ENDOCRINE SYSTEM

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ENDOCRINE SYSTEM

• PHYSIOLOGY

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Hormones

• A chemical secreted by a cell or groups of cells
  into the blood for transport to a distant target
  where it exerts its effect at very low
  concentrations
• Types
• Peptide Hormones
• Growth Hormone, Insulin, Vasopressin
• Steroid Hormones
• Cortisol, Testosterone, Estrogen
• Tyrosine Derivatives
• Thyroxine and Epinephrine

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Endocrine vs. Nervous System

• Major communication systems in the body
• Integrate stimuli and responses to changes in
  external and internal environment
• Both are crucial to coordinated functions of
  highly differentiated cells, tissues and organs
• Unlike the nervous system, the endocrine system
  is anatomically discontinuous.

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Nervous system

• The nervous system exerts point-to-point control
  through nerves, similar to sending messages by
  conventional telephone. Nervous control is
  electrical in nature and fast.

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Hormones travel via the bloodstream to target
cells

• The endocrine system broadcasts its hormonal
  messages to essentially all cells by secretion
  into blood and extracellular fluid. Like a radio
  broadcast, it requires a receiver to get the
  message - in the case of endocrine messages,
  cells must bear a receptor for the hormone being
  broadcast in order to respond.

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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.
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Mechanisms of Secretion
Ca
Neuron
Ca
Neurosecretory cell
Capillary
Ca
Simple Endocrine Cell
Ca
Intracellular Ca stores
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Hormones

• Types of Secretion
• Autocrine affects the secreting cell
• Paracrine affects neighbouring cell
• Endocrine secreted into bloodstream
• Exocrine secreted onto body surface, including
  surface of gut

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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.
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Types of hormones

• Hormones are categorized into four structural
  groups, with members of each group having many
  properties in common
• Steroids
• Thyroid Hormones
• Peptides and proteins
• Amino acid derivatives Catecholamines
• Fatty acid derivatives - Eicosanoids

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Two types of hormones

• Lipid Soluble
• Steroid hormones (eg estrogen, testosterone)
• Thyroid hormones
• Lipid Insoluble
• Peptides and Proteins (eg insulin)
• Catecholamines (eg adrenalin)

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Two types of hormones

1. Lipid-soluble

Carrier molecule
Hormone molecule
Cytoplasmic receptor
Nuclear receptor
Transcription Translation long lasting effects
Nucleus
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Two types of hormones

1. Lipid-insoluble

Hormone molecule
Plasma membrane receptor
Second Messenger
Effector Protein
Cellular effects
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Peptide/protein hormones

• Range from 3 amino acids to hundreds of amino
  acids in size.
• Often produced as larger molecular weight
  precursors that are proteolytically cleaved to
  the active form of the hormone.
• Peptide/protein hormones are water soluble.
• Comprise the largest number of hormones perhaps
  in thousands

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Peptide/protein hormones

• Are encoded by a specific gene which is
  transcribed into mRNA and translated into a
  protein precursor called a preprohormone
• Preprohormones are often post-translationally
  modified in the ER to contain carbohydrates
  (glycosylation)
• Preprohormones contain signal peptides
  (hydrophobic amino acids) which targets them to
  the golgi where signal sequence is removed to
  form prohormone
• Prohormone is processed into active hormone and
  packaged into secretory vessicles

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Amine hormones
There are two groups of hormones derived from the
amino acid tyrosine Thyroid hormones and
Catecholamines
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Hypothalamus and pituitary gland
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Hypothalamus and pituitary gland
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Hypothalamus and posterior pituitary
Midsagital view illustrates that magnocellular
neurons paraventricular and supraoptic nuclei
secrete oxytocin and vasopressin directly into
capillaries in the posterior lobe
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Pituitary gland

• Master gland
• Secretes 9 hormones that control other glands
• 2 distinct parts
• Anterior pituitary (adenohypophysis)
• Posterior pituitary (neurohypophysis)
• Both parts controlled by neurosecretory cells of
  the hypothalamus (part of the brain!)

