DOCSLIB.ORG

α-Cell Glucokinase Suppresses Glucose-Regulated Glucagon Secretion

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
α-Cell Glucokinase Suppresses Glucose-Regulated Glucagon Secretion View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Ulster University's Research Portal ARTICLE DOI: 10.1038/s41467-018-03034-0 OPEN α-cell glucokinase suppresses glucose-regulated glucagon secretion Davide Basco1, Quan Zhang 2, Albert Salehi 3, Andrei Tarasov2, Wanda Dolci1, Pedro Herrera 4, Ioannis Spiliotis2, Xavier Berney1, David Tarussio1, Patrik Rorsman2 & Bernard Thorens1 Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 1234567890():,; and type 2 diabetes. Here, we show that α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATP channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an α-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype. 1 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland. 2 Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK. 3 Department of Clinical Science, UMAS, Division of Islet Cell Physiology, Lund, Sweden. 4 Department of Genetic Medicine and Development, 1200 Geneva, Switzerland. Davide Basco and Quan Zhang contributed equally to this work. Correspondence and requests for materials should be addressed to B.T. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:546 | DOI: 10.1038/s41467-018-03034-0 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-03034-0 lucagon secretion by pancreatic α-cells is rapidly system5,8,9. On the other hand, suppression of glucagon secretion Gincreased when the blood glucose concentration falls by hyperglycemia relies on paracrine regulation, including below the normoglycemic level to increase hepatic glucose insulin-induced inhibition and/or somatostatin-induced inhibi- production, and is suppressed by hyperglycemia1,2. The tion of α-cells10. mechanisms controlling hypoglycemia-induced glucagon secre- In pancreatic β-cells, the dose response of glucose-stimulated tion remain debated, and both intrinsic and paracrine mechan- insulin secretion is controlled by the activity of glucokinase 3,4 11 isms have been postulated (reviewed in refs. ). There is (Gck), which has relatively high KM for glucose (8 mM) . evidence that hypoglycemia triggers glucagon secretion via a fall Mutations that increase the KM for glucose of this enzyme shifts in the cytoplasmic ATP/ADP ratio, leading to moderate KATP the dose response of GSIS to the right, causing Maturity Onset channel activity and increased activity of P/Q type Ca++ chan- Diabetes of the Young 2 (MODY2)12. Glucokinase is also nels3. The resulting increase in intracellular Ca2+ leads to gluca- expressed in α-cells13, but its role in the control of glucagon gon secretory granules exocytosis. Extrinsic factors also play an secretion is not known. Studies of MODY2 patients during important role in triggering glucagon secretion, in particular, the stepped hyperinsulinemic/hypoglycemic clamps showed that signals from the sympathetic and parasympathetic branches of glucagon secretion was stimulated at higher glucose concentra- the autonomic nervous system4,5, which are activated by tion than in control individuals, but whether this was due to a hypoglycemia-sensing neurons present in the extrapancreatic direct effect in the α-cells or secondary to altered glucose-sensing sites, such as the hepatoportal vein area6,7 and the central nervous by the central nervous system and altered autonomic nervous abIslets Liver Brainstem Ileum ccccKO KO KO KO Flox Del Glucagon Tdtomato Merge cdef 1.2 Ctrl 1.5 0.25 4 GckKO 0.20 3 0.8 1.0 0.15 2 0.10 (% of BW) 0.4 0.5 -cell mass (mg) -cell mass (mg) Pancreas mass 1 β Islet surface (%) α 0.05 0.0 0.0 0.00 0 g 1.5 1G 20G i Ctrl ** 1G 6G 1G+Tolb GckKO 10G 10msucc # § 3msucc 3G 1msucc 1msucc 1.0 *** 4FCCP ∞ F 0.5 0 (% of content) 0 F / Glucagon secretion F 0.1 0.0 5 min Ctrl GckKO h 3 2.0 1.8 2 Ctrl = 116) 1.6 n ( 1.4 1 1.2 (% of content) Insulin secretion 1.0 = 87) 0.8 GckKO n ( 0 0.6 Ctrl GckKO Fig. 1 Alpha-cell Gck inactivation and the suppression of glucagon secretion. a Representative immunofluorescence (out of n = 3 replicates) of the co- localization of glucagon (green) and tdtomato (red) in a pancreatic section