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Glucose Regulation by Dr Sarma (PowerPoint)

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                 Glucose Homeostasis
                  Counter Regulation


                  Dr.Sarma.R.V.S.N
                  M.D., (Med) M.Sc., (Canada)
                     Consultant Physician
                      and Chest Specialist




                     BioEd Online
Glucose Equilibrium – A Wonder !!

   Normal Blood Glucose
      Fasting state : 60 to 100 mg%

        Postprandial : 100 to 140 mg %
   What keeps the blood glucose in such a narrow range?
   Why are we not becoming hypoglycemic when we
    fast?
   Why is our blood sugar not shooting up to very high
    levels after a rich meal ?
   What are the regulatory and counter regulatory
    hormones ?

                                                          2
Glucose Equilibrium – A Wonder !!

   Normal Blood Glucose
      Fasting state : 60 to 100 mg%

        Postprandial : 100 to 140 mg %
 Let us grasp some of the fascinating
 What keeps the blood glucose in such a narrow range?
                     answers !!
   Why are we not becoming hypoglycemic when we
    fast?
   Why is our blood sugar not shooting up to very high
    levels after a rich meal ?
   What are the regulatory and counter regulatory
    hormones ?

                                                          3
    Glucose Homeostasis Research Timeline
1552BC       1st Century AD   1776   18th Century   1869   1889   1921-23       1983     2001



   1552 BC: Ebers Papyrus in ancient Egypt. First known written description of diabetes.
   1st Century AD: Arateus — ―Melting down of flesh and limbs into urine.‖
   1776: Matthew Dobson conducts experiments showing sugar in blood and urine of diabetics.
   Mid 1800s: Claude Bernard studies the function of the pancreas and liver, and their roles in
    homeostasis.
   1869: Paul Langerhans identifies cells of unknown function in the pancreas. These cells later
    are named ―Islets of Langerhans.‖
   1889: Pancreatectomized dog develops fatal diabetes.
   1921: Insulin ―discovered‖ — effectively treated pancreatectomized dog.
   1922: First human treated with insulin. Eli Lilly begins mass production.
   1923: Banting and Macleod win Nobel Prize for work with insulin.
   1983: Biosynthetic insulin produced.
   2001: Human genome sequence completed.

                                                                                             4
 Cell growth and energy metabolism

Carbohydrates
   Glucose            Pyruvate


                Fatty acids

    Fats

                Amino acids
                                        TCA Cycle
                                       Kreb’s Cycle
  Proteins
                                 ATP

                                                      5
Intermediary Metabolism of Fuels




                                   6
 Intermediary Metabolism of Fuels




                          Clinical Pearl
       1. All the fuels are inter changeable in the body
2. It is the total calorie restriction that is important in Obesity
                                and T2D




                                                                 7
Glucose-6-Phosphate – The Central Molecule




                                             8
Glucose-6-Phosphate – The Central Molecule




                     Clinical Pearl
 G-6-Phosphate is the Center Stage for CHO Metabolism
Glucose-6-Phosphate dehydrogenase (G6PD) is the crucial
                       enzyme




                                                        9
Homeostasis of Glucose
Counter Regulation Mechanisms
   A steady maintenance of blood glucose with in a narrow range
   Fasting state and fed states – their effects on BG
   Rate of glucose appearance Ra
   Rate of disappearance Rd must be in balance

   Blood Glucose (BG) = Ra   - Rd
   Control systems
       Glucose Receptors, GLUT 1-14

       Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,

       Insulin Signaling sequences, Glucagon signaling

       Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue

       Feedback loops

           Negative feedback

           Positive feedback




                                                                           10
Homeostasis of Glucose
Counter Regulation Mechanisms
   A steady maintenance of blood glucose with in a narrow range
   Fasting state and fed states – their effects on BG
   Rate of glucose appearance Ra

                              Clinical Pearl
    Rate of disappearance Rd must be in balance


             INSULIN R - R
    Blood Glucose (BG) = v/s GLUCAGON
                          a   d
                                                 and Rd V/s Ra
   Control systems
       Glucose Receptors, GLUT 1-14

       Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,

       Insulin Signaling sequences, Glucagon signaling

       Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue

       Feedback loops

           Negative feedback

           Positive feedback




                                                                           11
     Normal, Hyper and Hypoglycemic states
Ra
                         Ra is the rate of appearance of
                         Glucose
       100
       mg                Rd is rate of disappearance of
                   Rd    Glucose
                         When Ra = Rd; It is
Ra                Ra         Ra
                         Euglycemic state Ra
 200               200          50             50
 mg                mg           m              m
             Rd          Rd     g       Rd     g     Rd
     Ra > Rd; Ra ↑or Rd↓        Ra < Rd; Ra ↓or Rd ↑
         HYPERGLYCEMIA               HYPOGLYCEMIA
                                                     12
Effect of CHO intake on Glucose Metabolism


Gluconeogen        Glycogenoly        Exogenous
    esis               sis               CHO
Lipolysis
              Ra
      GLUCAG
        ON



                                      INSULIN
                                 Rd


                                                13
Glucose Homeostasis
                     Lower Blood         Between meals
                       Glucose



-cells release                     -cells release
Glucagon                            insulin
stimulate glycogen                  stimulate glucose
breakdown and                       uptake by
gluconeogenesis                     peripheral tissues

                     Higher Blood
  Food                 Glucose

                                                    14
High blood glucose affects the size of beta cells




                                                    15
Pancreatic Hormones

 Pancreas
    Exocrine Pancreas – P Lipase, P amylase etc
    Endocrine Pancreas – Islets of Langerhans
    Hormones secreted are –
         Alpha cells – Glucagon
         Beta cells – Insulin
         C cells - Somatostatin
         D cells - Somatostatin
         E cells - ?? Function
         F cells - Pancreatic polypeptide (PPP)

