bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional differences in lipid metabolism in resting skeletal muscle of various fiber types
Authors: Dyck D. J. , Peters S. J. , Glatz J. , Gorski J. , Keizer H. , Kiens B. , Liu S. , Richter E. A. , Spriet L. L. , van der Vusse G. J. , Bonen A.
Published: December 2017

Intramuscular lipid pool turnover [triacylglycerols (TG), phospholipids (PL), mono- and diacylglycerols (MG, DG)] and the oxidation of endogenous and exogenous lipids were determined with pulse-chase studies in incubated muscles of varied oxidative potential [soleus strips (SOL)--> epitrochlearis --> flexor digitorum brevis]. Incorporation of palmitate into TG and PL pools and its oxidation were linearly related to time and exogenous palmitate concentration in all muscles. Total palmitate incorporation (deposition and oxidation) was greatest in SOL. However, palmitate incorporation into TG was similar in all muscles when expressed as a percentage of the total incorporation. In contrast, palmitate incorporation into PL was greatest in the least oxidative muscle. Palmitate oxidation, incorporation into TG, and citrate synthase activity were all strongly correlated with muscle cytosolic fatty acid-binding protein content (r = 0.96, 1.0, and 0.98, respectively). During the chase, reducing exogenous palmitate from 1.0 mM to 0.5 or 0 mM resulted in a significant (approximately 30%) loss of [(14)C]palmitate from the TG pool in SOL and a significant increase in (14)CO(2) production from endogenous stores. No significant loss of (14)C label from lipid pools occurred in the less oxidative muscles, suggesting a closely regulated interaction between energy provision from exogenous and endogenous lipid pools in oxidative muscle. Glucose oxidation increased significantly in all muscles in the absence of palmitate. The loss of (14)C label from TG in SOL during the chase without palmitate was not accompanied by a significant change in TG content. This suggests that, during rest, there is a small subpool of TG with a relatively rapid turnover.
AT1 receptor blockade and the sympathoadrenal response to insulin-induced hypoglycemia in humans
Authors: Worck R. H. , Ibsen H. , Frandsen E. , Dige-Petersen H.
Published: December 2017

An important facilitating effect of angiotensin II on adrenal catecholamine release has been demonstrated in several species. To determine whether specific AT1 receptor blockade affects medullary epinephrine secretion and musculocutaneous norepinephrine release during insulin-induced hypoglycemia, 16 healthy volunteers received losartan vs. placebo followed by an intravenous insulin bolus and measurement of effect variables at short intervals for 150 min. AT1 receptor blockade was effective, as evidenced by substantially increased circulating renin and angiotensin II levels, a 60% inhibition of circulating aldosterone, and an 8.5% decrease of mean arterial pressure over time compared with placebo. Arterial glucose concentration fell to a nadir of 1.9 mM, arterial epinephrine concentration increased 23-fold, forearm musculocutaneous norepinephrine release increased 4-fold, heart rate increased 40%, and forearm blood flow increased 3-fold. All absolute values and the time course of these changes were independent of AT1 receptor blockade. It is concluded that a putative interaction between angiotensin II and the sympathoadrenal axis may not be mediated by AT1 receptors in humans.
Endothelin stimulates osteoblastic production of IL-6 but not macrophage colony-stimulating factor
Authors: Perkins S. L. , Sarraj E. , Kling S. J. , Kohan D. E.
Published: December 2017

Endothelins (ET) are vasoactive polypeptide hormones that stimulate osteoblastic signal transduction events. Using MC3T3-E1 and primary osteoblasts, we studied ET effects on interleukin-6 (IL-6) and macrophage colony-stimulating factor (M-CSF) production. Enzyme-linked immunosorbent assay analysis showed a dose-dependent 3- to 3.5-fold increase in IL-6 with 100 nM ET-1 stimulation within 4 (primary osteoblasts) to 8 (MC3T3-E1) h. ET-3 was less effective at enhancing IL-6 production, with a maximal twofold increase after 100 nM ET-3 after 4 h. No significant increase in M-CSF production was noted with ET-1 or ET-3 in either cell type. Reverse-transcriptase polymerase chain reaction analysis demonstrated both ET(A) and ET(B) receptors on primary osteoblasts and only ET(A) receptors on MC3T3-E1. ET-1-stimulated IL-6 production was blocked by the inhibitor BQ-123, implicating ET(A) receptor involvement. Increased IL-6 protein was coupled with elevated IL-6 mRNA levels and a twofold increase in IL-6 message half-life.
Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice
Authors: Palha J. A. , Hays M. T. , Morreale de Escobar G. , Episkopou V. , Gottesman M. E. , Saraiva M. J.
Published: December 2017

As part of a study on tissue uptake of thyroxine (T4) in a transthyretin (TTR)-null mouse strain, kinetic parameters of thyroxine metabolism in wild-type mice under normal physiological conditions are presented. Kinetic analysis of injected [(125)I]T4 showed that TTR-null mutants have markedly increased [(125)I]T4 transfer rate constants from plasma to the fast-exchange compartments of liver and kidney and from fast to slow kidney compartments. Transfer rates from plasma to brain, testes, and fat were little affected. The T4 tissue content in the mutants was greatly reduced in brain but relatively normal in liver and kidney. No major changes were observed in brain 3,3',5-triiodothyronine concentrations, suggesting that availability of this hormone is not markedly altered in the mutant mice. The low T4 brain content probably reflects the absence of T4-TTR complexes in the mutant choroid plexus and cerebrospinal fluid. This study indicates that TTR is not essential for T4 tissue uptake or for T4 to reach the brain across the choroid plexus-cerebrospinal fluid and/or blood-brain barriers.
Brain of the conscious dog is sensitive to physiological changes in circulating insulin
Authors: Davis S. N. , Dunham B. , Walmsley K. , Shavers C. , Neal D. , Williams P. , Cherrington A. D.
Published: December 2017

