DOCSLIB.ORG

In Situ Glucose Uptake and Glucokinase Activity of Pancreatic Islets in Diabetic and Obese Rodents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
In Situ Glucose Uptake and Glucokinase Activity of Pancreatic Islets in Diabetic and Obese Rodents In situ glucose uptake and glucokinase activity of pancreatic islets in diabetic and obese rodents. Y Liang, … , S Efrat, F M Matschinsky J Clin Invest. 1994;93(6):2473-2481. https://doi.org/10.1172/JCI117256. Research Article The present study evaluated the involvement of glucose transport and phosphorylation in glucose-stimulated insulin release from pancreatic islets. Using quantitative histochemical techniques, we investigated basal islet glucose content, islet glucose uptake in situ during acute extreme experimental hyperglycemia, and islet glucokinase activity in several animal models of diabetes and obesity. The basal islet glucose content in anaesthetized diabetic or obese rodents was either the same or higher than that in their relevant controls. The rate of glucose uptake of islet tissue in these animals after an i.v. glucose injection was different. The db+/db+ mouse and the obese Zucker rat exhibited significantly reduced islet glucose uptake rates. RIP-cHras transgenic mice, BHE/cdb rats and partially pancreatectomized rats showed normal islet glucose uptake rates. The activity of islet glucokinase was increased to a different degree related to the blood glucose level. All five animal models of diabetes or obesity exhibited either a delay or a reduction of insulin release in response to supra maximal glucose stimulation. Our results indicate that the impairment of glucose-induced insulin release in diabetes is not consistently associated with a reduction of islet glucose uptake nor a change of glucokinase activity. Find the latest version: https://jci.me/117256/pdf In Situ Glucose Uptake and Glucokinase Activity of Pancreatic Islets in Diabetic and Obese Rodents Yin Liang,* Susan Bonner-Weir,* Ying-Jian Wu,* Carolyn D. Berdanier,' Donna K. Berner,11 Shimon Efrat,' and Franz M. Matschinsky*11 *Department of Biochemistry and Biophysics and IlDiabetes Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104; tJoslin Diabetes Center, Boston, Massachusetts 02215; IDepartment ofFood and Nutrition, University of Georgia, Athens, Georgia 30602; and 'Department ofMolecular Pharmacology, Albert Einstein College ofMedicine, Bronx, New York 10461 Abstract kinase. GLUT2 is part of the ,3 cell plasma membrane ( 1, 2) and transports glucose into : cells in a facilitative manner with The present study evaluated the involvement of glucose trans- a Km of 15-20 mM (3, 4). Evidence favoring a role of GLUT2 port and phosphorylation in glucose-stimulated insulin release in glucose sensing is substantial: (a) In the obese, diabetic from pancreatic islets. Using quantitative histochemical tech- Zucker rat, GLUT2 expression is reduced at the mRNA and niques, we investigated basal islet glucose content, islet glucose protein levels. The function of GLUT2 in islets is impaired. uptake in situ during acute extreme experimental hyperglyce- These defects correlate with insufficient insulin secretion in mia, and islet glucokinase activity in several animal models of response to glucose (5). (b) An IgG preparation from patients diabetes and obesity. The basal islet glucose content in an- with newly diagnosed insulin-dependent diabetes mellitus re- aesthetized diabetic or obese rodents was either the same or duced the glucose uptake and decreased glucose-induced insu- higher than that in their relevant controls. The rate of glucose lin release of normal rat islets (6, 7). GLUT2 has therefore uptake of islet tissue in these animals after an i.v. glucose injec- been suggested as an essential element of the glucose sensor, tion was different. The db+/db+ mouse and the obese Zucker and it has been proposed that a defect of GLUT-2 may play a rat exhibited significantly reduced islet glucose uptake rates. crucial role in the pathogenesis of both insulin-dependent dia- RIP-cHras transgenic mice, BHE/cdb rats and partially pan- betes mellitus and non-insulin-dependent diabetes mellitus createctomized rats showed normal islet glucose uptake rates. (8). Glucokinase, on the other hand, is the pacemaker of the The activity of islet glucokinase was increased to a different glucose metabolism in islets (9, 10). The expression of gluco- degree related to the blood glucose level. All five animal models kinase in the islet is