                                                   16
Regulation of Blood Glucose levels

    Glucose is the major source of energy for cells
    Blood Glucose (BG) regulated by Insulin & Glucagon




                                                          17
 Regulation of beta-cell size by the level of Glucagon
Glucose Homeostasis – Insulin and blood glucose




                                                         18
Glucose Homeostasis Chart

                  High Blood Sugar            Low Blood Sugar
Condition
                 Toxic to the cells - AGP     Energy needs unmet


Receptor        Glucose transporter         Glucose transporter


Control Center -cell of the pancreas       -cell of the pancreas


Effector               Insulin                   Glucagon

                Glucose uptake by            Liver breaks down
Result           muscle/fat tissue          glycogen to glucose
               Lowers blood glucose         Raises blood glucose


                                                                   19
The Six Mechanisms of Transport - CM
                                2
       1
                                           3


   6



           5                           4

                                               20
Membrane Transport Proteins




                              21
Channel Proteins




                   22
Cell Membrane - Transporters




                               23
ATP Powered Receptors




                        24
Glucose Transport




               FIRST STEP
GLUCOSE ABSORPTION IN THE GI TRACT




                                 25
Intestinal Cell Transport




                            26
Intestinal Cell Transport




                    Clinical Pearl
New approach in T2D, MS and Obesity - GLUT-2 Blockers




                                                    27
The First Messengers from GI tract




            THE MESSERGERS
       INCRETINS – GLP1 and GIP_




                                     28
Entero-Insular Axis of Secretion

Insulin secretion is also increased
      By intestinal polypeptide hormones
      GLP-1 (glucagon like peptide) [exendin-4]
      Glucose-dependent insulinotropic peptide(GIP)
      GLP-1 and GIP are called Incretins
      Cholecystokinin and by pancreatic Glucagon.
      Insulin secretion is decreased by pancreatic
       somatostatin.


                                                       29
Entero-Insular Axis of Secretion

Insulin secretion is also increased
      By intestinal polypeptide hormones
      GLP-1 (glucagon like peptide) [exendin-4]
                      Clinical Pearl
New Glucose-dependent insulinotropic peptide(GIP)
   Drugs for T2D- Incretin (GLP-1 and GIP) Function

                     Enhancers
   GLP-1 and GIP are called Incretins

      Cholecystokinin and by pancreatic Glucagon.
      Insulin secretion is decreased by pancreatic
       somatostatin.


                                                      30
Response to Elevated Blood Glucose

 In the post prandial state (after a meal)
    Remember there are two separate signaling events

    First signal is from the ↑ Blood Glucose to pancreas
    To stimulates insulin secretion in to the blood stream
    The second signal from insulin to the target cells
    Insulin signals to the muscle, adipose tissue and liver
     to permit to glucose in and to utilize glucose
    This effectively lowers Blood Glucose



                                                               31
Response to Elevated Blood Glucose

 In the post prandial state (after a meal)
    Remember there are Clinical Pearl signaling events
                        two separate
    Insulin secretion must be triggered – First Signal
 1.First signal is from the ↑ Blood Glucose to pancreas
 

 2.To stimulates insulin secretion in to the blood stream–
 
    Secreted Insulin must trigger Glucose uptake
    Second signal
    The second signal from insulin to the target cells
 3. T2D may result from failure of either or both
    Insulin signals to the muscle, adipose tissue and liver
     to permit to glucose in and to utilize glucose
    This effectively lowers Blood Glucose



                                                               32
Glucose induced Insulin secretion

                            Glucose enters the beta cells
                             through uniporter GLUT 2
                            Oxidative phosphorylation
                            ATP closes the ATP gated K+
                             channel and depolarizes the
                             cell membrane
                            Depolarization opens the
                             voltage gated Ca+ channels
                            Ca+ enters the beta cells
                            This leads to exocytosis of
                             Insulin and secretion

                                                           33
Glucose induced Insulin secretion

                                Glucose enters the beta cells
                                 through uniporter GLUT 2
                   Clinical Pearl
                                Oxidative phosphorylation
    Closure of KATP Channels by Glucose is            +
                          ATP closes the ATP gated K
                 fundamental
                           channel and depolarizes the
   Glucose is necessary to cell membrane
                           stimulate Insulin
                              Depolarization opens the
      Insulin is necessary      let in glucose
                             tovoltage gated Ca+ channels
                                Ca+ enters the beta cells
                                This leads to exocytosis of
                                 Insulin and secretion

                                                               34
K+ATP Channel Closed by ↑ BG and SU




                                      35
K+ATP Channel Closed by ↑ BG and SU


                  Clinical Pearl
  1. SU Group close KATP Channels – Secrete
     Insulin
  2. Differences in action of SU are because of the
     differences
     in their action on KATP Channels
  3. Gliclazide and Glimiperide just hit the SUR
     closure and stop

                                                   36
Intricacies in the Beta Cell




                               37
K+ ATP – Sulfonylurea Receptor

                           K+ ATP channel has two sub
                            units – Kir6.2 and regulatory
                            sulfonylurea receptor(SUR)
                           ATP gated K+ channel is
                            coupled to SUR
                           K+ channel can be closed
                            independently of glucose
                           This leads to increased
                            insulin secretion
                           SUR1 are ATP binding
                            transporters superfamily


                                                        38
K+ ATP – Sulfonylurea Receptor

                               K+ ATP channel has two sub
                     Clinical Pearl – Kir6.2 and regulatory
                                units
                                sulfonylurea receptor(SUR)
 1. Glibenclamide, Tolbutamide cause prolonged
    closer of the SUR                       +
                               ATP gated K channel is

                                coupled to SUR
 2. This causes prolonged and intense pressure on
                              +
                            K channel can be closed
    Beta cells
                                   independently of glucose
 3. This is the cause of late hypoglycemia with these
                               This leads to increased
    SUs
                                   insulin secretion
                             in fast after a few years of
 4. Beta cell apoptosis sets  SUR1 are ATP binding
    use                        transporters superfamily


