AdrenalCortex
DAWollner, PhD
Hormones to know
• CRH
• ACTH
– beta lipotropin, beta endorphin, melanocyte
stimulating hormone
• Cortisol
• Aldosterone
• DHEA and androstenedione
2
Discussion objectives
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At the end of this discussion, you should be able to:
Characterize the major endocrine secretions of the adrenal glands.
Identify the stimuli of adrenal function.
Identify adrenocortical hormone synthesis, the nature of CRH and ACTH, and the
action of ACTH.
Define the transport processes for corticoids.
Identify the effects of adrenal mineralocorticoids, aldosterone.
Define the effects of aldosterone upon fluid volumes.
Identify the major glucocorticoids, and the effects of cortisol upon carbohydrate,
protein and fat metabolism.
Identify the actions and functions of cortisol during states of stress and upon
inflammatory responses and bodily functions.
Identify Addison’s disease, its causes and consequences.
Identify Cushing’s syndrome, primary aldosteronism, adrenogenital syndrome and
their causes and consequences.
3
Hormones of the adrenal cortex
• Steroid hormones
– Glucocorticoids
• Cortisol
– Mineralocorticoids
• Aldosterone
– Adrenal androgen
4
Adrenal anatomy
• Adrenal Location
– Superior Pole of each
Kidney
– Retroperitoneal
– Embedded in the
Perirenal fat pad.
– Left gland sits slightly
more superior than right
gland
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Adrenal anatomy
• Adrenal cortex
• Adrenal medulla
• Different embryological
origins
6
Histology of the adrenals
• Capsule
• Zona glomerulosa
– Aldosterone
• Zona fasciculata
– Thickest layer
– Cortisol
– Androgens
• Zona reticularis
– Cortisol
– Androgens
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Zona glomerulosa
• Cells arranged in
circular groups
• Secrete
mineralocorticoids
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Zona fasiculata
• Cells arranged in long
straight columns
• Capillaries between
columns
• Secrete glucocorticoids
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Zona reticularis
• Irregular cell columns
• Rich capillaries
• Secrete primarily
adrenal androgens
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Cells of the cortex
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Lipid droplets
Plentiful SER
Mitochondria
Rich capillary supply
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Vascular supply
• Arteries into cortex
• Veins in medulla
• Blood from the cortex
flows through the
medulla
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Embryology
• The adrenal medulla arises from the neural
crest
• Modified sympathetic ganglion
– Part of the sympathetic nervous system
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Biosynthesis
ADRENAL STEROIDS
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Cholesterol
Side Chain
• All steroid hormones
are derived from
cholesterol
• Cholesterol is dietary
• Also produced in the
liver
• LDL carries cholesterol
to the adrenal cells
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Biosynthesis of steroid hormones
• Cytochrome P450 enzymes
– Involved in many steps of the steroid biosynthetic
pathway
– Oxidation reduction reactions
– Generally located on microsomal membranes
• SER or mitochondria
• Hydroxysteroid dehydrogenases
– Generally located within the cytoplasm
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Steroidogenesis
• Different zones the
adrenal cortex express
different complement
of enzymes
• Also express different
receptors
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Zona glomerulosa
• Produces aldosterone
– No 17 a hydroxylase
– No pregnenolone, androgens, or cortisol
• Expresses P450 aldo
– Aldosterone synthase
• Responds to angiotensin
• Responds to potassium
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Zonulae fasciculata and reticularis
• Cortisol, androgens, estrogen
– Expresses 17 a hydroxylase
– Lacks the enzymes to make aldosterone
• ACTH receptors are present here
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Cholesterol
• LDL delivers cholesterol
to the cells of the
adrenal cortex from the
liver
• Steroidogenic acute
regulatory protein
– StAR
– Found in mitochondria
– Brings cholesterol to
inner mitochondrial
membrane
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Cholesterol is converted to
pregnenolone
• Rate limiting step
• Stimulated by ACTH
– CYP 11A1 (P450scc)
– Enzyme in mitochondria
– Requires NADPH, oxygen and electrons
– Requires P450 reductase
• Pregnenolone exits mitochondria
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Cortisol
GLUCOCORTICOIS
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Cortisol
• Pregnenolone is converted to 17
ahydroxypregnenolone
– By CYP17 in smooth ER
– Then 17ahydroxyprogesterone converts to 11deoxycortisol
• This returns to the mitochondria
• CYP11B1 encodes P450c11
– Converts deoxycortisol to cortisol
23
Androgens
• Pregnenolone and progesterone
– Converted to DHEA via CYP 17
– This converts to androstenedione
– CYP 17
• Androstenedione is converted to testosterone
– In peripheral tissues
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STIMULATION OF GLUCOCORTICOID
RELEASE
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Hormone secretion
• In response to ACTH
– Binds ACTH receptors
– In zonulae fasciculata and reticularis
– Stimulates the release of cortisol and androgens
– Stimulates synthesis of steroid
– Can cause hypertrophy and hyperplasia
