Endocrine Physiology

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					Endocrine Physiology
        Ernest Henry Starling
            (1866-1927)
• Besides "his" law of the heart, Starling
  discovered the functional significance of serum
  proteins.
• In 1902 along with Bayliss he demonstrated that
  secretin stimulates pancreatic secretion.
• In 1924 along with E. B. Vernay he
  demonstrated the reabsorption of water by the
  tubules of the kidney.
• He was the first to use the term hormone
   A cell is a target because is has a specific
             receptor for the hormone


Most hormones circulate in blood, coming into contact with essentially
all cells. However, a given hormone usually affects only a limited
number of cells, which are called target cells. A target cell responds
to a hormone because it bears receptors for the hormone.
   Response vs. distance traveled
Endocrine action: the hormone is distributed in blood and binds to
distant target cells.
Paracrine action: the hormone acts locally by diffusing from its
source to target cells in the neighborhood.
Autocrine action: the hormone acts on the same cell that produced
it.
 COMPARISON OF ENDOCRINE
   AND NERVOUS SYSTEMS
• NERVOUS SYSTEM     • ENDOCRINE SYSTEM
• ―WIRED‖            • ―WIRELESS‖
• CHEMICAL SIGNAL    • CHEMICAL SIGNAL
  AT TARGET CELL       AT TARGET CELL
• RAPID              • SLOW
• BRIEF DURATION     • LONG DURATION
• CLOSE ANATOMICAL   • SPECIFIC
  PROXIMITY            RECEPTORS
         Types of hormones
• Hormones are categorized into four
  structural groups, with members of
  each group having many properties in
  common:
  – Peptides and proteins
  – Amino acid derivatives
  – Steroids
  – Fatty acid derivatives - Eicosanoids
 Episodic secretion of hormones
• The most prominent episodes of release occur
  with a frequency of about one hour—referred to
  as circhoral
• An episode of release longer than an hour, but
  less than 24 hours, the rhythm is referred to as
  ultradian
• If the periodicity is approximately 24 hours, the
  rhythm is referred to as circadian
  – usually referred to as diurnal because the increase in
    secretory activity happens at a defined period of the
    day.
           Feedback control
• Negative feedback is most common: for
  example, LH from pituitary stimulates the testis
  to produce testosterone which in turn feeds back
  and inhibits LH secretion
• Positive feedback is less common: examples
  include LH stimulation of estrogen which
  stimulates LH surge at ovulation
       Classes of hormones

The hormones fall into two general classes
 based on their solubility in water.
  The water soluble hormones are the
   catecholamines (epinephrine and
   norepinephrine) and peptide/protein
   hormones.
  The lipid soluble hormones include thyroid
   hormone, steroid hormones and Vitamin D3
           Types of receptors
 Receptors for the water soluble hormones are
  found on the surface of the target cell, on the
  plasma membrane.
   These types of receptors are coupled to various
    second messenger systems which mediate the action
    of the hormone in the target cell.
 Receptors for the lipid soluble hormones reside
  in the nucleus (and sometimes the cytoplasm) of
  the target cell.
   Because these hormones can diffuse through the lipid
    bilayer of the plasma membrane, their receptors are
    located on the interior of the target cell
                     Pituatary Gland
• The pituitary gland, also called the hypophysis,
   – is a small gland—about 1 centimeter in diameter and 0.5 to 1
     gram in weight—
   – that lies in the sella turcica, a bony cavity at the base of the
     brain, and is
   – connected to the hypothalamus by the pituitary (or hypophysial)
     stalk.
• Physiologically, the pituitary gland is divisible into two
  distinct portions:
   – the anterior pituitary, also known as the adenohypophysis, and
   – the posterior pituitary, also known as the neurohypophysis.
   – Between these is a small, relatively avascular zone called the
     pars intermedia, which is almost absent in the human being but is much larger
      and much more functional in some lower animals.
  Hypothalamic Control of Pituitary
            Secretion
• Secretion from the posterior pituitary is
  controlled by nerve signals that originate in the
  hypothalamus and terminate in the posterior
  pituitary.