                                                              39
(F)PHHI

   (Familial) Persistent Hyperinsulinemic Hypoglycemia of Infancy
   Unregulated insulin secretion
   Profound hypoglycemia and brain damage
   Manifests at birth or at first year of life
   Under diagnosed
   Probably the cause of undiagnosed postnatal deaths
   Defect is KATP Channels mutation –
   Persistent closure with continuous trigger for Insulin release
   Treatment is pancreatectomy – (95% of pancreas)



                                                                     40
K+ATP Channel Opening is Cardio-protective




                                             41
K+ATP Channel Opening is Cardio-protective




                        Clinical Pearl
1. Glibenclamide, Tolbutamide close the SUR in myocardium
      2. This effect is deleterious to heart in ischemia




                                                           42
Tyrosine Kinase Pathway - Insulin




                                    43
Tyrosine Kinase Pathway - Insulin


                    Clinical Pearl
 1. Tyrosine Kinase (TK) phosphorylation is the
    fundamental step
 2. Its failure stops further cascade of intracellular
    signals
 3. This is one of the possible mechanisms of Insulin
    Resistance
 4. PPAR- Gamma (Pioglitazone) enhances TK
    signaling pathway

                                                         44
Insulin Receptor (IR)

    Insulin Receptor is a tyrosine kinase.
    Consists of 2 units -dimerize when bound with insulin.
    Inside cell - auto phosphorylation occurs,
    Increasing tyrosine kinase activity.
    Insulin Receptor phosphorylates intracellular
     signaling molecules.
    Stimulates insertion of GLUT-4 proteins
    which let in glucose
    Stimulate glycogen, fat and protein synthesis.


                                                              45
                        + HN        NH3+
                         3

                        S S
              Insulin                      -subunits
                        S S -S-S-



   EXTRACELLULAR
           -OOC
                    S                 S         COO-
           + HN     S                 S
            3                                  NH3+

              Plasma
             membrane                              CYTOPLASM
                                       Transmembrane
               Tyrosine                domain
                kinase
               domain -OOC       COO-
                            -subunits
Figure 2. The insulin receptor. Insulin binding to the -chains transmits
a signal through the transmembrane domain of the -chains to activate46
the tyrosine kinase activity
        Extracellular
    1                    2            IRTK (R) 3
  insulin             IRTK (L)        phosphorylated/
  binds               activated       activated




                                                  OP
                                                  OP
   L     R                                    P
                                          P
Cytoplasm                           P
                                P
                        P
                      ATPs                        ADPs

                             Phosphorylation
                             catalyzed by IRTK (L)

Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by
                                                                            47
insulin binding, followed by interchain autophosphorylation
        Extracellular
    1                    2            IRTK (R) 3                    4
  insulin             IRTK (L)        phosphorylated/            IRTK (L)
  binds               activated       activated                  phosphorylated




                                                    OP          PO           OP
                                                    OP          PO
                                                                P            OP
   L     R

                                  ATPs
                                    P           P    P    P P
Cytoplasm                                                        ADPs
                      ATPs                      ADPs

                             Phosphorylation
                             catalyzed by IRTK (L)

Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by
                                                                            48
insulin binding, followed by interchain autophosphorylation
Insulin Signaling – TK Receptor phosphorylation

Binding of insulin to the TK Receptor causes
   Transphosphorylation of tyrosines on the receptor
   Phosphotyrosine residues bind to
   IRS-1 (insulin receptor substrate – adopter protein)




                                                           49
Insulin Receptor (IR)
A key regulator of growth signaling
                         IR is hetero-tetramer

                         Insulin binding induces
                          conformation change and
                          stimulation of receptor
                          Tyrosine kinase activity

                         IR auto-phosphorylates and
                          phosphorylates downstream
                          second messengers, like IRS
                          (Insulin Receptor Substrate)

                         Obesity down regulation of IR

                         Diabetes up regulation of IR

                                                          50
Epidermal Growth Factor (EGF) Receptor
Auto-phosphorylation of TK (Obesity)
Receptor tyrosine kinases

                                 The interaction of the
                                 external domain of a
                                 receptor tyrosine kinase
                                 with the ligand, often a
                                 growth factor, up-
                                 regulates the enzymatic
                                 activity of the intra
                                 cellular catalytic
                                 domain, which causes
                                 tyrosine
                                 phosphorylation of
                                 cytoplasmic signaling
                                 molecules.



                                                      51
Epidermal Growth Factor (EGF) Receptor
Auto-phosphorylation of TK (Obesity)
Receptor tyrosine kinases

                                     The interaction of the
                                     external domain of a
                                     receptor tyrosine kinase
                      Clinical Pearl with the ligand, often a
                                     growth factor, up-
  1. Up regulation of TK receptor    regulates the enzymatic
     (autophosphorylation) in obesityactivity of the intra
                                     cellular catalytic
  2. Leads to Glucose entry into cells with out insulin
                                     domain, which causes
     signal                          tyrosine
                                     phosphorylation of
                                     cytoplasmic signaling
                                     molecules.