controlled by a (3 cell specific promoter of diabetes or obesity exhibited either a delay or a reduction of ( 11), and its enzymatic activity is regulated by the blood glu- insulin release in response to supra maximal glucose stimula- cose ( 12, 13). Recently > 20 mutations ofthe glucokinase gene tion. Our results indicate that the impairment of glucose-in- have been found in patients of mature onset diabetes of the duced insulin release in diabetes is not consistently associated young, who have impaired insulin secretion in response to glu- with a reduction of islet glucose uptake nor a change of gluco- cose ( 14). Kinetic studies of recombinant mutant human glu- kinase activity. (J. Clin. Invest. 1994. 93:2473-2481.) Key cokinase indicated a reduction of enzyme activity and an in- words: diabetic animal - glucokinase * GLUT2 * insulin release- crease of the glucose Km in many of the affected individuals pancreatic islet ( 15 ). These findings demonstrate that glucokinase is a crucial determinant of glucose metabolism in pancreatic islets and Introduction support the view that this enzyme may serve as a glucose sen- Under physiological conditions, pancreatic (3 cells sense the sor (16). change of blood glucose level and adjust insulin output accord- The function of the islet glucose transporter and of gluco- ingly. The mechanism of glucose sensing by (3 cells is, however, kinase has been intensively studied using dispersed pancreatic still unclear. There are two candidates for glucose sensors in (3 cells or isolated islets. However, the procedure of islet isola- pancreatic islets: the glucose transporter (GLUT2)' and gluco- tion by collagenase digestion of the pancreas may influence islet function and could compromise the outcome ofsuch stud- Portions of this study were presented as abstract at the 53rd Annual ies, in particular the function of the glucose transporter, which Meeting of the American Diabetes Association, Las Vegas, Nevada, is located in the ( cell membrane. In addition, one is unable to 12-15 June 1993. determine in these islets the basal glucose content, which is a Address correspondence to Dr. Franz M. Matschinsky, Diabetes reflection of the glucose transporter function in situ. To evalu- Research Center, 501 Stemmler Hall, 36th & Hamilton Walk, Philadel- ate further the involvement ofglucose transport and phosphor- phia, PA 19104-6015. ylation in the glucose-sensing mechanism, it is desirable to Receivedfor publication 20 August 1993 and in revisedform 7 Jan- study basal islet glucose content, islet glucose uptake in situ uary 1994. during hyperglycemia, and to determine glucokinase activity by optimal techniques in normal and diabetic animals. 1. Abbreviations used in this paper: GLUT2, glucose transporter-2;PX, The quantitative histochemical techniques as developed by pancreatectomy; RIP-cHras, transgene composed of human [Val'2] Hras oncoprotein regulated by the rat insulin promoter. 0. H. Lowry have been used since the 1950s ( 17). These tech- niques permit the precise quantitation of enzymes, metabo- J. Clin. Invest. lites, and cofactors in microscopic structures sampled such that 3 The American Society for Clinical Investigation, Inc. the in situ condition is virtually preserved. In its current ver- 0021-9738/94/06/2473/09 $2.00 sion, which employs an oil well technique to handle volumes as Volume 93, June 1994, 2473-2481 small as 0.05 ul and the method of enzymatic cycling, femto- Islet In Situ Glucose Uptake and Glucokinase Activity in Diabetic Rodents 2473 mol amounts of metabolites and cofactors, and picogram then embedded in paraffin. Sections were immunoperoxidase stained quantities ofenzymes can be determined accurately. The appli- for the non-(B cell islet hormones to show the boundaries of the is- cation of the methodology has already benefited the study of lets (22). glucose metabolism in pancreatic islets (9, 18, 19). Preparation of islet samplefor quantitative histochemical analysis. We therefore used quantitative histochemical methods to Sections of the pancreas were cut 20 Mm thick at -20'C in a cryostat, freeze dried overnight at -350C, and then stored under vacuum at investigate these aspects of glucose metabolism in islet samples -20'C. Islets were dissected from pancreatic sections with the aid of a dissected from freeze-dried cryostat sections ofpancreas and to stereo microscope at low magnification. The weights of the specimens study glucose-induced insulin release in rodents. Both normal were obtained with the