The aim of this study was to determine whether a selective, physiologically relevant increase in blood-borne insulin perfusing the brain has an impact on the counterregulatory response to hypoglycemia. Experiments were carried out on 12 conscious 18-h-fasted dogs. Insulin was infused (1 mU x kg(-1) x min(-1)) in separate, randomized studies into a peripheral vein (n = 6) or both carotid and vertebral arteries (n = 6). This resulted in equivalent systemic insulinemia (38 +/- 2 vs. 35 +/- 5 microU/ml) but differing head insulin levels (38 +/- 2 microU/ml during peripheral infusion and an estimated 90 microU/ml during head insulin infusion). Glucose was infused during peripheral insulin infusion to equate the level of hypoglycemia (58 +/- 2 mg/dl) to that obtained during head insulin infusion (57 +/- 2 mg/dl). Despite equivalent peripheral insulin levels and hypoglycemia, incremental area under the curve responses for epinephrine, glucagon and cortisol were increased during head insulin infusion (P < 0.05). Net hepatic glucose output, gluconeogenesis, and lipolysis were increased 50-100% (P < 0.05) during head compared with peripheral insulin infusion. We conclude that during hypoglycemia in the conscious dog 1) physiologically relevant increases of blood-borne insulin to the head can amplify neuroendocrine and metabolic counterregulatory responses and 2) glucagon secretion can be regulated, in part, by neural efferent activity.
Nongenomic effects of aldosterone on intracellular calcium in porcine endothelial cells
Authors: Schneider M. , Ulsenheimer A. , Christ M. , Wehling M.
Published: December 2017

Rapid in vitro effects of aldosterone on intracellular electrolytes, cell volume, and the sodium-proton antiport have been described in human mononuclear leukocytes and vascular smooth muscle cells. In the present study, we demonstrate rapid aldosterone effects on free intracellular calcium as determined by fura 2 fluorometry in single porcine endothelial cells. After addition of 100 nmol/l aldosterone, cells respond with a sustained rise in free intracellular calcium by approximately 50% of initial levels within 1-5 min. Elevations are predominantly seen in the subplasmalemmal space. Effective half-maximal concentration values for aldosterone are approximately 1 pmol/l and for cortisol approximately 1 nmol/l. These effects are blunted in calcium-free medium and absent after pretreatment by thapsigargine. They remain unchanged by a >1,000-fold excess of spironolactone. These findings indicate the existence of a nongenomic pathway for aldosterone action in porcine endothelial cells and may be related to known rapid cardiovascular effects of aldosterone in vivo mediated through the baroreceptor reflex.
rhIGF-I administration in humans: differential metabolic effects of bolus vs. continuous subcutaneous delivery
Authors: Mauras N. , Martha P. M. , Quarmby V. , Haymond M. W.
Published: December 2017

The metabolic effects of recombinant human insulin-like growth factor I (rhIGF-I) were compared using bolus vs. continuous subcutaneous infusions. Subjects (n = 5, 29 +/- 3 yr) received rhIGF-I as subcutaneous infusions by a Minimed pump (200 microg x kg(-1) x day(-1) over 16 h/day), and their data were compared with those of subjects (n = 6, 24 +/- 2 yr) who received subcutaneous 200 microg x kg(-1) x day(-1) injections twice a day. L-[1-14C]leucine and [6,6-2H2]glucose infusion studies and indirect calorimetry were performed, and total and free IGF-I, insulin, and glucose concentrations were measured before and after 5-7 days of rhIGF-I. Estimates of protein breakdown, oxidation, and synthesis did not change after pump therapy; in contrast, after bolus doses, protein oxidation decreased (P = 0.001) and whole body protein synthesis increased (P = 0.04). There was no change in lipid oxidation after pump treatment, whereas the bolus group had lower lipid oxidation (P = 0.035). Both treatment modalities increased glucose oxidation (P < 0.02) and glucose production rates (P < 0.03). Overnight fasting insulin concentrations decreased in both groups, whereas plasma glucose remained invariant in the bolus group and decreased modestly in the pump group. Total IGF-I concentrations increased comparably in both groups, but the increase in free IGF-I was greater in the bolus-treated group (P = 0.001). We conclude that, in GH-sufficient postabsorptive individuals, the metabolic effects of rhIGF-I are in part dependent on the mode of administration, with a robust protein-anabolic effect when rhIGF-I is given as twice daily bolus injections but no detectable effect on protein turnover after a continuous mode of delivery. There were higher free IGF-I levels in the bolus-treated subjects, suggesting that this form of the molecule may be important for mediating IGF-I's protein-anabolic effects at the tissue level. The data also suggest that carbohydrate metabolism is more responsive than protein metabolism to the continuous subcutaneous modality of rhIGF-I administration. Even though the mechanism of these differences in metabolic effects is not entirely clear, it should be taken into account when patients are given rhIGF-I as prolonged treatment.
Phosphatidylinositol 3-kinase and dynamics of insulin resistance in denervated slow and fast muscles in vivo
Authors: Elmendorf J. S. , Damrau-Abney A. , Smith T. R. , David T. S. , Turinsky J.
Published: December 2017

