AJP - Endocrinology and Metabolism

Nichols, C. G.; Koster, J. C.

doi: 10.1152/ajpendo.00168.2002pmid: 12169432

Abstract The critical involvement of ATP-sensitive potassium (K ATP ) channels in insulin secretion is confirmed both by the demonstration that mutations that reduce K ATP channel activity underlie many if not most cases of persistent hyperinsulinemia, and by the ability of sulfonylureas, which inhibit K ATP channels, to enhance insulin secretion in type II diabetics. By extrapolation, we contend that mutations that increase β-cell K ATP channel activity should inhibit glucose-dependent insulin secretion and underlie, or at least predispose to, a diabetic phenotype. In transgenic animal models, this prediction seems to be borne out. Although earlier genetic studies failed to demonstrate a linkage between K ATP mutations and diabetes in humans, recent studies indicate significant association of K ATP channel gene mutations or polymorphisms and type II diabetes. We suggest that further efforts to understand the involvement of K ATP channels in diabetes are warranted. ATP-sensitive potassium channels pancreas Kir6.2 SUR1 Footnotes Address for reprint requests and other correspondence: C. G. Nichols, Dept. of Cell Biology and Physiology, Washington Univ. School of Medicine, St. Louis, MO 63110 (E-mail: [email protected] ). 10.1152/ajpendo.00168.2002 Copyright © 2002 the American Physiological Society

Schoelch, Corinna; Hübschle, Thomas; Schmidt, Ingrid; Nuesslein-Hildesheim, Barbara

doi: 10.1152/ajpendo.00439.2001pmid: 12169455

Abstract Suckling-age rats display endogenous circadian rhythmicity of metabolic rate (MR) with energy-saving, torpor-like decreases, which are sympathetically controlled and suppressed by leptin treatment. We investigated whether neonatal monosodium glutamate (MSG) treatment, known to cause arcuate nucleus damage and adult-age obesity, alters energy balance in the first two postnatal weeks. Continuously recorded MR and core temperatures (T c ) show that MSG treatment disinhibits the periodic, sympathetically controlled, energy-saving drops of T c and MR. Increased energy expenditure thus explains reduced body fat at normal lean body mass found in MSG-treated pups artificially nourished identically to controls. In MSG-treated mother-reared pups, lean body mass is additionally reduced, suggesting that MSG also reduces suckling. Plasma leptin levels are similar in controls and MSG-treated pups but higher per unit of fat mass in the latter. We conclude that the postweaning development of MSG obesity and depressed thermogenesis are preceded by an early phase of increased energy expenditure with decreased fat deposition during suckling age and hypothesize cell damage in the arcuate nucleus to be involved in both. monosodium glutamate juvenile rat arcuate nucleus obesity leptin torpor Footnotes This work was supported by the Deutsche Forschungsgemeinschaft (Schm 680/2). Present addresses: C. Schoelch, Aventis Pharma Deutschland GmbH, DG Metabolic Diseases, D-65926 Frankfurt, Germany; T. Hübschle, Veterinärphysiologie der Justus-Liebig-Universität Giessen, Frankfurter-Str. 100, D-35392 Giessen, Germany; B. Nuesslein-Hildesheim, Novartis Pharma AG, Metabolic and Cardiovascular Diseases, CH-4002 Basel, Switzerland. Address for reprint requests and other correspondence: I. Schmidt, Max-Planck-Institut für Physiologische und Klinische Forschung, W. G. Kerckhoff-Institut, Parkstr. 1, D-61231 Bad Nauheim, Germany (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. April 23, 2002;10.1152/ajpendo.00439.2001 Copyright © 2002 the American Physiological Society