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Anterior pituitaryAdenohypophysis

• Anterior pituitary connected to the hypothalamus
  by the superior hypophyseal artery.
• The antererior pituitary is an amalgam of hormone
  producing glandular cells.
• The anterior pituitary produces six peptide
  hormones prolactin, growth hormone (GH), thyroid
  stimulating hormone (TSH), adrenocorticotropic
  hormone (ACTH), follicle-stimulating hormone
  (FSH), and luteinizing hormone (LH).

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Anterior Pituitary
Hypothalamus
Hormone 1
Portal blood vessels
Hormone 1
Anterior Pituitary
Target Tissue
Hormone 2
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Posterior Pituitary
Hypothalamus
Hormone 1
Portal blood vessels
Posterior Pituitary
Target Tissue
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• Neurosecretory neurons ? Anterior Pituitary
• Secrete hormones into portal blood vessels
• Regulate secretion of other hormones from
  anterior pituitary
• Neurosecretory neurons ? Posterior Pituitary
• Secrete hormones directly into capillaries

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Anterior Pituitary

• 2 hormone system
• 1st hormone stimulates or inhibits release of
  other hormones from anterior pituitary
• 2nd hormone has effect on target tissue

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Examples

• 1st hormone
• Corticotropin-releasing hormone (CRH)
• Thyroid hormone releasing hormone (TRH)
• Prolactin-inhibiting hormone (PIH)

• 2nd hormone
• Adrenocorticotropin hormone (ACTH)
• Thyroid stimulating hormone (TSH)
• Prolactin

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Posterior Pituitary

• Neurosecretory cells secrete hormones directly
  onto capillaries
• Only 2 hormones
• Antidiuretic hormone (ADH, also called
  vasopressin)
• Water retention by the kidney
• Oxytocin
• Uterine contractions during childbirth
• Milk ejection during breast feeding

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Hypothalamic releasing hormones
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Thyroid
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Thyroid Hormone

• Thyroid hormones are basically a "double"
  tyrosine with the critical incorporation of 3 or
  4 iodine atoms.
• Thyroid hormone is produced by the thyroid gland
  and is lipid soluble
• Thyroid hormones are produced by modification of
  a tyrosine residue contained in thyroglobulin,
  post-translationally modified to bind iodine,
  then proteolytically cleaved and released as T4
  and T3. T3 and T4 then bind to thyroxin binding
  globulin for transport in the blood

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• Thyroid Hormones
• Produced in the follicle cells of the thyroid
• T3 triiodothyronine
• T4 thyroxine
• Both require iodine to be produced
• Thyroid hormones increase metabolic rate in
  brain, muscle, heart, liver, kidney, etc.
• Produces heat as a by-product

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Thyroid hormones
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Hypothyroid

• Lack of iodine during fetal development
• Stunted growth, called cretinism

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Hypothyroid

• Lack of Iodine in diet
• Lack of selenium in diet
• Genetic defect on chromosome 15
• 15q25.3-26.1
• Receptor insensitivity
• Increased Antibody levels
• Due to Environmental Factors?
• Decreased Adrenal Function

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Enlargement of the thyroid, called goiter Due to
lack of thyroid hormones and overstimulation of
the thyroid gland by TSH Because no negative
feedback Thyroxine Triiodothyronine feedback on
the Anterior Pituitary and Hypothalamus to
decrease TSH levels If TSH levels are high then
there is a lack of negative feedback A lack of
negative feedback means low T4, T3 levels in the
circulation.
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Hoshimotos Thyroiditis