Regulation of glucose uptake by 1- and 3-day denervated soleus (slow-twitch) and plantaris (fast-twitch) muscles in vivo was investigated. One day after denervation, soleus and plantaris muscles exhibited 62 and 65% decreases in insulin-stimulated 2-deoxyglucose uptake, respectively, compared with corresponding control muscles. At this interval, denervated muscles showed no alterations in insulin receptor binding and activity, amount and activity of phosphatidylinositol 3-kinase, and amounts of GLUT-1 and GLUT-4. Three days after denervation, there was no increase in 2-deoxyglucose uptake in response to insulin in soleus muscle, whereas plantaris muscle exhibited a 158% increase in basal and an almost normal absolute increment in insulin-stimulated uptake. Despite these differences, denervated soleus and plantaris muscles exhibited comparable decreases in insulin-stimulated activities of the insulin receptor (approximately 40%) and phosphatidylinositol 3-kinase (approximately 50%) and a pronounced decrease in GLUT-4. An increase in GLUT-1 in plantaris, but not soleus, muscle 3 days after denervation is consistent with augmented basal 2-deoxyglucose uptake in plantaris muscle at this interval. These results demonstrate that, in denervated muscles, there is a clear dissociation between insulin-stimulated 2-deoxyglucose uptake and upstream events involved in insulin-stimulated glucose uptake.
Human skeletal muscle protein breakdown during spaceflight
Authors: Stein T. P. , Schluter M. D.
Published: December 2017

Human spaceflight is associated with a loss of body protein. Excretion of 3-methylhistidine (3-MH) in the urine is a useful measurement of myofibrillar protein breakdown. Bed rest, particularly with 6 degrees head-down tilt, is an accepted ground-based model for human spaceflight. The objectives of this report were to compare 3-MH excretion from two Life Sciences shuttle missions (duration 9.5 and 15 days, n = 9) and from 17 days of bed rest (n = 7) with 6 degrees head-down tilt. The bed rest study was designed to mimic an actual Life Sciences spaceflight and so incorporated an extensive battery of physiological tests focused on the musculoskeletal system. Results showed that nitrogen retention, based on excretion of nitrogen in the urine, was reduced during both bed rest [from 22 +/- 1 to 1 +/- 5 mg N x kg(-1) x day(-1) (n = 7; P < 0.05)] and spaceflight [from 57 +/- 9 to 19 +/- 3 mg N x kg(-1) x day(-1) (n = 9; P < 0.05)]. 3-MH excretion was unchanged with either bed rest [pre-bed rest 5.30 +/- 0.29 vs. bed rest 5.71 +/- 0.30 micromol 3-MH x kg(-1) x day(-1), n = 7; P = not significant (NS)] or spaceflight [preflight 4.98 +/- 0.37 vs. 4.59 +/- 0.39 micromol 3-MH x kg(-1) x day(-1) in-flight, n = 9; P = NS]. We conclude that 1) 3-MH excretion was unaffected by spaceflight on the shuttle or with bed rest plus exercise, and 2) because protein breakdown (elevated 3-MH) was increased on Skylab but not on the shuttle, it follows that muscle protein breakdown is not an inevitable consequence of spaceflight.
Comparative metabolism and distribution of rabbit heparin cofactor II and rabbit antithrombin in rabbits
Authors: Hatton M. W. , Hoogendoorn H. , Southward S. M. , Ross B. , Blajchman M. A.
Published: December 2017

The metabolic characteristics of two rabbit plasma thrombin inhibitors, heparin cofactor II (HCII) and antithrombin (AT), have been compared in healthy young rabbits. Purified HCII and AT-alpha were differentially radiolabeled (125I, 131I) and injected intravenously; blood samples were taken at prescribed intervals over 7 days. From the plasma clearance curves of protein-bound radioactivities, fractional catabolic rates and compartmental distributions were calculated using a three-compartment model. The whole body fractional catabolic rate for HCII (jt, 0.43/day, equivalent to t1/2 = 1.61 days) was significantly faster than for AT (jt, 0.37/day; t1/2 = 1.89 days; P < 0.005). The fractional distribution of HCII in the intravascular compartment (Ap, 0.20) and in the extravascular compartment (Ac, 0.63) differed significantly from AT (Ap, 0.30; Ac, 0.56). From the catabolic data and blood concentrations, absolute quantities of HCII and AT catabolized by a 3-kg rabbit amounted to 12.8 and 19.9 mg/day, respectively, equivalent to a molar ratio, AT/HCII, of 1.7. The catabolic molar ratio was compared with the relative release rates of HCII and AT from perfused rabbit livers. Both proteins were released from the liver, the molar ratio in the perfusate rising to approximately 1.4 at 2.5 h. This report increases our understanding of the in vivo dynamics of these two proteins.
Energy expenditure of adult male rhesus monkeys during the first 30 mo of dietary restriction
Authors: Ramsey J. J. , Roecker E. B. , Weindruch R. , Kemnitz J. W.
Published: December 2017

Energy expenditure, activity, and body composition were measured in 30 adult male rhesus monkeys used in a study having the long-term goal of determining the effects of moderate dietary restriction (DR) on aging. All animals were fed a defined diet, with the restricted animals maintained at approximately 70% of the caloric intakes of the controls. After 12 mo of DR, body fat mass of restricted monkeys was 33% less than that of controls (P = 0.004), whereas lean body mass differences were not present until after 24 mo. At the 24- and 30-mo assessments, nighttime energy expenditure was significantly reduced (P < 0.01) in the restricted compared with control monkeys after adjustment for lean body mass differences, whereas morning, afternoon, and total energy expenditure were not significantly different (P > 0.05). No significant differences (P > 0.05) in activity were noticed between treatment groups at any time point. DR resulted in a prolonged decrease in resting energy expenditure, which could contribute to the possible life-extending action of this treatment.
Intestinal function in mice with small bowel growth induced by glucagon-like peptide-2
Authors: Brubaker P. L. , Izzo A. , Hill M. , Drucker D. J.
Published: December 2017