                                                          52
Insulin Signaling – PKB and MAPK pathways


   Ras independent signaling – The PKB Signaling and
   Ras dependent – The MAPK Signaling
   Ras independent through activation of Protein Kinase B
   Responsible for immediate non-genomic effects
   Ras dependent – Activation of
   Mitogen Activated Protein Kinase (MAPK) pathway
   Responsible for genomic effects



                                                         53
Insulin Signaling – PKB and MAPK pathways




                                            54
Insulin Signaling – PKB and MAPK pathways




                  Clinical Pearl
1. Ras independent signaling cascade – PI3P – PKB
2. Ras dependent signaling cascade – MAP Kinase




                                               55
Glucose Uniporter - GLUTs




                            56
 Glucose Uniporter - GLUTs



                      Clinical Pearl
1. Translocation of GLUT-4 to cell surface is crucial for
                      Glu. uptake
2. Insulin resistance is usually due to failure of this step




                                                         57
Ras Independent – PI3K - PKB Signaling

   IRS1 binds PI3 kinase through SH2 domain
   This phosphorylates PIP2 to PIP3
   Increased concentration of PIP3 recruits
   PKB to the plasma membrane
   PKB is phosphorylated by
   two membrane associated kinases PKC λ and ξ
   Active PKB is released into the cytosol
   Where it translocates glucose transporter (GLUT-4)
   GLUT-4 (uniporter) moves on to the membrane
   GLUT-4 lets Glucose in and increases glucose uptake


                                                          58
PIP Signaling Pathway




                        59
Ras - Independent Insulin Signaling




                                      60
Insulin and PI3K Signaling




                             61
     Ras
 Independent          Extracellular
                      Space
                                              = GLUT-4


                      Cytoplasm                          Active IRTK   PO      OP
                                          IRS                          PO      OP
                                          
                                         tyr-OH
                                      ATP [1] IRTK

                                      ADP catalyzed          IRS   p85 [2] activated
                                                           IRS            by docking
                                                                   PI-     active IRS
                                                      IRS  tyr-OP 3K
                                          IRS IRSactive tyr-OP
                                                  IRS 
                                                                              PIP2
Figure 5. Mechanism for insulin to                           PIP3
mobilize GLUT-4 transporter to the              tyr-OPtyr-OP
                                           tyr-OP
plasma membrane in muscle & adipose                      +         [4] signals Golgi to
tissue.                                      PDK               PKB traffic GLUT-4 to
IRS, insulin-receptor substrate;                                   membrane
IRTK, insulin receptor tyrosine kinase;
PI-3K, phosphatidyl-inositol kinase;                     GOLGI
PDK; phospholipid-dependent kinase
PKB, protein kinase B
                                                                                62
Ras Dependent – MAPK Signaling
At the same time…
   Phosphorylated insulin receptor binds
   to adapter protein SHC through GRB2
   GRB2 also has SH3 domains that bind and activates Sos
   Binding of Sos to inactive Ras causes a
   conformational change that permits release of
   GDP and binding of GTP (activation of Ras)
   Sos is a GEF for monomeric G protein Ras
   Sos dissociates from activated Ras
   Linking insulin receptor to Ras

                                                            63
Ras - Dependent Insulin Signaling




                                    64
Ras Dependent – MAPK Signaling

   Activated Ras passes the signal to raf kinase
   Raf activates a cascade of kinases (MAP Kinase cascade)
   Mitogen Activated Protein Kinases (MAP Kinases)
   Highly conserved kinase cascades
   Last kinase in the cascade has to be double phosphorylated
   It has high specificity (since it is double phosphorylation)




                                                                   65
   Ras
Dependent
     Glucose
                                                                       Extracellular
    GLUT-4                                            PO          OP
                                                                     Cytoplasm
           Glucose transport                          PO          OP
           (muscle/adipose)
                                                      Activated IRTK


                               metabolic
                               responses        Signal transduction
                                                (e.g., phosphorylation of IRS, SHC, PLC)
   Activation of protein
   phosphatase
   Dephosphorylation of:                           KINASE CASCADE
   glycogen synthase                            (protein phosphorylation)
   glycogen phosphorylase                                  mitogenic
   phosphorylase kinase      Cell growth
                                                           response
   acetyl CoA carboxylase and replication
   hormone-sensitive lipase
   phosphofructokinase-2                   NUCLEUS
   pyruvate kinase
   HMG CoA reductase                  DNA synthesis
   regulatory kinases
                                         mRNA synthesis
                    Protein
                   synthesis                                                           66
Ras Dependent – MAPK Signaling

   MAPK regulates the activity of transcription factors
   Active MAPK translocates to the nucleus
   It phosphorylates several transcription factors
   And production of more GLUT4




                                                           67
Glucose Entry in to the Cell

   Insulin/GLUT4 is not the only pathway
   Insulin-dependent, GLUT 4 - mediated
        Cellular uptake of glucose into muscle and
         adipose tissue (40%)
   Insulin-independent glucose disposal (60%)
        GLUT 1 – 3 in the Brain, Placenta, Kidney
        SGLT 1 and 2 (sodium glucose symporter)
        Intestinal epithelium, Kidney



                                                      68
Fatty Acid Dysregulation impairs Insulin action




                                                  69
Fatty Acid Dysregulation impairs Insulin action




                 Clinical Pearl
    1.Excess FFA – cause dysregulation of
      IR
    2.GLUT-4 function is impaired – Insulin
      Resistance


                                                  70
Cyclic AMP Pathway - Glucagon




     Off switch
     PDE inactivates cAMP
     PDE stops signal transduction.
     Caffeine inhibits PDE!




                                       71
Glucose controls Insulin and Glucagon release




                                                72
Liver and Kidney

   Major source of net endogenous glucose production
   Accomplished by gluconeogenesis and glycogenolysis
    when glucose is low
   And of glycogen synthesis when glucose is high.
   Can oxidize glucose for energy and convert it to fat
    which can be incorporated into VLDL for transport.




                                                           73
Metabolic Effects of Insulin - in the Liver




                                              74
Muscle

   Can convert glucose to glycogen.
   Can convert glucose to pyruvate through glycolysis -
    further metabolized to lactate or transaminated to
    alanine or channeled into the TCA cycle.
   In the fasting state, can utilize FA for fuel and
    mobilize amino acids by proteolysis for transport
    to the liver for gluconeogenesis.
   Can break down glycogen
   But cannot liberate free glucose into the circulation.

                                                             75
Metabolic Effects of Insulin - in the Muscle




                                               76
Adipose Tissue (AKA fat)

   Can store glucose by conversion to fatty
    acids and combine these with VLDL to
    make triglycerides.
   In the fasting state can use fatty acids for
    fuel by beta oxidation.