from αGckKO-Rosa26tdtomato mice. Scale bar: 100 µm. b PCR analysis of recombination of the Gckflox allele in the indicated tissues of Ctrl and αGckKO mice. c Pancreas' weight normalized to BW. See also Supplementary Fig. 1. d Islet surface expressed as percentage of total pancreatic surface. e α-cell mass. f β-cell mass. Values in b–h were extracted from the analysis of three pancreata for each genotype. g Glucagon and h Insulin secretion from isolated islets in the presence of the indicated glucose (G) concentrations and of tolbutamide. g, h Data represent the average of three independent experiments, each performed in duplicates. ***p < 0.001 vs. Ctrl 1G; **p < 0.01 vs. αGckKO 1G + Tolb. #p < 0.01 vs. Ctrl 6 G. §p < 0.001 vs. Ctrl 20G. ∞p < 0.05 vs. Ctrl 1G + Tolb. One-way ANOVA for intra-group analysis and Student’s t- test for comparison between genotypes. i ATP/ADP ratio measurements in α-cells of Ctrl and αGckKO islets exposed to glucose and methyl-succinate (msucc). n = 116 for Ctrl and n = 86 for αGckKO α-cells. See also Supplementary Figs. 2 and 3. Data are represented as mean ± s.e.m. 2 NATURE COMMUNICATIONS | (2018) 9:546 | DOI: 10.1038/s41467-018-03034-0 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-03034-0 ARTICLE activity remains unclear14. Here we explore the role of Gck in the Results pancreatic α-cell by generating α-cell-specific Gck knockout Characterization of αGckKO islets. To generate mice with mice. Our data illustrate that Gck is critical to glucose sensing in inactivation of the Gck gene in α-cells (αGckKO mice), we crossed the α-cell and underscore the significance of intrinsic (exerted Gcklox/lox mice9 with preproglucagon-Cre (Gcg-Cre) mice15. These within the α-cell itself) as opposed to paracrine/systemic mice were further crossed with Rosa26-tdtomato mice and ~70% regulation. of the glucagon-positive cells also expressed tdtomato (Fig. 1a), a Ctrl 6G 20 1G 1G 6G 10 0 0 –20 –20 (mV) (mV) m –40 –40 m V V –60 –60 –80 –80 20 s 10 ms 6G GckKO 1G 6G 10 20 1G 0 0 –20 –20 (mV) –40 m (mV) V m –40 V –60 –60 –80 10 ms –80 20 s b 1G 6G c 4 1G 6G 15 0 20 0 3 ** 3 15 –20 10 –20 2 (mV) (mV) (mV) 2 (mV) 10 –40 peak peak V 5 anti-peak –40 1 V anti-peak V 1 V * (Hz) Frequency 5 –60 Frequency (Hz) Frequency 0 –60 0 0 –80 0 1G 6G * 1G 6G 1G 6G 1G 6G d e 150 80 Ctrl 5 pA * 60 100 20 ms (pF/pS) 40 (pF/pS) GckKO KATP 50 KATP G 5 pA G 20 20 ms 0 0 1G 6G 1G6G 1G 6G f 30 mV 0 mV g 120 –70 mV –30 mV Ctrl GckKO Ctrl Cm 80 50 fF (fF) m C 500 ms Δ 40 GckKO Cm 0 50 fF –40 –200 20 40 500 ms V (mV) NATURE COMMUNICATIONS | (2018) 9:546 | DOI: 10.1038/s41467-018-03034-0 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-03034-0 indicating that a large majority of α-cells express the Cre increasing glucose to 6 mM resulted in a small and reversible recombinase. The recombined Gck allele was detected in islets of membrane depolarization (+6 ± 2 mV, n = 5) and an ~10 mV αGckKO mice, but not in their liver, brainstem, and ileum tissues reduction of the action potential peak voltage in α-cells from Ctrl that also express the preproglucagon gene, but not the Cre islets. By contrast, increasing glucose neither depolarized nor recombinase in the Gcg-Cre mice utilized (Fig. 1b). Pancreas reduced the action potential peak voltage in αGckKO α-cells mass, islet surface area, α-cell mass and β-cell mass (Fig. 1c–f), as (Fig. 2a–c). In αGckKO α-cells, glucose, if anything, tended to well as pancreatic insulin and glucagon contents (Supplementary hyperpolarize the α-cell and increase action potential height. Fig. 1) were the same in Ctrl and αGckKO mice. These effects may reflect somatostatin release from the neigh- The impact of α-cell Gck gene inactivation on glucagon boring δ-cells17. α secretion was then examined by static incubations. At 1 mM In Ctrl -cells, increasing glucose reduced the resting KATP glucose, glucagon secretion by islets from 18-week-old Ctrl and conductance by 24 ± 11pA/pF; no such decrease was observed in αGckKO mice was comparable (Fig. 1g, black bars). When αGckKO α-cells (Fig. 2d, e). incubated with 6 and 20 mM glucose, glucagon release by Ctrl We ascertained (using capacitance measurements3) that islets was decreased by ~50%, but not in αGckKO islets (Fig.