Glucagon-like peptide-2 (GLP-2) stimulates small intestinal growth through induction of intestinal epithelial proliferation. To examine the physiology of GLP-2-induced bowel, mice were treated with GLP-2 (2.5 micrograms) or vehicle for 10 days. Small intestinal weight increased to 136 +/- 2% of controls in GLP-2-treated mice, in parallel with 1.4 +/- 0.1- and 1.9 +/- 0.5-fold increments in duodenal RNA and protein content, respectively (P < 0.05-0.001). Similarly, the activities of duodenal maltase, sucrase, lactase, glutamyl transpeptidase, and dipeptidyl-peptidase IV (215 +/- 28% of controls; P < 0.001) were increased by GLP-2. Oral or duodenal administration of glucose or maltose did not reveal any differences in the ability of GLP-2-treated mice to absorb these nutrients, possibly because of decreases in expression of the glucose transporters sodium-dependent glucose transporter-1 (SGLT-1) and GLUT-2. In contrast, absorption of leucine plus triolein was increased after duodenal administration in GLP-2-treated mice (P < 0.01-0.001). Finally, GLP-2 did not alter other markers of intestinal or pancreatic gene expression, including levels of mRNA transcripts for ornithine decarboxylase, multidrug resistance gene, amylase, proglucagon, proinsulin, and prosomatostatin. Thus induction of intestinal growth by GLP-2 in wild-type mice results in a normal-to-increased capacity for nutrient digestion and absorption in vivo.
Fate of insulin analogs in intact and nephrectomized rats determined by their receptor binding constants
Authors: Kruse V. , Jensen I. , Permin L. , Heding A.
Published: December 2017

After intravenous injection of 125I-labeled human insulin and analogs in normal and nephrectomized rats, we examined their kinetic fate by Q-Sepharose separation into intact ligand, "fragments" (genuine fragments and protein-bound radioactivity), and iodide. Receptor binding association and dissociation constants (kass and kdis, respectively) of the analogs were estimated dynamically in vitro by BIAcore. The very fast disappearance of intact ligand from serum was found to be determined by 1) both kass and kdis of receptor-bearing tissue, thus substantiating our primary hypothesis; 2) elimination by kidneys, and 3) fast extravascularization. The rate of appearance of degradation products from receptor-mediated intracellular processing seems determined by kdis. With the possible exception of a truncated analog, ligand appears protected against degradation while the intracellular receptor-ligand complex remains intact. Non-receptor-mediated processing in kidneys is slow, compared with the receptor-mediated uptake and degradation of ligands with rate constants comparable to those of insulin. We observed binding of insulin and analogs putatively to serum proteins; binding capacity and affinity appeared insignificant for insulin but considerable for some analogs.
Antihypertensive and vasculo- and renoprotective effects of pioglitazone in genetically obese diabetic rats
Authors: Yoshimoto T. , Naruse M. , Nishikawa M. , Naruse K. , Tanabe A. , Seki T. , Imaki T. , Demura R. , Aikawa E. , Demura H.
Published: December 2017

Although an improvement of insulin sensitivity has been shown to be a new therapeutic approach for treating diabetes mellitus, details of effects of this treatment on the cardiovascular system and possible renal complications remain unknown. In the present study, we investigated the effects of a thiazolidine derivative, pioglitazone, and examined the insulin-sensitizing action on blood pressure, nephropathy, and vascular changes in genetically obese diabetic Wistar fatty (WF) rats. Pioglitazone (3 mg.kg-1.day-1) was orally administered for 13 wk starting at the age of 5 wk, and the results were compared with those of vehicle-treated WF rats. At the age of 18 wk, vehicle-treated WF rats were associated with mild hypertension, nephropathy with proteinuria histological glomerular injury, and renal arteriolosclerosis in addition to hyperglycemia, hyperinsulinemia, and hyperlipidemia. Treatment with pioglitazone significantly improved glucose and lipid metabolism. In addition, it lowered blood pressure, decreased proteinuria, and prevented glomerular injury, renal arteriolosclerosis, and aortic medial wall thickening, whereas body weight, food intake, sodium balance, and urinary norepinephrine excretion were significantly increased. These results suggest that the insulin-sensitizing agent pioglitazone is effective in correcting not only glucose and lipid metabolism but also cardiovascular and renal complications in non-insulin-dependent diabetes mellitus.
Effect of methionine-free total parenteral nutrition and insulin-like growth factor I on tumor growth in rats
Authors: Yoshida S. , Ohta J. , Shirouzu Y. , Ishibashi N. , Harada Y. , Yamana H. , Shirouzu K.
Published: December 2017

The objectives of this study were to evaluate the effect of insulin-like growth factor I (IGF-I) on the fractional synthesis rate (FSR) of muscle and whole body protein breakdown rate (WPBR) during methionine-free total parenteral nutrition (MTPN). We also determined whether the inhibition of endogenous methionine availability reduced tumor protein synthesis. AH109A hepatoma cells were inoculated onto the backs of Donryu rats on day 0. On day 10, the rats were catheterized for TPN and assigned to one of four groups: 1) standard TPN (STPN), 2) STPN + IGF-I, 3) MTPN, or 4) MTPN + IGF-I. The addition of IGF-I to MTPN reduced the loss of body weight by both increasing muscle FSR and reducing WPBR. The tumor FSR did not differ between MTPN + IGF-I and MTPN. The methionine extraction ratio from the liver was negative with MTPN + IGF-I but positive in the other groups. We concluded that IGF-I blockage of endogenous methionine release from peripheral protein sites was associated with a shift to liver-derived methionine, with no change in tumor growth in MTPN-treated rats.
Exercise blunts declines in lipolysis and fat oxidation after dietary-induced weight loss in obese older women
Authors: Nicklas B. J. , Rogus E. M. , Goldberg A. P.
Published: December 2017

