LECTURE 6

• Pancreatic Hormones

• Adrenal Hormones
 Insulin
A. Regulation of release
1. Gastrointestinal nutrients and hormones — glucose, amino
acids, fatty acids, ketone bodies and gastrointestinal
hormones stimulate secretion

2. Autonomic mechanisms --
Norepinephrine and epinephrine inhibit secretion.
Selective ß-receptor stimulation stimulates release.
Cholinergic stimulation (e.g., vagus) stimulates release.

3. Hormones
a) glucagon
b) somatostatin

4. Glucose — increase in blood glucose increases release

decrease in blood glucose decreases release
• 51 amino acids
• 2 chains linked by disulfide bonds
• 5,800 Dalton molecular weight
 Insulin Affects Tissues Differently
• Muscle
– Uptake of glucose and immediate use (exercise) or
storage as glycogen (Exercising muscles can take up
glucose without insulin)
• Liver
– Uptake of glucose and storage as glycogen
• Inhibits glycogen phosphorylase
• Activates glycogen synthase
• Inhibits glucose synthesis
• Promotes excess glucose conversion to fatty acids
• Adipose Tissue- Promotes glucose uptake and conversion
to glycerol for fat production
 Insulin and Fat Metabolism
• Liver cells store glycogen only up to 5-6%
– Remaining glucose metabolized to fat
– Triglycerides are synthesized and release into blood

• Adipose cells store fat

– Inhibits breakdown of triglycerides
– Stimulates uptake and use of glucose to form glycerol
– Stimulates fatty acid uptake and conversion to triglycerides

• Lack of insulin
– Free fatty acids build up in blood
– Liver metabolizes to produce phospholipids and cholesterol
– Can lead to excess acetoacetic acid production and buildup of
acetone (acidosis, which can lead to blindness and coma)
 Insulin and Protein Metabolism
• Promotes
– Transport of amino acids
– Protein synthesis
– Gene transcription

• Inhibits protein degradation

• Prevents glucose synthesis in liver
– Preserves amino acids

• Lack of insulin causes elimination of protein

stores
 Most Cells  amino
Insulin  Protein synthesis acids

Control Muscle
 Glucose uptake
 Glycogen synthesis
Gastrointestinal
hormones
Adipose  triglycerides
 Glucose uptake
 Glycerol production
 Triglyceride breakdown
Amino
Pancreas  Insulin  Triglyceride synthesis
acids
Beta cells
Liver
Blood  Glucose uptake  glucose
glucose  Glycogen synthesis
 Fatty acid synthesis
 Glucose synthesis

Brain
No effect

Feedback
 B. Insulin- Mechanism of release
Leads to
depolarization
Glucose Decreases
potassium
Glucose Closes conductance
transporter Potassium
channel

ATP Calcium
R Glucose channels

Ca+
Metabolism
Insulin
granules

Insulin
 C. Insulin- Role in metabolic processes …
1. Review

Glucagon
Glucose

Glycogen
synthetase
R Glycogen
Gluco-1- Energy
phosphatase utilization
Gluconeogenesis

Lipase Free
Fatty Ketone
Protein Acids Bodies
Urea
excretion
Liver
Lipid
Amino
Acids
C. Insulin- Role in metabolic processes …
2. Insulin Effects
Increases

Glucose
Decreases
Glycogen
Insulin synthetase
R Glycogen
Gluco-1- Energy
phosphatase
utilization
Gluconeogenesis
Ketone
Bodies
Lipase Free
Fatty
Protein Acids
Urea
excretion Liver
Lipid
Amino
Acids
C. Insulin- Role in metabolic processes
3. Insulin deficiency