Angus, Damien J.; Febbraio, Mark A.; Hargreaves, Mark

doi: 10.1152/ajpendo.00443.2001pmid: 12169451

Abstract Nine endurance-trained men exercised on a cycle ergometer at ∼68% peak O 2 uptake to the point of volitional fatigue 232 ± 14 (SE) min while ingesting an 8% carbohydrate solution to determine how high glucose disposal could increase under physiological conditions. Plasma glucose kinetics were measured using a primed, continuous infusion of 6,6- 2 Hglucose and the appearance of ingested glucose, assessed from 3- 3 Hglucose that had been added to the carbohydrate drink. Plasma glucose was increased ( P < 0.05) after 30 min of exercise but thereafter remained at the preexercise level. Glucose appearance rate (R a ) increased throughout exercise, reaching its peak value of 118 ± 7 μmol · kg −1 · min −1 at fatigue, whereas gut R a increased continuously during exercise, peaking at 105 ± 10 μmol · kg −1 · min −1 at the point of fatigue. In contrast, liver glucose output never rose above resting levels at any time during exercise. Glucose disposal (R d ) increased throughout exercise, reaching a peak value of 118 ± 7 μmol · kg −1 · min −1 at fatigue. If we assume 95% oxidation of glucose R d , estimated exogenous glucose oxidation at fatigue was 1.36 ± 0.08 g/min. The results of this study demonstrate that glucose uptake increases continuously during prolonged, strenuous exercise when carbohydrate is ingested and does not appear to limit exercise performance. glucose uptake glucose production glycogenolysis Footnotes This study was supported by the National Health and Medical Research Council of Australia. Address for correspondence: M. Hargreaves, School of Health Sciences, Deakin Univ., Burwood, Victoria 3125, Australia (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. May 15, 2002;10.1152/ajpendo.00443.2001 Copyright © 2002 the American Physiological Society

Yuan, Pu-Qing; Yang, Hong

doi: 10.1152/ajpendo.00538.2001pmid: 12169436

Abstract Neuronal activation of brain vagal-regulatory nuclei and gastric/duodenal enteric plexuses in response to insulin (2 U/kg, 2 h) hypoglycemia was studied in rats. Insulin hypoglycemia significantly induced Fos expression in the paraventricular nucleus of the hypothalamus, locus coeruleus, dorsal motor nucleus of the vagus (DMN), and nucleus tractus solitarii (NTS), as well as in the gastric/duodenal myenteric/submucosal plexuses. A substantial number of insulin hypoglycemia-activated DMN and NTS neurons were choline acetyltransferase and tyrosine hydroxylase positive, respectively, whereas the activated enteric neurons included NADPH- and vasoactive intestinal peptide neurons. The numbers of Fos-positive cells in each above-named brain nucleus or in the gastric/duodenal myenteric plexus of insulin-treated rats were negatively correlated with serum glucose levels and significantly increased when glucose levels were lower than 80 mg/dl. Acute bilateral cervical vagotomy did not influence insulin hypoglycemia-induced Fos induction in the brain vagal-regulatory nuclei but completely and partially prevented this response in the gastric and duodenal enteric plexuses, respectively. These results revealed that brain-gut neurons regulating vagal outflow to the stomach/duodenum are sensitively responsive to insulin hypoglycemia. dorsal motor nucleus of the vagus nucleus tractus solitarii glucose vagus stomach Footnotes This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-50255 (H. Yang), and DK-41301 (CURE Animal Core). Address for reprint requests and other correspondence: H. Yang, CURE:DDRC, VA Greater Los Angeles Healthcare System, Bldg. 115, Rm. 203, 11301, Wilshire Blvd, Los Angeles, CA 90073 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajpendo.00538.2001 Copyright © 2002 the American Physiological Society