Weight loss (WL) by hypocaloric diet decreases adipocyte lipolysis and fat oxidation, adaptations that might predispose individuals to regain weight. Our hypothesis was that the addition of endurance exercise (EX) to dietary-induced WL (6 mo; 250-350 kcal/day deficit) would prevent declines in abdominal (ABD) and gluteal (GLT) adipocyte lipolysis and fat oxidation in obese older women. At baseline, the WL (n = 9) and WL+EX (n = 11) groups had similar body composition, fat distribution, aerobic fitness (VO2max), and resting fat metabolism. Reductions in body weight (WL = 11%, WL+EX = 8%), percent body fat, and intra-abdominal fat area with the interventions were similar in both groups, but VO2max increased (9%, P < 0.01) only in the WL+EX group. Basal and adrenergic receptor- and postreceptor-stimulated lipolysis in ABD and GLT adipocytes decreased (20-70%, P < 0.05) in the WL group but did not change in the WL+EX group. Fat oxidation decreased (38%, P < 0.05) in the WL group but not in the WL+EX group. The changes in fat oxidation and GLT lipolysis differed significantly between groups. Fat oxidation correlated positively with ABD and GLT adipocyte basal lipolysis at baseline (r = 0.45 and r = 0.53, P < 0.05), and the changes in fat oxidation with the interventions correlated positively with changes in ABD and GLT adipocyte basal lipolysis (r = 0.50 and r = 0.42. P < 0.05) in the entire group of women. These results indicate that exercise counteracts the decline in fat oxidation with WL, in part by maintaining adipocyte lipolytic responsiveness in some weight-reduced postmenopausal women.
Attenuation of leptin-mediated effects by monosodium glutamate-induced arcuate nucleus damage
Authors: Dawson R. , Pelleymounter M. A. , Millard W. J. , Liu S. , Eppler B.
Published: December 2017

Leptin is a protein secreted by adipocytes that is important in regulating appetite and adiposity. Recent studies have suggested the presence of leptin receptors in the arcuate nucleus of the hypothalamus (ANH). Neonatal administration of monosodium glutamate (MSG) damages the ANH, resulting in obesity and neuroendocrine dysfunction. Neonatal administration of MSG was utilized to test the hypothesis that the anatomic site for many of leptin's actions is the ANH. Female control (n = 6) and MSG-treated rats (n = 7) were implanted for 14 days with osmotic minipumps containing phosphate-buffered saline or leptin (1 mg.kg-1.day-1). Leptin suppressed (P < 0.05) body weight gain in controls but did not suppress weight gain in MSG-treated rats. Leptin decreased (P < 0.05) fat depots in controls but had no effect in MSG-treated rats. Night feeding was suppressed (P < 0.05) in leptin-treated control rats. MSG-treated rats showed a suppression in food intake that was of a smaller magnitude and appeared later in the course of leptin treatment. These findings suggest that leptin mediates some physiological actions related to fat mobilization via receptors located in the ANH.
Chronic electrical stimulation increases MCT1 and lactate uptake in red and white skeletal muscle
Authors: McCullagh K. J. , Poole R. C. , Halestrap A. P. , Tipton K. F. , O'Brien M. , Bonen A.
Published: December 2017

We examined whether chronic stimulation of red and white rat muscles increased the concentrations of the monocarboxylate transporter MCT1. Red and white tibialis anterior (RTA and WTA, respectively) and extensor digitorum longus (EDL) muscles were chronically stimulated via the peroneal nerve for 7 days. Stimulated and contralateral control muscles were examined for MCT1 content, L-lactate uptake, lactate dehydrogenase (LDH) isoforms, and muscle fiber composition. MCT1 was 1.5 times greater in stimulated RTA, 3 times greater in stimulated WTA, and 1.9 times greater in stimulated EDL compared with respective control muscles (P < 0.05). L-Lactate uptake increased in all stimulated muscles (P < 0.05), and this was highly correlated with the increase in MCT1 (r = 0.96). The heart-type LDH (H-LDH) subunits also increased in all stimulated muscles (P < 0.05). The H-LDH subunits correlated highly with MCT1 in the muscles (r = 0.83). There was no change in muscle-type LDH subunits (P > 0.05). There were negligible alterations in muscle fiber composition in the stimulated muscles, suggesting that the increase in MCT1 was independent of changes in muscle fiber composition. These studies are the first to demonstrate that chronic muscle contraction increases MCT1 concentrations in both red and white skeletal muscles.
Effects of triiodothyronine administration on the adenylyl cyclase system in brown adipose tissue of rat
Authors: Adli H. , Bazin R. , Vassy R. , Perret G. Y.
Published: December 2017

This study was undertaken to investigate the effect of triiodothyronine (T3) administration to euthyroid rats on beta 3-adrenoceptor (beta 3-AR) expression and on the different components of the adenylyl cyclase (AC) system in brown adipose tissue (BAT). In rats treated with T3, the beta 3-AR density (assessed by the binding of [3H]CGP-12177) showed a decrease of 50%, as did their mRNA, as analyzed by reverse transcriptase-polymerase chain reaction. In hyperthyroid rats, compared with control rats, there was a 40% increase in G alpha s activity (stimulated by NaF or GTP gamma S) and a fourfold increase in the protein concentration (Western blotting). In contrast, the level of the pertussis toxin substrate Gi declined by 35% in response to T3. Analysis of dose-response curves for isoproterenol and CGP-12177 revealed that neither basal nor stimulated AC activities nor 50% stimulatory concentration for these agonists was changed by T3 administration. In conclusion, these results suggest that downregulation of the beta 3-AR by T3 was counter-balanced by changes in other components of the AC cascade (i.e., Gs and Gi), so no change occurred in the capacity of BAT to generate adenosine 3',5'-cyclic monophosphate.
Interaction of corticosterone and gonadal steroids on lipid deposition in the female rat
Authors: Deshaies Y. , Dagnault A. , Lalonde J. , Richard D.
Published: December 2017