Hyperglycemia Increases

Decreases
Glycogen
Insulin synthetase
R Glycogen
Gluco-1- Energy (Ketonemia
phosphatase
utilization and Acidosis)
Gluconeogenesis Ketone
Bodies
Lipase Free
Fatty
Urea Acids
Protein
excretion Liver
(Azoturia)
Lipid
Amino
Acids Hyperlipemia
 Glucagon
A. Glucagon - secreted by ?-cells
1. Physiological actions
a) Insulin and glucagon are mutual antagonists
Glucagon mobilizes fuel -- increases [glucose] plasma
Increased glucose leads to increase in insulin and
decrease in glucagon
b) Following a meal- decreased glucagon secretion.
c) Starvation (decrease in blood glucose) causes increase in
glucagon secretion

2. In the liver– gluconeogenesis, glycogenolysis

In adipose tissue—fat catabolism, release fatty acids

3. Therapeutic use -- used to treat insulin-induced hypoglycemia

 Effects of Glucagon
• Prevents hypoglycemia
– Powerful system to degrade glycogen

– Increases glucose synthesis from amino acids

• Increases with exercise independent of blood

glucose

• Exerts effects through cAMP second messenger

system
 Glucagon
Control
Adipose
 Triglyceride breakdown  Fatty acids
 Triglyceride storage
Exercise

Glucagon
Amino acids
Pancreas
Alpha cells Liver
 Glycogen breakdown
 Glucose synthesis  Blood glucose
Epinephrine
 Glucose release
(stress)

Brain
No effect

Feedback
 Importance of Glucose Regulation

• Too little – Brain problems

• Too much
– Osmotic water loss (cellular and systemic)

– Damages blood vessels

 Diabetes mellitus
Type I (10%)– Insulin-dependent diabetes mellitus;
juvenile diabetes
– Cause– the destruction of beta cells by
autoantibodies

– Treatment– meal planning, exercise, the self-

monitoring of blood glucose level, periodic
insulin injections (or delivery by a pump)
 Diabetes mellitus…
Type II (90%)– Non-insulin-dependent
diabetes mellitus; Adult-onset DM
– Cause– Insulin resistance;
– Three major risk factors- heredity, age, and
obesity

– Treatment– weight-loss program of diet and

exercise, oral medications
 Treatment of NIDDM
• Thiazolidinediones (antihyperglycemic)
Troglitazone (Rezulin)
Ciglitazone, Pioglitazone (Actos)
Rosiglitazone (Avandia)

Mechanism of action - reduce plasma glucose and and lipid levels

- increases synthesis of insulin transporters

• Alpha-glucosidase inhibitors like Acarbose (Precose)

Mechanism of action - reduces intestinal absorption of starch

dextrin, and disaccharides — reduction in plasma glucose achieved
Adrenal Hormones

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Adrenal zones and hormones
Adrenocorticotropin Hormone, ACTH
 ACTH is made up of 39 amino acids
 Regulates adrenal cortex and synthesis of
adrenocorticosteroids
 α-MSH resides in first 13 AA of ACTH
 α-MSH stimulates melanocytes and can
darken skin
 Overproduction of ACTH may accompany
increased pigmentation due to α-MSH
 ACTH synthesis
• ACTH is synthesized from pre-pro-opiomelanocortin (pre-
POMC)

• The removal of the signal peptide during translation

produces the 241-amino acid polypetide POMC

• POMC then undergoes a series of post-translational

modifications such as phosphorylation and glycosylation
before it is proteolytically cleaved by endopeptidases to
yield various polypetide fragments with varying
physiological activity

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ACTH synthesis…
 Synthetic corticotropin tetracosactide
- Has the advantage that contains shorter amino acid chain
(devoid of amino acids 25–39). Less likely to cause serious allergy.
- In addition, they are not contaminated by animal proteins
which are potent allergens.
- It consists of the biologically active first 24 amino acids of
natural corticotropin (from man or animals) and so it has
similar properties, e.g. t1/2 10 min.
Corticotropin stimulates the synthesis of corticosteroids
(of which the most important is hydrocortisone) and to a
lesser extent of androgens, by the cells of the adrenal
cortex.