• Secretion by the anterior pituitary is controlled
  by hormones called hypothalamic releasing and
  hypothalamic inhibitory hormones (or factors)
  secreted within the hypothalamus itself and then
  conducted to the anterior pituitary through
  minute blood vessels called hypothalamic-
  hypophysial portal vessels.
    Hormone Secreting Cells of the Human Anterior
                  Pituitary Gland
                                                                  % of Total
       Cell Type                Hormones Secreted
                                                                Secretory Cells
     Somatotrope                   Growth hormone                       50
       Lactotrope                      Prolactin                      10–30
      Corticotrope                       ACTH                           10
      Thyrotrope                          TSH                            5
     Gonadotrope                       FSH, LH                          20

   Hormone Secreting Cells of the Human Posterior
                  Pituitary Gland
•The bodies of the cells that secrete the posterior pituitary hormones are not located
in the pituitary gland itself but are large neurons, called magnocellular neurons,
located in the supraoptic and paraventricular nuclei of the hypothalamus.

•The hormones are then transported in the axoplasm of the neurons‘ nerve fibers
passing from the hypothalamus to the posterior pituitary gland
    Hormones of Anterior Pituitary
• Growth hormone promotes growth of the entire body by affecting
  protein formation, cell multiplication, and cell differentiation

• Adrenocorticotropin (corticotropin) controls the secretion of some of the
  adrenocortical hormones, which affect the metabolism of glucose,
  proteins, and fats

• Thyroid-stimulating hormone (thyrotropin) controls the rate of secretion
  of thyroxine and triiodothyronine by the thyroid gland, and these
  hormones control the rates of most intracellular chemical reactions in the
  body

• Prolactin promotes mammary gland development and milk production

• Two separate gonadotropic hormones, follicle-stimulating hormone
  and luteinizing hormone, control growth of the ovaries and testes, as
  well as their hormonal and reproductive activities.
Hormones of Posterior Pituitary.
• Antidiuretic hormone (also called vasopressin)
  controls the rate of water excretion into the
  urine, thus helping to control the concentration
  of water in the body fluids

• Oxytocin helps express milk from the glands of
  the breast to the nipples during suckling and
  possibly helps in the delivery of the baby at the
  end of gestation.
           Growth hormone
Growth hormone, in contrast to other
 hormones, does not function through a
 target gland…………

………but exerts its effects directly (!!!!!) on
 all or almost all tissues of the body
         Functions of Growth Hormone
•   It causes growth of almost all tissues of the body that are capable of growing by,
          • promoting increased sizes of the cells
          • increasing mitosis, with development of greater numbers of cells and
          • specific differentiation of certain types of cells such as bone growth cells
            and early muscle cells

•   Growth hormone exerts much of its growth effect through intermediate
    substances called ―somatomedins‖ (also called ―insulin-like growth factors‖)
    secreted by Liver and lesser extent in other tissues
         • At least four somatomedins have been isolated, but by far the most important of these is
           somatomedin C (also called IGF-I).



•   Growth hormone has multiple specific metabolic effects, including
        • increased rate of protein synthesis in most cells of the body
        • increased mobilization of fatty acids from adipose tissue, increased free
           fatty acids in the blood, and increased use of fatty acids for energy
        • decreased rate of glucose utilization throughout the body
     Thyroid Gland
• Described first by Thomas Wharton
  (1616-1673)

• Thyroid : shield

• Largest Endocrine Gland

• Weighing 15 – 20 g

• Highly Vascular ( 5 ml / g / min )
Thyroid histology
 Synthesis & secretion of T. H.
1. Formation & secretion of thyroglobulin (123
  Tyrosine but 5 to 7 active)
2. Iodide Trapping – NIS & Pendrin transporters
3. Fabrication of thyroid hormones is conducted by
  the enzyme thyroid peroxidase :
  1. Oxidation of iodide ions
  2. Iodination of tyrosine
   3. Coupling
4. Storage of TG
5. Release of T.H. : T & T
      Transport of Thyroxine and
      Triiodothyronine to Tissues
                    Type                         Percent
The function of protein-binding appears to be
 bound to thyroxine-binding globulin (TBG) can
  •maintenance of a large pool of hormone that
                                               70%

  readily transthyretin or "thyroxine-binding
bound to be mobilized as needed.                   10-15%
  •In addition, at least for T3, or TBPA)binding prevents
         prealbumin" (TTR hormone
   excess uptake by the first cells encountered and
                paraalbumin
   promotes uniform tissue distribution.
                                                  15-20%


               unbound T4 (fT4)                   0.03%


               unbound T3 (fT3)                    0.3%
       T4: A Prohormone for T3
• T4 is biologically inactive in target tissues until
  converted to T3 by Deiodinases
  – 5‗ Carbon de-iodination(40%) of the outer ring of
    T4 yields T3 – Active Hormone
  – 5‗ Carbon de-iodination(33%) of the inner ring of
    T4 yields Reverse T3 - little or no biologic activity
    Sites of T4 Conversion