• Increased sensitivity to cold
• Constipation
• Pale, dry skin
• A puffy face
• Hoarse voice
• An elevated blood cholesterol level
• Unexplained weight gain occurring infrequently
  and rarely more than 10 to 20 pounds, most of
  which is fluid
• Muscle aches, tenderness and stiffness,
  especially in your shoulders and hips
• Pain and stiffness in your joints and swelling in
  your knees or the small joints in your hands and
  feet
• Muscle weakness, especially in your lower
  extremities
• Excessive or prolonged menstrual bleeding
  (menorrhagia)
• Depression

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Control of Thyroid
If ve feedback lost Too much TSH Get goiter
Cold
Hypothalamic neurons
Thyroid releasing hormone (TRH)
Anterior Pituitary
Thyroid Stimulating Hormone (TSH)
Thyroid
Release of thyroid hormones T3 and T4
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Hyperthyroid

• Also known as Graves Disease
• Excessive secretion of T4
• An antibody called thyrotropin receptor antibody
  (TRAb) stimulates the thyroid to make excessive
  amounts of thyroid hormone.

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Graves Disease

• Anxiety
• Irritability
• Difficulty sleeping
• Fatigue
• A rapid or irregular heartbeat
• A fine tremor of your hands or fingers
• An increase in perspiration
• Sensitivity to heat
• Weight loss, despite normal food intake
• Brittle hair
• Enlargement of your thyroid gland (goiter)
• Light menstrual periods
• Frequent bowel movements

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Control of extracellular Calcium

• Two hormones
• Parathyroid hormone
• Calcitonin

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Parathyroid Gland
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Parathyroid

• Low blood Ca stimulates release of parathyroid
  hormones
• Act to increase blood Ca by
• ? Ca release from bone
• ? Ca absorption in gut
• ? Ca reabsorption in kidney

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Calcitonin

• Produced in parafollicular cells of the thyroid
  gland
• High Blood Ca stimulates release of calcitonin
• Act to decrease blood Ca by
• ? Ca release from bone
• ? Ca reabsorption in kidney

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High Ca
Low Ca
Calcitonin
Parathyroid hormone
Mobilize Ca From Bone
Reabsorb Ca In the kidney
Increase absorption of Ca from intestine
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Growth HormoneSomatostatin

• Direct effects are the result of growth hormone
  binding its receptor on target cells. Fat cells
  (adipocytes), for example, have growth hormone
  receptors, and growth hormone stimulates them to
  break down triglyceride and suppresses their
  ability to take up and accumulate circulating
  lipids.
• Indirect effects are mediated primarily by a
  insulin-like growth factor-I (IGF-I), a hormone
  that is secreted from the liver and other tissues
  in response to growth hormone. A majority of the
  growth promoting effects of growth hormone is
  actually due to IGF-I acting on its target cells.
  

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• Growth hormone-releasing hormone (GHRH) is a
  hypothalamic peptide that stimulates both the
  synthesis and secretion of growth hormone.
• Somatostatin (SS) is a peptide produced by
  several tissues in the body, including the
  hypothalamus. Somatostatin inhibits growth
  hormone release in response to GHRH and to other
  stimulatory factors such as low blood glucose
  concentration.
• Ghrelin is a peptide hormone secreted from the
  stomach. Ghrelin binds to receptors on
  somatotrophs and potently stimulates secretion of
  growth hormone.
• Growth hormone secretion is also part of a
  negative feedback loop involving IGF-I. High
  blood levels of IGF-I lead to decreased secretion
  of growth hormone not only by directly
  suppressing the somatotroph, but by stimulating
  release of somatostatin from the hypothalamus.
• Growth hormone also feeds back to inhibit GHRH
  secretion and probably has a direct (autocrine)
  inhibitory effect on secretion from the
  somatotroph.

