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Glucose Transporters

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Title: Glucose Transporters


1
???? ???? ????
  • Glucose Transporters
  • (GLUT or SLC2A family)
  • ???? ??????
  • ???? ??? ???

2
Insulin
  • ??????? ??????? ??? ?? ?? ???? ??? ???? ?????????
    ???? ?? ???.
  • ?? ???? ??? ???? ????? ????? ? ??? ?? ??????
    ????? ??? ?? ?????? ???? ?? ?? ???? ??????? ? ??
    ?? ???? ??????? ????? ??????.
  • ?????? ??????? ? ??? ?? ???? ? ?? ??? ?? ????
    ?????? ??? (diabetes) ??? ?? ?? ????? ????? ??
    ????? ??? ?????? ??? ???.

3
Definition of Diabetes
  • Diabetes is any disorder characterized by
    excessive urine excretion.
  • 1- Diabetes mellitus A metabolic disorder in
    which there is an inability to oxidize
    carbohydrate due to disturbances in insulin
    function.
  • 2- Diabetes insipidus Is the result of a
    deficiency of antidiuretic hormone.
  • 3- Brittle diabetes Is a form that is very
    difficult to control. It is characterized by
    unexplained oscillations between hypoglycemia and
    acidosis

4
Types of Diabetes Mellitus
  • Diabetes mellitus is a heterogeneous clinical
    disorder with numerous causes. Two main
    classifications of diabetes mellitus are
    Idiopathic and Secondary
  • Idiopathic Which is divided into two main types.
  • 1- (IDDM) Insulin Dependent Diabetes Mellitus
    (type 1 diabetes) which most often manifests in
    childhood and is the result of an autoimmune
    destruction of the ß-cells of the pancreas.
  • 2- (NIDDM) Non-Insulin-Dependent Diabetes
    Mellitus (type 2 diabetes) is characterized by
    persistent hyperglycemia but rarely leads to
    ketoacidosis. Type 2 diabetes generally manifests
    after age 40.
  • There are two main forms of type 2 diabetes
  • 1. Late onset associated with obesity.
  • 2. Late onset not associated with obesity.

5
Types of Diabetes Mellitus
  • Secondary or other specific types of diabetes
    mellitus are the result of many causes including
  • 1-Maturity onset type diabetes of the young
    (MODY)1-6
  • 2-Pancreatic disease.
  • 3-Endocrine disease. Counter-regulatory hormones
    are glucagon, epinephrine, growth hormone and
    cortisol.
  • 4-Drug-induced diabetes.
  • 5-Anti-insulin receptor autoantibodies (Type B
    insulin resistance).
  • 6-Mutations in the insulin gene.

6
Types of Diabetes Mellitus
  • 7-Mutations in insulin receptor gene.
  • a. Leprachaunism
  • b. Rabson-Mendenhall syndrome
  • c. Type A insulin resistance
  • 8-Gestational diabetes.
  • 9-Many other genetic syndromes include
  • Wolfram syndrome, Down syndrome, Huntington
    disease, Werner syndrome,

7
Glucose transporter
  • Glucose
  • 1- Glucose is an essential substrate for the
    metabolism of most cells
  • 2- Glucose is a polar molecule
  • Thus transport through biological membranes
    requires specific transport proteins.
  • Glucose transporter (GLUT)

8
(No Transcript)
9
Glucose transporter
  • Transport of glucose through the membrane of
    intestinal and kidney epithelial cells depends on
    the presence of secondary active Na/glucose
    symporters, SGLT-1 and SGLT-2 which concentrate
    glucose inside the cells, using the energy
    provided by cotransport of Na ions down their
    electrochemical gradient.

10
(No Transcript)
11
Glucose transporter
  • GLUTs are integral membrane proteins which
    contain 12 membrane-spanning helices with both
    the C and N terminal exposed on the cytoplasmic
    side of the plasma membrane.
  • GLUT proteins transport glucose and related
    hexoses according to a model of alternate
    conformation.
  • Binding of glucose to one site provokes a
    conformational change associated with transport,
    and releases glucose to the other side of the
    membrane.
  • glucose-binding sites are probably located in
    transmembrane segments 9, 10, 11.
  • the QLS motif located in the seventh
    transmembrane segment could be involved in the
    selection and affinity of transported substrate.