• Lack of ACTH leads to atrophy
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ACTH receptor
• Associates with Gs
– Stimulates adenylate cyclase, increasing cAMP
– Leads to the activation of StAR
• Phosphorylates StAR
• Stimulates cholesterol conversion to
pregnenolone
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Release of ACTH
• Biorhythms
– Highest levels released just before awakening
• Also in response to stress
– Low blood sugar
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Feedback inhibition
• Cortisol on hypothalamus
– Fast
– Immediate response
– Not caused by intracellular receptors
• Delayed
– Over time with continuous presence of
corticosteroids
– Atrophies fasciculata and reticularis
– Can no longer respond to stress
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PLASMA TRANSPORT OF CORTISOL
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Transport of cortisol
• Half life 60-90 minutes
• Cortisol is transported through plasma
– Binds cortisol binding globulin (CBG)
• Androstenedione and DHEA
– Bind albumin
• Testosterone
– Binds SHBG
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METABOLISM OF CORTISOL
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Metabolism and clearance
• Primarily conjugation
– Liver
• Excretion
– Kidney
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CORTISOL TARGETS
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Glucocorticoid targets
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All tissues have glucocorticoid receptors
Binds response elements
Stimulates expression of specific genes
Different gene target in different tissues
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GLUCOCORTICOID EFFECTS
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Glucocorticoids
• Liver
– Increase gluconeogenesis
– Increase blood sugar
• Pancreas
– Stimulate insulin secretion
– Increase glucose uptake
• Adipose
– Increase lipolysis
– Increase lipid in the blood
• Increase blood glucose
– Allow the uptake of glucose to the tissues
38
Anti-inflammatory
Inhibit phospholipase A2
Decreases production of prostaglandins
Inhibits secretion of interleukin 1
Reduces movement of lymphocytes,
monocytes and others into areas of injury
• Decrease production of lymphocytes
• Inhibit inflammation
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Growth
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Glucocorticoids inhibit mitosis
Reduce bone formation and mineralization
Decrease intestinal absorption of calcium
This causes stimulation of PTH
Leads to bone loss
Major cause of drug induced osteoporosis
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Connective tissue
• Inhibits collagen formation
• Contributes to thin skin and striae
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Blood
• Decreased levels of lymphocytes, monocytes
and eosinophils
• Decreased immune response
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Cardiovascular
• Increases blood pressure
– Increases CO
– Increases adrenergic receptors
• More response to sympathetic stressors
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Effects on the CNS
• Passes through blood/brain barrier
• Glucocorticoid receptors on neurons
• May have effects on behavior and cognitive
function
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Other hormones
• Effects many other hormones
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Digestive tract
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Blocks prostaglandin production
Reduces mucus and bicarbonate
Increases ulcer production
Suppresses the immune response
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Commonly used medications- hydrocortisone, dexamethasone
PROBLEMS ASSOCIATED WITH
EXCESS GLUCOCORTICOIDS
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Pharmacological uses
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Commonly used for many conditions
Childhood asthma
Allergy
Rheumatoid arthritis
Inflammatory bowel disease
Other Inflammatory conditions
Premature newborns
– Stimulates maturation of the lungs prenatally
– Increases production of surfactant
48
Excess glucocorticoids
• Fibroblast inhibition
– Thin skin, bruising, poor wound healing
• Bone
– Inhibit bone formation
– Stimulate bone reabsorption
• Calcium
– Decrease calcium absorption from GI
– Stimulates PTH
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Actions
• Development
– Excess slows growth
• Alters blood cells
– Decrease lymphocytes
• Anti-inflammatory
– Increase infections
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Actions
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Increases cardiac output
Increases sodium and water excretion
Alters thyroid function
Inhibits gonadal secretion
Increases intraocular pressure
– May cause cataracts
• CNS unclear
51
ADRENAL ANDROGENS
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DHEA, androstenedione
and DHEA sulfate
• Converts to testosterone
– Then converts to dihydrotestosterone
• In males, little compared to amount produced
in testicles
• In females, excess DHEA from adrenals
– Virilizing
– Acne
– Hirsutism
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Aldosterone
MINERALOCORTICOIDS
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Mineralocorticoid
• Stimulants of release
– ACTH
– High potassium
– Renin-angiotensin
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Mineralocorticoid targets
• Kidney
• Other organs
– Inhibits natriuresis