quartz fiber fishpole balance (23). and five different models of diabetes or obesity were used. Our Determination of islet insulin, glucose, and inulin contents. The results indicate that the impairment ofglucose-induced insulin islet insulin content was determined by radioimmunoassay. The glu- release in these diabetic or obese animals is not consistently cose and inulin content in the pancreatic islet tissue were measured by associated with a reduction of islet glucose uptake nor with a a fluorometric oil well method combined with enzymatic cycling of change in glucokinase activity. Defects in late steps of islet glu- NADP ( 18, 20). For islet glucose content determination, islet samples cose metabolism, metabolic coupling or insulin secretion per se were first
Load more

Recommended publications
  • Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training
    nutrients Review Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training Parker L. Evans 1,2,3, Shawna L. McMillin 1,2,3 , Luke A. Weyrauch 1,2,3 and Carol A. Witczak 1,2,3,4,* 1 Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA; [email protected] (P.L.E.); [email protected] (S.L.M.); [email protected] (L.A.W.) 2 Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA 3 East Carolina Diabetes & Obesity Institute, East Carolina University, Greenville, NC 27834, USA 4 Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA * Correspondence: [email protected]; Tel.: +1-252-744-1224 Received: 8 September 2019; Accepted: 8 October 2019; Published: 12 October 2019 Abstract: Aerobic exercise training and resistance exercise training are both well-known for their ability to improve human health; especially in individuals with type 2 diabetes. However, there are critical differences between these two main forms of exercise training and the adaptations that they induce in the body that may account for their beneficial effects. This article reviews the literature and highlights key gaps in our current understanding of the effects of aerobic and resistance exercise training on the regulation of systemic glucose homeostasis, skeletal muscle glucose transport and skeletal muscle glucose metabolism. Keywords: aerobic exercise; blood glucose; functional overload; GLUT; hexokinase; insulin resistance; resistance exercise; SGLT; type 2 diabetes; weightlifting 1. Introduction Exercise training is defined as planned bouts of physical activity which repeatedly occur over a duration of time lasting from weeks to years.
    [Show full text]
  • Alterations in Net Glucose Uptake and in the Pancreatic B-Cell GLUT2 Transporter Induced by Diazoxide and by Secretory Stimuli
    291 Alterations in net glucose uptake and in the pancreatic B-cell GLUT2 transporter induced by diazoxide and by secretory stimuli L Zhao, Z Li, M Kullin,LAHBorg1 and F A Karlsson Department of Medical Sciences, University Hospital, SE-751 85 Uppsala, Sweden 1Department of Medical Cell Biology, University of Uppsala, PO Box 571, SE-751 23 Uppsala, Sweden (Requests for offprints should be addressed to L A H Borg; Email: [email protected]) Abstract The pancreatic B-cell GLUT2 transporter and glucose which may reflect a lowered energy requirement. Con- metabolism were examined in isolated rat islets subjected versely, islets subjected to a stimulated insulin secretion to treatments affecting insulin secretion. Diazoxide was with glipizide or a high extracellular K+ concentration used to inhibit, while glipizide or depolarization of the showed a reduced staining of the GLUT2 transporter. The plasma membrane with a high extracellular K+ concen- net glucose uptake and glucose oxidation were also tration were used to stimulate insulin release in short-term reduced. In islets exposed to the high K+ concentration no experiments. Islet GLUT2 and insulin were determined change in the molecular weight or phosphorylation of by quantitative immunohistochemistry and GLUT2 was GLUT2 was observed but a lesser amount of the trans- also determined by Western blot analysis. Islet net glucose porter was found by Western blot analysis. Thus, GLUT2 uptake and glucose oxidation were measured using radio- and glucose uptake in the pancreatic B-cell are modified actively labelled glucose. Exposure of the islets to diaz- by the secretory process, which suggests that changes in oxide was associated with a marked increase in the B-cell the glucose transporter have a functional role in normal plasma membrane staining for GLUT2 and increased net B-cell physiology.
