Insulin receptors and insulin action in the brain: review and clinical implications

https://doi.org/10.1016/S0149-7634(00)00040-3Get rights and content

Abstract

Insulin receptors are known to be located on nerve cells in mammalian brain. The binding of insulin to dimerized receptors stimulates specialized transporter proteins that mediate the facilitated influx of glucose. However, neurons possess other mechanisms by which they obtain glucose, including transporters that are not insulin-dependent. Further, insulin receptors are unevenly distributed throughout the brain (with particularly high density in choroid plexus, olfactory bulb and regions of the striatum and cerebral cortex). Such factors imply that insulin, and insulin receptors, might have functions within the central nervous system in addition to those related to the supply of glucose. Indeed, invertebrate insulin-related peptides are synthesized in brain and serve as neurotransmitters or neuromodulators. The present review summarizes the structure, distribution and function of mammalian brain insulin receptors and the possible implications for central nervous system disorders. It is proposed that this is an under-studied subject of investigation.

Introduction

Insulin receptors are widely dispersed throughout tissues of the periphery, and their function is well known — namely, mediation of glucose transport into cells. The existence of insulin receptors within the brain is less well known, and the function of these receptors is somewhat of an enigma. It is noteworthy that brain cells are not fully reliant upon insulin for glucose supply, i.e. they have insulin-independent means of obtaining glucose. Also, brain insulin receptors (InsRb) differ somewhat from their peripheral counterparts. What then is the physiological role of insulin receptors in the brain? The answer appears to be two-fold: (1) for tight control of glucose transport in specific brain regions, and (2) for as yet incompletely understood function in central nervous system (CNS) development and function. Aberrant function of the InsRb has been hypothesized to be involved in CNS dysfunction.

Section snippets

Rats

It might be expected that insulin receptors would be evenly distributed throughout all regions of the brain, particularly if their only function was to mediate insulin-induced glucose transport into neurons as a source of energy, and not as a signal-transduction pathway. In fact, insulin receptor density within the CNS is distributed irregularly and in distinct regional patterns. In rat brains, the highest InsRb densities are found in the olfactory bulb, cerebral cortex, hypothalamus,

Clinical implications

As summarized in the previous sections, neurons rely on glucose for energy, but only a small percentage of the glucose supply to neurons is delivered via insulin-dependent transport mechanisms. The rest of the glucose is obtained through non-insulin-dependent mechanisms. Further, insulin receptors are found in high density in some regions of brain, but in only low density in other regions of the brain [2], [3]. This uneven distribution is somewhat correlated with neuronal activity [1] and,

Summary

Brain insulin receptors, which are structurally slightly different from peripheral insulin receptors, are present — but not evenly distributed — throughout the brain. There are suggestions that the role of these receptors exceeds mediation of insulin utilization. First, the distribution of InsRb in the brain is neither homogeneous nor a simple function of glucose-utilization (energy-demand) patterns, second, InsRb have been shown to be present on synapses, and third, InsRb modulates

References (188)

  • P.A Tulloch et al.

    Single-molecule imaging of human insulin receptor ectodomain and its Fab complexes

    J Struct Biol

    (1999)
  • S.R Keller et al.

    Insulin signalling: the role of insulin receptor substrate 1

    Trends Pharmacol Sci

    (1994)
  • J.L Carpentier et al.

    Receptor binding and internalization of biosynthetic human insulin in isolated rat hepatocytes

    Mol Cell Endocrinol

    (1982)
  • W.S Young et al.

    Radiohistochemical localization of insulin receptors in the adult and developing rat brain

    Neuropeptides

    (1980)
  • S.A Baldwin

    Mammalian passive glucose transporters: members of an ubiquitous family of active and passive transport proteins

    Biochim Biophys Acta

    (1993)
  • A.M Brant et al.

    Immunological analysis of glucose transporters expressed in different regions of the rat brain and central nervous system

    Biochem Biophys Res Commun

    (1993)
  • C Livingstone et al.

    Hypothalamic GLUT4 expression: a glucose- and insulin-sensing mechanism?

    Mol Cell Endocrinol

    (1995)
  • P.S Walker et al.

    Glucose-dependent regulation of glucose transport activity, protein and mRNA in primary cultures of rat brain glial cells

    J Biol Chem

    (1988)
  • K Takata et al.