                                                   77
Effects of Insulin - in the Adipose tissue




                                             78
Metabolic Effects of Glucagon




                                79
Insulin – Anabolic and Glucagon - Catabolic
 Metabolic Action              Insulin   Glucagon
 Glycogen synthesis              ↑          ↓
 Glycolysis (energy release)     ↑          ↓
 Lipogenesis                     ↑          ↓
 Protein synthesis               ↑          ↓
 Glycogenolysis                  ↓          ↑
 Gluconeogenesis                 ↓          ↑
 Lipolysis                       ↓          ↑
 Ketogenesis                     ↓          ↑

                                                    80
Glucose Uniporters - GLUTs




     Transport can work in both directions

                                             81
The GLUT – Glucose Transporters

   14 transporters of Glucose are identified
   Their genes are located and cloned
   The function of some is yet under evaluation
   Some genetic defects produce specific diseases like
    GLUT-1-DS
   In breast and prostate cancer GLUT- 11 is hyper
    expressed and supplies the high needs of glucose
    to the cancer cells. – Anti GLUT – 11 drugs might
    be a therapeutic approach for these cancers.


                                                          82
The GLUT – Glucose Transporters

   14 transporters of Glucose are identified
 Their genes are located and cloned
                      Clinical Pearl
 The function of some is yet under evaluation
 1. GLUT -1 DS – a genetic disorder of Glucose
 Some genetic defects produce specific diseases like
    metabolism
  GLUT-1-DS
 2. Anti GLUT -11 drugs in breast & prostate Ca are
 In breast and prostate cancer GLUT- 11 is hyper
    underway
  expressed and supplies the high needs of glucose
  to the cancer cells. – Anti GLUT – 11 drugs might
  be a therapeutic approach for these cancers.


                                                        83
Glucose Transporter Proteins - GLUTs

    GLUT - 1 - Responsible for feeding muscle during
     exercise (that is how exercise lowers blood glucose)
     Placenta, BB, RBC, Kidney and many tissues. Low in
     liver. Mainly ―house keeping‖
    GLUT – 2 – Uniporter of glucose into the beta cells and
     stimulates insulin secretion. Beta cells of pancreas.
     Liver, small intestinal epithelium, Kidney. Has high
     Km (60 mM). Never saturates.
    GLUT - 3 – Insulin independent glucose disposal in to
     the tissues. Abundant in neuronal tissue, placenta and
     kidney. It feeds the high glucose requirement with out
     insulin.

                                                               84
Glucose Transporter Proteins - GLUTs

    GLUT - 1 - Responsible for feeding muscle during
                         Clinical lowers
     exercise (that is how exercisePearl blood glucose)
     Placenta, BB, RBC, Kidney and many tissues. Low in
       1. The GLUT-3 Receptors
     liver. Mainly ―house keeping‖ are Insulin
         independent
    GLUT – 2 – Uniporter of glucose into the beta cells and
     stimulates insulin secretion. Beta cells of pancreas.
       2. In brain GLUT-3 mediate glucose uptake
     Liver, small intestinal epithelium, Kidney. Has high
       3. In mM). Never saturates.
     Km (60 placenta also GLUT-3 mediate Glucose
         uptake
    GLUT - 3 – Insulin independent glucose disposal in to
       4. Foetal growth in not affected very much
     the tissues. Abundant is neuronal tissue, placenta andin
     kidney. It feeds the high glucose requirement with out
          IR
     insulin.

                                                               85
Glucose Transporter Proteins – GLUTs contd..

   GLUT – 4 – Insulin dependent – It is the main channel
    for glucose entry into cells. Muscle, Heart and adipose
    tissues depend on GLUT –4 for glucose entry in to cells
   GLUT – 5 – Rich in small intestine and conduct
    absorption of dietary glucose and fructose transport.
    Mediate glucose for spermatogenesis
   GLUT – 6 – Pseudo gene – Mediates none so far
   GLUT – 7 – Only in liver endoplasmic reticulum and it
    conducts glucose back out – G6P transporter in ER
   SGLT 1 and 2 - Sodium - Glucose symporter in the
    intestinal epithelium and renal tubular epithelium

                                                              86
Glucose Transporter Proteins – GLUTs contd..

   GLUT – 4 – Insulin dependent – It is the main channel
    for glucose entry into cells. Muscle, Heart and adipose
    tissues depend on GLUT –4 for glucose entry in to cells
                       Clinical Pearl
   GLUT – 5 – Rich in small intestine and conduct
      1. GLUT-4 is main Glucose transporter in
    absorption of dietary glucose and fructose transport. all
         tissues
    Mediate glucose for spermatogenesis

      2. It cannot function without TK so far
    GLUT – 6 – Pseudo gene – Mediates none signaling of
   GLUT – 7 – Only in liver endoplasmic reticulum and it
         Insulin
    conducts glucose back out – G6P transporter in ER
   SGLT 1 and 2 - Sodium - Glucose symporter in the
    intestinal epithelium and renal tubular epithelium

                                                                87
Brain

    Converts glucose to CO2 and H2O.
    Can use ketones during starvation.
    Is not capable of gluconeogenesis.
    Has no glycogen stores.