12
Glucose transporter
13
Glucose transporter
14
Glucose transporter
  • ???? ?????? ????? ????? ?? ?? ???? ? ?????
    ??????? ?? ???.
  • 1- protein symbol GLUT (Glucose transporter).
  • 2- gene symbol SLC2 (Solute Carrier Family 2) .
  • ???? ????? ??? ?? ?? ????? ?? ????? ? ?? ??? A
    ?????? ??????? ?? ???.
  • ?????? ???? GLUT 1 ?? SLC2 A1.

15
GLUTs Types
  • Most mammalian cells transport glucose through a
    family of membrane proteins known as glucose
    transporters.
  • Each glucose transporter isoform plays a specific
    role in glucose metabolism determined by
  • 1- pattern of tissue expression.
  • 2- substrate specificity.
  • 3- transport kinetics.
  • 4- regulated expression in different
    physiological conditions.

16
GLUTs Types
  • GLUT1 Is widely distributed in fetal tissues.
    In adult, mediates glucose transport into red
    cells, and throughout the blood brain barrier.
  • GLUT2 Is expressed by renal tubular and small
    intestinal epithelial cells. It provides glucose
    to liver and pancreatic ß cells.
  • GLUT3 Is the main transporter in neurons.
  • GLUT4 Is the insulin-regulated glucose
    transporter found in adipose tissues and striated
    muscle (skeletal and cardiac) that is responsible
    for insulin-regulated glucose disposal.

17
GLUTs Types
  • GLUT5 Transports fructose in intestine and
    testis.
  • GLUT6 Name was previously assigned to a
    pseudoegene. It is highly expressed in brain,
    spleen, and leukocytes.
  • GLUT7 Expressed in liver and other
    gluconeogenic tissues, mediates glucose flux
    across endoplasmic reticulum membrane.

18
GLUTs Types
  • GLUT8 High levels are found in adult testis
    and placenta.
  • GLUT9 It is expressed in kidney and liver. It
    is also detected in placenta, lung, blood
    leukocytes, heart, and skeletal muscle.
  • GLUT10 Has been identified as a candidate
    gene for NIDDM susceptibility. It is widely
    expressed with highest levels in liver and
    pancreas.

19
GLUTs Types
  • GLUT11 It is expressed in heart and skeletal
    muscle.
  • GLUT12 It is expressed in skeletal muscle,
    adipose tissue, and small intestine.
  • GLUT13 (H myo-inositol transporter - HMIT)
    It is predominantly expressed in brain.

20
GLUTs Types
  • 13 ??? GLUT/SLC2 ??????? ???? ?? ???? ????? ?
    ?????? ?? 3 ???? ????? ?? ????.
  • ???? ??? GLUT4 - GLUT3 - GLUT2 - GLUT1
  • ???? ??? GLUT11 - GLUT9 - GLUT7 - GLUT5
  • ???? ??? GLUT12 - GLUT10 - GLUT8 - GLUT6 - GLUT
    13 (H/myoinositol transporter HMIT)
  • Most members of classes II and III have been
    identified recently in homology searches.

