaneously plasma glucose, FFA, and ketone body concentrations and increased the specific activity of FFA, but it did not affect the plasma concentration of FFA-3H. The findings indicate that insulin deprivation increased and insulin injection decreased the release of FFA from body tissues in fasting rats.
The plasma FFA concentration in fasting rats was increased by infusing chylomicrons and heparin, but this had very little effect on either plasma ketone body or glucose concentrations. Insulin injection (20 mU i.v.) lowered the plasma ketone body concentration in these animals. Studies using β-hydroxybutyrate-14C showed that insulin (50 mU i.v.) decreased ketogenesis in the presence of a sustained high plasma FFA concentration and had no effect on uptake of circulating ketone bodies.
The results indicate that plasma FFA concentration is not the sole determinant of plasma ketone body concentration and that insulin can suppress ketone body production through some means other than lowering plasma FFA concentration.
Related Articles
Fifth-Generation Model for Corticosteroid Pharmacodynamics: Application to Steady-State Receptor Down-Regulation and Enzyme Induction Patterns during Seven-Day Continuous Infusion of Methylprednisolone in Rats
Ramakrishnan, Rohini
DuBois, Debra C.
Almon, Richard R.
Pyszczynski, Nancy A.
Jusko, William J.
Journal of pharmacokinetics and pharmacodynamics
A fifth-generation model for receptor/gene-mediated corticosteroid effects was proposed based on results from a 50 mg/kg IV bolus dose of methylprednisolone (MPL) in male adrenalectomized rats, and confirmed using data from other acute dosage regimens. Steady-state equations for receptor down-regulation and tyrosine aminotransferase (TAT) enzyme induction patterns were derived. Five groups of male Wistar rats (n=5/group) were subcutaneously implanted with Alzet mini-pumps primed to release saline or 0.05, 0.1, 0.2, and 0.3 mg/kg/hr of MPL for 7 days. Rats were sacrificed at the end of the infusion. Plasma MPL concentrations, blood lymphocyte counts, and hepatic cytosolic free receptor density, receptor mRNA, TAT mRNA, and TAT enzyme levels were quantitated. The pronounced steroid effects were evidenced by marked losses in body weights and changes in organ weights. All four treatments caused a dose-dependent reduction in hepatic receptor levels, which correlated with the induction of TAT mRNA and TAT enzyme levels. The 7 day receptor mRNA and free receptor density correlated well with the model predicted steady-state levels. However, the extent of enzyme induction was markedly higher than that predicted by the model suggesting that the usual receptor/gene-mediated effects observed upon single/intermittent dosing of MPL may be countered by alterations in other aspects of the system. A mean IC50 of 6.1 ng/mL was estimated for the immunosuppressive effects of methylprednisolone on blood lymphocytes. The extent and duration of steroid exposure play a critical role in mediating steroid effects and advanced PK/PD models provide unique insights into controlling factors.
pharmacodynamics; pharmacogenomics; methylprednisolone; tyrosine amino-transferase
Related Articles
Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance.
Groop, L C
Bonadonna, R C
DelPrato, S
Ratheiser, K
Zyck, K
Ferrannini, E
DeFronzo, R A
Journal of Clinical Investigation
The effect of graded, physiologic hyperinsulinemia (+5, +15, +30, +70, +200 microU/ml) on oxidative and nonoxidative pathways of glucose and FFA metabolism was examined in nine lean non-insulin dependent diabetic patients (NIDDM) and in eight age- and weight-matched control subjects. Glucose and FFA metabolism were assessed using stepwise insulin clamp in combination with indirect calorimetry and infusion of [3H]3-glucose/[14C]palmitate. The basal rate of hepatic glucose production (HGP) was higher in NIDDM than in control subjects, and suppression of HGP by insulin was impaired at all but the highest insulin concentration. Glucose disposal was reduced in the NIDD patients at the three highest plasma insulin concentrations, and this was accounted for by defects in both glucose oxidation and nonoxidative glucose metabolism. In NIDDs, suppression of plasma FFA by insulin was impaired at all five insulin steps. This was associated with impaired suppression by insulin of plasma FFA turnover, FFA oxidation (measured by [14C]palmitate) and nonoxidative FFA disposal (an estimate of reesterification of FFA). FFA oxidation and net lipid oxidation (measured by indirect calorimetry) correlated positively with the rate of HGP in the basal state and during the insulin clamp. In conclusion, our findings demonstrate that insulin resistance is a general characteristic of glucose and FFA metabolism in NIDDM, and involves both oxidative and nonoxidative pathways. The data also demonstrate that FFA/lipid and glucose metabolism are interrelated in NIDDM, and suggest that an increased rate of FFA/lipid oxidation may contribute to the impaired suppression of HGP and diminished stimulation of glucose oxidation by insulin in these patients.
Related Articles
Differential regulation of PGC-1α expression in rat liver and skeletal muscle in response to voluntary running
Matiello, Renata
Fukui, Rosa T
Silva, Maria ER
Rocha, Dalva M
Wajchenberg, Bernardo L
Azhar, Salman
Santos, Rosa F
Nutrition & Metabolism
The beneficial actions of exercise training on lipid, glucose and energy metabolism and insulin sensitivity appear to be in part mediated by PGC-1α. Previous studies have shown that spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin, lower plasma insulin levels and increased skeletal muscle insulin sensitivity. This study was initiated to examine the functional interaction between exercise-induced modulation of skeletal muscle and liver PGC-1α protein expression, whole body insulin sensitivity, and circulating FFA levels as a measure of whole body fatty acid (lipid) metabolism.
Two groups of male Wistar rats (2 Mo of age, 188.82 ± 2.77 g BW) were used in this study. One group consisted of control rats placed in standard laboratory cages. Exercising rats were housed individually in cages equipped with running wheels and allowed to run at their own pace for 5 weeks. At the end of exercise training, insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG) concentrations at constant plasma insulin levels attained during the continuous infusion of glucose and insulin to each experimental group. Subsequently, soleus and plantaris muscle and liver samples were collected and quantified for PGC-1α protein expression by Western blotting. Collected blood samples were analyzed for glucose, insulin and FFA concentrations.
Rats housed in the exercise wheel cages demonstrated almost linear increases in running activity with advancing time reaching to maximum value around 4 weeks. On an average, the rats ran a mean (Mean ± SE) of 4.102 ± 0.747 km/day and consumed significantly more food as compared to sedentary controls (P < 0.001) in order to meet their increased caloric requirement. Mean plasma insulin (P < 0.001) and FFA (P < 0.006) concentrations were lower in the exercise-trained rats as compared to sedentary controls. Mean steady state plasma insulin (SSPI) and glucose (SSPG) concentrations were not significantly different in sedentary control rats as compared to exercise-trained animals. Plantaris PGC-1α protein expression increased significantly from a 1.11 ± 0.12 in the sedentary rats to 1.74 ± 0.09 in exercising rats (P < 0.001). However, exercise had no effect on PGC-1α protein content in either soleus muscle or liver tissue. These results indicate that exercise training selectively up regulates the PGC-1α protein expression in high-oxidative fast skeletal muscle type such as plantaris muscle.
These data suggest that PGC-1α most likely plays a restricted role in exercise-mediated improvements in insulin resistance (sensitivity) and lowering of circulating FFA levels.
Related Articles
Effects of Metformin on the Regulation of Free Fatty Acids in Insulin Resistance: A Double-Blind, Placebo-Controlled Study
Castro Cabezas, Manuel
van Wijk, Jeroen P. H.
Elte, Jan Willem F.
Klop, Boudewijn
Journal of Nutrition and Metabolism
Introduction. Impaired free fatty acid (FFA) metabolism is closely linked to insulin resistance. Our aim was to evaluate plasma FFA changes in insulin resistance in a physiological situation after improvement of insulin sensitivity by metformin. Methods. A double-blind, placebo-controlled intervention with metformin was carried out in patients with insulin resistance. Nineteen patients were randomized to receive metformin 850 mg b.i.d. during 6 weeks or placebo. Participants underwent a mental stress test and an oral glucose tolerance test (OGTT) before and after treatment. Results. Fasting plasma glucose, FFA, and HOMA-IR tended to decrease after metformin, suggesting improved insulin sensitivity. FFA concentrations during the mental stress test showed a similar pattern after metformin, albeit lower at all time points, in contrast to the placebo group. The decrease in fasting plasma FFAs was positively associated to the decrease in HbA1c (r = 0.70; P = 0.03) and in fasting glucose (r = 0.74; P = 0.01). The suppression of plasma FFAs during OGTT did not change by metformin or placebo. Conclusion. Metformin in insulin resistance did not lead to improved FFA dynamics despite a trend of improved insulin sensitivity. Metformin most likely decreases plasma FFAs mainly by suppressing fasting FFA concentrations and not by suppression of acute stress-induced lipolysis.
Related Articles
Effects of nonesterified fatty acid availability on tissue-specific glucose utilization in rats in vivo.