    Erythrocyte/HepG2-type glucose transporter is concentrated in cells of blood–tissue barriers

    Biochem Biophys Res Commun

    (1990)
  • N Longo et al.

    Glucose transport by cultured human fibroblasts: regulation by phorbol esters and insulin

    Biochim Biophys Acta

    (1992)
  • B Thorens et al.

    Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney and beta-pancreatic islet cells

    Cell

    (1988)
  • B Thorens

    Molecular and cellular physiology of GLUT-2: a high-Km facilitated diffusion glucose transporter

    Int Rev Cytol

    (1992)
  • T Kayano et al.

    Evidence for a family of human glucose transporter-like proteins: sequence and gene localization of a protein expressed in fetal skeletal muscle and other tissues

    J Biol Chem

    (1988)
  • S Nagamatsu et al.

    Glucose transporter expression in brain: cDNA sequence of mouse GLUT3, the brain facilitative glucose transporter isoform, and identification of sites of expression by in situ hybridization

    J Biol Chem

    (1992)
  • G.I Bell et al.

    Structure and function of mammalian facilitative sugar transporters

    J Biol Chem

    (1993)
  • M Wozniak et al.

    The cellular and physiological actions of insulin in the central nervous system

    Neurochem Int

    (1993)
  • W.A Banks et al.

    Differential permeability of the blood–brain-barrier to two pancreatic peptides; insulin and amylin

    Peptides

    (1998)
  • G.A Werther et al.

    Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry

    Endocrinology

    (1987)
  • F Folli et al.

    The early intracellular signaling pathway for the insulin/insulin-like growth factor family in the mammalian central nervous system

    Mol Neurobiol

    (1996)
  • S Kar et al.

    Quantitative autoradiographic of [125]I-insulin-like growth factor I, [125]I-insulin-like growth factor II, and [125]I-insulin receptor binding sites in developing rat brain

    J Comp Neurol

    (1993)
  • D.G Baskin et al.

    Insulin in the brain

    Annu Rev Physiol

    (1987)
  • M.A Lesniak et al.

    Receptors for insulin-like growth factors I and II: autoradiographic localization in rat brain and comparison to receptors for insulin

    Endocrinology

    (1988)
  • M Adamo et al.

    Insulin and insulin-like growth factor receptors in the nervous system

    Mol Neurobiol

    (1989)
  • J.L Marks et al.

    Localization of insulin receptor mRNA in rat brain by in situ hybridization

    Endocrinology

    (1990)
  • M.A Abbott et al.

    The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses

    J Neurosci

    (1999)
  • N Potau et al.

    Ontogenesis of insulin receptors in human cerebral cortex

    J Endocrinol Investig

    (1991)
  • R.U Margolis et al.

    Insulin in the cerebrospinal fluid

    Nature

    (1967)
  • S.C Woods et al.

    Relationship between plasma and cerebrospinal fluid insulin levels of dogs

    Am J Physiol

    (1977)
  • O Szabo et al.

    Evidence for an insulin sensitive receptor in the central nervous system

    Am J Physiol

    (1972)
  • J Havrankova et al.

    Identification of insulin in rat brain

    Proc Natl Acad Sci USA

    (1978)
  • J Havrankova et al.

    Insulin receptors are widely distributed in the central nervous system of the rat

    Nature

    (1978)
  • A.B Smit et al.

    Towards understanding the role of insulin in the brain: lessons from insulin-related signalling systems in the invertebrate brain

    Prog Neurobiol

    (1997)
  • J.B Collip

    The demonstration of an insulin-like substance in the tissues of the clam (Mya arenaria)

    J Biol Chem

    (1923)
  • S Falkmer et al.

    Insulin in invertebrates and cyclosomes

    Am Zool

    (1973)
  • H.A.R Fritsch et al.

    On the ultrastructure of polypeptide hormone-producing cells in the gut of the ascidian, Ciona intestinalis L. and the bivalve Mytilus edulis L

    Cell Tissue Res

    (1977)
  • S van Noorden et al.

    Gut-islet endocrinology — some evolutionary aspects

    Investig Cell Pathol

    (1980)
  • S Wilson et al.

    Starfish insulin

    Can J Biochem

    (1965)
  • A Ullrich et al.

    Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes

    Nature

    (1985)
  • Cited by (0)

    View full text