• Sodium loss through urine
– Increases blood pressure
– Stimulates potassium uptake into cells
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Hyper
Hypo
DISEASES OF THE ADRENAL CORTEX
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Hypercortisolism
CUSHING’S
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Cause of hypercortisolism
• Chronic glucocorticoid excess
• May be iatrogenic
• May be due to tumor
– Pituitary
– Adrenal cortex
– Ectopic tumor
• Frequently lung
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Symptoms
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Excess ACTH
High cortisol
High androgen
Women
– Hirsutism, acne, amenorrhea
• Men
– Acne, Decreased libido, sperm and impotence in
men
– Due to negative feedback inhibition of testes
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Symptoms of hypercortisol
• Atrophy of the epidermis
– Thin skin, easy bruising, striae
– Fungal infections, acne
– Hirsutism
• Obesity
– Face, neck, trunk, abdomen
– Moon face, buffalo hump
• Hypertension
• Gonadal dysfunction
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Hypercortisol
• Psychological symptoms
– Anxiety, depression, mania
• Osteoporosis
• Renal calculi
• Thirst and polyuria
– Hyperglycemia
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Types of hypercortisol
• Cushing’s syndrome
– Tumor of adrenal secretes excess cortisol
– Low ACTH
• Cushing’s disease
– ACTH hypersecretion
– High ACTH levels
– High cortisol
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Things that affect testing
• Time of day of testing
• Stresses
• Liver function
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Dexamethasone
• Cortisol agonist
– Used in suppression test
– Suppresses pituitary ACTH
– Decreases cortisol release in normal healthy
individual
• Diagnostic for Cushing’s disease
– Rule out lung tumor secreting ACTH
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ACTH dependent
• Chronic hypersecretion of ACTH
• Cushing’s disease
• Leads to hyperplasia of the zonulae fasciculata
and reticularis
• Excessive secretion of cortisol and androgens
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ACTH independent
• Adrenal tumor
• ACTH is suppressed
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Cushing’s disease
• More often strikes women
• Usually between 24-40 years
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Ectopic ACTH production
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Non-pituitary tumor
Secretes ACTH
May be difficult to find
Often found in lung
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Excess aldosterone
• May be cause of some hypertension
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ADRENAL INSUFFICIENCY
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Hypo-adrenal
• Primary adrenal insufficiency
– High ACTH
• Secondary insufficiency
– Low ACTH
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Primary adrenocortical insufficiency
• Addison’s
• Often autoimmune
• Often a result of tuberculosis
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Symptoms of adrenal insufficiency
• Glucocorticoid deficiency
– Weakness, fatigue, anorexia, nausea and vomiting,
and hypoglycemia
• Mineralocorticoid deficiency
– Sodium loss, hyponatremia, hypotension, acidosis,
dehydration, hyperkalemia
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Addison’s
• Hyperpigmentation
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Acute adrenal crisis
• May be precipitated by acute infection or
stress
• Leads to volume depletion and dehydration
• Hypovolemic shock
• Coma, death
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Secondary adrenocortical insufficiency
• ACTH deficiency
– Decreased cortisol and androgen
• Usually aldosterone is normal
• ACTH is not the only aldosterone stimulator
– No hyperpigmentation
– Weakness, lethargy, fatigue, anorexia, nausea
• Can stimulate cortisol secretion with
exogenous ACTH
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Treatment of adrenal insufficiency
• Hormone replacement therapy
• Supportive measures
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SPECIFIC ENZYME DEFICIENCIES
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21-hydroxylase Deficiency
21-hydroxylase
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21 hydroxylase deficiency
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Androstenedione high
Androgen excess
Virilism
Cortisol and aldosterone low
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11b-Hydroxylase Deficiency
11b-hydroxylase
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11b-hydroxylase deficiency
• Androstenedione high
• Cortisol and aldosterone low
• Androgen excess
• Congenital in female leads to ambiguous
external genitalia, normal internal
• Early puberty, short stature
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3b-Hydroxysteroid Dehydrogenase
Deficiency
3b-OH
dehydrogenase
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3b hydroxysteroid deficiency
• DHEA high
• Plasma cortisol and aldosterone low
• Congenital in males may have ambiguous or
misformed external genitalia
• Females usually diagnosed at puberty
– Develop hirsutism
• Usually infertile in both male and female
86
Pancreatic islets
DA Wollner, PhD
1
Objectives
• At the end of this discussion, you should be able to:
• Identify the effect of insulin upon blood glucose level and glucose transport
through cellular membranes.