The present study was designed to evaluate the interaction of corticosterone (CORT) and female gonadal steroids on energy balance and lipid metabolism. To this end, a 2 x 4 factorial experiment was carried out in which two cohorts of rats differing in their ovary status [OV status: intact (INT) and ovariectomy (OVX)] were each divided into four groups defined by their CORT status [CORT status: nonadrenalectomized (non-ADX), ADX without CORT replacement (placebo subcutaneous pellet), ADX with low-dose CORT replacement, and ADX with high-dose CORT replacement]. After 3 wk of treatment and a 12-h fast, rats were killed and their carcasses analyzed for energy (lipid and protein) content. In addition, indexes of endogenous triglyceride (TRIG) production (liver TRIG content), transport into plasma (triglyceridemia), and incorporation into fat stores [lipoprotein lipase (LPL) activity in adipose tissue (AT)] were assessed. OV and CORT status interacted on body weight gain, total energy, and fat gains. The interactions arose from the fact that the twofold increase in these variables brought on by OVX was abolished by ADX and restored by CORT replacement. Although in ADX groups there was a dose-related restoration of total energy and fat gain by CORT replacement in both INT and OVX cohorts, the impact thereupon of OVX observed in the non-ADX group reappeared only in ADX animals receiving the high dose of CORT. Protein gain was increased by OVX solely in non-ADX rats, whereas the high dose of CORT prevented any net protein gain independently of the OV status. Consistent with treatment effects on total body fat gain, OVX resulted in an increase in liver TRIG content, AT weight, AT LPL activity, and plasma insulin. All these effects of OVX were abolished by ADX and restored by the high dose of CORT. Plasma TRIG were unaffected by OV status but were highly responsive to CORT status. All treatment effects were highly correlated with cumulative food intake. This study shows that the presence of CORT is required for OVX to exert its action on global energy balance and the concomitant, closely integrated adaptations of lipid metabolism.
Inhibition of cholesterogenesis decreases hepatic secretion of apoB-100 in normolipidemic subjects.
Authors: Watts G F , Naoumova R P , Kelly J M , Riches F M , Croft K D , Thompson G R
Published: December 2017

We examined the effect of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the kinetics of very low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in 13 normolipidemic men in a placebo-controlled crossover study. Simvastatin significantly decreased the plasma concentrations of low-density lipoprotein (LDL) cholesterol by 36%, triglycerides by 26%, mevalonic acid by 34%, and lathosterol by 32%. Hepatic secretion of VLDL apoB was measured using a primed constant intravenous infusion of [1-13C]leucine with monitoring of isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional turnover rate was derived using a monoexponential function. Simvastatin decreased VLDL apoB pool size by 53% and the hepatic secretion rate of VLDL apoB by 46% but did not significantly alter its fractional catabolism. The change in hepatic VLDL apoB secretion was significantly and independently correlated with changes in plasma mevalonic acid and lathosterol concentrations and the lathosterol-to-cholesterol ratio. The data support the hypothesis that the rate of de novo cholesterol synthesis directly regulates the hepatic secretion of VLDL apoB in normal subjects.
Differential regulation of glycogen synthase by insulin and glucose in vivo in skeletal muscles of the rat.
Authors: Sugden M C , Holness M J , Fryer L G
Published: December 2017

Glucose 6-phosphate (G-6-P)-independent glycogen synthase (GSa) and glycogen synthase (GS) total activities were measured in muscles from 24-h-starved rats. Intravenous glucose tolerance tests (0.5 g/kg body wt) were used to produce physiological, transient increases in insulin and glucose concentrations. GS activation occurred at approximately 10 min after glucose administration with peak activation at approximately 15 min. GS activation was reversed approximately 15 min after insulin and glucose concentrations had returned to basal. No differences existed between fast- and slow-twitch muscles. Hyperinsulinemia (approximately 160 mU/ml) in the absence of hyperglycemia elicited 1.5-fold activation of GS (P < 0.001) in two of three fast-twitch muscles but did not activate GS in slow-twitch muscles. Glucose infusion (glycemia approximately 8 mM; insulin approximately 40 mU/ml) significantly (P < 0.01) increased the percentage of total GS in the GSa form in four of the five muscles. Hyperglycemia with modest hyperinsulinemia evoked greater enhancement of GSa activity in fast-twitch muscle than insulin alone at a higher concentration (P < 0.01). In summary, hyperinsulinemia without hyperglycemia does not result in maximal activation of GS in fast-twitch muscle, and a rise in glycemia is obligatory for GS activation by insulin in slow-twitch muscle. The data support an important role for glycemia in modulating the response of skeletal muscle GS to insulin and provide further evidence of heterogeneity among skeletal muscle types.
Absolute concentrations of glycerol and lactate in human skeletal muscle, adipose tissue, and blood.
Authors: Hagström-Toft E , Enoksson S , Moberg E , Bolinder J , Arner P
Published: December 2017