Jenkins, A B
Storlien, L H
Chisholm, D J
Kraegen, E W
Journal of Clinical Investigation
The pathophysiological significance of the glucose-fatty acid cycle in skeletal muscle in vivo is uncertain. We have examined the short term effects of increased availability of nonesterified FFA on tissue-specific glucose uptake and storage in rat tissues in vivo basally and during a hyperinsulinemic (150 mU/liter) euglycemic clamp. Circulating FFA were elevated to 2 mmol/liter (FFA 1) or 4 mmol/liter (FFA 2). Elevated FFA produced a dose-dependent inhibition of myocardial glucose utilization in both basal (FFA1, 42%; FFA2, 68%; P less than 0.001, by analysis of variance) and clamp groups (FFA1, 39%; FFA2, 49%; P less than 0.001) and also suppressed brown adipose tissue glucose utilization during the clamp (-42%, P less than 0.001). In contrast to heart, glucose utilization in skeletal muscle was suppressed by FFA only in the FFA1 basal group (-36%, P less than 0.001); in other groups (e.g., FFA2 clamp) elevated FFA produced increased skeletal muscle glucose utilization (+68%, P less than 0.001) that was directed toward glycogen (+175%, P less than 0.05) and lipid deposition (+125%, P less than 0.005). FFA stimulated basal glucose utilization in white (e.g., FFA2, +220%, P less than 0.005) and brown adipose tissue (e.g., FFA2, +200%, P less than 0.005). Thus elevated FFA can acutely inhibit glucose utilization in skeletal muscle in addition to cardiac muscle in vivo supporting a possible role for the glucose-fatty acid cycle in skeletal muscle in acute insulin resistance. However, at high levels or with elevated insulin, FFA stimulates glucose utilization and storage in skeletal muscle. By promoting accumulation of glucose storage products, chronic elevation of FFA may lead to skeletal muscle (and therefore whole body) insulin resistance.
Related Articles
Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids
Hazra, Anasuya
Pyszczynski, Nancy
DuBois, Debra C.
Almon, Richard R.
Jusko, William J.
Journal of pharmacokinetics and pharmacodynamics
Receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase (TAT) were evaluated in normal rats. A group of normal male Wistar rats were injected with 50 mg/kg methylprednisolone (MPL) intramuscularly at the nadir of their plasma corticosterone (CST) rhythm (early light cycle) and sacrificed at various time points up to 96 h post-treatment. Blood and livers were collected to measure plasma MPL, CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density, TAT mRNA, and TAT activity. The pharmacokinetics of MPL showed bi-exponential disposition with two first-order absorption components from the injection site and bioavailability was 21%. Plasma CST was reduced after MPL dosing, but resumed its daily circadian pattern within 36 h. Cytosolic receptor density was significantly suppressed (90%) and returned to baseline by 72 h resuming its biphasic pattern. Hepatic GR mRNA follows a circadian pattern which was disrupted by MPL and did not return during the study. MPL caused significant down-regulation (50%) in GR mRNA which was followed by a delayed rebound phase (60–70 h). Hepatic TAT mRNA and activity showed up-regulation as a consequence of MPL, and returned to their circadian baseline within 72 and 24 h of treatment. A mechanistic receptor/gene-mediated pharmacokinetic/pharmacodynamic model was able to satisfactorily describe the complex interplay of exogenous and endogenous corticosteroid effects on hepatic GR mRNA, cytosolic free GR, TAT mRNA, and TAT activity in normal rats.
Methylprednisolone; Corticosteroids; Pharmacokinetics; Pharmacodynamics; Tyrosine aminotransferase; Glucocorticoid receptors
Related Articles
Regulation by insulin of myocardial glucose and fatty acid metabolism in the conscious dog.
Barrett, E J
Schwartz, R G
Francis, C K
Zaret, B L
Journal of Clinical Investigation
In vivo small doses of insulin inhibit lipolysis, lower plasma FFA, and stimulate glucose disposal. Lowering of plasma FFA, either in the absence of a change in insulin or during combined hyperglycemia and hyperinsulinemia, promotes glucose uptake by heart muscle in vivo. In the isolated perfused heart, large doses of insulin directly stimulate heart glucose uptake. To assess the effect of physiological elevations of plasma insulin upon myocardial glucose and FFA uptake in vivo independent of changes in plasma substrate concentration, we measured arterial and coronary sinus concentrations of glucose, lactate, and FFA, and coronary blood flow in conscious dogs during a 30 min basal and a 2 h experimental period employing three protocols: (a) euglycemic hyperinsulinemia (insulin clamp, n = 5), (b) euglycemic hyperinsulinemia with FFA replacement (n = 5), (c) hyperglycemic euinsulinemia (hyperglycemic clamp with somatostatin, n = 5). In group 1, hyperinsulinemia (insulin = 73 +/- 13 microU/ml) stimulated heart glucose uptake (7.3 +/- 4.4 vs. 28.2 +/- 2.8 mumol/min, P less than 0.002), lowered plasma FFA levels by 80% (P less than 0.05), and decreased heart FFA uptake (28.4 +/- 4 vs. 1.5 +/- 0.9, P less than 0.01). When the fall in plasma FFA was prevented by FFA infusion (group 2), hyperinsulinemia (86 +/- 10 microU/ml) provoked a lesser (P less than 0.05) stimulation of glucose uptake (delta = 8.2 +/- 4.2 mumol/min) than in group 1, and there was no significant change in FFA uptake (25.3 +/- 16 vs. 16.5 +/- 4). Hyperglycemia (plasma glucose = 186 +/- 8 mg/100 ml) during somatostatin infusion resulted in only a small rise in plasma insulin (delta = 12 +/- 7 microU/ml), and although plasma FFA tended to decline, heart glucose uptake did not rise significantly (delta = 5.5 +/- 3.2 mumol/min, P = NS). There was no significant change in coronary blood flow during any of the three study protocols. We conclude that, in the dog, insulin at physiologic concentrations: (a) stimulates heart glucose uptake, both directly and by suppressing the plasma FFA concentration, and (b) does not alter coronary blood flow. Hyperglycemia per se has little effect on heart glucose uptake.
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Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.
Stein, D T
Esser, V
Stevenson, B E
Lane, K E
Whiteside, J H
Daniels, M B
Chen, S
McGarry, J D
Journal of Clinical Investigation
We asked whether the well known starvation-induced impairment of glucose-stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acid-treated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal beta cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences.
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Salsalate Attenuates Free Fatty Acid–Induced Microvascular and Metabolic Insulin Resistance in Humans
Chai, Weidong
Liu, Jia
Jahn, Linda A.
Fowler, Dale E.
Barrett, Eugene J.
Liu, Zhenqi
Diabetes Care
Insulin recruits muscle microvasculature, thereby increasing endothelial exchange surface area. Free fatty acids (FFAs) cause insulin resistance by activating inhibitor of κB kinase β. Elevating plasma FFAs impairs insulin's microvascular and metabolic actions in vivo. Whether salsalate, an anti-inflammatory agent, prevents FFA-induced microvascular and/or metabolic insulin resistance in humans is unknown.
Eleven healthy, young adults were studied three times in random order. After an overnight fast, on two occasions each subject received a 5-h systemic infusion of Intralipid ± salsalate pretreatment (50 mg/kg/day for 4 days). On the third occasion, saline replaced Intralipid. A 1 mU/kg/min euglycemic insulin clamp was superimposed over the last 2-h of each study. Skeletal and cardiac muscle microvascular blood volume (MBV), microvascular flow velocity (MFV), and microvascular blood flow (MBF) were determined before and after insulin infusion. Whole body glucose disposal rates were calculated from glucose infusion rates.
Insulin significantly increased skeletal and cardiac muscle MBV and MBF without affecting MFV. Lipid infusion abolished insulin-mediated microvascular recruitment in both skeletal and cardiac muscle and lowered insulin-stimulated whole body glucose disposal (P < 0.001). Salsalate treatment rescued insulin's actions to recruit muscle microvasculature and improved insulin-stimulated whole body glucose disposal in the presence of high plasma FFAs.
High plasma concentrations of FFAs cause both microvascular and metabolic insulin resistance, which can be prevented or attenuated by salsalate treatment. Our data suggest that treatments aimed at inhibition of inflammatory response might help alleviate vascular insulin resistance and improve metabolic control in patients with diabetes.
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Effect of ketone bodies on glucose production and utilization in the miniature pig.