    [Show full text]
  • REVIEW the Molecular Basis of Insulin
    1 REVIEW The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets Sophie E Leney and Jeremy M Tavare´ Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK (Correspondence should be addressed to J M Tavare´; Email: [email protected]) Abstract The search for the underlying mechanism through which GLUT4 translocation and will attempt to address the spatial insulin regulates glucose uptake into peripheral tissues has relationship between the signalling and trafficking com- unveiled a highly intricate network of molecules that function ponents of this event. We will also explore the degree to in concert to elicit the redistribution or ‘translocation’ of which components of the insulin signalling and GLUT4 the glucose transporter isoform GLUT4 from intracellular trafficking machinery may serve as potential targets for membranes to the cell surface. Following recent technological the development of orally available insulin mimics for the advances within this field, this review aims to bring together treatment of diabetes mellitus. the key molecular players that are thought to be involved in Journal of Endocrinology (2009) 203, 1–18 Introduction Levine & Goldstein 1958). However, the mechanism by which insulin is able to stimulate glucose uptake was not Glucose homeostasis and diabetes mellitus elucidated until the early 1980s when two independent groups demonstrated that insulin promoted the movement of The ability of insulin to stimulate glucose uptake into muscle and adipose tissue is central to the maintenance of whole- a ‘glucose transport activity’ from an intracellular membrane body glucose homeostasis. Autoimmune destruction of the pool to the plasma membrane (Cushman & Wardzala 1980, pancreatic b-cells results in a lack of insulin production Suzuki & Kono 1980).
    [Show full text]
  • Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes
    H OH metabolites OH Review Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes Marlon E. Cerf 1,2,3 1 Grants, Innovation and Product Development, South African Medical Research Council, Tygerberg 7505, South Africa; [email protected] 2 Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa 3 Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg 7505, South Africa Received: 14 August 2020; Accepted: 10 October 2020; Published: 10 November 2020 Abstract: Beta cells adapt their function to respond to fluctuating glucose concentrations and variable insulin demand. The highly specialized beta cells have well-established endoplasmic reticulum to handle their high metabolic load for insulin biosynthesis and secretion. Beta cell endoplasmic reticulum therefore recognize and remove misfolded proteins thereby limiting their accumulation. Beta cells function optimally when they sense glucose and, in response, biosynthesize and secrete sufficient insulin. Overnutrition drives the pathogenesis of obesity and diabetes, with adverse effects on beta cells. The interleukin signaling system maintains beta cell physiology and plays a role in beta cell inflammation. In pre-diabetes and compromised metabolic states such as obesity, insulin resistance, and glucose intolerance, beta cells biosynthesize and secrete more insulin, i.e., hyperfunction. Obesity is entwined with inflammation, characterized by compensatory hyperinsulinemia, for a defined period, to normalize glycemia. However, with chronic hyperglycemia and diabetes, there is a perpetual high demand for insulin, and beta cells become exhausted resulting in insufficient insulin biosynthesis and secretion, i.e., they hypofunction in response to elevated glycemia.
    [Show full text]
  • Development of Insulin-Responsive Glucose Uptake and GLUT4 Expression in Differentiating Human Adipocyte Precursor Cells
    International Journal of Obesity (1998) 22, 448±453 ß 1998 Stockton Press All rights reserved 0307±0565/98 $12.00 http://www.stockton-press.co.uk/ijo Development of insulin-responsive glucose uptake and GLUT4 expression in differentiating human adipocyte precursor cells H Hauner, K RoÈhrig, M Spelleken, LS Liu and J Eckel Diabetes Research Institute at the Heinrich-Heine-University DuÈsseldorf, D-40225 DuÈsseldorf, Germany OBJECTIVE: In differentiating human preadipocytes glucose uptake in the presence of insulin is a prerequisite for lipid accumulation. The aim of this study was to characterize the insulin-regulated glucose transport system during and after differentiation. DESIGN AND METHODS: Human adipocyte precursor cells kept in primary culture were allowed to differentiate into fat cells under serum-free hormone-supplemented conditions. 2-Deoxy-glucose uptake was measured as a functional parameter of the glucose transport system, the amount of GLUT1 and GLUT4 protein was determined by Western blotting. RESULTS: In the undifferentiated state, cells did not increase 2-deoxy-glucose uptake in response to insulin. On day 16, when cells have acquired the adipocyte phenotype, there was a 3±4-fold stimulation of glucose transport by insulin compared to basal rates, whereas basal glucose uptake was dramatically diminished. Measurement of GLUT4 protein in cell extracts, showed a marked increase in the amount of this insulin-regulated transporter isoform during the differentiation period. On average, the amount of GLUT4 was 16.7-fold greater after than before differentiation. In contrast, the amount of GLUT1 protein decreased during differentiation to almost undetectable levels on day 16. When newly developed adipocytes were maintained in culture for another 14 d, the stimulation of glucose uptake and the amount of GLUT4 remained stable.