The absolute concentrations of glycerol and lactate were studied with microdialysis of adipose tissue and skeletal muscle in normal-weight subjects. The basal interstitial glycerol concentration was 232 +/- 33, 96 +/- 8, and 59 +/- 6 mumol/l in fat, muscle, and arterialized plasma, respectively (P = 0.0002). This relationship was maintained during both euglycemic hyperinsulinemia, when glycerol decreased in all three compartments, and hypoglycemia, when glycerol first decreased and then increased in fat, muscle, and blood (P = 0.0001 for both). Basal interstitial lactate concentrations were similar in adipose tissue (1.1 +/- 0.2 mmol/l) and skeletal muscle (1.9 +/- 0.4 mmol/l) and higher than in arterialized blood (0.6 +/- 0.1 mmol/l, P = 0.002). During hyperinsulinemia and hypoglycemia, lactate increased (P = 0.0001) and the tissue-blood relationship was maintained (P = 0.04). In conclusion, adipose tissue and skeletal muscle mobilize glycerol and lactate at rest. Glycerol and lactate production are influenced by hyperinsulinemia and hypoglycemia in both tissues. Adipose tissue appears to be the major site of glycerol production, whereas skeletal muscle and fat may be equally important for lactate production.
Dopamine requires ascorbic acid to be the prolactin release-inhibiting factor.
Authors: Shin S H , Si F , Chang A , Ross G M
Published: December 2017

A high concentration of dopamine (10(-6) mol/l) inhibited prolactin release for < 60 min during a 2-h perifusion period by use of primary cultured pituitary cells. However, when dopamine (10(-6) mol/l) and control medium were alternately perifused, dopamine inhibited prolactin release for a longer period, indicating that the inability of dopamine to sustain an inhibitory action is likely caused by decreased sensitivity of the lactotrophs to dopamine. When 3 x 10(-7) mol/l dopamine was perifused, prolactin release was inhibited for only 15 min, and the rate of prolactin release was decreased to a nadir by addition of ascorbic acid (10(-4) mol/l) 15 min after the start of dopamine perifusion. Dopamine decreased density of dopamine D2 receptors, and ascorbic acid inhibited the receptor downregulation in GH4ZR7 cells. These results support our hypothesis that dopamine requires a supplementary agent to be the prolactin release-inhibiting factor and that the supplementary agent is ascorbic acid.
Plasma leptin responses to fasting in Pima Indians.
Authors: Pratley R E , Nicolson M , Bogardus C , Ravussin E
Published: December 2017

Leptin is believed to play a role in the regulation of energy balance, but little is known about factors influencing plasma leptin concentrations. To determine the effect of short-term changes in energy balance, we measured plasma leptin concentrations as well as plasma glucose, insulin, triglyceride, nonesterified fatty acid concentrations, and metabolic rate in response to a standard test meal followed by a 24-h fast in 21 healthy Pima Indians. Plasma leptin concentrations decreased by 8% (P < 0.05) 2-4 h after the test meal. They returned to baseline 6-12 h after the subjects ate, then subsequently decreased, and, by the end of the fast, were an average of 37% below baseline (P < 0.0001). Changes in plasma leptin concentrations did not correlate with changes in plasma glucose, insulin, triglyceride, or nonesterified fatty acid concentrations or with changes in metabolic rate. The results of this study indicate that plasma leptin concentrations decrease in response to short-term energy restriction. These changes were not due to changes in glucose, insulin, triglycerides, or nonesterified fatty acids, nor did they relate to changes in metabolic rate. The decrease in plasma leptin concentrations with fasting may be an important homeostatic response to an energy deficit, stimulating food intake and thus restoring energy balance.
Electrical stimulation induces fiber type-specific translocation of GLUT-4 to T tubules in skeletal muscle
Authors: Roy Denis , Jóhannsson Erlingur , Bonen Arend , Marette André
Published: December 2017

Insulin and contraction independently stimulate glucose transport in skeletal muscle. Whereas insulin activates glucose transport more in muscles composed of type I and IIa fibers, electrical stimulation increases glucose transport at least as much in type IIb fiber-enriched muscles despite the fact that the latter fiber type contains less GLUT-4 glucose transporters. The aim of the present study was to test the hypothesis that a greater GLUT-4 translocation to the cell surface may underlie the higher contraction-stimulated glucose transport in type IIb myofibers. Leg muscles from rats were stimulated in situ at 100 Hz (200 ms) each 2 s via the sciatic nerve over a period of 20 min while the contralateral leg was kept at rest. Muscle 2-[3H]deoxy-d-glucose uptake (2-DG) was measured in separated red gastrocnemius (RG, type I and IIa fibers) and white gastrocnemius (WG, type IIb fibers) muscles. Resting 2-DG uptake was greater in RG than WG. Electrical stimulation increased 2-DG uptake over resting values similarly in WG and RG. Fractions enriched with either plasma membranes, transverse (T) tubules, triads, or GLUT-4-enriched intracellular membranes were isolated from RG and WG using a recently developed subcellular fractionation procedure. Electrical stimulation similarly increased GLUT-4 protein content in plasma membranes of RG and WG, whereas it stimulated GLUT-4 translocation more (∼50%) in T tubules of WG than in RG. GLUT-4 content was not changed in triads of both muscle types. The increments in cell surface GLUT-4 protein levels were paralleled by significant reductions in the amount of the transporter in the intracellular membrane fractions of both muscle types (by 60% in RG and 56% in WG). It is concluded that electrically induced contraction stimulates GLUT-4 translocation more in T tubules of WG than RG. The physiological implications of this finding for glucose uptake by contracting RG and WG muscles is discussed.
Impaired adaptation of first-phase insulin secretion in postmenopausal women with glucose intolerance
Authors: Ahrén Bo , Pacini Giovanni
Published: December 2017