Load more

Recommended publications
  • Secretin and Autism: a Clue but Not a Cure
    SCIENCE & MEDICINE Secretin and Autism: A Clue But Not a Cure by Clarence E. Schutt, Ph.D. he world of autism has been shaken by NBC’s broadcast connections could not be found. on Dateline of a film segment documenting the effect of Tsecretin on restoring speech and sociability to autistic chil- The answer was provided nearly one hundred years ago by dren. At first blush, it seems unlikely that an intestinal hormone Bayless and Starling, who discovered that it is not nerve signals, regulating bicarbonate levels in the stomach in response to a but rather a novel substance that stimulates secretion from the good meal might influence the language centers of the brain so cells forming the intestinal mucosa. They called this substance profoundly. However, recent discoveries in neurobiology sug- “secretin.” They suggested that there could be many such cir- gest several ways of thinking about the secretin-autism connec- culating substances, or molecules, and they named them “hor- tion that could lead to the breakthroughs we dream about. mones” based on the Greek verb meaning “to excite”. As a parent with more than a decade of experience in consider- A simple analogy might help. If the body is regarded as a commu- ing a steady stream of claims of successful treatments, and as a nity of mutual service providers—the heart and muscles are the pri- scientist who believes that autism is a neurobiological disorder, I mary engines of movement, the stomach breaks down foods for have learned to temper my hopes about specific treatments by distribution, the liver detoxifies, and so on—then the need for a sys- seeing if I could construct plausible neurobiological mechanisms tem of messages conveyed by the blood becomes clear.
    [Show full text]
  • Glucagon and Gastrointestinal Motility in Relation to Thyroid-Parathyroid Function
    Upsala J Med Sci 77: 183-188, 1972 Glucagon and Gastrointestinal Motility in Relation to Thyroid-Parathyroid Function HENRY JOHANSSON and ANDERS SEGERSTROM From the Department of Surgery, University Hospital, Uppsala, Sweden ABSTRACT MATERIAL Gastrointestinal propulsive motility was studied after The material consisted of 109 male albino rats (Sprague- inhgastric deposition of a non-absorbable isotope in Dawley) fed on laboratory food and with free access to rats after subcutaneous glucagon injections. Glucagon water. The animals were distributed at random in fol- administration was followed by retardation of gastric lowing series: emptying. The results indicated that the retarding effect Series I of glucagon on gastrointestinal propulsion was independent The influence of glucagon on gastrointestinal motility in of the presence of both thyroid and parathyroid tissue. intact rats. The observation period was 7 days. The hypocalcemic effect of glucagon was exerted in- dependently of the presence of thyroid tissue, Le. thyro- 1. Intact rats given 1.2 mg glucagon/kg body weight calcitonin. (GN-A, n= 6) 2. Intact rats given 4.8 mg glucagon/kg body weight (GN-B, n= 5) 3. Intact rats given 9.6 mg glucagon/kg body weight INTRODUCTION (GN-C, n= 12) 4. Intact rats given glucine buffert (GLY, n= 10). Glucagon is known to influence gastrointestinal Series I1 motility. In man, Dotevall & Kock (2) observed The influence of glucagon on gastrointestinal motility in that glucagon retarded gastrointestinal motility parathyroidectomized rats. The animals were given 4.8 independently of the hyperglucemia. In dogs, mg glucagon/kg body weight. The observation period glucagon retarded motility of the stomach ani was 90 days.