• Identify the extra- hepatic effects of insulin upon glucose utilization, glycogen
storage and fat storage, and the hepatic effects of insulin upon glucose
metabolism.
• Describe the effect of insulin on lipid metabolism, protein metabolism and
growth.
• Identify and characterize the regulatory mechanism and factors which enhance
insulin secretion.
• Describe the target actions of glucagon, its means of regulation and factors
influencing its secretion.
• Identify diabetes mellitus, its potential causes and major pathophysiological
consequences.
• Contrast the characteristics of diabetic coma with the characteristics of
hyperinsulinism.
2
Hormones to know
• Insulin
• Glucagon
Pancreas
• Exocrine
• Endocrine
• Islets
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A, B, D and F type cells
Glucagon
Insulin
Somatostatin
Pancreatic polypeptide
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Exocrine pancreas
5
Exocrine pancreas
• Acinar glands
• Drain secretions into ducts
• Secretions released in response to stomach and duodenal
hormones
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Exocrine pancreas
• Aqueous portion
• Water, bicarbonate, ions
• Stimulated by secretin
• Due to acid chyme in duodenum
• Enzymatic portion
• Proteases, amylases, nucleases, lipases..
• Stimulated by cholecystokinin
• Due to lipids and proteins in the duodenum
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Endocrine pancreas
8
Endocrine pancreas
• Pancreatic islets
• Several cell types
• a, b,d, e and PP
• Scattered throughout the pancreas
• Not associated with ductile system
• Endocrine, secretes to the capillaries
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Endocrine pancreas islets
• Excellent vascular supply
• Posterior lobe of the head of the pancreas receives blood from the
superior mesenteric arteries
• Rest of the pancreas receives blood from the celiac artery
• PP cells are found mostly posterior in the head of the pancreas
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Endocrine pancreas
• Islets
• a cells
• glucagon
• b cells
• insulin
• d cells
• somatostatin
• e cells
• ghrelin
• PP cells
• Pancreatic polypeptide
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Beta cells
Insulin
C peptide
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Insulin
• Synthesized as preproinsulin
• b cells
• Proinsulin packaged in Golgi
• Processed to insulin in secretory granules
• Processing produces a C peptide
• 2 critical disulfide bonds between A and B peptides
• Some plasma insulin is really proinsulin (up to 20%)
• Half life of insulin is 3-5 minutes
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Beta cell
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Secretion of Insulin
• 40-50 units of insulin per day
• Into portal circulation
• 10 µU/ml normal blood levels- basal
• 8-10 minutes after eating, levels rise
• Peak within 30-45 minutes
• Return to baseline in 90-120 minutes
• Basal secretion
• Released in fasting state
• Pulse every 5 minutes
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Degradation of insulin
• Peptide
• Half life 3-5 minutes
• Taken up by liver, kidney, other organs
• Degraded by proteases
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Unitage of insulin
• Therapeutically express insulin concentration in units
• Bioassay determination
• 1 U = amount required to reduce the concentration of blood glucose
in a fasting rabbit to 45 mg/dl (2.5 mM)
• 100 U = about 0.6 mM
• One international unit is equivalent to 0.0347mg
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Insulin secretion
• Basal secretion
• Constant release of small amounts of insulin during the fasting state
(blood glucose 126 mg/dL fasting
• Or >200 at time 120
• Diagnostic for DM
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Classifications of IGT/IFT
• Impaired glucose tolerance (IGT)
• 2 hr PG >= 140, but < 200 mg/dl
• Impaired fasting glucose (IFG)
• FPG > 100, but < 126 mg/dl
• Plasma glucose is higher than normal
• Not high enough for diagnosis of diabetes
• Risk factors for diabetes and CVD