• The liver is the major extrathyroidal
  T4 conversion site for production of T3
• Some T4 to T3 conversion also occurs
  in the kidney and other tissues
Hypothalamic-Pituitary-Thyroid Axis
 Negative Feedback Mechanism
           Iodine Sources

• Available through certain foods (eg,
  seafood, bread, dairy products), iodized
  salt, or dietary supplements, as a trace
  mineral
• The recommended minimum intake is
  150 g/day
  Physiologic Effects of Thyroid Hormones
 Target
                 Effect                             Mechanism
 Tissue
                                    Increased number of β-adrenergic receptors
              Chronotropic
  Heart            &            Enhanced responses to circulating catecholamines
               Inotropic        Increased proportion of α-myosin heavy chain (with
                                             higher ATPase activity)
 Adipose
                Catabolic                       Stimulated lipolysis
  tissue
 Muscle         Catabolic                  Increased protein breakdown
  Bone        Developmental      Promote normal growth and skeletal development
 Nervous
              Developmental             Promote normal brain development
 system
   Gut          Metabolic            Increased rate of carbohydrate absorption
Lipoprotein     Metabolic                   Formation of LDL receptors
                               Stimulated oxygen consumption by metabolically active
                              tissues (exceptions: testes, uterus, lymph nodes, spleen,
  Other        Calorigenic                        anterior pituitary)
                                              Increased metabolic rate
                  Clinical Features of
                    Hypothyroidism
          Tiredness                       Puffy Eyes

Forgetfulness/Slower Thinking     Enlarged Thyroid (Goiter)
    Moodiness/ Irritability             Hoarseness/
                                     Deepening of Voice
         Depression
                                 Persistent Dry or Sore Throat
   Inability to Concentrate
   Thinning Hair/Hair Loss           Difficulty Swallowing
      Loss of Body Hair                Slower Heartbeat

      Dry, Patchy Skin             Menstrual Irregularities/
                                       Heavy Period
       Weight Gain                         Infertility
      Cold Intolerance
    Elevated Cholesterol                 Constipation
                                      Muscle Weakness/
  Family History of Thyroid               Cramps
    Disease or Diabetes
               Signs and Symptoms of
                  Hyperthyroidism
                                      Hoarseness/
     Nervousness/Tremor            Deepening of Voice
                                  Persistent Dry or Sore
     Mental Disturbances/                 Throat
          Irritability
                                  Difficulty Swallowing
      Difficulty Sleeping
Bulging Eyes/Unblinking Stare/        Palpitations/
       Vision Changes                 Tachycardia

   Enlarged Thyroid (Goiter)          Impaired Fertility
                                  Weight Loss or Gain
    Menstrual Irregularities/
         Light Period                Heat Intolerance
                                   Increased Sweating
  Frequent Bowel Movements
                                   Sudden Paralysis
      Warm, Moist Palms

                                    Family History of
  First-Trimester Miscarriage/
                                    Thyroid Disease
Excessive Vomiting in Pregnancy
                                      or Diabetes
 Adrenocortico-medullary Hormones
• There are two endocrine organs in the adrenal gland, one surrounding
  the other:
        • Cortex
        • Medulla

• The adrenal cortex secretes
        • glucocorticoids, steroids with widespread effects on the metabolism of
          carbohydrate and protein
        • mineralocorticoid essential to the maintenance of Na+ balance and extracellular
          fluid (ECF) volume; and
        • sex hormones that exert effects on reproductive function

• The adrenal medulla is in effect a sympathetic ganglion in which the
  postganglionic neurons have lost their axons and become secretory
  cells that secrete when stimulated by the preganglionic nerve fibers that
  reach the gland via the splanchnic nerves

• The main secretions of the inner adrenal medulla are the
  catecholamines
        • Epinephrine
        • Nor-epinephrine
        • Dopamine
& formation of new cortical cells.
The adrenal medulla does not
regenerate, but when the inner two
zones of the cortex are removed, a
new zona fasciculata and zona
reticularis regenerate from glomerular
cells attached to the capsule