21
New Nomenclature (HUGO) of Gluts
Protein Other Names Gene Chromos.
Accession MajorTissue Major
Isoform Name Locuse
Numbers Experssion GLUT1 GTR1, Hu 492aa
SLC2A1 1p35-31.3 AC023331 Erythrocytes, brain
GLUT2 GTR2, Hu 524 aa SLC2A2 3q26.2-27
AC068853 Liver, islets GLUT3 GTR3, Hu 496
aa SLC2A3 12p13.3 AC007536 Brain (neuronal)
GLUT4 GTR4, Hu 509 aa SLC2A4 17p13
AC003688 Muscle, fat, heart GLUT5 GTR5, Hu
501 aa SLC2A5 1p36.2 AC041046 Intestine,
testis, kidney GLUT6 GTR6, Hu 507 aa SLC2A6
9q34 AC002355 Spleen, leukocytes, brain GLUT7
GTR7, Rt 528 aa SLC2A7 1p36.2 AL356306
Liver GLUT8 GTR8, Hu 477 aa SLC2A8 9
AL445222 Testis, blastocyst, brain GLUT9 GTR9,
Hu 511/540aa SLC2A9 4p15.3-16 AC005674
Liver, kidney GLUT10 GTR10, Hu 541 aa
SLC2A10 20q12-13.1 AC031055 Liver, pancreas
GLUT11 GTR11, Hu 496 aa SLC2A11 22q11.2
AP000350 Heart, muscle GLUT12 GTR12, Hu 617
aa SLC2A12 6q23.2 AL449363 Heart, prostate
GLUT13 HMIT, Hu 618/629 aa SLC2A13
AJ315644 Brain
22
Regulation of insulin secretion
Na
GLUT2
K
K
KIR
Na
K
K
Ca2
Ca2
Ca2
Pancreatic ß cell
Voltage-gated Ca2 channel
Ca2
Ca2
Insulin granules
23
Basal insulin secretion
Pacemaker ß cells
Na
GLUT2
K
Signal
K
KIR
Na
K
Vm
K
Ca2
Ca2
Ca2
Pancreatic ß cell
Voltage-gated Ca2 channel
Ca2
Ca2
Insulin granules
24
Glucose-stimulated insulin secretion
Glucose
ß cell integrates input from various metabolites,
hormones and neurotransmitters
Na
Na
GLUT2
K
K
K
KIR
Na
Glucokinase Km 7-9 mM
K
K
Vm
K
ATP
Ca2
Ca2
Pancreatic ß cell
Ca2
Voltage-gated Ca2 channel
Ca2
Insulin granules
25
Sulfonylureas Mechanism of Action
Sulfonylureas
Na
GLUT2
K
K
KIR
Na
K
Vm
K
Ca2
Ca2
Ca2
Pancreatic ß cell
Voltage-gated Ca2 channel
Ca2
Insulin granules
26
Insulin mechanism of action
Cell-surface receptors
a subunits contain insulin binding sites
plasma membrane
b subunits have tyrosine kinase activity
27
Insulin receptor signaling
Insulin binding to a subunit regulates b subunit
activity
PO4?
autophosphorylation of b subunit
IRS-1 ATP
IRS-1?PO4
? tyr kinase activity
Glucose transporter translocation to plasma
membrane
phosphorylation of other substrates
activation of phospho- inositide 3-kinase
28
Insulin receptor signaling
Insulin binding to a subunit regulates b subunit
activity
PO4?
autophosphorylation of b subunit
IRS-1 ATP
IRS-1?PO4
? tyr kinase activity
phosphorylation of other substrates
29
Insulin receptor signaling
Insulin binding to a subunit regulates b subunit
activity
PO4?
autophosphorylation of b subunit
IRS-1 ATP
IRS-1?PO4
Glycogen deposition
? tyr kinase activity
phosphorylation of other substrates
30
Normal kinetics of intestinal glucose absorption
in the absence of GLUT2
  • ?? ??? ????? ?? ??? ??? ????? ????? ???? GLUT2-/-
    ( ???? ?????) ??????? ?? ?? ??? ??? ???? (????
    ?????)? ????? ?? ????? ?? Phlorizin ???? ?????.
  • ????? ??? ??????? ?? ?? ?? ?? ???? ??.
  • ?? RNA ???? ??? ????? (acid guanidinium
    thiocyanate technique) ???? ???.
  • ???? ???? ?????? GLUT1, 2, 3, 5, 8, and 9 mRNA ??
    ??? Northern blot analysis ??????? ??.
  • ????? ??? ?? ???? ?? ??? ?? ???? ????? ??????
    ?????? ????.
  • ?? ??? ????? ?? ?????? ?? Fanconi-Bickel syndrome
    ?? ?? ??? ??? ???? ??? ?? ?? ?? GLUT2 ????? ??
    ???? ??? ? ??? ??? ????? ?? ?????????? ???? ?????.