Müller, M J
Paschen, U
Seitz, H J
Journal of Clinical Investigation
The effect of ketone bodies on glucose production (Ra) and utilization (Rd) was investigated in the 24-h starved, conscious unrestrained miniature pig. Infusing Na-DL-beta-OH-butyrate (Na-DL-beta-OHB) and thus shifting the blood pH from 7.40 to 7.56 resulted in a decrease of Ra by 52% and of Rd by 45%, as determined by the isotope dilution technique. Simultaneously, the concentrations of arterial insulin and glucagon were slightly enhanced, whereas the plasma levels of glucose, lactate, pyruvate, alanine, alpha-amino-N, and free fatty acids (FFA) were all reduced. Infusion of Na-bicarbonate, which yielded a similar shift in blood pH, did not mimick these effects. Infusion of equimolar amounts of the ketoacid, yielding a blood pH of 7.35, induced similar metabolic alterations with respect to plasma glucose, Ra, Rd, and insulin; however, plasma alanine and alpha-amino-N increased. Infusing different amounts of Na-DL-beta-OHB resulting in plasma steady state levels of ketones from 0.25 to 1.5 mM had similar effects on arterial insulin and glucose kinetics. No dose dependency was observed. Prevention of the Na-DL-beta-OHB-induced hypoalaninemia by simultaneous infusion of alanine (1 mumol/kg X min) did not prevent hypoglycemia. Infusion of Na-DL-beta-OHB plus insulin (0.4 mU/kg X min) showed no additive effect on the inhibition of Ra. Ketones did not inhibit the insulin-stimulated metabolic clearance rate (MCR) for glucose. Infusion of somatostatin (0.2 micrograms/kg X min) initially decreased plasma glucose, Ra, and Rd, which was followed by an increase in plasma glucose and Ra; however, on infusion of somatostatin plus Na-DL-beta-OHB, hypoglycemia and the reduced Ra were maintained. In the anaesthetized 24-h starved miniature pig, Na-DL-beta-OHB infusion decreased the hepatic exchange for glucose, lactate, and FFA, whereas the exchange for glycerol, alanine, and alpha-amino-N as well as liver perfusion rate were unaffected. Simultaneously, portal glucagon and insulin as well as hepatic insulin extraction rate were elevated. Leg exchange for glucose, lactate, glycerol, alanine, alpha-amino-N, and FFA were decreased, while ketone body utilization increased. Repeated infusion of Na-DL-beta-OHB at the fourth, fifth, and sixth day of starvation in the conscious, unrestrained mini-pig resulted in a significant drop in urinary nitrogen (N)-excretion. However, this effect was mimicked by infusing equimolar amounts of Na-bicarbonate. In contrast, when only the ketoacid was given, urinary N-excretion accelerated. To summarize: (a) Ketone bodies decrease endogenous glucose production via an insulin-dependent mechanism; in addition, ketones probably exert a direct inhibitory action on gluconeogenesis. The ketone body-induced hypoalaninemia does not contribute to this effect. (b) The counterregulatory response to hypoglycemia is reduced by ketones. (c) As a consequence of the decrease in R(a), glucose utilization declines during ketone infusion. (d)The insulin-stimulated MCR for glucose is not affected by ketones. (e) Ketones in their physiological moiety do not show a protein-sparing effect.
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Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats
Hazra, Anasuya
Pyszczynski, Nancy A.
DuBois, Debra C.
Almon, Richard R.
Jusko, William J.
Pharmaceutical research
This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA and plasma lipids associated with increased risks for atherosclerosis.
Materials and methods
Normal male Wistar rats were given 50 mg/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA, and plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG).
MPL showed bi-exponential disposition with two first-order absorption components. Hepatic GR and LDLR mRNA exhibited circadian patterns which were disrupted by MPL. Down-regulation in GR mRNA (40–50%) was followed by a delayed rebound phase. LDLR mRNA exhibited transient down-regulation (60–70%). Cytosolic GR density was significantly suppressed but returned to baseline by 72 h. Plasma TC and LDLC showed increases (55 and 142%) at 12 h. A mechanistic receptor/gene pharmacokinetic/pharmacodynamic model was developed to describe CS effects on hepatic LDLR mRNA and plasma cholesterols.
Our PK/PD model was able to satisfactorily capture the MPL effects on hepatic LDLR, its relationship to various plasma cholesterols, and builds the foundation to explore this area in the future.
cholesterol; corticosteroids; glucocorticoid receptors; LDL receptors; lipids; pharmacodynamics
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Effect of fatty acids on glucose production and utilization in man.
Ferrannini, E
Barrett, E J
Bevilacqua, S
DeFronzo, R A
Journal of Clinical Investigation
Since the initial proposal of the glucose fatty acid cycle, considerable controversy has arisen concerning its physiologic significance in vivo. In the present study, we examined the effect of acute, physiologic elevations of FFA concentrations on glucose production and uptake in normal subjects under three controlled experimental conditions. In group A, plasma insulin levels were raised and maintained at approximately 100 microU/ml above base line by an insulin infusion, while holding plasma glucose at the fasting level by a variable glucose infusion. In group B, plasma glucose concentration was raised by 125 mg/100 ml and plasma insulin was clamped at approximately 50 microU/ml by a combined infusion of somatostatin and insulin. In group C, plasma glucose was raised by 200 mg/100 ml above the fasting level, while insulin secretion was inhibited with somatostatin and peripheral glucagon levels were replaced with a glucagon infusion (1 ng/min X kg). Each protocol was repeated in the same subject in combination with a lipid-heparin infusion designed to raise plasma FFA levels by 1.5-2.0 mumol/ml. With euglycemic hyperinsulinemia (study A), lipid infusion caused a significant inhibition of total glucose uptake (6.3 +/- 1.3 vs. 7.4 +/- 0.6 mg/min X kg, P less than 0.02). Endogenous glucose production (estimated by the [3-3H]glucose technique) was completely suppressed both with and without lipid infusion. With hyperglycemic hyperinsulinemia (study B), lipid infusion also induced a marked impairment in glucose utilization (6.2 +/- 1.1 vs. 9.8 +/- 1.9 mg/min X kg, P less than 0.05); endogenous glucose production was again completely inhibited despite the increase in FFA concentrations. Under both conditions (A and B), the percentage inhibition of glucose uptake by FFA was positively correlated with the total rate of glucose uptake (r = 0.69, P less than 0.01). In contrast, when hyperglycemia was associated with relative insulinopenia and hyperglucagonemia (study C), thus simulating a diabetic state, lipid infusion had no effect on glucose uptake (2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/min X kg) but markedly stimulated endogenous glucose production (1.4 +/- 0.5 vs. 0.5 +/- 0.4 mg/min X kg, P less than 0.005). Under the same conditions as study C, a glycerol infusion producing plasma glycerol levels similar to those achieved with lipid-heparin, enhanced endogenous glucose production (1.5 +/- 0.5 vs. 0.7 +/- 0.6 mg/min X kg, P less than 0.05). We conclude that, in the well-insulinized state raised FFA levels effectively compete with glucose for uptake by peripheral tissues, regardless of the presence of hyperglycemia. When insulin is deficient, on the other hand, elevated rates of lipolysis may contribute to hyperglycemia not by competition for fuel utilization, but through an enhancement of endogenous glucose output.
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Turnover and splanchnic metabolism of free fatty acids and ketones in insulin-dependent diabetics at rest and in response to exercise.
Wahren, J
Sato, Y
Ostman, J
Hagenfeldt, L
Felig, P
Journal of Clinical Investigation
Nine insulin-dependent diabetics and six healthy controls were studied at rest, during, and after 60 min of bicycle exercise at a work load corresponding to 45% of their maximal oxygen intake. The catheter technique was employed to determine splanchnic and leg exchange of metabolites. FFA turnover and regional exchange was evaluated using [14C]oleate infusion. Basal glucose (13.8 +/- 1.1 mmol/l), ketone body (1.12 +/- 0.12 mmol/l), and FFA (967 +/- 110 mumol/l) concentrations were elevated in the diabetics in comparison with controls. In the resting state, splanchnic ketone acid production in the diabetics was 6-10-fold greater than in controls. Uptake of oleic acid by the splanchnic bed was increased 2-3-fold, and the proportion of splanchnic FFA uptake converted to ketones (61%) was threefold greater than in controls. In contrast, splanchnic fractional extraction of oleic acid was identical in diabetics and controls. A direct relationship was observed between splanchnic uptake and splanchnic inflow (plasma concentration X hepatic plasma flow) of oleic acid that could be described by the same regression line in the diabetic and control groups. During exercise, splanchnic ketone production rose in both groups. In the control group the increase in ketogenesis was associated with a rise in splanchnic inflow and in uptake of oleic acid, a rise in splanchnic fractional extraction of oleate, and an increase in the proportion of splanchnic FFA uptake converted to ketone acids from 20-40%. In the diabetic group, the increase in ketogenesis occurred in the absence of a rise in splanchnic inflow or uptake of oleic acid, but was associated with an increase in splanchnic fractional extraction of oleic acid and a marked increase in hepatic conversion of FFA to ketones, so that the entire uptake of FFA was accountable as ketone acid output. Splanchnic uptake of oleic acid correlated directly with splanchnic oleic acid inflow in both groups, but the slope of the regression line was steeper than in the resting state. Plasma glucagon levels were higher in the diabetic group at rest and during exercise, while plasma norepinephrine showed a twofold greater increment in response to exercise in the diabetic group (to 1,400-1,500 pg/ml). A net uptake of ketone acids by the leg was observed during exercise but could account for less than 5% of leg oxidative metabolism in the diabetics and less than 1% in controls. Despite the increase in ketogenesis during exercise, a rise in arterial ketone acid levels was not observed in the diabetics until postexercise recovery, during which sustained increments to values of 1.8-1.9 mmol/l and sustained increases in splanchnic ketone production were observed at 30-60 min. The largest increment in blood ketone acids and in splanchnic ketone production above values observed in controls thus occurred in the diabetics after 60 min of recovery from exercise. We concluded that: (a) In the resting state, increased ketogenesis in the diabetic is a consequence of augmented splanchnic inflow of FFA and increased intrahepatic conversion of FFA to ketones, but does not depend on augmented fractional extraction of circulating FFA by the splanchnic bed. (b) Exercise-induced increases in ketogenesis in normal subjects are due to augmented splanchnic inflow and fractional extraction of FFA as well as increased intrahepatic conversion of FFA to ketones. (c) When exercise and diabetes are combined, ketogenesis increases further despite the absence of a rise in splanchnic inflow of FFA. An increase in splanchnic fractional extraction of FFA and a marked increase intrahepatic conversion of FFA to ketones accounts for the exaggerated ketogenic response to exercise in the diabetic. (d) Elevated levels of plasma glucagon and/or norepinephrine may account for the increased hepatic ketogenic response to exercise in the diabetic. (e) Ketone utilization by muscle increases during exercise but constitutes a quantitatively minor oxidative fuel for muscle even in the diabetic. (f) The accelerated ketogenesis during exercise in the diabetic continues unabated during the recovery period, resulting in an exaggerated postexercise ketosis.