    [Show full text]
  • Normal Muscle Glucose Uptake in Mice Deficient in Muscle GLUT4
    313 Normal muscle glucose uptake in mice deficient in muscle GLUT4 Barbara C Fam, Laura J Rose, Rebecca Sgambellone, Zheng Ruan, Joseph Proietto and Sofianos Andrikopoulos Department of Medicine (Austin Health), Austin Hospital, University of Melbourne, Level 7, Lance Townsend Building, Studley Road, Heidelberg, Victoria 3084, Australia (Correspondence should be addressed to B C Fam; Email: [email protected]) Abstract Skeletal muscle insulin resistance is a major characteristic hearts compared with control mice. Basally, plasma glucose and underpinning type 2 diabetes. Impairments in the insulin plasma insulin were significantly lower in the KO compared responsiveness of the glucose transporter, Glut4 (Slc2a4),have with control mice, which conferred normal glucose tolerance. been suggested to be a contributing factor to this disturbance. Despite the lack of GLUT4 in the KO mouse muscle, glucose We have produced muscle-specific Glut4 knockout (KO) mice uptake was not impaired in skeletal muscle but was reduced in using Cre/LoxP technology on a C57BL6/J background and heart under insulin-stimulated conditions. Neither GLUT1 nor shown undetectable levels of GLUT4 in both skeletal muscle GLUT12 protein levels were altered in the skeletal muscle or and heart. Our aim was to determine whether complete heart tissue of our KO mice. High-fat feeding did not alter deletion of muscle GLUT4 does in fact lead to perturbations glucose tolerance in the KO mice but led to elevated plasma in glucose homoeostasis. Glucose tolerance, glucose turnover insulin levels during the glucose tolerance test. Our study and 2-deoxyglucose uptake into muscle and fat under basal and demonstrates that deletion of muscle GLUT4 does not adversely insulin-stimulated conditions were assessed in 12-week-old KO affect glucose disposal and glucose tolerance and that and control mice using the oral glucose tolerance test (OGTT) compensation from other transporters may contribute to this and hyperinsulinaemic/euglycaemic clamp respectively.
    [Show full text]
  • Crystal Structure of a Glucose/H Symporter and Its Mechanism of Action
    + Crystal structure of a glucose/H symporter and its mechanism of action Cristina V. Iancua, Jamillah Zamoonb, Sang Bum Wooa, Alexander Aleshinc, and Jun-yong Choea,1 aDepartment of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago,IL 60064; bDepartment of Biological Sciences, Faculty of Science, Kuwait University, Kuwait City 13060, Kuwait; and cDepartment of Infectious Diseases, Sanford Burnham Medical Research Institute, La Jolla, CA 92037 Edited* by H. Ronald Kaback, University of California, Los Angeles, CA, and approved September 26, 2013 (received for review June 25, 2013) + Glucose transporters are required to bring glucose into cells, of a Staphylococcus epidermidis glucose/H symporter (GlcPSe) where it is an essential energy source and precursor in protein by single anomalous dispersion methods. GlcPSe shares high se- and lipid synthesis. These transporters are involved in important quence identity (27–34%) and homology (49–58%) with the hu- common diseases such as cancer and diabetes. Here, we report the man GLUTs (Table S1), is highly specific for glucose, and is + crystal structure of the Staphylococcus epidermidis glucose/H sym- inhibited by the well-characterized inhibitors of human GLUTs porter in an inward-facing conformation at 3.2-Å resolution. The phloretin, cytochalasin B, and forskolin. In contrast to GlcP , + Se Staphylococcus epidermidis glucose/H symporter is homologous XylE transports xylose but not glucose, which is an inhibitor, and is to human glucose transporters, is very specific and has high avidity impervious to inhibition by cytochalasin B (13, 24). On the basis of for glucose, and is inhibited by the human glucose transport inhib- the GlcPSe structure and functional studies of wild-type and mu- itors cytochalasin B, phloretin, and forskolin.