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Diagnosis
• Must meet ONE of the following criteria
• Symptoms of diabetes plus random PG or >=200 mg/dl
• Or FPG >= 126 mg/dl
• Or 2 hr PG >= 200 mg/dl during OGTT
• Must confirm test on subsequent day
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Treatment
• Diet
• Exercise
• Oral hypoglycemics
• Insulin promotors
• Over time, ability to produce insulin declines
• Insulin shots become necessary
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Glycemic index
• Comparitive test
• Test food given with 50 gm carbohydrate
• Drop in blood glucose plotted
• Glucose or white bread given with 50 gm
• Drop in blood glucose plotted
GI = blood glu area of test food/referenced food
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Figure 1.The
Reference food
two hour blood sugar response of a high-GI
food vs a low-GI food
Test food
Glucose, GI score = 100
Lentils, GI score = 40
The amount of carbohydrate (starch & sugars) in the reference and test foods must be the
same.
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Glycemic index
• How much does blood sugar increase in response to different foods?
• Lower glycemic index foods have less impact on blood sugar
• Low GI (70)
• Potatoes, white bread
Oral hypoglycemics
• Used in type 2 only
• Sulfonylureas
• Glypizide/Glucotrol®
• Prevents K efflux, depolarizing beta cells
• Stimulate insulin secretion
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Oral hypoglycemics
• Biguanides
• Metformin/Glucophage®
• Reduces hepatic gluconeogenesis
• May enhance insulin activity
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Oral hypoglycemics
• Thiazolidinediones
• Pioglitazone/Actos®
• Alter expression of several genes
• Stimulates PPAR gamma
• Increase Glut 1 and 4 expression
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Other hypoglycemics
• a glucosidase inhibitors
• Acarbose
• Prevents uptake of glucose from intestines
• Causes flatulence and GI discomfort
• Incretins
• Binds GLP-1 receptor
• Use alone or in combination with sulfonylurea and/or metformin
• Comes in pen injector
82
Type 2 insulin treatment
• Sometimes effective particularly when metformin and
thiazolidinediones don’t work
• May be one injection in morning.
• Insulin may be added to metformin
• Not useful when added to sulfonylureas
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Long term consequences
• Vascular disease
• Renal failure, blindness, atherosclerosis
• Neuropathy
• Thickening of the capillary basement membrane
84
Prophylaxis
• Prevent or delay kidney failure
• ACE inhibitors
• Enalapril
• Angiotensin II causes vasoconstriction
• Inhibits blood flow to the kidney
• ACE I lower formation of angiotensin II
• Increase blood flow to the kidney
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Acute complications
• Infections
• Loss of consciousness
• Hypo- or hyperglycemia
• Coma
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Hypoglycemia
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Hypoglycemia
• Appears as stress induced sympathetic response
• Dizziness, shakes, anxiety, sweating, palpitations
• Possible loss of consciousness and convulsions
• Excessive insulin
• Lack of calories with insulin
• Reactive hypoglycemia
• Hypoglycemia shortly after ingestion of a meal
• Treat with dietary changes
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Recap of this lecture
• Endocrine pancreas
• Insulin, glucagon, somatostatin,…
• Disorders of the pancreatic hormones
• Diabetes’s
89
Hormones of the digestive
tract
DAWollner, PhD
Hormones to know
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Gastrin
Cholecystokinin (CCK)
Histamine
Somatostatin
Secretin
GIP
GLPs
PPP
Motilin
Ghrelin
Leptin
Discussion objectives
• At the end of this discussion, you should be able to:
• List specific hormones of the digestive tract
• Describe the stimuli of each hormone discussed, and where they
come from
• Describe the target of each hormone discussed, and their effects
Hormones of the digestive tract
• Coordinate digestive function with