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Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis
Albaugh, Vance L.
Judson, Jessica G.
She, Pengxiang
Lang, Charles H.
Maresca, Kevin P.
Joyal, John L.
Lynch, Christopher J.
Molecular psychiatry
Olanzapine and other atypical antipsychotics cause metabolic side effects leading to obesity and diabetes; while these continue to be an important public health concern, their underlying mechanisms remain elusive. Therefore, an animal model of these side effects was developed in male Sprague-Dawley rats. Chronic administration of olanzapine elevated fasting glucose, impaired glucose and insulin tolerance, increased fat mass but, in contrast to female rats, did not increase body weight or food intake. Acute studies were conducted to delineate the mechanisms responsible for these effects. Olanzapine markedly decreased physical activity without a compensatory decline in food intake. It also acutely elevated fasting glucose, and worsened oral glucose and insulin tolerance, suggesting these effects are adiposity independent. Hyperinsulinemic-euglycemic clamp studies measuring 14C-2-deoxyglucose (14C-DOG) uptake revealed tissue-specific insulin resistance. Insulin sensitivity was impaired in skeletal muscle, but either unchanged or increased in adipose tissue depots. Consistent with the olanzapine-induced hyperglycemia there was a tendency for increased 14C-DOG uptake into fat depots of fed rats and, surprisingly, free fatty acid (FFA) uptake into fat depots was elevated approximately 2-fold. The increased glucose and FFA uptake into adipose tissue was coupled with increased adipose tissue lipogenesis. Finally, olanzapine lowered fasting plasma FFA and whereas it had no effect on isoproterenol-stimulated rises in plasma glucose, it blunted isoproterenol-stimulated in vivo lipolysis in fed rats. Collectively, these results suggest olanzapine exerts several metabolic effects that together favor increased accumulation of fuel into adipose tissue, thereby increasing adiposity.
atypical antipsychotics; insulin resistance; nutrient partitioning; hyperinsulinemic-euglycemic clamp; free fatty acid uptake; lipogenesis
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β-Cell Lipotoxicity in Response to Free Fatty Acid Elevation in Prepubertal Youth
Michaliszyn, Sara F.
Bonadonna, Riccardo C.
Sjaarda, Lindsey A.
Lee, SoJung
Farchoukh, Lama
Arslanian, Silva A.
Prepubertal African American (AA) youth compared with their Caucasian (C) peers have higher insulin secretion, which correlates positively with free fatty acid (FFA) concentration. In our continued efforts to explain the racial disparity in insulinemia, and because FFAs modulate insulin secretion, we hypothesized that AA youth would have a greater response to FFA-induced β-cell insulin secretion than C youth. We compared the short-term effects of FFA elevation on fasting and glucose-stimulated C-peptide–modeled insulin secretion in prepubertal normal-weight AA versus C peers during a 2-h hyperglycemic clamp (12.5 mmol/L) on two occasions: 1) infusion of normal saline and 2) infusion of 20% intralipid (IL). During IL infusion, insulin sensitivity (IS) declined comparably in AA and C youth. Glucose sensitivity of first- and second-phase insulin secretion showed a significant condition × race interaction being higher in AA youth. Disposition index, β-cell function relative to IS, declined with IL infusion in AA and C youth, with a significantly greater decrease in Cs compared with AAs. In conclusion, AA and C prepubertal youth both demonstrated a decline in β-cell function relative to IS during IL infusion, indicative of acute lipotoxicity. The greater decline in C youth compared with AAs may suggest that C youth are more susceptible to β-cell lipotoxicity than AA youth, or alternatively, that AA youth are hypersensitive to FFA stimulation of β-cell insulin secretion, consistent with our theory.
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Mathematical Modeling of Corticosteroid Pharmacogenomics in Rat Muscle following Acute and Chronic Methylprednisolone Dosing
Yao, Zhenling
Hoffman, Eric P.
Ghimbovschi, Svetlana
DuBois, Debra C.
Almon, Richard R.
Jusko, William J.
Molecular pharmaceutics
The pharmacogenomic effects of a corticosteroid (CS) were assessed in rat skeletal muscle using microarrays. Adrenalectomized (ADX) rats were treated with methylprednisolone (MPL) by either 50 mg/kg intravenous injection or 7-day 0.3 mg/kg/h infusion through subcutaneously implanted pumps. RNAs extracted from individual rat muscles were hybridized to Affymetrix Rat Genome Genechips. Data mining yielded 653 and 2316 CS-responsive probe sets following MPL bolus and infusion treatments. Of these, 196 genes were controlled by MPL under both dosing conditions. Cluster analysis revealed that 124 probe sets exhibited three typical expression dynamic profiles following acute dosing. Cluster A consisted of up-regulated probe sets which were grouped into five subclusters each exhibiting unique temporal patterns during the infusion. Cluster B comprised down-regulated probe sets which were divided into two subclusters with distinct dynamics during the infusion. Cluster C probe sets exhibited delayed down-regulation under both bolus and infusion conditions. Among those, 104 probe sets were further grouped into subclusters based on their profiles following chronic MPL dosing. Several mathematical models were proposed and adequately captured the temporal patterns for each subcluster. Multiple types of dosing regimens are needed to resolve common determinants of gene regulation as chronic exposure results in unexpected differences in gene expression compared to acute dosing. Pharmacokinetic/pharmacodynamic (PK/PD) modeling provides a quantitative tool for elucidating the complexities of CS pharmacogenomics in skeletal muscle.
Microarray studies; pharmacokinetics; pharmacodynamics; mathematical models; computational biology
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Pharmacokinetics of Methylprednisolone after Intravenous and Intramuscular Administration in Rats
Hazra, Anasuya
Pyszczynski, Nancy
DuBois, Debra C.
Almon, Richard R.
Jusko, William J.
Biopharmaceutics & drug disposition
Methylprednisolone (MPL) pharmacokinetics was examined in adrenalectomized (ADX) and normal rats to assess the feasibility of intramuscular (i.m.) dosing for use in pharmacodynamic studies. Several study phases were pursued. Parallel group studies were performed in normal and ADX rats given 50 mg/kg MPL (i.v. or i.m.) and blood samples were collected up to 6 h. Data from studies where normal rats were dosed with 50 mg/kg MPL i.m. and killed over either 6 or 96 h were combined to determine muscle site and plasma MPL concentrations. Lastly, ADX rats were dosed with 50 mg/kg MPL i.m. and killed over 18 h to assess hepatic tyrosine aminotransferase (TAT) dynamics. MPL exhibited bi-exponential kinetics after i.v. dosing with a terminal slope of 2.1 h−1. The i.m. drug was absorbed slowly with two first-order absorption rate constants, 1.26 and 0.219 h−1 indicating flip-flop kinetics with overall 50% bioavailability. The kinetics of MPL at the injection site exhibited slow, dual absorption rates. Although i.m. MPL showed lower bioavailability compared with other corticosteroids in rats, TAT dynamics revealed similar i.m. and i.v. response profiles. The more convenient intramuscular dosing can replace the i.v. route without causing marked differences in pharmacodynamics.
methylprednisolone; corticosteroids; pharmacokinetics; intramuscular injection; tyrosine aminotransferase
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A fatty acid- dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion.
Dobbins, R L
Chester, M W
Stevenson, B E
Daniels, M B
Stein, D T
McGarry, J D
Journal of Clinical Investigation
Lowering of the plasma FFA level in intact fasted rats by infusion of nicotinic acid (NA) caused essentially complete ablation of insulin secretion (IS) in response to a subsequent intravenous bolus of arginine, leucine, or glibenclamide (as previously found using glucose as the beta-cell stimulus). However, in all cases, IS became supranormal when a high FFA level was maintained by co-infusion of lard oil plus heparin. Each of these secretagogues elicited little, if any, IS from the isolated, perfused "fasted" pancreas when tested simply on the background of 3 mM glucose, but all became extremely potent when 0.5 mM palmitate was also included in the medium. Similarly, IS from the perfused pancreas, in response to depolarizing concentrations of KCl, was markedly potentiated by palmitate. As was the case with intravenous glucose administration, fed animals produced an equally robust insulin response to glibenclamide regardless of whether their low basal FFA concentration was further reduced by NA. In the fasted state, arginine-induced glucagon secretion appeared to be independent of the prevailing FFA concentration. The findings establish that the essential role of circulating FFA for glucose-stimulated IS after food deprivation also applies in the case of nonglucose secretagogues. In addition, they imply that (i) a fatty acid-derived lipid moiety, which plays a pivotal role in IS, is lost from the pancreatic beta-cell during fasting; (ii) in the fasted state, the elevated level of plasma FFA compensates for this deficit; and (iii) the lipid factor acts at a late step in the insulin secretory pathway that is common to the action of a wide variety of secretagogues.
Related Articles
The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation.