Yu, Shunjiang; Zheng, Lei; Asa, Sylvia L.; Ezzat, Shereen

doi: 10.1152/ajpendo.00166.2002pmid: 12169442

Abstract Fibroblast growth factor receptors (FGFRs) have been implicated in a multitude of activities. Signaling of the 23 members of the FGF family is mediated through FGFR1–4. We show that FGF-19, which selectively binds FGFR4, can induce prolactin (PRL) but not growth hormone expression. FGF-19 also stimulated MAPK activation, an effect that was abrogated by a soluble dominant negative (dn) form of FGFR4. The response of the pituitary PRL promoter to FGF maps to an Ets-Pit1 binding site. We have previously shown that the hematopoietic zinc finger-containing transcription factor Ikaros (Ik) regulates FGFR4 as part of an overlapping site with that for an Ets-type factor in the FGFR4 promoter. Thus, we examined whether FGF-19 might regulate its own receptor through the Ets-Ik element in the FGFR4 promoter. Ets stimulated and dn-Ets inhibited basal FGFR4 and PRL promoter activity. In contrast, Ets enhanced FGF-19-induced PRL activation but failed to confer an effect for FGF-19 on the FGFR4 promoter. We conclude that FGFR4 mediates FGF-19 signaling to the PRL promoter. Our data also suggest a possible functional role for Ik in sorting Ets signals to the FGFR4 promoter, as distinct from the PRL promoter, where Ets partners with Pit1. fibroblast growth factor receptor 4 fibroblast growth factor-19 pituitary Ikaros Ets1 Footnotes Address for reprint requests and other correspondence: S. L. Asa, Univ. Health Network, 610 Univ. Ave. 4–302, Toronto, Ontario, Canada M5G 2M9 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. May 7, 2002;10.1152/ajpendo.00166.2002 Copyright © 2002 the American Physiological Society

Hall, Jennifer L.; Gibbons, Gary H.; Chatham, John C.

doi: 10.1152/ajpendo.00072.2002pmid: 12169439

Abstract 13 C-nuclear magnetic resonance (NMR) spectroscopy was used to test our hypothesis that insulin-like growth factor I (IGF-I) stimulates glucose flux into both nonoxidative and oxidative pathways in vascular smooth muscle cells (VSMC). Rat VSMC were exposed to uniformly labeled 13 Cglucose (U- 13 Cglucose; 5.5 mM) and 3- 13 Cpyruvate (1 mM) in the presence and absence of IGF-I (100 ng/ml). IGF-I increased glucose flux through glycolysis and the tricarboxylic acid (TCA) cycle as well as total anaplerotic flux into the TCA cycle. Previous work in our laboratory identified an increase in GLUT1 content and glucose metabolism in neointimal VSMC that was sufficient to promote proliferation and inhibit apoptosis. To test whether IGF-I could potentiate the GLUT1-induced increased flux in the neointima, we utilized VSMC harboring constitutive overexpression of GLUT1. Indeed, IGF-I markedly potentiated the GLUT1-induced increase in glucose flux through glycolysis and the TCA cycle. Taken together, these findings demonstrate that upregulation of glucose transport through either IGF-I or increased GLUT1 content stimulates glucose flux through both nonoxidative and oxidative pathways in VSMC. glucose transporter-1 glucose vascular smooth muscle insulin-like growth factor I anaplerosis Footnotes This study was supported by a National Institutes of Health (NIH) Center of Excellence Award (G. H. Gibbons, Morehouse School of Medicine), American Heart Association Grants 0030136N (J. Hall) and 0050545N (J. C. Chatham), and National Heart Lung and Blood Institute Grants HL-48789 and HL-67464 (J. C. Chatham). Address for reprint requests and other correspondence: J. L. Hall, Division of Cardiology, Dept. of Medicine, MMC 508, 420 Delaware St. SE, Minneapolis, MN 55455 (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. April 30, 2002;10.1152/ajpendo.00072.2002 Copyright © 2002 the American Physiological Society

Bouthegourd, Jean-Christophe J.; Roseau, Suzanne M.; Makarios-Lahham, Lina; Leruyet, Pascale M.; Tomé, Daniel G.; Even, Patrick C.