                                          88
Know Our Brain !!

   Brain is the major glucose consumer
   Consumes 120 to 150 g of glucose per day
   Glucose is virtually the sole fuel for brain
   Brain does not have any fuel stores like glycogen
   Can‘t metabolize fatty acids as fuel
   Requires oxygen always to burn its glucose
   Can not live on anaerobic pathways
   One of most fastidious and voracious of all organs
   Oxygen and glucose supply can not be interrupted

                                                         89
Know Our Brain !!

   Brain is the major glucose consumer
   Consumes 120 to 150 g of glucose per day
                     Clinical Pearl
   Glucose is virtually the sole fuel for brain
      1. Brain does not need Insulin for glucose
        does not
    Brainuptake have any fuel stores like glycogen

      2. metabolize fatty acids as mediate it without
    Can‘tThe GLUT-3 Receptorsfuel
   Requires oxygen always to burn its glucose
         Insulin
     3. In live on anaerobic pathways
    Can not hypoglycemia we need to give Glucose
   One of most fastidious and voracious of all organs
         only
   Oxygen and glucose supply can not be interrupted

                                                         90
Second Signaling

                      Now Insulin that is secreted
                       in to the blood starts the
                       second signaling event
                      Insulin binds to the Insulin
                       Receptors (IR) on the muscle
                       and fat cells
                      Muscle and fat cells increase
                       glucose uptake
                      This leads to lowering of
                       blood glucose



                                                       91
Insulin – C peptide

                         Insulin is dimer of two
                          peptides
                         Each peptide consists of
                          A and B chains
                         A has 21 amino acids
                         B has 30 amino acids
                         2 chains are linked by
                          pair of S – S bonds
                         C peptide has 35 amino
                          acids and is cleaved



                                                    92
Insulin – C peptide

                                     Insulin is dimer of two
                                      peptides
                     Clinical Pearl
                                  Each peptide consists of
                                  
 1. Insulin Analogs are substitutions of AA in α and ß
                                  A and B chains
   chains
                                     A has 21 amino acids
                                      Insulin lispro etc.,
 2. Insulin Glargine, Insulin aspart, has 30 amino acids
                                  B
    RAIA, LAIA
                                     2 chains are linked by
                                      pair of S – S bonds
                                     C peptide has 35 amino
                                      acids and is cleaved



                                                                93
Preproinsulin – Proinsulin – Insulin




                                       94
Preproinsulin – Proinsulin – Insulin


                    Clinical Pearl
    1. C – Peptide assay is simpler, less costly than
       Insulin assay
    2. It is the surrogate for endogenous Insulin
       secretion
    3. It is not affected by exogenously administered
       Insulin
    4. It is not largely influenced by food intake


                                                        95
PPAR Family of Nuclear Receptors
      Peroxisome Proliferator Activated
                Receptors




                                          96
PPAR Family of Nuclear Receptors
       Peroxisome Proliferator Activated
                 Receptors
                   Clinical Pearl
    1. PPAR alpha are essential regulators of serum
       lipids
    2. PPAR gamma are essential for Insulin
       Sensitivity
    3. In Insulin Resistance the PPAR Gamma are
       inactivated
    4. Glitazones enhance the PPAR Gamma activity


                                                      97
The Role of Pancreas

Insulin
      Hypoglycemic hormone
      Beta cells of pancreas
      Two chain polypeptide – Anabolic in nature
      Receptor interactions
      Intracellular interactions
      Transporters
      Clinical correlation


                                                    98
Insulin - Mechanism of action

   Insulin binds to its trans-membrane receptor.
   β subunits of the receptor become phosphorylated
   Receptor has intrinsic tyrosine kinase activity.
   Intracellular proteins are activated/inactivated—
   IRS-1, IRS-2 and seven PI-3-kinases
   GLUT-4, Transferrin, LDL-R, IGF-2-R move to the cell
    surface.
   Cell membrane permeability increases:
   Glucose, K+, amino acids, PO4 enter


                                                           99
Insulin

Insulin Release
      In a 24 hour period, 50% of the insulin secreted is
       basal and 50% is stimulated.
      The main stimulator for secretion is glucose.
      Amino acids also stimulate insulin release,
       especially lysine, arginine and leucine.
      This effect is augmented by glucose.




                                                             100
Control of Insulin Secretion

   Glucose interacts with the GLUT-2 transporter on the
    pancreatic beta cell.
   Glucose enters the cell releases - hexokinase→ G-6-P
   Increased metabolism of glucose → ATP →
   Excess of ATP- blocks ATP dependent K channels →
   Membrane depolarization →
   ↑ Cytosolic Ca++ →
   This stimulates degranulation and
   Releases ↑ insulin secretion.


                                                           101
Control of Insulin Secretion

Insulin secretion is also increased by
      Growth hormone (acromegaly)
      Glucocorticoids (Cushings‘)
      Prolactin (lactation)
      Placental lactogen (pregnancy)
      Sex steroids




                                         102
Regulation of Insulin Secretion
Summary of feedback mechanism for regulation
                   ↑ blood glucose
                         ↓
                      ↑ insulin
                          ↓
           ↑ transport of glucose into cells,
         ↓ gluconeogenesis, ↓ glycogenolysis
                         ↓
                   ↓ blood glucose
                         ↓
                      ↓ insulin

                                                103
Role of Insulin

Metabolic Effects of Insulin
      Main effect is to promote storage of nutrients
      Paracrine effects
      Decreases Glucagon secretion
      Carbohydrate metabolism
      Lipid metabolism
      Protein metabolism and growth



                                                        104
Role of Insulin

Carbohydrate metabolism
     Increases uptake of glucose
     Promotes glycogen storage
     Stimulates glucokinase
     Inhibits gluconeogenesis
     Inhibits hepatic glycogenolysis
     Inactivates liver phophorylase



                                        105
Sources of Glucose in to blood

   Glucose is derived from 3 sources
   Intestinal absorption of dietary carbohydrates
   Glycogen breakdown in liver and in the kidney.
   Only liver and kidney have glucose-6-phosphatase.
   Liver stores 25-138 grams of glycogen, a 3 to 8 hour supply.
   Gluconeogenesis, the formation of glucose from precursors
   These include lactate and pyruvate, amino acids (alanine
    and glutamine), and to a lesser degree, from glycerol



                                                               106
Fasting State
   Short fast
         Utilizes free glucose (15-20%)
         Break down of glycogen (75%)
   Overnight fast
         Glycogen breakdown (75%)
         Gluconeogenesis (25%)
   Prolonged fast
         Only 10 grams or less of liver glycogen remains.
         Gluconeogenesis becomes sole source of glucose
         Muscle protein is degraded for amino acids.
         Lipolysis generates ketones for additional fuel.