Stein, D T
Stevenson, B E
Chester, M W
Basit, M
Daniels, M B
Turley, S D
McGarry, J D
Journal of Clinical Investigation
Lowering of the elevated plasma FFA concentration in 18- 24-h fasted rats with nicotinic acid (NA) caused complete ablation of subsequent glucose-stimulated insulin secretion (GSIS). Although the effect of NA was reversed when the fasting level of total FFA was maintained by coinfusion of soybean oil or lard oil (plus heparin), the more saturated animal fat proved to be far more potent in enhancing GSIS. We therefore examined the influence of individual fatty acids on insulin secretion in the perfused rat pancreas. When present in the perfusion fluid at 0.5 mM (in the context of 1% albumin), the fold stimulation of insulin release from the fasted pancreas in response to 12.5 mM glucose was as follows: octanoate (C8:0), 3.4; linoleate (C18:2 cis/cis), 5.3; oleate (C18:1 cis), 9.4; palmitate (C16:0), 16. 2; and stearate (C18:0), 21.0. The equivalent value for palmitoleate (C16:1 cis) was 3.1. A cis--> trans switch of the double bond in the C16:1 and C18:1 fatty acids had only a modest, if any, impact on their potency. A similar profile emerged with regard to basal insulin secretion (3 mM glucose). When a subset of these fatty acids was tested in pancreases from fed animals, the same rank order of effectiveness at both basal and stimulatory levels of glucose was seen. The findings reaffirm the essentiality of an elevated plasma FFA concentration for GSIS in the fasted rat. They also show, however, that the insulinotropic effect of individual fatty acids spans a remarkably broad range, increasing and decreasing dramatically with chain length and degree of unsaturation, respectively. Thus, for any given level of glucose, insulin secretion will be influenced greatly not only by the combined concentration of all circulating (unbound) FFA, but also by the makeup of this FFA pool. Both factors will likely be important considerations in understanding the complex interplay between the nature of dietary fat and whole body insulin, glucose, and lipid dynamics.
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Fenofibrate Reduces Age-related Hypercholesterolemia in Normal Rats on a Standard Diet
Han, Ying
Do, Mi-Hyang
Kim, Mi Sun
Seo, Eunhui
Park, Mi-Kyoung
Kim, Duk Kyu
Lee, Hye-Jeong
Seo, Su-Yeong
The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology
Plasma cholesterol is increased in normal aging in both rodents and humans. This is associated with reduced elimination of cholesterol and decreased receptor-mediated clearance of plasma low-density lipoprotein (LDL) cholesterol. The aims of this study were: (1) to determine age-related changes in plasma lipid profiles, and (2) to determine the effect of fenofibrate, an activator of peroxisome proliferator activated receptor alpha (PPAR α), on plasma lipid profiles in normal rats on a standard diet. Male Sprague-Dawley (SD) rats (n=15) were fed standard chow and water from 10 to 25 weeks of age. During that period, we measured daily food intake, body weight, fasting and random blood glucose levels, plasma total cholesterol (TC), triglycerides (TG), and free fatty acid (FFA) levels. At 20 weeks of age, all rats were randomly divided into two groups: a fenofibrate group (in which rats were gavaged with 300 mg/kg/day of fenofibrate) and a control group (gavaged with water). Fenofibrate treatment lasted 5 weeks. There were no significant changes in daily food intake, blood glucose, and plasma TG level with age. Body weight, plasma TC, and FFA levels were significantly increased with age. Fenofibrate significantly decreased plasma concentrations of TC and FFA, which had been increased with age. However, fenofibrate did not influence the plasma concentration of TG, which had not increased with age. These results suggest that fenofibrate might have a novel role in preventing age-related hypercholesterolemia in SD rats on a normal diet.
Fenofibrate; PPAR α; Sprague-Dawley rats; Hypercholesterolemia; Aging
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Yi-Qi-Zeng-Min-Tang, a Chinese medicine, ameliorates insulin resistance in type 2 diabetic rats
Zhang, Zeng
Xue, Hong-Li
Liu, Yi
Wang, Wen-Jian
World Journal of Gastroenterology : WJG
AIM: To investigate the effects of the Chinese herbal decoction, Yi-Qi-Zeng-Min-Tang (YQZMT), on insulin resistance in type 2 diabetic rats.
METHODS: Sprague-Dawley rats were divided into two dietary regiments by feeding either normal pellet diet (NPD) or high fat diet (HFD). Four weeks later, the HFD-fed rats were injected intraperitoneally with low-dose streptozotocin (STZ). Rats with non-fasting blood glucose level ≥ 16.67 mmol/L were considered type 2 diabetic and further divided into five subgroups: the type 2 diabetes model group, low-dose, medium-dose and high-dose YQZMT groups, and rosiglitazone group. Age-matched NPD-fed rats served as controls. YQZMT or rosiglitazone were administered for 8 wk. Intraperitoneal glucose and insulin tolerance tests were performed before and after the treatment to measure the glucose tolerance and insulin sensitivity. Serum levels of biochemical parameters, adipocytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), as well as free fatty acids (FFAs), were also analyzed.
RESULTS: There was significant elevation of insulin resistance and serum levels of fasting glucose (12.82 ± 1.08 mmol/L vs 3.60 ± 0.31 mmol/L, P < 0.01), insulin (7197.36 ± 253.89 pg/mL vs 4820.49 ± 326.89 pg/mL, P < 0.01), total cholesterol (TC) (8.40 ± 0.49 mmol/L vs 2.14 ± 0.06 mmol/L, P < 0.01), triglyceride (2.24 ± 0.12 mmol/L vs 0.78 ± 0.05 mmol/L, P < 0.01), low-density lipoprotein cholesterol (LDL-c) (7.84 ± 0.51 mmol/L vs 0.72 ± 0.04 mmol/L, P < 0.01) and decrease in high-density lipoprotein cholesterol (HDL-c) (0.57 ± 0.03 mmol/L vs 1.27 ± 0.03 mmol/L, P < 0.01) in the low-dose STZ and high-fat diet induced type 2 diabetic group when compared with the control group. Administration of YQZMT induced dose- and time-dependent changes in insulin resistance, glucose and lipid profile, and reduced levels of FFA, TNF-α and IL-6 in the type 2 diabetic rats. After the treatment, compared with the diabetic group, the insulin resistance was ameliorated in the high-dose YQZMT (2.82 g/100 g per day) group, with a significant reduction in serum glucose (12.16 ± 1.00 mmol/L vs 17.65 ± 2.22 mmol/L, P < 0.01), homeostasis model assessment of basal insulin resistance (22.68 ± 2.37 vs 38.79 ± 9.02, P < 0.05), triglyceride (0.87 ± 0.15 mmol/L vs 1.99 ± 0.26 mmol/L, P < 0.01), TC (3.31 ± 0.52 mmol/L vs 6.50 ± 1.04 mmol/L, P < 0.01) and LDL-c (2.47 ± 0.50 mmol/L vs 6.00 ± 1.07 mmol/L, P < 0.01), and a significant increase in HDL-c (0.84 ± 0.08 mmol/L vs 0.50 ± 0.03 mmol/L, P < 0.01). But the body weight was not changed significantly.
CONCLUSION: YQZMT, which ameliorates insulin resistance and does not cause increase in body weight, may be a suitable therapeutic adjunct for the treatment of type 2 diabetes.
Yi-Qi-Zeng-Min-Tang; Insulin resistance; Type 2 diabetes; Lipids; Adipocytokines; Free fatty acids
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SUMMER 2016 Offerings
1) DROP IN OR CALL – Call the Library Arts Center office at 603-863-3040 or stop by during gallery hours (Tues-Fri. 11am-4pm, Sat. 10am-2pm) Your registration is complete when we have received your competed registration form, as well as payment for the class.
2) PRINT & MAIL a registration form with your check. Download the ADULT REGISTRATION FORM.
3) REGISTER ONLINE NOW by clicking the link below.
*PLEASE NOTE: If the class of your choice is full or canceled due to lack of enrollment, you will be notified and entitled to a full refund. Class tuition is due in full on or before the first day of the class session. Make-up classes will only be offered when the instructor is unable to teach his/her class.
Members of the Library Arts Center may subtract 10% from tuition prices of all classes. Scholarships for children's classes are available; please inquire.
Drop- in Figure Drawing/Painting Sessions
ONGOING, Fridays, 1-3pm
$10 for LAC members, $12 for non- members, per session
Facilitator: Becky Bense
For each session, there will be a live model who will hold a variety of poses, both long and short. Artists, both professional and amateur of all styles are welcome take part in these sessions. Artists bring their own materials; there are easels in the studio that can be used, or participants can bring their own if they prefer. Facilitator Becky Bense will assure a professional and inviting studio environment and will facilitate model posing and timing. This is not an instructional session, rather an opportunity for artists to work with a live model in a welcoming community of artists.
CALL FOR LIVE MODELS The Arts Center is looking for several models to book for different weeks to ensure variety of subjects for participating artists. Models will hold a variety of poses, set by studio facilitator, both long and short in the Arts Center studio while artists draw and paint from the figure in this professional and friendly environment. Interested individuals should contact director Kate N. Luppold at 603-863-3040 or email: info[at]libraryartsenter[dot]org.
Adult Open Studio Art Group
Facilitator: Heidi Lorenz
DROP-IN FEE per session: $8 members / $12 non-members
ONGOING, WEDNESDAYS, 9am-12noon
** Summer brings Open Studio out of the studio and into the beauty of nature to paint on location in stunning natural settings. All are welcome to join this group for any of the sessions you are able. Click HERE for Summer Info.
Description: Looking for a time to work on current projects? Be inspired to work in a studio environment alongside other area artists in this drop-in group that meets on a weekly basis. The class facilitator, Heidi Lorenz, is available for light guidance. All mediums are welcome. No prior experience is necessary. Please bring all supplies you will need for your projects. Call the Arts Center at 603.863.3040 for more information.