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Gigantism v Acromegaly
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The Adrenal Glands

• An example of Pituitary control over other
  endocrine tissue
• One gland attached to the top of each kidney

Adrenal Medulla
Adrenal Cortex
Kidney
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• Adrenal Cortex
• Steroid hormones
• Mineralcorticoids
• Aldosterone
• Glucocorticoids
• Cortisol
• Small amounts of estrogen, testosterone,
  progesterone

• Adrenal Medulla
• Catecholamine
• Epinipherine (adrenalin)
• Norepinipherine (noradrenalin)

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Control of Adrenal Cortex
Stress, circadian rhythm and other neural input
Hypothalamic neurons
Corticotropin releasing hormone (CRH)
Anterior Pituitary
Adrenocorticotropic hormone (ACTH)
Adrenal cortex
Release of steroid hormones
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Adrenal Cortex

• Glucocorticoids cortisol is the major
  representative in most mammals
• Mineralocorticoids aldosterone being most
  prominent
• Androgens such as testosterone
• Estrogens, including estrodiol and estrone
• Progestogens (also known a progestins) such as
  progesterone

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Adrenal Cortical Steroids

• Mineralocorticoids
• eg. aldosterone
• Controls ion transport in the kidney function
• Regulates expression of a Na Channel
• Important for water reabsorption

• Glucocorticoids
• eg. cortisol
• Important for metabolism esp. glucose
• Activate enzymes (in liver) that increase glucose
  production
• ? blood glucose

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Cortex Zona Glomerulosa mineralocorticoids (aldosterone)
Cortex Zona fasiculata glucocorticoids (cortisol)
Cortex Zonareticularis sex steroids (androgens)
Medulla Medulla catecholamines (epinephrine and norepinephrine)
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Adrenal Medulla

• Catecholamines stored in large vesicles within
  chromaffin cells of the adrenal medulla
• Chromaffin cells innervated by neurons of the
  sympathetic nervous system
• Fight or flight response

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Adrenal Medulla

• Ach depolarizes chromaffin cell by activating
  nicotinic Ach receptors
• Opens voltage-gated Ca channels
• Ca causes fusion of vesicles
• Release of catecholamine into blood stream

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Catecholamines

• Catecholamines released by adrenal medulla
• epinipherine 80
• norepiniphrine 20
• Also neurotransmitter
• Norepinephrine primary SNS

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Effects of Catecholamines depend upon receptor
type

• Activate adrenoreceptors
• Two types ? and ?

?1
?2
?2
?1
Adenylate cyclase
Phospholipase C
cAMP
IP3 DAG
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Potential effects of catecholamine receptor
activation

• Heart
• ?,? mediated ? - contraction, HR
• Smooth Muscle (Blood vessels and lungs)
• ? contraction
• ? relaxation
• Metabolism
• ? - ? glycogenolysis ? glucose
• Neural
• ? - ? K channel conductance

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Some clinical stuff

• ? adrenoreceptor agonists used to treat asthma
• ? blockers used to treat high blood pressure

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Addisons Disease

• Severe or total deficiency of the hormones made
  in the adrenal cortex, caused by the destruction
  of the cortex
• Symptoms
• steadily worsening fatigue
• a loss of appetite, and some weight loss
• Blood pressure is low and falls further when a
  person is standing, producing lightheadedness
• Nausea, sometimes with vomiting, and diarrhea are
  common
• The muscles are weak and often go into spasm
• There are often emotional changes, particularly
  irritability and depression
• Because of salt loss, a craving for salty foods
  is common
• Finally, the increase in ACTH due to the loss of
  cortisol will usually produce a darkening of the
  skin that may look like an inappropriate tan on a
  person who feels very sick.

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Cushings Disease/Syndrome

•     Cushing's Syndrome is a disease caused by an
  excess of cortisol production or by excessive use
  of cortisol or other similar steroid
  (glucocorticoid) hormones.
• Symptoms
• General physical features include a tendency to
  gain weight, especially on the abdomen, face
  (moon face), neck and upper back (buffalo hump)
• fatigue, weakness, depression, mood swings,
  increased thirst and urination, and lack of
  menstrual periods in women.