    [Show full text]
  • WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic B-Cells
    Diabetes Volume 68, February 2019 377 WASH Regulates Glucose Homeostasis by Facilitating Glut2 Receptor Recycling in Pancreatic b-Cells Li Ding, Lingling Han, John Dube, and Daniel D. Billadeau Diabetes 2019;68:377–386 | https://doi.org/10.2337/db18-0189 WASH is an endosomal protein belonging to the Wiskott- family 2 (SLC2A) genes (8). Glut2 is well established as the Aldrich syndrome protein superfamily that participates in principal membrane Glut with low affinity in rodent endosomal receptor trafficking by facilitating tubule fis- pancreatic b-cells (9,10), and previous studies using sion via activation of the ubiquitously expressed Arp2/3 a transgenic mouse model showed that Glut2-null mice complex. While several studies have begun to elucidate generated by homologous recombination provoked severe an understanding of the functions of WASH in cells lines, glycosuria and died at around the weaning period with the in vivo function of WASH has not been fully eluci- a diabetic phenotype (11). Importantly, pancreatic-specific dated, since total body deletion in mice leads to early expression of Glut2 in Glut2-null mice restored normal embryonic lethality. To circumvent this problem, we have glucose-stimulated insulin secretion (GSIS) and glucose- PATHOPHYSIOLOGY used a WASH conditional knockout mouse model to stimulated insulin biosynthesis (12). In addition, Glut2 investigate the role of WASH in the pancreas. We find protein levels in pancreatic islets are strongly reduced that pancreas-specific deletion of WASH leads to im- with loss of GSIS in numerous animal models of diabe- paired blood glucose clearance and reduced insulin re- tes (13–17). Although the mechanism for Glut2 protein lease upon glucose stimulation.
    [Show full text]
  • GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake Or Hypertrophic Growth in Mouse Skeletal Muscle
    Diabetes Volume 66, June 2017 1491 GLUT4 Is Not Necessary for Overload-Induced Glucose Uptake or Hypertrophic Growth in Mouse Skeletal Muscle Shawna L. McMillin,1,2,3,4,5 Denise L. Schmidt,1,2,3,4,5 Barbara B. Kahn,6 and Carol A. Witczak1,2,3,4,5 Diabetes 2017;66:1491–1500 | https://doi.org/10.2337/db16-1075 GLUT4 is necessary for acute insulin- and contraction- Lifestyle modification, including an increase in physical induced skeletal muscle glucose uptake, but its role in activity, has been demonstrated to reduce the incidence of chronic muscle loading (overload)-induced glucose type 2 diabetes (1). Resistance exercise training has been uptake is unknown. Our goal was to determine whether specifically recommended due to its ability to reduce fasted GLUT4 is required for overload-induced glucose up- blood glucose levels (2,3), fasted blood insulin levels (3), and take. Overload was induced in mouse plantaris muscle hemoglobin A1c levels (2–4), as well as to increase whole- by unilateral synergist ablation. After 5 days, muscle body glucose disposal (2,5), skeletal muscle mass (2–4), and 3 weights and ex vivo [ H]-2-deoxy-D-glucose uptake muscle glucose uptake (5). Given the importance of muscle were assessed. Overload-induced muscle glucose in maintaining systemic glucose homeostasis, understand- uptake and hypertrophic growth were not impaired in ing how resistance training alters muscle glucose metabo- METABOLISM fi muscle-speci c GLUT4 knockout mice, demonstrat- lism may lead to new treatments for type 2 diabetes. ing that GLUT4 is not necessary for these processes.
    [Show full text]
  • Docosahexaenoyl Ethanolamide Improves Glucose Uptake and Alters Endocannabinoid System Gene Expression in Proliferating and Differentiating C2C12 Myoblasts
    ORIGINAL RESEARCH ARTICLE published: 21 March 2014 doi: 10.3389/fphys.2014.00100 Docosahexaenoyl ethanolamide improves glucose uptake and alters endocannabinoid system gene expression in proliferating and differentiating C2C12 myoblasts Jeffrey Kim , Morgan E. Carlson and Bruce A. Watkins* Center on Aging, University of Connecticut Health Center, Farmington, CT, USA Edited by: Skeletal muscle is a major storage site for glycogen and a focus for understanding Lucas Guimarães-Ferreira, Federal insulin resistance and type-2-diabetes. New evidence indicates that overactivation of the University of Espirito Santo, Brazil peripheral endocannabinoid system (ECS) in skeletal muscle diminishes insulin sensitivity. Reviewed by: Specific n-6 and n-3 polyunsaturated fatty acids (PUFA) are precursors for the biosynthesis Lucas Guimarães-Ferreira, Federal University of Espirito Santo, Brazil of ligands that bind to and activate the cannabinoid receptors. The function of the ECS David Lee Hamilton, Stirling and action of PUFA in skeletal muscle glucose uptake was investigated in proliferating University, UK and differentiated C2C12 myoblasts treated with either 25 μM of arachidonate (AA) or *Correspondence: docosahexaenoate (DHA), 25 μM of EC [anandamide (AEA), 2-arachidonoylglycerol (2-AG), Bruce A. Watkins, Department of docosahexaenoylethanolamide (DHEA)], 1 μM of CB1 antagonist NESS0327, and CB2 Nutrition, University of California, Davis, Davis, CA 95616-5270, USA inverse agonist AM630. Compared to the BSA vehicle control cell cultures in both e-mail: [email protected] proliferating and differentiated myoblasts those treated with DHEA, the EC derived from the n-3 PUFA DHA, had higher 24 h glucose uptake, while AEA and 2-AG, the EC derived from the n-6 PUFA AA, had lower basal glucose uptake.