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Behavior (eating, fasting)
Autonomic activity of the digestive tract
Intrinsic neuronal activity of the digestive tract
Digestive processes
• Secretion of enzymes and mucus
• Motility of the digestive tract
Endocrine cells of the digestive tract
• Found throughout the entire
tract
• In the mucosa
• Stimulated by chemicals
• In food
• In blood
• Mechanical activity
• Motility
• Constriction or Dilation of wall of
the digestive tract
Major targets of the digestive hormones
• Smooth muscle of the wall of the digestive tract
• Affects motility
• Smooth muscles of the arterioles in the digestive tract
• Affects blood flow and absorption of nutrients
• Excretory cells
• Affects secretion of enzymes and mucus
• Neural cells
• Brain
Functions of the hormones of the digestive
tract
• Coordination and control of digestion
• Integrate digestive reflexes
• Work with the liver and pancreas
Hormones of the digestive tract
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Gastrin
Cholecystokinin
Histamine
Somatostatin
Secretin
GIP
GLP
PPP
Neurotensin
Motilin
Ghrelin
Adiponectin
Many others…
Gastrin
Gastrin
• Synthesized as a prohormone
• Processed to 101 amino acids
• Further processed to multiple final active forms prior to release
• Similar amino acid sequence to cholecystokinin
• Half lives less than 1 hour
Production of gastrin
• Secreted by G cells in gastric antrum
• Secreted by G cells in duodenum
Gastrin receptor
• Called CCK1R and CCK2R receptor
• Found throughout the brain, stomach, small intestine
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Cross the membrane 7 times
Associate with Gq
Increase phospholipase C and DAG, stimulating Ca
Some receptors may be associated with Gs
Action of gastrin
• Stimulates parietal cells
• Works with histamine, vagus nerve (ACh)
• Increase gastric acid secretion and intrinsic factor
• Also stimulates enterochromaffin like cells (ECL)
• Secrete histamine
• Stimulates histidine decarboxylase, increase formation of histamine
• Gastrin promotes stomach contractility
• Stimulates stomach muscle contraction
• Stimulates production and maintenance of the gastric mucosa
Early regulation of gastrin
• Vagus
• Stimulated by smell or thought of food
• Releases GRP (gastrin releasing peptide)
• GRP is similar to bombesin
• Stimulates release of gastrin
Later release of gastrin
• Food enters stomach
• Distension through mechanoreceptor signals G cells to release gastrin
• Nutrients in the stomach stimulate G cells to release gastrin
Inhibition of gastrin
• Chyme enters duodenum
• pH in duodenum drops
• Enterogastrones released
• Including Somatostatin
• Inhibits gastrin release
• Limits gastric acid production
Problems associated with gastrin
• Loss of G cells and inhibition of gastrin causes atrophy of gastric
mucosa
• Excess gastrin production
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G cell tumor
Excessive production of acid
Hypertrophy of mucosa
Extensive ulcers
Zollinger-Ellison syndrome
Cholecystokinin
CCK
Cholecystokinin
• Synthesized as a prohormone
• Produced in I cells of the duodenum and jejunum
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Processed to 115 amino acids
Further processed to multiple final active forms prior to release
Similar amino acid sequence to gastrin
Tyrosine sulfate is necessary for CCK function
• Without this alteration, enzyme acts like gastrin
Stimulation of CCK
• Nutrients in duodenum
• Particularly lipids
• Stimulate CCK releasing factors
• Stimulate secretion of CCK
• Inhibited by bile salts in intestinal lumen
CCK receptor
• CCKR-1
• Increases Ca level in target cell
Effects of CCK
• Plasma levels rise 5-10 fold within 30 minutes of a meal
• Contract the gall bladder
• Relax the sphincter of Oddi
• Stimulates vagus nerve
• Stimulates secretion of digestive enzymes from pancreas
• Neurotransmitter
• Stimulates satiety center in hypothalamus
CCK
• Inhibits acid production in stomach
• Stimulates production of somatostatin
• Delays gastric emptying
• Slows gastric motility
Histamine