   90% of the cells are the (Larger)
   epinephrine-secreting type and
   10% are the (smaller) nor epinephrine-
   secreting type
Pathways for Adrenal Medullary
hormone Biosynthesis




glucocorticoids are apparently necessary for the
normal development of the adrenal medulla
Adrenal medullary PNMT is induced by
glucocorticoids
        Effects of Epinephrine & Nor
                 epinephrine
•   mimicking the effects of noradrenergic nervous discharge

•   norepinephrine and epinephrine exert metabolic effects that include
          •   glycogenolysis in liver and skeletal muscle
          •   mobilization of free fatty acids (FFA)
          •   increased plasma lactate, and
          •   stimulation of the metabolic rate


•   Norepinephrine and epinephrine both increase the force and rate of contraction of the
    isolated heart

•   The catecholamines also increase myocardial excitability, causing extrasystoles and,
    occasionally, more serious cardiac arrhythmias.

•   Norepinephrine produces vasoconstriction, but epinephrine dilates the blood vessels
    in skeletal muscle and the liver. This usually overbalances the vasoconstriction
    produced by epinephrine elsewhere, and the total peripheral resistance drops.

•   When norepinephrine is infused slowly in normal animals or humans, the systolic
    and diastolic blood pressures rise. The hypertension stimulates the carotid and
    aortic baroreceptors, producing reflex bradycardia that overrides the direct
    cardioacceleratory effect of norepinephrine. Consequently, cardiac output per
    minute falls.
Adrenocortical Hormones (Cortex)
• the mineralocorticoid
     • Aldosterone
• the glucocorticoids
     • cortisol and corticosterone
• the androgens
     • dehydroepiandrosterone (DHEA) and
       androstenedione
Outline of hormone biosynthesis in the zona
fasciculata and zona reticularis of the adrenal cortex
               Effects of Glucocorticoids
•   Glucocorticoid effects may be broadly classified into two major
    categories:
          • Immunologica
          • Metabolic
          • fetal development.
     – Immune
          • up-regulate the expression of anti-inflammatory proteins
          • down-regulate the expression of pro-inflammatory proteins
          • development and homeostasis of T lymphocytes.
     – Metabolic - cortisol stimulates several processes that collectively serve to increase
       and maintain normal concentrations of glucose in blood.
          • Stimulation of gluconeogenesis, particularly in the liver: from non - hexose substrates
          • Mobilization of amino acids from extrahepatic tissues: These serve as substrates for
            gluconeogenesis.
          • Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose.
          • Stimulation of fat breakdown in adipose tissue
     – Developmental
          • promoting maturation of the lung and production of the surfactant necessary for extrauterine
            lung function.
          • necessary for normal brain development, by initiating terminal maturation, remodelling axons
            and dendrites, and affecting cell survival.
     – Arousal and cognition
          • Glucocorticoids act on the hippocampus, amygdala, and frontal lobes. Along with adrenaline
            these enhance the formation of flashbulb memories of events associated with strong
            emotions both positive and negative
Mechanism for regulation of
glucocorticoid secretion
                                                    Cushing‘s
                                                    Syndrome
C - Central obesity, Cervical fat pads, Collagen fibre weakness, Comedones (acne)
U - Urinary free cortisol and glucose increase
S - Striae, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycaemia, Hirsutism
I - Iatrogenic (Increased administration of corticosteroids)
N - Noniatrogenic (Neoplasms)
G - Glucose intolerance, Growth retardation

                                               Cushing's syndrome (also called
                                               hyperadrenocorticism or
                                               hypercorticism) is a hormone
                                               (endocrine) disorder caused by
                                               high levels of cortisol
                                               (hypercortisolism) in the blood.
• Excessive glucocorticoid levels resulting
  from administration as a drug or
  hyperadrenocorticism have effects on
  many systems.
     • inhibition of bone formation,
     • suppression of calcium absorption (both of which
       can lead to osteoporosis),
     • delayed wound healing,
     • muscle weakness, and
     • increased risk of infection
                 Mineralocorticoids
• Removal of the adrenal glands leads to death within just a few days.
  Observation of such a unfortunate subject would reveal several key
  derangements:
        • the concentration of potassium in extracelluar fluid becomes dramatically
          elevated
        • urinary excretion of sodium is high and the concentration of sodium in
          extracellular fluid decreases significantly
        • volume of extracellular fluid and blood decrease
        • the heart begins to function poorly, cardiac output declines and shock
          ensues
• These phenomena are a direct result of loss of mineralocorticoid
  activity, and can largely be prevented by replacement of salts and
  mineralocorticoids.