doi: 10.1152/ajpendo.00132.2002pmid: 12169450

Abstract The composition of the preexercise food intake is known to affect substrate utilization during exercise and thus can affect long-term changes in body weight and composition. These parameters were measured in male rats exercised 2 h daily over 5 wk, either in the fasting state or 1 h after they ingested a meal enriched with glucose (Glc), whole milk protein (WMP), or α-lactalbumin-enriched whey protein (CPαL). Compared with fasting, the Glc meal increased glucose oxidation and decreased lipid oxidation during and after exercise. In contrast, the WMP and CPαL meals preserved lipid oxidation and increased protein oxidation, the CPαL meal increasing protein oxidation more than the WMP meal. At the end of the study, body weight was larger in the WMP-, Glc-, and CPαL-fed rats than in the fasted ones. This resulted from an increased fat mass in the WMP and Glc rats and to an increased lean body mass, particularly muscles, in the CPαL rats. We conclude that the potential of the CPαL meal to preserve lipid oxidation and to rapidly deliver amino acids for use during exercise improved the efficiency of exercise training to decrease adiposity. indirect calorimetry glucose lactate glycerol free fatty acids Footnotes Address for reprint requests and other correspondence: P. C. Even, UMR INRA/INA P-G, Physiologie de la Nutrition et du Comportement Alimentaire, Institut National de la Recherche Agronomique, 16 rue Claude Bernard, 75005 Paris, France (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. May 15, 2002;10.1152/ajpendo.00132.2002 Copyright © 2002 the American Physiological Society

Perseghin, Gianluca; Scifo, Paola; Danna, Massimo; Battezzati, Alberto; Benedini, Stefano; Meneghini, Elena; Del Maschio, Alessandro; Luzi, Livio

doi: 10.1152/ajpendo.00127.2002pmid: 12169449

Abstract Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% ( n = 7) or >30% ( n = 7) and 14 young, nonobese men with body fat <25% ( n = 7) or >25% ( n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized 1 H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal ( P = 0.80), IMCL content in both soleus ( P = 0.22) and tibialis anterior ( P = 0.75) muscles, and plasma free fatty acid levels ( P = 0.075) compared with leaner subjects in association with increased lipid oxidation ( P < 0.05), resting energy expenditure ( P = 0.046), resting oxygen consumption ( P = 0.049), and plasma leptin levels ( P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain. intramyocellular lipid content lipid oxidation insulin resistance leptin tumor necrosis factor-α nuclear magnetic resonance spectroscopy Footnotes This work was supported by grants from the Italian Ministry of Health (030.5/RF96.305 and 030.5/RF98.49) and the Italian National Research Council (CNR 97.00485.CT04). The financial support of Telethon, Italy (1032C), is also gratefully acknowledged. Address for reprint requests and other correspondence: G. Perseghin, Nutrition/Metabolism, Laboratory of Amino Acids and Stable Isotopes/Unit of Clinical Spectroscopy, via Olgettina 60, 20132 Milan, Italy (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 10.1152/ajpendo.00127.2002 Copyright © 2002 the American Physiological Society

Luiken, Joost J. F. P.; Arumugam, Yoga; Bell, Rhonda C.; Calles-Escandon, Jorge; Tandon, Narendra N.; Glatz, Jan F. C.; Bonen, Arend