Histamine
• Stored in enterochromaffin like cells in gastric mucosa
• Released in response to gastrin
• Targets H2 histamine receptors in parietal cells of the stomach
• Increase stomach acid production
• Inhibited by anti-histamines
• Block most acid secretion
• Cimetidine/Tagamet®, famotidine/Pepcid®
Histamine
• Also found in the blood vessels of the upper respiratory tract
• H1 receptors associated with allergy
Somatostatin
Somatostatin
• Inhibits release of gastrin
• Inhibits release of gastric acid
• Same as hormone in hypothalamus
• Secreted by D cells in the pancreatic islets
• Also synthesized and secreted by D cells throughout the stomach and
intestines
• Two forms, 14 and 28 amino acids produced from larger precursor
• Half lives up to 15 minutes
Somatostatin receptor
• 5 isoforms
• All 7 membrane spanning
• Associate with different G proteins depending on location
Stimulus for somatostatin
• Acid pH in the chyme
• Somatostatin inhibits acid production in the stomach
• Prevents overproduction of acid
Secretin
Secretin
• Similar to glucagon, GIP, GLPs (glucagon like peptides 1 and 2)
• Secretin receptors
• Associate with Gs
Production of secretin
• S cells in duodenum and jejunum
• Stimulated by low pH of chyme
Secretin action
• Stimulates the release of bicarbonate from the pancreas
• Gs increase cAMP
• Stimulates activity of Na/HCO3 cotransporter, and Cl/HCO3 exchanger across
the pancreatic ductile cells
• Chloride channel (CFTR) is activated
• Neutralizes acid in the duodenum
Secretin
• Also stimulates D cells to release somatostatin
• Thus inhibiting gastrin and reducing acid in the stomach
GIP
Glucose dependent insulinotropic polypeptide
Used to be called Gastric inhibitory peptide
GIP
• Glucose dependent insulinotropic polypeptide
• 42 amino acids
• One of the incretins
• These stimulate secretion of insulin
• Exenatide/Byetta®
Incretin effect
• Stimulation of insulin secretion
• Jejunal glucose more effect than
iv glucose
Synthesis and secretion of GIP
• K cells of the duodenum and jejunum
• Rapid increase after carb rich meal
• Glucose, galactose, and glucose analogs all stimulate secretion of GIP
• May also be released in response to sweet on the tongue
• Not responsive to plasma glucose
Termination of GIP effect
• Degraded by DPP IV (dipeptidyl peptidase IV)
• Half life about 5-7 minutes
• Terminates the effect on insulin
• DPP IV inhibitors are used to increase incretin levels
• Used in type 2 diabetes to increase insulin levels
• Sitagliptan/Januvia®
GIP targets
• Beta cells of the pancreatic islets
• Only operates when plasma glucose is elevated above fasting levels
• The more glucose, the more GIP released
• Stimulates beta cell proliferation
GLP 1 and 2
Glucagon like peptides
GLP 1 and 2
• Glucagon like peptides
• Derived from proglucagon
• Produced by L cells
• Found through small and large intestines
• Most in distal ileum and colon
• Monitors glucose, amino acid and fatty acid in chyme
• Nutrients in ileum and colon signal the L cells to release GLPs
GLP 1
• Secretion increases rapidly with eating
• Similar time frame to GIP
• May be internal communication between K and L cells
Action of GLP1
• Incretin
• Stimulates insulin secretion
• Inhibits glucagon secretion
• Slows gastric emptying
• Relaxes smooth muscle in pylorus
• Inhibits food intake through hypothalamus and brainstem appetite
centers
Exenatide/Byetta®
• Incretin mimetic
• Found in gila monster saliva
• Used in type 2 diabetes
Ileal brake mechanism
• Nutrient stimulation of the ileum
• Incretin slows gastric and pancreatic exocrine secretion
• Slowing of stomach emptying and intestinal motility
GLP 2
• Similar effects to GLP 1 on motility and exocrine secretion
• Stimulates growth of intestinal mucosa
• Stimulates glucose and aa transport in mucosa
• Reduces inflammation
• No effect on insulin
Pancreatic polypeptides
PPP
• Similar to neurotransmitters PYY and NPY
• Regulate food intake
• PPP produced in F cells in pancreatic islet
• Receptors associate with G proteins
Stimulation of PPP
• Plasma concentration of PPP and PYY increase within moments of