Clearly mineralocorticoids are acutely critical for maintenance of life!
Hormone synthesis in the zona glomerulosa




           11-beta-hydroxysteroid dehydrogenase
           the protector for cells from Cortisol
           Physiologic Effects of
            Mineralocorticoids
The major target of aldosterone is the distal tubule of the
  kidney, and also on sweat glands, salivary glands and
  the colon, where it stimulates exchange of sodium and
  potassium.

Three primary physiologic effects of aldosterone result:
   – Increased resorption of sodium: sodium loss in urine is
     decreased under aldosterone stimulation.
   – Increased resorption of water, with consequent expansion of
     extracellular fluid volume. This is an osmotic effect directly
     related to increased resorption of sodium.
   – Increased renal excretion of potassium.
Control of Aldosterone secretion
 Disorders of Mineralocorticoids
• Hyperaldosteronism (the syndrome caused by
  elevated aldosterone) generally results from
  adrenal cancers. The two main resulting
  problems:
     • Hypertension and edema due to excessive Na+ and water
       retention.
     • Accelerated excretion of potassium ions (K+). With extreme
       K+ loss there is muscle weakness and eventually paralysis.
• Underproduction, or Hypoaldosteronism, leads
  to the salt-wasting state associated with
  Addison's disease
Congenital Adrenal Hyperplasia
    Physiological importance of
             Calcium
• Calcium salts in bone provide structural integrity
  of the skeleton
• Calcium ions in extracellular and cellular fluids is
  essential to normal function of a host of
  biochemical processes
   –   Neuoromuscular excitability
   –   Blood coagulation
   –   Hormonal secretion
   –   Enzymatic regulation
     Hormonal Control of Calcium &
        Phosphate Metabolism
•   The components of the system that maintain calcium homeostasis include
         • cell types that sense changes in extracellular calcium and
         • release calcium-regulating hormones, and
         • the targets of these hormones, including the kidneys, bones, and intestine, that respond
           with changes in calcium mobilization, excretion, or uptake.


•   Three hormones are primarily concerned with the regulation of calcium
    metabolism.
         • 1,25-Dihydroxycholecalciferol is a steroid hormone - primary action is to increase
           calcium absorption from the intestine
         • Parathyroid hormone (PTH) is secreted by the parathyroid glands - main action is to
           mobilize calcium from bone and increase urinary phosphate excretion
         • Calcitonin, a calcium-lowering hormone that in mammals is secreted primarily by cells
           in the thyroid gland, inhibits bone resorption.


•   Phosphate homeostasis
         • given its inclusion in adenosine triphosphate (ATP),
         • its role as a biological buffer, and
         • its role as a modifier of proteins, thereby altering their functions.
      Distribution of Calcium &
             Phosphate
• Calcium
    • 99% is stored in bones (serve as large reservoirs)
    • 1 per cent - cells, and
    • 0.1 per cent - extracellular fluid


• Phosphate
    • 85 per cent - bones,
    • 14 to 15 per cent - cells, and
    • less than 1 per cent - extracellular fluid.
Calcium in the Plasma and
     Interstitial Fluid
Vitamin D Synthesis &
  ACTIONS
• Increases Calcium
  absorption in Intestines
• Increases Calcium
  reabsorption in Kidneys
  via increased TRPV5
  expression in the
  proximal tubules
                             TRPV6
• increases the synthetic
  activity of osteoblasts,
  and
• Normal calcification of
  matrix
The
Parathyroid
Glands
             Parathyroid Gland
• Humans usually have four parathyroid glands:
     • two embedded in the superior poles of the thyroid and
     • two in its inferior poles
• Each parathyroid gland is a
     • richly vascularized disk,
     • about 3 x 6 x 2 mm,
     • containing two distinct types of cells
         – abundant chief cells, which contain a prominent Golgi
           apparatus plus endoplasmic reticulum and secretory
           granules, synthesize and secrete parathyroid hormone (PTH).
         – less abundant and larger oxyphil cells contain oxyphil
           granules and large numbers of mitochondria in their
           cytoplasm, few are seen before puberty, and thereafter they
           increase in number with age. Their function is unknown
               Parathormone
• The normal plasma level of intact PTH is 10 to
  55 pg/mL.