Fiber Arts Drop-in Group
Facilitator: Ann Stout
ONGOING, Wednesdays, 10:00am-12noon
Location: 15 Main Street
$4 a session
This is a great opportunity to work on your creative projects in a fun community group setting. Bring your sewing, embroidery, felting, knitting, spinning, quilting, or whatever it may be for fiber based arts and crafts. Enjoy a welcoming atmosphere, cup of coffee or tea, and the inspiring community of makers. No need to preregister, just show up to any or all of the sessions listed. This is the first session of what we are hoping to run as a more permanent weekly group after this session.
Uncork Your Inner Artist
Instructor: Patti Warren
Thursday, July 21, 6-8:30pm
Tuition: $35, includes all materials, a complimentary beverage and appetizers
Description: Come to the Library Art Center for an evening of creativity, community, and cobalt blue! This is an opportunity for the non-artist to explore his/her expressive side while following step-by-step directions from a certified art instructor. In a relaxed and supportive environment, students will complete a painting suitable for framing. All studio materials will be provided as well as a complimentary glass of wine, so we ask that students are a minimum of 21 years old.
Basket Weaving
Instructor: Ray Lagasse
Dates/Times: FULL!: Saturday, July 9, 8:30am-4:30pm (bring a bag lunch).
Just Added! August 20th, 8:30am-4:30pm (bring a bag lunch).
September 10th, 8:30am-4:30pm (bring a bag lunch).
November 5th, 8:30am-4:30pm (bring a bag lunch).
Tuition: $95.00 for Bread Basket or $110 for all other basket options.
Description: In this one-day workshop students can choose to make one of four large-sized baskets: a wool gathering basket, laundry basket, double-pie, or pack basket. The baskets will be woven using reed with a hardwood base, rails, and rim. All materials are created and prepared by Ray Lagasse. Each participant will be asked to choose which basket he or she will be making upon registration. Each Student will leave the workshop with the completed basket of his or her choosing. Registration will close a week before the class starts. **Students who cancel before the class will still owe a $35 fee for materials preparation.
BASKET OPTIONS: Bread Basket – Small Table-top Basket ($95) Wool Gathering Basket 12x12x12 w/ leather handles and a wooden bottom ($110) Laundry Basket 11x18x12 basket form with leather handles ($110) Double Pie Basket 10x20x6 basket form with wooden handles ($110) Pack Basket 7x14x18 basket form with straps ($110)
Color Mixing with a special emphasis on Greens
Instructor: Peter Granucci
Dates: Saturday and Sunday, June 11 & 12: Saturday 9am-3pm, Sunday 10am-2pm
Tuition: $175
Green is one color that the landscape artist is confronted with immediately after setting out the palette and starting to paint. The grass is green, the trees are green, the hills are green, even the typical New England mountain will look green. How can one make sense of all these greens? This workshop will explain how to understand green as it occurs in Nature and give you the ability to mix the color you want when you want it. There will be lectures, demos and lots of time for you to paint.
Plein Aire Painting
Instructor: Peter Granucci
Level: Advanced, Intermediate and Beginner
Dates and Times: Thursdays, July 7, 14, 21, 28, August,4, 11 & 18, 5-7:30 PM
Tuition: $360.00 for all seven sessions
NOTE: If a student's summer schedule makes it so he or she must miss a session, Peter is willing to generously work with students to arrange make-up sessions.
All Media welcome including for Painting; oils, acrylic, pastel, watercolor. Including for drawing; Pencil (Graphite or Colored) or charcoal. ** Each artist can make their own choice of the medium they'd like to work with for this class. Peter will be happy to discuss it with you if you have any questions.
Description: Enjoy a relaxing evening painting in and around this beautiful area. In this class Peter will discuss all the why's and how to's relating to Plein Aire painting and Drawing. Including (but not limited to): how to start, how to finish, color mixing, values, form, and drawing. Class will be held outside whenever possible and will be moved into the studio in cases of inclement weather. Each class will have a brief opening presentation and a final gathering to appreciate each other's accomplishments.
About the Instructor: Peter is a respected landscape and portrait painter. He began exhibiting in NYC in 1975 and has continued to exhibit throughout New England and other parts of the country. He has won multiple national awards including from the Salmagundi Club in NYC. He has been teaching privately and in groups since 1985.
Try Your Hand at Watercolor Workshop
Instructor: Margaret Dwyer
Dates & Times: Tuesday, June 7, 9:30-1:30
Tuition: $45
Description: If you have never done watercolor before, or if you have some experience, but really want to get more comfortable with the medium, this class is for you! From brushes to papers to paints, try out all sorts of artist quality materials while doing playful paint experiments and easy techniques. Everyone will go home with artwork to be proud of and more confidence and skill with watercolor.
Explore New Water Media Supplies
Instructor: Margaret Dwyer
Dates & Times: Tuesday, June 14, 9:30am-1:30pm
Tuition: $54- ALL materials included
Description: Have you seen all the new water media materials in the art catalogues? Do you dog –ear the pages, but want to try these new materials out to know what you really want to add to your supplies before you make any big material investments? Try out fluid acrylics, and acrylic inks as well as traditional watercolors on surfaces such as aqua board and watercolor canvas. It's a great class that expands on watercolor and bridges into fluid acrylic mediums. Come experiment with these great new materials.
The Essence of Painting Flowers with Still Life & in the Garden
Instructor: Tatiana Yanovskaya-Sink
Dates & Times: Wednesday & Thursday, June 22 & 23, 9am-4:30pm
Tuition: $115
Description: This workshop includes studies on how to approach painting of all kind of flowers including peonies of the season within a still life setting and outside in the garden. Students will learn the concept of the direct approach while focusing on values; seeing shapes; color temperature; edges and design either within the still life setting or among natural chaos and abundance of greens of the garden. The topics on the starting points and determination when to stop will be covered during demos and plenty individual attention. Bring your own flowers if you can or and you go home with beautiful painting/s.
Medium Oils/acrylics. All levels are welcome. No more than 8 students
Suggested supply list will be provided upon registration.
To see Tatiana work please visit www.Tatianafinearts.com or Instagram /FB
Felted Flowers
Instructor: Margaret Dwyer
Dates & Times: Wednesday, July 13, 9:30am-12:30noon
Tuition: $35
Ages: 11-teens, adults welcome to sign up too
Location: 15 Main Street
Description: Create stunning 3D flowers and leaves out of a vast color array of wools. Learn color blending and basic needle felting techniques. Beads and buttons will be on hand to embellish your felted creations. Attach to pin backs at the end of class if you like to make your felted flowers wearable art. These are great to decorate hats, purses, backpacks, and to wear as jewelry!
Intuitive Collage Paintings
Instructor: Camille Gibson
Dates & Times: Tuesdays, July 12 & 19,26 & August 2, 5-8pm
Tuition: $200
Description: Moving on? Healing from something or just want to explore yourself or techniques? Learn the process of intuitive collage painting with Camille Gibson. This class teaches a great process for people who haven't ever done art, painting or drawing before as well as being good for the beginning artist or more experienced artist who wants to free mental pathways for further development in their current medium. Create two art pieces in these sessions, each one intuitively designed in this engaging and inspiring process. From image selection and placement as well as paint application, this process will be a creative flow resulting in unique and highly personal art pieces.
Bracelets with a Twist
Instructor: Margaret Dwyer
Dates & Times: Friday, July 15, 9am-1pm
Tuition: $30
Ages: Teens and Adults
Description: Take the basics of macramé and transform them into a sophisticated twisting bracelet. Choose from an array of colorful waxed linen as your base and then design with vibrant glass beads to accentuate the spiral design.
Portraits – Self Exploration in Collage
Instructor: Jennifer Stark
Dates & Times: July 14, 19 and 21, 6:30-8:30pm
Tuition: $32
Description: Using cut and torn paper, a selfie and cut words from magazines as well as paint, create a unique self-portrait in this fun and comfortable studio environment. The class is designed for beginners, intermediate artists, and those of great experience- the hope is that the process will not only have great results with a finished product, but will also be a source of creative self-exploration.
Watercolor Outdoors
Instructor: Becky Bense
Dates & Times: Saturdays July 16, August 27 or September 24, 9:30-3:30 (Each is a separate session, sign up for one or all three!)
Tuition: $35 for each session
Description: There is not much that is more fun that painting outside on a beautiful day for an artist! If weather permits, this group will meet at the Arts Center, then head out to paint on location. Should it rain the group will work in the studio from photo reference. The painting location will be abundant with flower gardens rolling fields and mountainous views as well as many beautiful nooks and crannies from which to tuck yourself away to paint. Class will start with a demo after which students will have ample time to paint with guidance and encouragement from Becky. This class is great for the beginner and intermediate painter. Bring your lunch, bug spray and sunblock and prepare for a day of wonderful creative fun.
Bursts of Color with Alcohol Inks
Instructor: Ann Stout
Dates & Times: Monday, July 18, 6:30-8:30pm OR Monday, September 12, 6:30-8:30pm
Tuition: $15 includes materials
Description: Using Alcohol Inks, a relatively new medium on the arts and crafts scene, create bursts of concentrated color on a non-porous surface. In this class, students will combine and manipulate colors using the interaction of inks, rubbing alcohol, gusts of air and gravity. Go home with a 5X5 panel for display (or to use as the background of another project) and a ceramic tile with your colorful creations on it which can be used as a trivet. This class will give you the confidence to use alcohol inks on your own at home. It is a medium that requires very little space and no unusual supplies, yet makes a big impact. This will be a fun evening in the studio where everyone will go home with colorful masterpieces.