doi: 10.1152/ajpendo.00011.2002pmid: 12169456

Abstract We have examined the effects of streptozotocin (STZ)-induced diabetes (moderate and severe) on fatty acid transport and fatty acid transporter (FAT/CD36) and plasma membrane-bound fatty acid binding protein (FABPpm) expression, at the mRNA and protein level, as well as their plasmalemmal localization. These studies have shown that, with STZ-induced diabetes, 1 ) fatty acid transport across the plasma membrane is increased in heart, skeletal muscle, and adipose tissue and is reduced in liver; 2 ) changes in fatty acid transport are generally not associated with changes in fatty acid transporter mRNAs, except in the heart; 3 ) increases in fatty acid transport in heart and skeletal muscle occurred with concomitant increases in plasma membrane FAT/CD36, whereas in contrast, the increase and decrease in fatty acid transport in adipose tissue and liver, respectively, were accompanied by concomitant increments and reductions in plasma membrane FABPpm; and finally, 4 ) the increases in plasma membrane transporters (FAT/CD36 in heart and skeletal muscle; FABPpm in adipose tissue) were attributable to their increased expression, whereas in liver, the reduced plasma membrane FABPpm appeared to be due to its relocation within the cell in the face of slightly increased expression. Taken together, STZ-induced changes in fatty acid uptake demonstrate a complex and tissue-specific pattern, involving different fatty acid transporters in different tissues, in combination with different underlying mechanisms to alter their surface abundance. fatty acid transporter CD6 plasma membrane-bound fatty acid binding protein muscle heart liver adipose tissue Footnotes We thank Dr. N. A. Abumrad (SUNY, Stony Brook, NY) for providing FAT/CD36 cDNA, and Dr. A. Iriarte (University of Missouri, MO) for providing mAspAT/FABPpm cDNA. These studies were supported by grants from the Canadian Institutes of Health Research (A. Bonen), the Heart and Stroke Foundation of Ontario (A. Bonen), the Netherlands Heart Foundation (D98.012; J. J. F. P. Luiken and J. F. C. Glatz), and the Natural Sciences and Engineering Research Council of Canada (R. C. Bell). J. J. F. P. Luiken is a Dekker postdoctoral fellow of the Netherlands Heart Foundation. Address for reprint requests and other correspondence: A. Bonen, Dept. of Kinesiology, Univ. of Waterloo, Waterloo, Ontario N2L 3G1, Canada (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. May 28, 2002;10.1152/ajpendo.00011.2002 Copyright © 2002 the American Physiological Society

Watt, Matthew J.; Hargreaves, Mark

doi: 10.1152/ajpendo.00098.2002pmid: 12169452

Abstract This study examined the effect of epinephrine on glucose disposal during moderate exercise when glycogenolytic flux was limited by low preexercise skeletal muscle glycogen availability. Six male subjects cycled for 40 min at 59 ± 1% peak pulmonary O 2 uptake on two occasions, either without (CON) or with (EPI) epinephrine infusion starting after 20 min of exercise. On the day before each experimental trial, subjects completed fatiguing exercise and then maintained a low carbohydrate diet to lower muscle glycogen. Muscle samples were obtained after 20 and 40 min of exercise, and glucose kinetics were measured using 6,6- 2 Hglucose. Exercise increased plasma epinephrine above resting concentrations in both trials, and plasma epinephrine was higher ( P < 0.05) during the final 20 min in EPI compared with CON. Muscle glycogen levels were low after 20 min of exercise (CON, 117 ± 25; EPI, 122 ± 20 mmol/kg dry matter), and net muscle glycogen breakdown and muscle glucose 6-phosphate levels during the subsequent 20 min of exercise were unaffected by epinephrine infusion. Plasma glucose increased with epinephrine infusion (i.e., 20–40 min), and this was due to a decrease in glucose disposal (R d ) (40 min: CON, 33.8 ± 3; EPI, 20.9 ± 4.9 μmol · kg −1 · min −1 , P < 0.05), because the exercise-induced rise in glucose rate of appearance was similar in the trials. These results show that glucose R d during exercise is reduced by elevated plasma epinephrine, even when muscle glycogen availability and utilization are low. This suggests that the effect of epinephrine does not appear to be mediated by increased glucose 6-phosphate, secondary to enhanced muscle glycogenolysis, but may be linked to a direct effect of epinephrine on sarcolemmal glucose transport. glucose transport exercise Footnotes This study was supported by the Australian Research Council. Address for correspondence: M. Hargreaves, School of Health Sciences, Deakin Univ., Burwood, Victoria 3125, Australia (E-mail: [email protected] ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. May 21, 2002;10.1152/ajpendo.00098.2002 Copyright © 2002 the American Physiological Society