• The half-life of PTH is approximately 10 min

• the secreted polypeptide is rapidly cleaved by
  the Kupffer cells in the liver into fragments that
  are probably biologically inactive.
• PTH and these fragments are then cleared by
  the kidneys
        Parathormone Actions
• Increases blood calcium level by
     • Increases the formation of 1,25-dihydroxycholecalciferol, and
       this increases Ca2+ absorption from the intestine
     • Increases reabsorption of Ca2+ in the distal tubules
     • increase bone resorption


• Phosphaturic action - increases phosphate
  excretion in the urine and thereby depresses
  plasma phosphate levels

• PTH stimulates both osteoblasts and osteoclasts
      Parathyroid hormone-related
            protein (PTHrP)
        Parathormone                               PTHrP
            84 aminoacid                     140 aminoacid
              residues                         residues
           Chromosome 11                    Chromosome 12
             Endocrine                         Paracrine
1. PTHrP has a marked effect on the growth and development of cartilage in
   utero.
2. PTHrP is also expressed in the brain, where evidence indicates that it
   inhibits excitotoxic damage to developing neurons.
3. Ca2+ transport in the placenta.
4. PTHrP is also found in keratinocytes in the skin, in smooth muscle, and in
   the teeth, where it is present in the enamel epithelium that caps each tooth.
               Calcitonin
• The Ca2+-lowering hormone has been
  named calcitonin.

• In mammals, calcitonin is produced by the
  parafollicular cells of the thyroid gland,
  which are also known as the Clear or C
  cells.
        Secretion & Metabolism
• Secretion of calcitonin is increased when the thyroid
  gland is exposed to plasma calcium level of
  approximately 9.5 mg/dL

• β-adrenergic agonists, dopamine, and estrogens also
  stimulate calcitonin secretion.

• Gastrin, cholecystokinin (CCK), glucagon, and secretin
  have all been reported to stimulate calcitonin secretion

• half-life of less than 10 min in humans

• Receptors for calcitonin are found in bones and the
  kidneys
                   Actions
• Calcitonin lowers circulating calcium and
  phosphate levels.
• It exerts its calcium-lowering effect by
  inhibiting bone resorption
• inhibits the activity of osteoclasts in vitro.
• It also increases Ca2+ excretion in the
  urine.
Effects of Other Hormones & Humoral
    Agents on Calcium Metabolism
 • Glucocorticoids
         • lower plasma Ca2+ levels by inhibiting osteoclast formation and activity
         • over long periods they cause osteoporosis by decreasing bone formation by
           inhibiting protein synthesis in osteoblasts and increasing bone resorption.
         • They also decrease the absorption of Ca2+ and PO43– from the intestine
           and increase the renal excretion of these ions
 • Growth hormone
         • increases calcium excretion in the urine
         • increases intestinal absorption of Ca2
         • Insulin-like growth factor I (IGF-I) generated by the action of growth hormone
           stimulates protein synthesis in bone
 • Thyroid hormones may cause hypercalcemia, hypercalciuria, and,
   in some instances, osteoporosis.
 • Estrogens prevent osteoporosis by inhibiting the stimulatory effects
   of certain cytokines on osteoclasts.
 • Insulin increases bone formation, and there is significant bone loss
   in untreated diabetes.
       Pancreas
Insulin was first isolated from
the pancreas in 1922 by
Banting and Best
    Physiologic Anatomy of the
            Pancreas
• The pancreas is composed of two major types of
  tissues:
     • Acini – Exocrine part
     • Islets of Langerhans – Endocrine Part


• The islets contain Four major types of cells,
     •   A or Alpha – 25 % - Glucagon
     •   B or Beta – 60 % - Insulin and Amylin (islet amyloid polypeptide (IAPP))
     •   D or Delta cells – 10% - Somatostatin
     •   F Cells – 5% - Pancreatic Polypeptide
                Insulin
• Insulin is synthesized in the Rough endoplasmic
  reticulum of the B cells
• The gene for insulin is located on the short arm
  of chromosome 11 in humans
• When insulin is secreted into the blood, it
  circulates almost entirely in an unbound form
• Plasma half-life ~ 6 minutes
• Degraded by the enzyme Insulinase mainly in
  the liver
Human insulin molecule
1. The insulin receptor is composed of two alpha
   subunits and two beta subunits linked by disulfide    The Insulin
   bonds.
                                                         Receptor and
2. The alpha chains are entirely extracellular and
   house insulin binding domains, while the linked
                                                         Mechanism of
   beta chains penetrate through the plasma              Action
   membrane.