Polymer Bead Making
Instructor: Margaret Dwyer
Dates & Times: Tuesday, July 19, 12:30-3:30pm
Tuition: $25
Ages: 11-teen, adults welcome
Description: Starting with a vast selection of polymer clay colors plus inclusions such as micro glitter and gold leaf, learn a variety of techniques to create stunning beads. You'll have access to tons of great clay tools, cutters, and texture plates. Leave the studio with a variety of sophisticated finished beads and the know how to make more on your own.
Polymer Pendants: Taking it to the Next Level
Instructor: Margaret Dwyer
Dates & Times: Wednesday, July 20, 5:30-9pm
Tuition: $27
Ages: Adults and Teens
Description: From basics to beyond, learn multiple techniques to make sophisticated pendant jewelry with polymer clay. This class will focus on sculptural pendants using detailing tools, molds, inclusions, and metallic surface treatments. Pasta machines and tons of clay cutters and tools will be available for classroom use. Go home with a variety of pendants and a whole new skill set for jewelry making.
Polymer Clay Canes: Designs Multiplied!
Instructor: Margaret Dwyer
Dates & Times: Friday, July 22 1-4pm
Tuition: $25
Ages: 11-teen (adults welcome to sign up too!)
Description: Starting with traditional techniques that go back to ancient glass blowing, then adding a vast color array of polymer clay, pasta machines and clay tools, learn to create colorful canes of clay. Then cut those canes into slices to create surprising, colorful and highly detailed beads or tiles that all match. This is a great technique that can be used to create all sorts of art projects. This will be a fun, colorful and hands on experience that will end with incredible design results!
Barn Quilts
Instructor: Becky Luppold
Dates & Times: Saturday, July 23, 9am-3pm (bring a bag lunch)
Tuition: $47 (includes all materials)
Description: Help us bring the tradition of barn quilts to our region by creating your own to hang on your house or barn. Barn quilts are quilt designs painted onto wooden boards that are weatherized and can be hung on barns and other exterior surfaces. As this is an introductory course, barn quilts will be made on 1 ft.X1 ft. boards. There will be an option of three different quilt squares to choose from for your design, as well as a variety of paint colors to choose from. Learn all the steps needed to create your own square and leave with your fully completed square ready to hang outdoors! With this class under your belt you will have the know-how to make more barn quilts on your own should you choose.
Wine Cork Cork Boards
Instructor: Ann Stout
Dates & Times: Monday, July 25, 6:30-8:30 OR Thursday, September 22, 6:30-8:30
Tuition: $25
Min. Max. enrollment: up to 10 students
Description: Create a mosaicked cork board with wine corks. Start with 16X16 wooden frames & wine corks. An ample assortment of corks provided, or feel free to bring your own if you have a collection you would like to use. Leave class with a finished project ready to hang on the wall and use! Enjoy a complimentary glass of wine while making your board in the spirit in the class; participants in this class must be 21 or older.
Face to Face: Portrait Studies in Watercolor
Instructor: Margaret Dwyer
Dates & Times: Tuesday & Wednesday, July 26 & 27, 1-4:30pm
Ages: Adults and Teens
Tuition: $40
Location: 15 Main Street
Min. Max. enrollment: 4-10
Description: Learn various ways to address scale, proportion through gesture and contour drawing techniques; combine these with traditional watercolor techniques that focus on highlight and shadow to create candid watercolor portraits. Work from life, and other sources provided by the instructor.
Silk Screens
Instructor: Margaret Dwyer
Dates & Times: Tuesday & Wednesday, July 26 & 27, 5-8:30pm
Tuition: $75
Min. Max. enrollment:
Description: Learn the basics of hand pulled silkscreen prints. Create your own hand cut stencil and then create a series of your own prints that can be used to make wall art pieces, cards, fabric design or t-shirts with this fun and engaging process.
Instructor: Stacey Hammerlind
Dates & Times: Tuesday & Wednesday, August 9 & 10, 6-8pm
Tuition: $30
Description: make a beautiful mosaic using broken plates and ceramic pieces. This ancient technique creates incredible artwork out of things as simple as broken dishes that would otherwise be thrown away. Supplies will be provided, but feel free to bring your own broken dish pieces if you have saved some and want to use them. Leave this class with a small finished piece and the skills to make more on your own, participants will never look at a broken dish the same way!
Before Summer's End – Flowers and Watercolor
Instructor: Margaret Dwyer
Dates & Times: Tuesday & Wednesday, August 23 &24, 1-4pm
Tuition: $75
Ages: Adults and teens
Description: Capture the essence of summer in watercolor painting by not just using nature as subject, but as material as well. Layering of leaves, vines and paints as part of the painting process. This is an experimental painting class with knock-out results. On the second day in the studio combine more traditional painting technique such as glazing and negative space painting to pull your art piece together.
Copperplate Calligraphy Workshop
Instructor: Laura Di Piazza
Dates & Times: Thursdays September 29, October 6, 13, 20, 27 and November 3, 6-8pm
Tuition: $215 includes all materials and a calligraphy set for you to keep
Description: In this calligraphy workshop we will examine and practice letterforms in the Copperplate hand. Copperplate, a pointed-pen script hand, was developed in 16th century England. We will work with an oblique pen holder, pointed pen nib, ink and practice pads with grid and slant lines. Our main focus will be on practicing varying amounts of pressure to apply to our pens to produce thick (shaded) and thin (hairline) strokes. We will begin our practice with minuscule and later majuscule letters, which
will be grouped according to similar letterforms. All materials will be supplied. Feel free to bring in your favorite quote and/or project ideas for practice and discussion.
Instructor: Patricia Wild
Wednesday, September 14, 1-3pm
Tuition: $38 (max. 10 students)
You know you're the
hero(ine) of your own life – now discover why! Using guided visualization,
meditations, and other exercises we will explore the many facets of who you are
in images, sounds, words, and movement. These
forms are like puzzle pieces, each containing vital information, and some
surprises, about the journey of your life. By arranging and rearranging these
pieces a beautiful whole is formed. Celebrate the life that you are, using
simple book techniques, as you create your visual autobiography.
Instructor: Patricia Wild
Saturday, October 8, 1-3pm
Tuition: $38 (max. 10 students)
Everyone is born with the impulse to make images; it's an integral part of our human-ness, and a rich part of our human heritage. Your artistic impulse and inner imagery is as unique to you as your fingerprints. In this workshop we will use guided visualization, meditation, and other exercises to access, explore, and express your inner imagery. You will also learn techniques for "dialoging" with your images to discover what wisdom they hold for you as you create and keep a journal of your true Self.
INSTRUCTOR'S BIO: Patricia Wild holds a
certificate of graduate study in Expressive Arts from Salve
Regina University. She also holds a BFA from Washington University, and
an MA and EdD from the University of Cincinnati. She has taught art at
every level from pre-school through graduate school, as well as numerous
workshops in the Expressive Arts. She's also a published writer,
exhibiting artist, and inveterate seeker and learner.


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Hotels near Mallory-Neely House
Search hotels near Mallory-Neely House in Memphis
Trending now in Memphis
- Most bookedThe Peabody Memphis
269 people looked at this hotel in the last hour
Most recent review
"It's always great to stay at the Peabody! I'm in the service, polite employees, very nice room. Easy access to Beale Street a big plus"
A Traveller, Jun 2016, US
255 people looked at this hotel in the last hour
Most recent review
"Great 2 night stay after staying 2 nights at neighboring hotel with tiny bathroom but opulent lobby."
A Traveller, May 2016, US
124 people looked at this hotel in the last hour
Most recent review
"a older hotel but was fine. my grandsons remarked about how good it smelled. Within walking distance of Beale Street"
A Traveller, Apr 2016, US
86 people looked at this hotel in the last hour
Most recent review
"The staff was very helpful and gave great suggestions on things to do and sights to see. The room was decent. I say decent only because the hotel is going through renovations. The staff was on top of making sure the guest needs were met. The neighborhood is part of Memphis downtown and around ..."
A Traveller, Jun 2016, US
75 people looked at this hotel in the last hour
Most recent review
"Stayed for 4 days and found both the location and hotel perfect for our needs. Bar and restaurant were a bit expensive so we avoided them since the were so many other choices in Memphis"
A Traveller, Jun 2016, CA
73 people looked at this hotel in the last hour
Most recent review
"Short stay while visiting Graceland. Beale streets a wonderful location. Highly recommend. You can stay here and walk into the Peabody to see the ducks without paying a heafty price. Would definitely stay again. Safe location."
A Traveller, Jun 2016, CA
72 people looked at this hotel in the last hour
Most recent review
"Good hotel in walking distance of Beale Street and the Flying Saucer pub (100's of ales and beers available). The hotel has valet parking which works fine at a reasonable cost (for such things). Next door, up a very unprepossessing alley is one of the best Ribs restaurants in Memphis. The Hotel o..."
A Traveller, Jun 2016, GB
70 people looked at this hotel in the last hour
Most recent review
"My overalls stay was pretty good, my only real concern was the ice machine was broken we have to go on multiple floors to find ice. The staff was very courteous and kind."
A Traveller, May 2016, US
64 people looked at this hotel in the last hour
Most recent review
"We needed a quality hotel in walking distance to our meeting location. This hotel met our criteria. The price was also very nice."
A Traveller, Jun 2016, US
23 people looked at this hotel in the last hour
Most recent review
"The location was great. The room was amazing. We had food that needed to be refig and this was perfect. We spend out last night enjoying many cable channels. Our bed was so comfortable and taking the shower was great. We had a wonderful view of the Mississippi river and the court yard."