    [Show full text]
  • AVP-Induced Counter-Regulatory Glucagon Is Diminished in Type 1 Diabetes
    bioRxiv preprint doi: https://doi.org/10.1101/2020.01.30.927426; this version posted January 31, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. AVP-induced counter-regulatory glucagon is diminished in type 1 diabetes Angela Kim1,2, Jakob G. Knudsen3,4, Joseph C. Madara1, Anna Benrick5, Thomas Hill3, Lina Abdul Kadir3, Joely A. Kellard3, Lisa Mellander5, Caroline Miranda5, Haopeng Lin6, Timothy James7, Kinga Suba8, Aliya F. Spigelman6, Yanling Wu5, Patrick E. MacDonald6, Ingrid Wernstedt Asterholm5, Tore Magnussen9, Mikkel Christensen9,10,11, Tina Vilsboll9,10,12, Victoria Salem8, Filip K. Knop9,10,12,13, Patrik Rorsman3,5, Bradford B. Lowell1,2, Linford J.B. Briant3,14,* Affiliations 1Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. 2Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX4 7LE, UK. 4Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen. 5Institute of Neuroscience and Physiology, Metabolic Research Unit, University of Göteborg, 405 30, Göteborg, Sweden. 6Alberta Diabetes Institute, 6-126 Li Ka Shing Centre for Health Research Innovation, Edmonton, Alberta, T6G 2E1, Canada. 7Department of Clinical Biochemistry, John Radcliffe, Oxford NHS Trust, OX3 9DU, Oxford, UK. 8Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, W12 0NN, UK.
    [Show full text]
  • Localization of Glucokinase Gene Expression in the Rat Brain Ronald M
    Localization of Glucokinase Gene Expression in the Rat Brain Ronald M. Lynch, Linda S. Tompkins, Heddwen L. Brooks, Ambrose A. Dunn-Meynell, and Barry E. Levin The brain contains a subpopulation of glucosensing neu- rons that alter their firing rate in response to elevated glucose concentrations. In pancreatic ␤-cells, gluco- ammalian feeding behavior and general energy kinase (GK), the rate-limiting enzyme in glycolysis, medi- homeostasis appear to be regulated by circu- ates glucose-induced insulin release by regulating intra- lating levels of nutrients (glucose) and pep- cellular ATP production. A similar role for GK is pro- tides (e.g., leptin, insulin). Sensors to detect lev- posed to underlie neuronal glucosensing. Via in situ M els of these factors have been found to reside within specific hybridization, GK mRNA was localized to hypothalamic areas that are thought to contain relatively large popu- nuclei of the hypothalamus (1–8), where central regulation of lations of glucosensing neurons (the arcuate, ventrome- energy homeostasis is believed to be coordinated. For exam- dial, dorsomedial, and paraventricular nuclei and the lat- ple, large changes in blood glucose are correlated with cen- eral area). GK also was found in brain areas without trally mediated responses such as thermogenesis through known glucosensing neurons (the lateral habenula, the activation of the sympathetic nervous system. These changes bed nucleus stria terminalis, the inferior olive, the are monitored by the brain (9–11), and such responses are retrochiasmatic and medial preoptic areas, and the thal- altered in obesity-prone animals (11–13). Moreover, lesions amic posterior paraventricular, interpeduncular, oculo- of the ventromedial hypothalamus (VMH) prevent the hypo- motor, and anterior olfactory nuclei).