    [Show full text]
  • Understanding the Kidneys' Role in Blood Glucose Regulation
    n REPORTS n Understanding the Kidneys’ Role in Blood Glucose Regulation Curtis L. Triplitt, PharmD, CDE ublished studies over the last 60 years have provided considerable evidence regarding the ability of the kid- Abstract neys to make and release glucose under various physi- While not traditionally discussed, the kid- ologic conditions. Yet traditionally, the kidneys have neys’ contributions to maintaining glucose Pnot been considered an important source of glucose (except during homeostasis are significant and include acidosis or after prolonged fasting), with most clinical discussions such functions as release of glucose into on glucose dysregulation centering on the intestine, pancreas, the circulation via gluconeogenesis, uptake liver, adipose tissue, and muscle.1-3 More recently, however, the of glucose from the circulation to satisfy full significance of the kidneys’ contribution to glucose homeosta- their energy needs, and reabsorption of glucose at the level of the proximal tubule. sis, under both physiologic and pathologic conditions, has become Renal release of glucose into the circula- well recognized, and is thought to involve functions well beyond tion is the result of glycogenolysis and glucose uptake and release. Besides the liver, the kidney is the gluconeogenesis, respectively involving the only organ capable of generating sufficient glucose (gluconeogen- breaking down and formation of glucose- esis) to release into ©the Managed circulation, Care and it & is also responsible for 6-phosphate from precursors (eg, lactate, glycerol, amino acids). With regard to filtration and subsequent reabsorption or excretion of glucose.2-4 Healthcare Communications, LLC renal reabsorption of glucose, the kidneys These findings have provided considerable insight into the myriad normally retrieve as much glucose as pos- of pathophysiologic mechanisms involved in the development of sible, rendering the urine virtually glucose hyperglycemia and type 2 diabetes mellitus (T2DM).5,6 This article free.
    [Show full text]
  • Renal Tubular Metabolism Reviewed in Health and Disease
    nutrients Review Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease Leslie S. Gewin 1,2,3 1 Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, TN 37232, USA; [email protected] 2 Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, TN 37212, USA 3 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37212, USA Abstract: The kidney is a highly metabolically active organ that relies on specialized epithelial cells comprising the renal tubules to reabsorb most of the filtered water and solutes. Most of this reabsorption is mediated by the proximal tubules, and high amounts of energy are needed to facilitate solute movement. Thus, proximal tubules use fatty acid oxidation, which generates more adenosine triphosphate (ATP) than glucose metabolism, as its preferred metabolic pathway. After kidney injury, metabolism is altered, leading to decreased fatty acid oxidation and increased lactic acid generation. This review discusses how metabolism differs between the proximal and more distal tubular segments of the healthy nephron. In addition, metabolic changes in acute kidney injury and chronic kidney disease are discussed, as well as how these changes in metabolism may impact tubule repair and chronic kidney disease progression. Keywords: proximal tubule; acute kidney injury; chronic kidney disease; fatty acid oxidation; kidney injury; kidney metabolism Citation: Gewin, L.S. Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease. Nutrients 2021, 1. Introduction 13, 1580. https://doi.org/10.3390/ The kidney receives 25% of the cardiac output and filters approximately 180 L of nu13051580 water daily, while only excreting 1 to 2 L.
    [Show full text]