A Traveller, Jun 2016, US
Map of hotels near Mallory-Neely House
- Beale Street
- Graceland
- Memphis Zoo
- Wolfchase Galleria
- FedEx Forum
- Landers Center
- University of Memphis
- Mud Island River Park
- National Civil Rights Museum at the Lorraine Motel
- Snowden Grove Amphitheater
- Orpheum Theatre
- AutoZone Park
- Snowden Grove Baseball
- Liberty Bowl Memorial Stadium
- Mississippi River Museum at Mud Island
- Mike Rose Soccer Complex
- Memphis Botanic Gardens- Hardin Hall
- Sun Studio
- Pink Palace Museum
- Overton Park
Hotels in Memphis near Mallory-Neely House
Are you looking for a cheap Mallory-Neely House hotel, a 5 star Mallory-Neely House hotel or a family friendly Mallory-Neely House hotel? You just landed in the best site to find the best deals and offers on the most amazing accommodations for your stay.
When you search for hotels near Mallory-Neely House with Hotels.com, you need to first check our online map and see the distance you will be from Mallory-Neely House, Tennessee.
Our maps are based on hotel search and display areas and neighborhoods of each hotel so you can see how close you are from Mallory-Neely House and refine your search within Memphis or Tennessee based on closest public transportation, restaurants and entertainment so you can easily get around the city. All the hotels details page show an option for free or paid onsite parking.
If you wish to see the hotels with the highest featuring discounts and deals near Mallory-Neely House, simply filter by price/ average nightly rate. We recommend you filter by star rating and read our genuine guest reviews so you can get the best quality hotel with the best discount.
One of the new features on Hotels.com guest reviews is that also show reviews from Expedia for Mallory-Neely House hotels and the TripAdvisor Mallory-Neely House hotels reviews so you can make sure that you checking with a reliable source. See the review scores on our Memphis hotel information pages.
Make the most out of your family vacation when you book your accommodation with Hotels.com – book your hotel near Mallory-Neely House, Memphis after reviewing the facilities and amenities listed for each hotel.
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Sealy® Classic Sleep™ Crib Mattress152065a
web ID: 7985831
Product Description
This Sealy® crib mattress offers 150 coil firmness and lasting comfort for your infant or toddler.
- thick hypoallergenic comfort layer
- reinforced cover and binding resists liquids and stains and wipes clean with soap and water
- waterproof lock-stitched binding helps prevent mold, mildew, and odor on the inside
- airflow pocket helps keep mattress fresh without the use of small metal vents
- fits standard-size cribs and toddler bed frames
- 52x27½x5¾"H
- meets or exceeds all flammability, phthalate, and lead testing and does not contain toxic fire retardants
- made in America
Rated 5 out of 5 by Verified Reviewer it's comfortable for my baby we love it,especially our baby,it's soft,and it match to the crib we bought,i would recommend this to my friends... March 29, 2012
Rated 5 out of 5 by luv2sleep Love it! I bought this mattress for my 3 month old son and he has slept great on it. It Is a good combination of soft but firm so he is comfortable through the entire night. Received the mattress quicker than expected in just a few days. Overall I am very happy with this mattress for the price paid. November 7, 2015
Rated 5 out of 5 by Shopping1 Wonderful Crib Mattress! This mattress is great! The delivery was quick and the mattress quality is great! A great and dependable brand. November 12, 2015
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Rated 5 out of 5 by WindowGurl I think baby's going to like it! This mattress seems like it is well made. It fits perfectly inside the crib that we just bought (also from JCPenney). It has the nice waterproof covering. It is nice and firm but has a little give to it. We have yet to put sheets on it- hopefully they fit well. It is great that we can also use this mattress as part of the toddler bed. We will definitely get good use out of it. October 17, 2011
Rated 5 out of 5 by Ladybug258 Simply The Best! Purchased this mattress along with a crib for my great granddaughter. When it arrived my grandaughter said it looked so comfortable she could even sleep on it! Sealy in my opinion, is the best mattress you can buy. This mattress will stand up for years to come! You won't go wrong by this purchase. November 29, 2010
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Try it once for free. Then I ask for 10 to 15CHF to help with room rental cost. We'll start at 8:00 but come 20 minutes in advance for a chance to chat :)
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Chicago, ILUSA
February 14, 2012
All sorts of card games,backgammon,Scrabble (with condition),Monopoly, Risk,checkers and willing to learn more.
Hi I love getting together with fun folks for games and good conversation. A light amount of competitive spirit with fun is a great way to spend an evening or afternoon
Fun and games
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BEIRUT Syrian air force jets fired four rockets at a remote section of the border with Lebanon on Monday, security sources said, four days after Damascus warned it may strike at Syrian rebels taking refuge across the frontier.
There were no immediate reports of casualties from the air strike near the Bekaa Valley town of Arsal, whose Sunni Muslim residents mainly support Syrian rebels fighting to topple President Bashar al-Assad.
Lebanon has a policy of "dissociation" from the two-year civil war in Syria but officials say they feel their country is increasingly at risk of being dragged into a conflict that the United Nations says has killed 70,000 Syrians.
Syria's Foreign Ministry said on Thursday that a "large number" of militants had crossed Lebanon's northern border into the Syrian town of Tel Kalakh last week.
"Syria expects the Lebanese side to prevent these armed terrorist groups from using the borders as a crossing point, because they target Syrian people and are violating Syrian sovereignty," it said in a message to the Lebanese government, according to state media.
It said Syria's "patience is not unlimited", even though "Syrian forces have so far exercised restraint from striking at armed gangs inside Lebanese territory." (Editing by Louise Ireland)
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VIP Conference
The 2016 VIP Conference will feature Warren Graham, author of The Black Belt Librarian and take place on August 12 at the University of South Florida's Marshall Center.
Ultimate Guide to Successful Digital Promotions
Join this interactive workshop on August 18 to develop successful digital promotion strategies.
Outreach Group Meeting
Let's talk about Community Collaborations – August 25
Learn best practices, aspirations and ideas to connect and engage with your community outside the library!


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looks like at last we are waking up from our summer kip!!!! obviously lowly opposition last night, but I thought our performance in turkey was very good ...bring on the blues ...hehe
oh wasnt it good to see the boys bang in 5. and a nice draw for the next round. pleased to see the gooners got everton . hope they crash and burn . c.o.y.s
Well if we can teh results we watn the next couple of gaems leading up to chelsea, i'd be more than confident that we can get a drawer, at least. We shall see.


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8 Reasons
K Couture is the best place for your Wedding Party or Special Occasion attire!
One of a kind dresses made to order
Want bridesmaid dresses with sleeves? We've got you covered. Need a larger or smaller size than most places carry? Don't even worry. We'll work with you to find or create that perfect dress, no matter how crazy your needs may be. It's all made to order, just for you!
Attire for the whole wedding party
The struggle to find menswear to perfectly match your dress is real. At K Couture, we design and sew all of our dresses, and most of our menswear in house, which means your entire wedding party can wear the exact same fabric. No "almost matching" colors here!
All dresses are made in the USA
All of our dresses and most of our menswear are made in our very own K Couture Headquarters in Tempe, Arizona. Staying local not only helps to grow our economy and community, but gives us full control over the quality of our products to ensure you receive the quality you pay for!
Additional sizes available
"One size fits all" is not in our vocabulary. We understand that everyone is built differently and our job is to HELP you find the perfect fit. With our extended plus sizes, junior sizes, and the ability to create a complete custom dress for an unconventional fit, we will find the perfect fit for you.
Affordable pricing
With custom dresses starting at $85 and full menswear packages starting at $99, we don't know anyone who can beat our prices while still maintaining the highest quality. How do we do it? We make our products ourselves so no one is raising prices on us and we won't raise prices on you.
Fast turnaround
Need a dress ASAP? With our stylists, production, sewing, and customer service teams all working in the same building, things can happen fast! Plan to have your item in your hands in less than 8 weeks! Need it even faster? Give us a call and we may be able to pull some strings!
Fabric swatches
Ordering directly from a computer without seeing the fabric yourself, it's scary, we totally get it! That's exactly why we offer fabric swatches so you can touch, feel or match the fabric before you make the purchase!
Free Shipping: Just when you thought it couldn't get any better, we offer free shipping anywhere within the United States! That's right, from New York to California and everywhere in between; we'll send it to you for free!
Looks We Love
Everyone loves a celebration, whether it's an acknowledgment of a milestone for an important event or the celebration of a special occasion! Anniversary of the day you met…your first kiss…the first "I love you"… celebrate the anniversary of your engagement and of course, your wedding anniversary, one of the most important days in the life […]
The post Celebrate Love appeared first on KCouture Blog.
When it comes to wedding planning there are so many elements to remember that keeping it all together can be a bit overwhelming. Luckily, you and your future husband have enlisted some help in the form of your bridesmaids and groomsmen. These lucky individuals get to stand next to you on your big day and […]
The post Bridal Party Gifts appeared first on KCouture Blog.
Leading Actor and Actress for Mr. & Mrs. aka: The Bride: totally smitten with Groom, to marry the man of her dreams! The Groom: thinks he is the luckiest man alive that she said YES!! Cast of Characters: Maid of Honor: sister and/or best friend of bride with whom they share all their secrets, hopes […]
The post Unexpected Attendants! appeared first on KCouture Blog.