3. The insulin receptor is a tyrosine kinase = an
   enzyme that transfers phosphate groups from ATP
   to tyrosine residues on intracellular target
   proteins.

4. Binding of insulin to the alpha subunits causes the
   beta subunits to phosphorylate themselves
   (autophosphorylation)

5. The activated receptor then phosphorylates a
   number of intracellular proteins (insulin receptor
   substrate 1 or IRS-1), which in turn alters their
   activity, thereby generating a biological response
Glucose Transporters                Function               Major Sites of Expression
   Secondary active
      transport
(Na1-glucose cotransport)
         SGLT 1               Absorption of glucose       Small intestine, renal tubules
         SGLT 2               Absorption of glucose                Renal tubules
 Facilitated diffusion
         GLUT 1               Basal glucose uptake        Placenta, blood-brain barrier,
                                                             brain, red cells, kidneys,
                                                            colon, many other organs
         GLUT 2               B-cell glucose sensor;      B cells of islets, liver, epithelial
                            transport out of intestinal      cells of small intestine,
                            and renal epithelial cells                 kidneys
         GLUT 3               Basal glucose uptake           Brain, placenta, kidneys,
                                                               many other organs
         GLUT 4             Insulin-stimulated glucose    Skeletal and cardiac muscle,
                                       uptake             adipose tissue, other tissues
         GLUT 5                Fructose transport                 Jejunum, sperm
         GLUT 6                       None                          Pseudogene
         GLUT 7               Glucose 6-phosphate              Liver, ? other tissues
                                transporter in ER
Cycling of GLUT 4 transporters through
endosomes in insulin-sensitive tissues.
         Activation of the insulin receptor causes activation of phosphatidylinositol 3-
kinase, which speeds translocation of the GLUT 4-containing endosomes into the cell
membrane. The GLUT 4 transporters then mediate glucose transport into the cell.
Principal Actions of Insulin
Rapid (seconds)
Increased transport of glucose, amino acids, and K+ into insulin-sensitive cells
Intermediate (minutes)
Stimulation of protein synthesis
Inhibition of protein degradation
Activation of glycolytic enzymes and glycogen synthase
Inhibition of phosphorylase and gluconeogenic enzymes
Delayed (hours)
Increase in mRNAs for lipogenic and other enzymes
 Effects of Insulin on Various Tissues
Adipose tissue                            Liver
 Increased glucose entry                   Decreased ketogenesis
 Increased fatty acid synthesis            Increased protein synthesis
 Increased glycerol phosphate synthesis    Increased lipid synthesis
 Increased triglyceride deposition          Decreased glucose output due to
 Activation of lipoprotein lipase         decreased gluconeogenesis,
                                          increased glycogen synthesis, and
 Inhibition of hormone-sensitive lipase   increased glycolysis
 Increased K+ uptake                      General
Muscle                                     Increased cell growth
 Increased glucose entry
 Increased glycogen synthesis
 Increased amino acid uptake               Decreased release of Gluconeogenic
  Increased protein synthesis in          Amino acids
ribosomes                                  Increased ketone uptake
 Decreased protein catabolism              Increased K+ uptake
Disordered plasma glucose homeostasis in insulin deficiency
                                    Hypoglycemia
Compensatory Mechanisms:
1. One important compensation for hypoglycemia is cessation of the secretion of
   endogenous insulin. Inhibition of insulin secretion is complete at a plasma glucose
   level of about 80 mg/dL
2. Hypoglycemia triggers increased secretion of at least four counter-regulatory
   hormones: glucagon, epinephrine, growth hormone, and cortisol.
     1. Glucagon and epinephrine increase the hepatic output of glucose by increasing
        glycogenolysis. The epinephrine response is reduced during sleep.
     2. Growth hormone and cortisol decreases the utilization of glucose in various
        peripheral tissues
    Factors Affecting Insulin Secretion
           Stimulators                                Inhibitors
Glucose                                   Somatostatin
Mannose                                   2-Deoxyglucose
Amino acids (leucine, arginine, others)   Mannoheptulose
Intestinal hormones (GIP, GLP-1 [7–36],   α-Adrenergic stimulators
gastrin, secretin, CCK; others?)          (norepinephrine, epinephrine)
β-Keto acids                              β-Adrenergic blockers (propranolol)
Acetylcholine                             Microtubule inhibitors
Glucagon                                  Galanin
Cyclic AMP and various cAMP-generating    Diazoxide
substances                                Thiazide diuretics
β-Adrenergic stimulators                  K+ depletion
Theophylline                              Phenytoin
Sulfonylureas                             Alloxan
                                          Insulin
                        Glucagon
• Human Glucagon, a linear polypeptide
• molecular weight of 3485
• produced by the A cells of the pancreatic islets and
  the upper gastrointestinal tract
• contains 29 amino acid residues
• Glucagon has a half-life in the circulation of 5 to 10
  min
• Human PREPROGLUCAGON is a 179-amino-acid
  protein that is found in
      • pancreatic A cells,
      • L cells in the lower gastrointestinal tract, and
      • Brain
•   Glucagon is
                                     Actions
         •   Glycogenolytic
         •   Gluconeogenic
         •   Lipolytic
         •   Ketogenic.
•   It acts on G-protein coupled receptors with a molecular weight of about 190,000.