31
Normal kinetics of intestinal glucose absorption
in the absence of GLUT2
32
Normal kinetics of intestinal glucose absorption
in the absence of GLUT2
  • mRNA ????? ?? GLUT1 ?? ??? ????? ???? ???.
  • mRNA ????? ?? GLUT2 ??? ?? ???? ????? ???? ??.
  • mRNA ????? ?? GLUT3 ?? ??? ????? ???? ???.
  • ??? GLUT8 ????? ?? ???? ?? ?? ???? ????? ? ????
    GLUT2 ?? ??? ?????? ???? ????.
  • ??? GLUT5 ?? ???? ????? ????? ??? ???? ?? ????
    ????GLUT2 ?????? ????.
  • ??? G6Pase ? G6PTase ?? ???? ???? ?? ????? ???.

33
Normal kinetics of intestinal glucose absorption
in the absence of GLUT2
34
Normal kinetics of intestinal glucose absorption
in the absence of GLUT2
  • ?? ?????? ???? GLUT2 ?????? ????? ??????? ?????
    ??? ??? ???? ????? ????? ???? ????? ???? ?? ??
    ???? ????? ???? ???? ????? ???? ?????? ???? ????
    ?? ???????? ????? ?? ???? ???? ?????? ???????? ??
    ???? ????? ????? ?? ??? ? ????? ????? ????? ???
    ?? ????? ??? ??????? ?? ????. Membrane
    Traffic-based Pathway
  • ??? ???? ?? ???? ??? ????? ???? ???? ???? ????
  • 1- ?? ???? SGLT-1 ??????? 15 ???? ?? ??? ?????
    ????? ???.
  • 2- ???? (MTP) ??????? ????? GLUT2 ?? ????? ???.

35
(No Transcript)
36
glucose transporter 4
  • In most insulin-resistant states, such as obesity
    and NIDDM, GLUT4 gene expression is reduced in
    adipose cells, in skeletal muscle GLUT4
    expression is normal.
  • Thus, the decreased glucose uptake in response to
    insulin (insulin resistance) in skeletal muscle
    results from alterations in the translocation,
    docking, or fusion of glucose transporters at the
    plasma membrane or T tubules, or potentially from
    changes in the specific activity of the
    transporters (moles of glucose transported/transpo
    rter/unit of time)

37
glucose transporter 4
  • Exercise and insulin utilize distinct signaling
    pathways that lead to the activation of glucose
    transport in skeletal muscle.
  • In insulin-resistant, defective activation of
    PI3-kinase, results impaired intracellular
    signaling.
  • However, the activation of PI 3-kinase is not
    important for the effects of exercise to
    stimulate glucose transport.
  • Some of the beneficial effects of exercise
    training on insulin action may be indirect,
    resulting from weight loss or changes in body
    composition (increased lean body mass).

38
glucose transporter 4
  • Training cessation for 14 days in
    endurance-trained (runners) or strength-trained
    (weight lifters) subjects was associated with a
    decrement in insulin sensitivity but no reduction
    in GLUT4 expression in muscle, suggesting that
    multiple factors are involved in the changes in
    insulin sensitivity with detraining.

39
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40
Dynamic traffic of GLUT4
  • In unstimulated fat or muscle cells (i.e., the
    basal state), 310 of GLUT4 is located at the
    cell surface and gt90 is in intracellular
    compartments.
  • Insulin shifts the steady-state distribution of
    GLUT4 toward the PM by elevating the exocytic
    rate of GLUT4 and minimally reducing its
    endocytic rate.
  • The excursion of GLUT4-containing vesicles to and
    from the PM, the dynamic traffic of GLUT4 between
    multiple intracellular compartments, and
    vesicle-membrane fusion are exquisitely regulated.