                                                             107
Role of Insulin

Lipid Metabolism
     Insulin promotes fatty acid synthesis
     Stimulates formation of α-glycerol phosphate
     α-glycerol phosphate + FA CoA = TG
     TG are incorporated into VLDL and transported to
      adipose tissues for storage.
     Insulin inhibits hormone-sensitive lipase,
     Thus decreasing fat utilization.


                                                     108
Role of Insulin

   Protein Metabolism and Growth
        Increases transport of amino acids
        increases mRNA translation and new Proteins,
        A direct effect on ribosomes
        Increases transcription of selected genes,
        Especially enzymes for nutrient storage
        Inhibits protein catabolism
        Acts synergistically with growth hormone


                                                        109
Role of the Pancreas
Lack of insulin
      Occurs between meals, and in diabetes.
      Transport of glucose and amino acids into the cells
       decreases, leading to hyperglycemia.
      Hormone sensitive lipase is activated,
      Causing TG hydrolysis and FFA release.
      ↑ FFA conversion in liver →
      Phospholipids and cholesterol →
      Lipoproteinemia,
      FFA breakdown leads to ketosis and acidosis.

                                                        110
Insulin Resistance

   Associated with obesity
   Underlying metabolic defect in
        Type 2 diabetes
        Polycystic ovarian disease
   Associated with
        Hypertension, gout, high triglyceride
   30% of general population




                                                 111
What causes insulin resistance?

   Decreases in receptor concentration
   Decreases in tyrosine kinase activity,
   Changes in concentration and phosphorylation of
    IRS-1 and IRS-2,
   Decreases in PI3-kinase activity,
   Decreases in glucose transporter translocation,
   Changes in the activity of intracellular enzymes.



                                                        112
What causes insulin resistance?

   Decreases in receptor concentration
                       Clinical Pearl
   Decreases in tyrosine kinase activity,

     1. T2D in concentration and phosphorylation
    Changesis mostly a question of Insulin of
        Resistance
    IRS-1 and IRS-2,
   Decreases in PI3-kinase activity,
    2. Drugs which improve Insulin resistance are
     crucial
    Decreases in glucose transporter translocation,
   Changes in the activity of intracellular enzymes.
    3. Quantitative deficiency is only a late
       feature in T2D


                                                        113
The Role of Pancreas

Other pancreatic hormones
   Somatostatin
        14 amino acid paracrine factor
        Potent inhibitor of glucagon release
        Stimili: glucose, arginine, GI hormones
        It is anti GH (somatotrophin) in its actions
   Pancreatic polypeptide
      36 amino acids, secreted in response to food


   Glucagon

                                                        114
Counter Regulatory Hormones

   Early response
      Glucagon

        Epinephrine
   Delayed response
      Cortisol

        Growth hormone




                              115
Counter Regulatory Hormones

   Glucagon
      Acts to increase blood glucose

      Secreted by alpha cells of the pancreas

      Chemical structure 29 amino acids

      Derived from 160 aminoacid proglucagon
       precursor
   GLP-1 (Glucagon Like Peptide -1)
      The most potent known insulin Secretagogue

      It is made in the intestine by alternative
       processing of the same precursor
   Intracellular actions

                                                    116
Role of Glucagon

    Metabolic Effects of Glucagon
       Increases hepatic glycogenolysis

         Increases gluconeogenesis
         Increases amino acid transport
         Increases fatty acid metabolism (ketogenesis)




                                                          117
Role of Glucagon

    Metabolic Effects of Glucagon
                      Clinical Pearl
       Increases hepatic glycogenolysis
      1. Glucagon is the treatment for hypoglycemia
       Increases gluconeogenesis

      2. Glucagon Kit – 1 mg s/c or IM or IV injection
       Increases amino acid transport
         –
       Increases fatty acid metabolism (ketogenesis)

      3. In 2 to 3 minutes recovery
      4. Costs Rs. 400 per dose




                                                   118
Glucagon Secretion

Stimulation of Glucagon secretion
      Blood glucose < 70 mg/dL
      High levels of circulating amino acids
      Especially arginine and alanine
      Sympathetic and parasympathetic stimulation
      Catecholamines
      Cholecystokinin, Gastrin and GIP
      Glucocorticoids


                                                     119
Responses to decreasing Glucose levels

Response          Glycemic     Physiological   Role in counter
                  theshhold       effects        regulation
↓ Insulin        80 - 85 mg%   ↑ Ra (↓ Rd)         Primary
                                                First Defense
↑ Glucagon       65 - 70 mg%   ↑ Ra               Primary
                                               Second Defense
↑ Epinephrine    65 - 70 mg%   ↑ Ra ↓ Rd          Critical
                                               Third Defense
↑ Cortisol, GH   65 - 70 mg%   ↑ R a ↓ Rd       Not Critical


↑ Food ingestion 50 - 55 mg%   ↑ Exogenous   < 50mg% no
                                 Glucose   cognitive change


                                                                 120
Role of Epinephrine
Epinephrine
      The second early response hyperglycemic hormone.
      This effect is mediated through the hypothalamus in
       response to low blood glucose
      Stimulation of sympathetic neurons causes release of
       epinephrine from adrenal medulla .
      Epinephrine causes glycogen breakdown,
       gluconeogenesis, and glucose release from the liver.
      It also stimulates glycolysis in muscle
      Lipolysis in adipose tissue,
      Decreases insulin secretion and
      Increases glucagon secretion.

                                                              121
Role of Cortisol and GH

    These are long term hyperglycemic hormones
    Activation takes hours to days.
       Cortisol and GH act to decrease glucose
        utilization in most cells of the body
       Effects of these hormones are mediated

        through the CNS.