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Blood Glucose Regulation

• Endocrine pancreas
• Only 2 of entire pancreas,
• the rest produces digestive enzymes (exocrine)
• Islets of Langerhans
• Insulin (? cells)
• Glucagon (? cells)
• Somatostatin (? cells)

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Islets of Langerhans

• Alpha cells (A cells) secrete the hormone
  glucagon.
• Beta cells (B cells) produce insulin and are the
  most abundant of the islet cells.
• Delta cells (D cells) secrete the hormone
  somatostatin, which is also produced by a number
  of other endocrine cells in the body.

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Diabetes

• Diabetes
• 2 million Canadians
• 9 billion per year health care costs
• Insulin isolated by Banting Best 1922, U of T
  Dept of Physiology (1923 Nobel Prize)
• Type 1
• No or very little insulin produced
• Type 2
• Reduced cellular response to insulin
• Consequences
• Death
• Blindness
• Kidney disease
• Limb amputation

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Hormonal control of blood glucose
In the GI tract, 80 of all carbohydrate is
digested to glucose
Basically
Glycogen
Glucose
Used for glucose storage
Used for ATP production
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Insulin

• Stimulus for secretion is high blood glucose
• Secreted by ? cells
• Leads to glucose uptake and storage in liver,
  muscle and fat tissue.
• Effect is to ? blood glucose
• Danger of Diabetes is hyperglycemia

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Insulin Effects on Muscle and Fat Tissue

• Insulin initiates transfer of glucose
  transporters to cell membrane
• ? blood glucose
• ? production of glycogen

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Effects in Muscle Fat
Glycogen synthesis
glucose
storage vesicle
SNARE dependent transport
Insulin
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In the Liver

• Insulin stimulates the synthesis of an enzyme
  (glucokinase)
• Required to trap glucose in the cell
• initiates glycogen production

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Effects in Liver
GLUT2
Glycogen synthesis
X
glucose
Glucose 6-phosphate
glucose
glucokinase
trapped
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Hemoglobin

• Hemoglobin is the oxygen-carrying pigment that
  gives blood its red color and also the
  predominant protein in red blood cells.
• About 90 of hemoglobin is hemoglobin A. (The "A"
  stands for adult type.) Although one chemical
  component accounts for 92 of hemoglobin A,
  approximately 8 of hemoglobin A is made up of
  minor components that are chemically slightly
  different.
• These minor components include hemoglobin A1c,
  A1b, A1a1, and A1a2. Hemoglobin A1c (HbA1c) is a
  minor component of hemoglobin to which glucose is
  bound. HbA1c also is referred to as glycosylated
  or glucosylated hemoglobin.

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Hemoglobin A1c

• Sugar sticks, and when it's around for a long
  time, it's harder to get it off. In the body,
  sugar sticks too, particularly to proteins.
• The red blood cells that circulate in the body
  live for about 3 months before they die off.
• When sugar sticks to these cells, it gives us an
  idea of how much sugar is around for the
  preceding 3 months. In most labs, the normal
  range is 4-5.9 .
• In poorly controlled diabetes, its 8.0 or above,
  and in well controlled patients it's less than
  7.0. The benefits of measuring A1c is that is
  gives a more reasonable view of what's happening
  over the course of time (3 months)

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ADAs Goal is Less than 7

• A1c() Mean blood sugar (mg/dl)
• 6 135
• 7 170
• 8 205
• 9 240
• 10 275
• 11 310
• 12 345

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Other hormones

• Glucagon
• Secretion stimulated by low blood glucose
• Activates enzymes for gluconeogenesis and
  glycogenolysis
• Leads to ? blood glucose levels
• Somatostatin
• Regulates secretion of insulin and glucagon

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Glucose Regulation Summary

• Endocrine pancreas
• Secretion of several hormones important for blood
  glucose regulation
• Insulin ? glucose uptake and storage
• Different effects on liver and muscle fat
• Glucagon ? glucose production

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Signal Transduction
Signal
Reception, Transduction
Amplification
Second Messengers
Regulators
Specific Effectors
Cellular Response
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