    [Show full text]
  • And Oxytocin-Induced Glucagon Secretion in V1b Vasopressin Receptor Knockout Mice
    361 Mutual regulation of vasopressin- and oxytocin-induced glucagon secretion in V1b vasopressin receptor knockout mice Yoko Fujiwara, Masami Hiroyama, Atsushi Sanbe, Junji Yamauchi, Gozoh Tsujimoto1 and Akito Tanoue Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan 1Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University Faculty of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan (Requests for offprints should be addressed to A Tanoue; Email: [email protected]) Abstract [Arg8]-vasopressin (AVP) and oxytocin (OT) are neurohy- CL-14-26 further inhibited AVP- and OT-induced glucagon pophysial hormones which exert various actions, including secretions in islets of V1bRC/C mice (57 and 69% of the the control of blood glucose, in some peripheral tissues. To stimulation values respectively). In addition, both AVP and investigate the type of receptors involved in AVP- and OT stimulated glucagon secretion with the same efficacy in OT-induced glucagon secretion, we investigated the effect V1bRK/K mice as in V1bRC/C mice. AVP- and of these peptides on glucagon secretion in islets of OT-induced glucagon secretion in V1bRK/K mice was wild-type (V1bRC/C) and vasopressin V1b receptor significantly inhibited by CL-14-26. These results demonstrate knockout (V1bRK/K) mice. AVP-induced glucagon that V1b receptors can mediate OT-induced glucagon secretion secretion was significantly inhibited by the selective V1b and OTreceptors can mediate AVP-induced glucagon secretion receptor antagonist, SSR149415 (30%), and OT-induced in islets from V1bRC/C mice in the presence of a heterologous glucagon secretion by the specific OT receptor antagonist, antagonist, while AVP and OT can stimulate glucagon secretion ð Þ ½ ð Þ2; 4; 9 d CH2 5 Tyr Me Thr Tyr-NH2 OVT (CL-14-26) through the OTreceptors in V1bRK/K mice, suggesting that C C (45%), in islets of V1bR / mice.
    [Show full text]
  • Biomoleculesbiomolecules
    1414Unit Objectives BiomoleculesBiomolecules After studying this Unit, you will be able to • explain the characteristics of “It is the harmonious and synchronous progress of chemical biomolecules like carbohydrates, reactions in body which leads to life”. proteins and nucleic acids and hormones; • classify carbohydrates, proteins, A living system grows, sustains and reproduces itself. nucleic acids and vitamins on the The most amazing thing about a living system is that it basis of their structures; is composed of non-living atoms and molecules. The • explain the difference between pursuit of knowledge of what goes on chemically within DNA and RNA; a living system falls in the domain of biochemistry. Living • describe the role of biomolecules systems are made up of various complex biomolecules in biosystem. like carbohydrates, proteins, nucleic acids, lipids, etc. Proteins and carbohydrates are essential constituents of our food. These biomolecules interact with each other and constitute the molecular logic of life processes. In addition, some simple molecules like vitamins and mineral salts also play an important role in the functions of organisms. Structures and functions of some of these biomolecules are discussed in this Unit. 14.114.114.1 Carbohydrates Carbohydrates are primarily produced by plants and form a very large group of naturally occurring organic compounds. Some common examples of carbohydrates are cane sugar, glucose, starch, etc. Most of them have a general formula, Cx(H2O)y, and were considered as hydrates of carbon from where the name carbohydrate was derived. For example, the molecular formula of glucose (C6H12O6) fits into this general formula, C6(H2O)6. But all the compounds which fit into this formula may not be classified as carbohydrates.
    [Show full text]
  • Biomolecules Y
    Biomolecules MODULE - 7 Chemistry of Organic Compounds 31 Notes BIOMOLECULES You are aware that our body, plants and other animals are made up of many chemical substances. There are certain complex organic molecules which form the basis of life. These build up living organisms and are also required for their growth and maintenance. Such molecules are called biomolecules. The main classes of biomolecules are carbohydrates, proteins, lipids, nucleic acids, enzymes, hormones etc. In this lesson, you will study about the structures and functions of some important biomolecules. Objectives After reading this lesson you will be able to : identify and define different types of biomolecules; describe the important structural features of biomolecules; classify carbohydrates, proteins and lipids on the basis of their structure & functions; give the composition of proteins and nucleic acids; explain the difference between DNA and RNA; differentiate between oils and fats; explain the action of enzymes and their characteristic features and list the functions of biomolecules in biological systems. 31.1 Carbohydrates Carbohydrates form a very large group of naturally occurring organic compounds which play a vital role in daily life. They are produced in plants by the process ofphotosynthesis. The most common carbohydrates are glucose, fructose, sucrose, starch, cellulose etc. Chemically, the carbohydrates may be defined as polyhydroxy aldehydes or ketones 261 MODULE - 7 Chemistry Chemistry of Organic or substances which give such molecules on hydrolysis. Many carbohydrates are Compounds sweet in taste and all sweet carbohydrates are called as sugars. The chemical name of the most commonly used sugar in our homes is sucrose. 31.1.1 Classification of Carbohydrates Carbohydrates are classified into three groups depending upon their behaviour on hydrolysis.