41
regulated recycling
42
Insulin-stimulated glucose uptake
  • Two signaling pathways downstream of insulin
    receptor appear to control the movement of GLUT4
    to the membrane1- The phosphatidylinositol
    3-kinase (PI3-kinase) pathway.
  • 2- The Rho-family GTPase TC10 pathway.

43
The phosphatidylinositol 3-kinase (PI3-kinase)
pathway
44
The Rho-family GTPase TC10 pathway
45
The Rho-family GTPase TC10 pathway
  • The caveolin gene family has three members in
    vertebrates CAV1, CAV2, and CAV3, coding for the
    proteins caveolin-1, caveolin-2 and caveolin-3,
    respectively. All three members are membrane
    proteins with similar structure.
  • Caveolin forms oligomers and associates with
    cholesterol and sphingolipids in certain areas of
    the cell membrane, leading to the formation of
    caveolae.
  • Oligomers of caveolin form the coat of a domains
    . Many functions are ascribed to these domains,
    ranging from endocytosis and transcytosis to
    signal transduction.

46
The Rho-family GTPase TC10 pathway
  • Caveolin-1 is most prominently expressed in
    endothelial, fibrous and adipose tissue.
  • The expression pattern of caveolin-2 is similar
    to that of caveolin-1 it seems to be
    co-expressed with caveolin-1.
  • The expression of caveolin-3 is restricted to
    skeletal muscle.

47
Insulin-stimulated glucose uptake
48
Insulin-stimulated glucose uptake
49
Exercise-stimulated glucose uptake
50
Exercise-stimulated glucose uptake (Ca2
concentration)
  • In rats muscle, raising intracellular Ca2 by
    treatment with caffeine in vitro also increases
    glucose transport.
  • In contrast, no effect of Ca2 ionophores on
    basal skeletal muscle glucose transport, with an
    inhibition of insulin-stimulated glucose
    transport .
  • The discrepancies between these findings may
    relate to the magnitude and duration of the
    increase in cytosolic Ca2 .

51
Exercise-stimulated glucose uptake (Calmodulin)
  • CaM inhibitors show reductions in
    contraction-stimulated glucose transport, perhaps
    because CaM inhibition leads to reduced tension
    development.
  • Specific inhibition by KN62/93 that are activated
    by Ca2-bound CaM (i.e., CaMKI, -II, -IV) leads
    to partial reduction in contraction-stimulated
    glucose transport without affecting tension
    development.
  • CaMKII activity is increased in contracting
    skeletal muscle of humans during
    exercise/contraction and KN62/93 impairs the
    activation of CaMKII .

52
Exercise-stimulated glucose uptake (Nitric oxide
synthase)
  • Nitric oxide synthase (NOS) is also activated by
    Ca2-bound CaM. NOS activity and its production
    are increased during exercise in skeletal muscle
    cells.
  • Inhibition of NOS leads to reduced glucose uptake
    without affecting total blood flow across the
    working limb of humans.
  • The effect of NOS inhibition on glucose uptake in
    humans might be explained by regulation of
    nutritive flow rather than membrane transport,
    although this remains to be established .

53
Exercise-stimulated glucose uptake (AMPK)
  • Energy-sensing signaling system is likely to be
    involved in stimulating glucose transport with
    contractions.
  • 5'-AMP-activated protein kinase (AMPK) may be the
    enzyme that fulfils this role as reflected by the
    ratios of AMP/ATP and creatine/phosphocreatine.
  • Because activation of AMPK in resting muscle by
    the drug 5'-aminoimidazole-4-carboxyamide-ribonucl
    eoside (AICAR) increases glucose
    transport/uptake, it would seem logical to
    ascribe a role for AMPK in contraction-stimulated
    glucose transport.

54
Exercise-stimulated glucose uptake (AMPK)
  • Thus, although AMPK is an attractive candidate
    for signaling in contraction-stimulated muscle
    glucose uptake, the available evidence at this
    time does not lead to a clear conclusion
    regarding its role.

55
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    ????? ?????.
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