This study examined whether insulin secretion, insulin sensitivity, glucose effectiveness, and hepatic extraction of insulin are altered in subjects with impaired glucose tolerance (IGT). The frequently sampled intravenous glucose tolerance test was performed in postmenopausal women (age 63 yr, body mass index range 21.6–28.9 kg/m2) with IGT ( n = 10) or normal glucose tolerance (NGT; n = 10). Insulin sensitivity (SI) was significantly lower in IGT than in NGT ( P = 0.030). In contrast, insulin secretion was not significantly different between the two groups as determined by area under the curve for insulin and C-peptide, acute insulin response to glucose (AIRG), and glucose sensitivity of first-phase (φ1) or of second-phase (φ2) insulin secretion. In NGT ( r = −0.68, P = 0.029) but not in IGT ( r = −0.05, not significant), SIcorrelated negatively with φ1. The B-cell “adaptation index” (SI× φ1) was lower in IGT than in NGT [83 ± 25 vs. 171 ± 29 min−2/(mmol/l), P = 0.042]. Also, the B-cell “disposition index” (SItimes AIRG) was lower in IGT (83 ± 25 10−4min−1) than in NGT (196 ± 30 10−4min−1, P = 0.011). In contrast, glucose effectiveness or hepatic extraction of insulin was not different between IGT and NGT. We conclude that postmenopausal women with IGT fail to adequately adapt to lowered SIby increasing first-phase insulin secretion.
Effects of exercise in diabetic rats before and during gestation on maternal and neonatal outcomes
Authors: Vanheest Jaci L. , Rodgers Carol D.
Published: December 2017

This study was designed to evaluate the effects of chronic endurance training on glucose and lipid homeostasis in diabetic mothers and their offspring. Female Sprague-Dawley rats were rendered diabetic (>20 mmol/l glucose) by streptozotocin and subdivided into three treatments ( n = 10/group): exercise (20 m/min; 0% grade; 1 h/day; 5 days/wk) before and during gestation (EE), exercise before gestation with cessation on conception (ES), and sedentary before and during gestation (SS). Response of dams to a preconception and third trimester glucose tolerance test, litter number (EE = ES = SS = 3), and average litter size (EE = 9.7 ± 1.5; ES = 9.0 ± 1.5; SS = 8.3 ± 0.3) did not differ among groups. Number of offspring remaining viable was significantly different among groups (EE = 17; ES = 0; SS = 14). Response to a glucose challenge and fasting glucose and insulin were different between the EE and SS pups. Exercise before and during gestation did not reduce the viability of offspring. Cessation of exercise during early pregnancy negatively affected offspring viability.
Intestinal growth is associated with elevated levels of glucagon-like peptide 2 in diabetic rats
Authors: Fischer Kirk D. , Dhanvantari Savita , Drucker Daniel J. , Brubaker Patricia L.
Published: December 2017

Glucagon-like peptide 2 (GLP-2) has recently been identified as a novel intestinal growth factor. Because experimental diabetes is associated with bowel growth, we examined the relationship between GLP-2 and intestinal growth in rats made diabetic by streptozotocin (STZ) injection and treated with or without insulin for 3 wk. Ileal concentrations of the intestinal proglucagon-derived peptides, i.e., glicentin + oxyntomodulin, and GLPs 1 and 2, were increased by 57 ± 20% above those of controls in untreated STZ diabetes ( P < 0.05–0.001). Similar increases in plasma concentrations of glicentin + oxyntomodulin (77 ± 15% above controls, P < 0.01) and GLP-2 (91 ± 32% above controls, P < 0.05) were seen in untreated STZ diabetes. Both wet and dry small intestinal weight increased by 74 ± 20% above controls ( P < 0.01) in STZ diabetes, and macromolecular analysis indicated parallel increases in both protein ( P < 0.001) and lipid ( P < 0.05) content. Villus height ( P < 0.001) and crypt depth ( P < 0.01) were also increased in untreated diabetic rat intestine. Insulin therapy prevented the changes in plasma GLP-2 and intestinal mass seen in untreated STZ diabetes. Thus STZ diabetes is associated with both increased production of GLP-2 and enhanced bowel weight, thereby suggesting a role for GLP-2 in diabetes-associated bowel growth.
A kinetic mass balance model for 1,5-anhydroglucitol: applications to monitoring of glycemic control
Authors: Stickle Douglas , Turk John
Published: December 2017

The polyol 1,5-anhydroglucitol (AG) present in human plasma is derived largely from ingestion and is excreted unmetabolized. Reduction of plasma [AG] has been noted in diabetics and is due to accelerated excretion of AG during hyperglycemia. Plasma [AG] has therefore been proposed as a marker for glycemic control. A precise understanding of its utility relies on a quantitative understanding of the mass balance for AG. In this study, non-steady-state data from the literature were analyzed to develop a dynamic mass balance model for AG that is based on the two-compartment model proposed by Yamanouchi et al. [T. Yamanouchi, Y. Tachibana, H. Akanuma, S. Minoda, T. Shinohara, H. Moromizato, H. Miyashita, and I. Akaoka. Am. J. Physiol. 263 ( Endocrinol. Metab. 26): E268—E273, 1992]. The data are consistent with a model in which exchange between tissue and plasma pools is rapid and in which the tissue compartment mass is two to three times the mass of the plasma compartment. According to model estimates, accelerated excretion of AG due to hyperglycemia can cause marked net depletion of total AG over a time scale of days. Recovery from a depleted state is slow because the total body capacity represents >5 wk of normal intake. Accordingly, AG monitoring should be able to indicate the presence of past glucosuric hyperglycemic episodes during a period of days to weeks, as well as provide information on the extent to which high deviations from the average plasma glucose concentration are operative.