    [Show full text]
  • Structure-Function of the Glucagon Receptor Family of G Protein–Coupled Receptors: the Glucagon, GIP, GLP-1, and GLP-2 Receptors
    Receptors and Channels, 8:179–188, 2002 Copyright c 2002 Taylor & Francis 1060-6823/02 $12.00 + .00 DOI: 10.1080/10606820290005155 Structure-Function of the Glucagon Receptor Family of G Protein–Coupled Receptors: The Glucagon, GIP, GLP-1, and GLP-2 Receptors P. L. Brubaker Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada D. J. Drucker Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, Toronto, Ontario, Canada convertases results in the liberation of glucagon in the pancreatic The glucagon-like peptides include glucagon, GLP-1, and A cell, and GLP-1 and GLP-2 in the intestinal L cell and brain GLP-2, and exert diverse actions on nutrient intake, gastrointesti- (Mojsov et al. 1986; Orskov et al. 1987). As discussed below, nal motility, islet hormone secretion, cell proliferation and apopto- all three proglucagon-derived peptides (PGDPs) play impor- sis, nutrient absorption, and nutrient assimilation. GIP, a related member of the glucagon peptide superfamily, also regulates nutri- tant roles in the physiologic regulation of nutrient homeosta- ent disposal via stimulation of insulin secretion. The actions of these sis, through effects on energy intake and satiety, nutrient fluxes peptides are mediated by distinct members of the glucagon recep- through and across the gastrointestinal tract, and energy as- tor superfamily of G protein–coupled receptors. These receptors similation. Several of these biological activities are shared by exhibit unique patterns of tissue-specific expression, exhibit consid- a fourth glucagon-related peptide hormone, glucose-dependent erable amino acid sequence identity, and share similar structural and functional properties with respect to ligand binding and sig- insulinotropic peptide (GIP) (Table 1).
    [Show full text]
  • Role of Leptin in the Regulation of Glucagon-Like Peptide-1 Secretion Younes Anini1 and Patricia L
    Role of Leptin in the Regulation of Glucagon-Like Peptide-1 Secretion Younes Anini1 and Patricia L. Brubaker1,2 Glucagon-like peptide-1 (GLP-1), released from intesti- ior (13,14), and central GLP-1 administration reduces food nal endocrine L cells, is a potent insulinotropic hor- intake in rodents, whereas peripheral administration of mone. GLP-1 secretion is diminished in obese patients. GLP-1 promotes satiety and decreases body weight in Because obesity is linked to abnormal leptin signaling, humans (13,15). These pleiotropic actions of GLP-1 there- we hypothesized that leptin may modulate GLP-1 secre- fore offer great potential for the treatment of hyperglyce- tion. Leptin significantly stimulated GLP-1 secretion mia in patients with type 2 diabetes (1,15). (by up to 250% of control) from fetal rat intestinal cells, It has recently been shown that plasma GLP-1 levels are a mouse L cell line (GLUTag), and a human L cell line reduced in obesity (16–19), a condition that is highly (NCI-H716) in a dose-dependent manner (P < 0.05– correlated to type 2 diabetes (20). The mechanisms lead- 0.001). The long form of the leptin receptor was shown to be expressed, and leptin induced the phosphorylation ing to decreased GLP-1 secretion in obesity have not been of STAT3 in the three cell types. The leptin receptor elucidated. However, because plasma leptin levels are was also expressed by rodent and human intestinal L proportional to fat mass, we postulated the existence of an cells, and leptin (1 mg/kg i.p.) significantly stimulated adipo-enteroendocrine interaction between leptin and GLP-1 secretion in rats and ob/ob mice.