                                                  122
Cortisol

   Cortisol is a steroid hormone
        It is synthesized in the adrenal cortex.
        Synthesis is regulated via the hypothalamus
         (CRF) and anterior pituitary (ACTH).
   Clinical correlation: Cushing‘s Disease




                                                       123
Growth Hormone (GH)

    GH is a single chain polypeptide hormone.
    Source is the anterior pituitary somatotrophs.
    It is regulated by the hypothalamus.
    GHRH has a stimulatory effect.
    Somatostatin (GHIF) has an inhibitory effect.
    Clinical correlation: Gigantism and Acromegaly
     cause insulin resistance.
    Glucose intolerance—50%
    Hyperinsulinemia—70%

                                                      124
What is T2D or T1D ?




                       125
Normal, T2D and T1D
Normal Subject                Type 2 Diabetes (T2D)           Type 1 Diabetes (T1D)
 High blood glucose            High blood glucose              High blood glucose

                                                                           -cells destroyed by
                                                                           autoimmune reaction
                              Blood glucose remains high      Blood glucose remains high
 Detected by -cells
                               Poor function of -cells       No -cells to detect & respond


 -cells release insulin      -cells release of insulin is    Insulin secretion is nil
                               inadequate or inefficient



Peripheral cells respond to    Peripheral cells poorly          Peripheral cells have no
insulin & take up glucose      respond to insulin and           insulin to respond and
                               glucose up take is poor              take up glucose



 Lower blood glucose           Blood glucose remains high     Blood glucose remains very high

                                                                                           126
Type 2 Diabetes Mellitus

Peripheral Tissue Insulin                      -cell Insulin                             Disease
Resistance v. Time                             Production v. Time                         Progression
Relative Insulin Resistance




                                              -cell Insulin Production
                                                                                                Diabetic




                                                                                                Pre-Diabetic




                                                                                          Age
                                                                                                Normal Glucose
                                                                                                Homeostasis



                              Time in years                               Time in years   Birth


                                                                                                           127
T2D – It is Question of Balance !

                          Non-Diabetic State

     PERIPHERAL INSULIN                        ß-CELL MASS
        RESISTANCE                             & FUNCTION




                            Diabetic State




                                                             128
Pathology of Type 2 Diabetes




                               129
Time Sequence of Events in T2D




                                 130
Insulin Kinetic Defect in T2D




                                131
   Natural History of T2D
                        Obesity       IGT*   Diabetes       Uncontrolled
                                                            Hyperglycemia

                                               Post-meal
  Plasma                                       Glucose
  Glucose
                                                           Fasting Glucose
        120 (mg/dL)


   Relative -Cell                                  Insulin Resistance
     Function
             100 (%)                                        Insulin Level


                              -20   -10    0     10    20      30
*IGT = impaired glucose tolerance         Years of T2D

                                                                             132
Net Beta Cell Mass

            Replication




   Neoformation                         Apoptosis
 Neoformation                           Apoptosis




                          -cell mass

                                                    133
Net Beta Cell Mass

            Replication


                          Clinical Pearl
    1. Crucial determinant of the course of T2D
       patient
   2. Beta cell apoptosis is the cause of
   Neoformation                       Apoptosis
 Neoformation
       secondary OHA failure         Apoptosis




                                   -cell mass

                                                  134
Net Beta Cell Mass

  THE FORMULA FOR ß-CELL MASS -


  (Mitogenesis + Size + Neogenesis) - Apoptosis = Growth


    Increased ß-mass (i.e. compensation for insulin resistance):
           (Mitogenesis + Size + Neogenesis) > Apoptosis


              Decreased ß-mass (i.e. Type-2 diabetes):

           Apoptosis > (Mitogenesis + Size + Neogenesis)




                                                                   135
Approaches to lower Blood Glucose




                                    136
Approaches to lower Blood Glucose



                Clinical Pearl
       1. Various approaches to treat T2D and
          T1D
       2. To restore normoglycemia is the goal
       3. These approaches have additive effect




                                                 137
Evolution of the Modern Cardio-metabolic Man




      Grotesque not in physical appearance alone !!
                                                      138
Fatty Acid Oxidation - What is the Switch ?

       Glucose




            Stearoyl CoA Desaturase (SCD)
               Thrifty Gene Hypothesis


                                              139
Fatty Acid Oxidation - What is the Switch ?

       Glucose

                  Clinical Pearl
SCD SWITCH MANIPULATION might be the answer




            Stearoyl CoA Desaturase (SCD)
               Thrifty Gene Hypothesis


                                              140
The Web of Cardio-metabolic pathogenesis




                                           141
Leptin

   Produced almost exclusively by adipose tissues
   Regulates appetite via ‗satiety signal‘ to Hypothalamus
   Has beneficial effects on muscle fat oxidation and
    insulin resistance
   These are compromised by Leptin insensitivity
   Has a suggested role in the development of various
    cardiac risk factors – including high blood pressure



                                                           142
Adipsin (ASP)

   ASP – Acylation Stimulation Protein
   Role in the uptake and esterification of Fatty Acids
   Facilitates fatty acid storage through Triacylglycerols
   Stimulates Triacylglycerol synthesis via Diacylglycerol
    Acyl Transferase (DGAT)
   Stimulates translocation of GLUT to cell surface
   ASP release is induced by HDLc



                                                           143
Adiponectin
   Significant homology to complement factor C1q
   Accumulates in vessel walls in response to ET injury
   Reduced in obesity
   Weight loss causes increase in its levels
   Reduced in patients with CAD
   Beneficial effects on CAD may be through
      Inhibition of mature macrophage function

      Modulation of endothelial inflammatory response

      Inhibition of TNFα induced release of adhesion

       molecules
                                                       144
WISH YOU ALL A HAPPY NEW YEAR




                                145

				
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