eating a meal
• Remain elevated for several hours
• Increases when stomach is distended
• Increased with chewing without stomach distention
Function of PPP
• Part of the ileal brake mechanism
• Antagonizes CCK and secretin in the pancreas and gall bladder
• Slows motility
• May increase feeling of satiety
Neurotensin
Neurotensin
• 13 amino acids secreted by N cells in jejunum and ileum
• May be part of ileal brake
• Stimulated by fatty acids in intestine
• Inhibits gastric acid secretion
• Slows gastric emptying
• Decreases motility of small intestine
• May increase motility of colon
Neurotensin
• Aids fat digestion and absorption
• Stimulates uptake of bile acids by ileum
• Increases their return to hepatocytes
• Stimulates bile secretion
Neurotensin receptor
• NTR1
• Works through Gq
• Stimulates IP3/DAG
Motilin
Motilin
• 22 amino acids long
• Expressed in brain and GI
• Receptors couple to Gq
Effects of motilin
• Migrating motility complex
• Empty stomach is quiescent for 90 minutes
• Then brief major contractions for up to 10 minutes
• Contractions may be due to release of motilin
• Also stimulates enzyme secretion by stomach and pancreas, and gall
bladder contractions
• Helps clear the intestinal tract of last meal
Ghrelin
Ghrelin
• Similar to motilin
• 28 amino acid peptide
• Secreted by X/A cells of the stomach
• Also small and large intestine and pancreas
• Receptor is GHS-R (Growth Hormone secretagogue receptor)
Stimulus of ghrelin
• Major stimulus for release of ghrelin seems to be empty stomach
• Released prior to meal
• Lowest level after eating
• Increases motility and secretion of the stomach prior to meals
Function of ghrelin
• Stimulates GH secretion
• Inhibits insulin secretion
• Regulates glucose
• Decreases heat production to regulate energy output
”Hunger hormone”
• Ghrelin stimulates hunger
• Increases food intake
• Increases fat deposition
• Associated with obesity, increasing fat and weight
Changes in ghrelin
• Lowering ghrelin improves glucose control in diabetes
• Loss of GHS-R worsens glucose control
• Increases energy and lowering obesity and insulin resistance
•
•
•
•
Ghrelin reduces sympathetic responses
Prevents muscle atrophy
Regulates bone formation
May promote cancer
Adiponectin
Adiponectin
• Produced by the adipose cells
• The more adipose, the less adiponectin is found in circulation
• Associated with increase in insulin sensitivity, decrease in plasma
glucose
• High plasma adiponectin is associated with lean body type
• May be a target for treatment of obesity and diabetes
Leptin
Leptin
• 167 amino acid protein hormone
• Produced by the adipose cells
Leptin stimulus
• Amount of leptin in blood depends on amount of adipose tissue
• Highest secretion in early morning
Leptin target
• Obr receptors
• Found in the brain, particularly hypothalamus
• Location of the satiety center
• Also found in other tissues throughout the body
Leptin effects
• Balances body energy expenditure with energy stores
• Regulates appetite, reducing food intake
• Low leptin leads to infertility
• Extreme athletes
Problems associated with leptins
• Lack of leptin
• Excess eating, obesity, diabetes
• Lack of leptin receptors
• High leptin levels
• Common in human obesity
Peptide
Secreted from
Targets
Actions
Gastrin
G cells
ECL cells, parietal cells
Histamine,
Acid production
Somatostatin
D cells
G cells, ECL cells
parietal cells
Decrease gastrin,
histamine and acid
Ghrelin
A/X cells
Smooth muscle
Increase gastric
motility
Motilin
Duodenum and
jejunum
Smooth muscle
Increase gastric
motility
GLP1 and 2
L cells
D cell, parietal cells
Increase SST
Decrease acid
Decrease motility
Oxytomodulin
L cells, alpha cells
D cell, parietal cells
“
PPP
F cells
neurons
Slows motility
Secretin
S cells
Oxyntic and D cells,
chief cells
Increase SST
Decrease acid
Increase pepsin and
lipase
Cholecystokinin
I cells
Oxyntic and D cells
chief cells, smooth ms
Increase SST
Decrease acid, pesin
Contract gall bladder
Slow motility
Neurotensin
N cells
D cells?
Decrease acid
Decrease motility
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