•   Glucagon does not cause glycogenolysis in muscle rather
         • increases gluconeogenesis from available amino acids in the liver
         • elevates the metabolic rate
         • increases ketone body formation by decreasing malonyl-CoA levels in the liver. Its lipolytic
           activity, which leads in turn to increased ketogenesis
         • calorigenic action of glucagon is not due to the hyperglycemia per se but probably to the
           increased hepatic deamination of amino acids.


•   Large doses of exogenous glucagon exert a positively inotropic effect on the
    heart without producing increased myocardial excitability, presumably because
    they increase myocardial cAMP.

•   Glucagon also stimulates the secretion of growth hormone, insulin, and
    pancreatic somatostatin.
Factors Affecting Glucagon Secretion
    Stimulators                      Inhibitors
   Amino acids (particularly the
 glucogenic amino acids: alanine,
                                           Glucose
   serine, glycine, cysteine, and
             threonine)
          CCK, gastrin                   Somatostatin
             Cortisol                      Secretin
            Exercise                         FFA
            Infections                     Ketones
         Other stresses                     Insulin
    β -Adrenergic stimulators       α-Adrenergic stimulators
          Theophylline                     Phenytoin
          Acetylcholine                     GABA
                                 Somatostatin
•   Somatostatin 14 (SS 14), more active its amino terminal-extended form somatostatin 28
    (SS 28) are found in the D cells of pancreatic islets.

•   Both forms inhibit the secretion of insulin, glucagon, and pancreatic polypeptide and act
    locally within the pancreatic islets in a paracrine fashion.

•   inhibiting insulin secretion, and it apparently acts via the SSTR5 receptor

•   Patients with somatostatin-secreting pancreatic tumors (somatostatinomas) develop
    hyperglycemia and other manifestations of diabetes that disappear when the tumor is
    removed.

•   They also develop
     –   dyspepsia due to slow gastric emptying
     –   decreased gastric acid secretion, and
     –   gallstones, which are precipitated by decreased gallbladder contraction due to inhibition of CCK
         secretion.

•   The secretion of pancreatic somatostatin is increased by several of the same stimuli that
    increase insulin secretion, that is, glucose and amino acids, particularly arginine and
    leucine and also increased by CCK.

•   Somatostatin is released from the pancreas and the gastrointestinal tract into the
    peripheral blood.
                      Pineal Gland
• A pea-sized mass of nerve tissue attached by a stalk to the posterior
  wall of the third ventricle of the brain, deep between the cerebral
  hemispheres at the back of the skull.

• It functions as a gland, secreting the hormone melatonin - which
  regulates the pituitary gland and is associated with the biological
  clock

• Melatonin
    – A hormone produced by the pineal gland in darkness but not in bright
      light.
    – Melatonin receptors in the brain react to this hormone and synchronize
      the body to the 24 hour day/night rhythm, thus informing the brain when
      it is day and when it is night.
    – Melatonin is derived from seratonin, with which it works to regulate the
      sleep cycle.
                  Thymus Gland
• The thymus grows during childhood but gradually decreases in size
  after puberty.
• Lymphocytes that have passed through the thymus are
  transformed into T cells.
• Thymus hormones called thymosins stimulate the development and
  differentiation of T lymphocytes. They play a role in regulating the
  immune system by stimulating other kinds of immune cells as well.