    [Show full text]
  • Insulin As a Growth Factor
    003 1-3998/85/1909-0879$02.00/0 PEDIATRIC RESEARCH Vol. 19, No. 9, 1985 Copyright O 1985 International Pediatric Research Foundation, Inc Printed in U.S. A. Insulin as a Growth Factor D. J. HILL AND R. D. G. MILNER Departrnenl c!j'Pucdiutricc, Unive,:sitj. of Sl~effield,Cliildren :s Hospital, Shefic~ld,England ABSTRACT. Insulin is a potent mitogen for many cell attention than its well known, acute metabolic actions. Insulin types in vitro. During tissue culture, supraphysiological also can influence growth in vivo. The poor growth of a chilld concentrations of insulin are necessary to promote cell with diabetes (1) contrasts with the overgrowth of the hyperin- replication in connective or musculoskeletal tissues. Insulin sulinemic infant of a diabetic mother (2). The growth-promoting promotes the growth of these cells by binding, with low effect of insulin in vivo was demonstrated experimentally by affinity, to the type I insulin-like growth factor (IGF) Salter and Best in 1953 (3); these investigators restored growth receptor, not through the high affinity insulin receptor. In to hypophysectomized rats by treatment with insulin and a high other cell types, such as hepatocytes, embryonal carcinoma carbohydrate diet. Rats given insulin grew as well as those given cells, or mammary tumor cells, the type I IGF receptor is growth hormone but consumed substantially more food. Any virtually absent, and insulin stimulates the growth of these analysis of the action of insulin in promoting growth must clearly cells at physiological concentrations by binding to the high separate those effects which are due to anabolism resulting frc~m affinity insulin receptor.
    [Show full text]
  • Relation Between Leptin and the Regulation of Glucose Metabolism
    Diabetologia (2000) 43: 3±12 Ó Springer-Verlag 2000 Review Relation between leptin and the regulation of glucose metabolism G.Frühbeck, J.Salvador Department of Endocrinology, University Clinic, University of Navarra, Pamplona, Spain Keywords Leptin, ob gene, insulin, glucagon, chole- also to an increased basal metabolic rate with selec- cystokinin, glucose homeostasis, obesity, satiety. tive promotion of fat metabolism [2, 7±10]. Leptin was discovered through a very specific bio- logical action consisting in its involvement in body Overview weight and appetite regulation. Interestingly, leptin has structural similarities to the family of helical cyto- The identification of the ob gene through positional kines [11]. Many cytokines, originally isolated cloning [1] and the discovery that its encoded protein, through particular biological actions, have subse- leptin, is essential for body weight homeostasis [2±4] quently been shown to be capable of stimulating a va- have permanently altered the field of metabolic phys- riety of biological responses in a wide spectrum of cell iology. Over a 5-year period a substantial and rapidly types. Thus, leptin shares with other cytokines an ex- changing body of knowledge has been created. treme functional pleiotropy and has been shown to Leptin, a 16 kDa circulating hormone produced be involved in quite diverse physiological functions, and released primarily by adipocytes, exerts a regula- such as reproduction [12], angiogenesis [13], haema- tory control on food intake and energy expenditure topoiesis [14] and immune responsiveness [15]. [2±4]. Plasma leptin concentrations are correlated Consistent with leptin's role in controlling appetite with total fat mass, per cent body fat and body mass and energy metabolism, leptin receptors (OB-R) index acting as a sensing hormone or ªlipostatº in a have been found in the hypothalamus and adjacent negative feedback control from adipose tissue to the brain regions [16, 17].
    [Show full text]
  • Glucagon FAQ's
    Glucagon FAQ’s What is Glucagon? Glucagon is an injected medicine that causes the release of glucose from the liver where it is stored. It is a safe emergency treatment that is used when the blood sugar is so low that a person may pass out or have a seizure. Who should use Glucagon? If you take insulin for your diabetes, you need to be prepared for the possibility of severe hypoglycemia. If you keep your blood sugar in tight control with multiple daily doses of insulin, are on an insulin pump, or have difficulty feeling the typical symptoms of a low blood sugar, you are more likely to have a very low blood sugar. When should Glucagon be used? Make sure that your family and/or friends are trained on how to seek medical assistance and inject Glucagon in the case that you become disoriented and are not able to take anything by mouth, become unconscious, or have a seizure. A prescription is needed for a Glucagon emergency kit. It is important to have someone practice giving a shot before an emergency occurs. What is in the Glucagon Kit? The kit contains all of the supplies you will need. Your diabetes educator can show you and your family how to use glucagon correctly. The kit contains one vial of powdered glucagon and one syringe containing sterile water for mixing. The kit may be stored up to 24 months at room temperature and should not be used after the expiration date on the vial. How is glucagon administered? Administering glucagon is a multi-step process which involves a vial of glucagon powder and a syringe prefilled with saline.
    [Show full text]