The release of natural corticotropin

by the pituitary gland is controlled
by the hypothalamus via CRH.

Production corticotropin is
influenced by stress as well as
by the level of circulating
hydrocortisone.
Regulation
of ACTH
secretion
Regulation
of ACTH…
 ACTH…
• Circadian pattern of release
– Highest levels of cortisol are in early AM
following ACTH release
– Depends on sleep-wake cycle, jet-lag can
result in alteration of pattern

• ACTH opposes the circadian pattern of

growth hormone secretion
The Adrenal Cortex produces glucocorticoids
• Typically referred to as steroids
• Regulate the metabolism of carbohydrates and
proteins
• Demand for cortisol rises during stress and tissue
repair (e.g. wound healing)
• Produce and conserve glucose
• Promote protein catabolism and gluconeogenesis
• Some mineralocorticoid activity i.e., sodium
retention
Adrenal cortex produces glucocorticoids- Cortisol
• Cortisol regulates blood glucose levels

• Cortisol causes amino acids to be converted to

glucose in the liver

• Cortisol is secreted in times of stress to maintain

glucose and energy levels

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34
Actions Of Glucocorticoids
Corticosteroid action in target cell
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Actions of Epinephrine/Norepinephrine Target
 Adrenal
hormone
disorders

Examples?

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 Addison’s Disease…
• Disease in which patients lack cortisol from zona
fasiculata, and thus lacks negative feedback that
suppresses ACTH production

• Result: overproduction of ACTH

• Skin color will darken

• JFK had Addison’s disease and was treated with

cortisol injections
 Addison’s disease…

Hormones involved
• Adrenocorticotropic (ACTH)
• Glucocorticoids (cortisol)
• Mineralocorticoids (aldosterone)
 Addison’s disease…
- Bronze coloration of skin, Hypoglycemia, Fatigue,
muscle weakness, Weight loss
- Decreased tolerance for stress, anxious, irritable,
confused
 How Are the Hormones Affected?

• When Addison’s disease goes into affect, the

Anterior pituitary produces excessive but
ineffective amounts of Adrenocorticotropic
(ACTH) to the adrenal cortex thus hindering its
ability to produce and release hormones
(Glucocorticoids and Mineralocorticoids)
 Negative Feedback Loops
Within a normal negative feedback loop involving the
adrenal cortex the following would happen:
• The hypothalamus releases hypothalamic inhibitory or releasing
hormones to the anterior pituitary.
• The anterior pituitary then releases ACTH to the adrenal cortex.
• The adrenal cortex will then release Glucocorticoids (to raise blood
glucose levels or to replenish glucose during or after stressful
situations) or Mineralocorticoids (to reabsorb sodium and excrete
potassium in order to balance water in the body).
• When their functions are completed, the target tissues of the
hormones will release their own hormones back to the
hypothalamus in order to stop the release of hormones to affect
the body.
• This represents a negative feedback loop in which the mechanism
fluctuates around homeostasis.
Diagram of Normal Feedback Loop

Hormone of
target tissue

Target tissue
 Negative Feedback Loops (Continued)
In Addison’s diseases, the feedback loop is disrupted.
 The anterior pituitary releases excessive yet ineffective amounts
of ACTH which is supposed to stimulate the adrenal cortex.
 The adrenal cortex as a result is affected negatively and does not
release Glucocorticoids or Mineralocorticoids.
 Since Glucocorticoids are not produced, glucose cannot be
replenished when stressful situations occur.
 Since Mineralocorticoids are not produced, there is a lack of
sodium and water in the body thus leading to severe
dehydration.
 Also, because ACTH exists in excessive yet ineffective amounts,
bronzing of the skin occurs because ACTH is linked to melanin
production.
 Diagram of Addison’s Disease

Excessive and
ineffective
amounts of ACTH

Adrenal cortex
hormones are
not released
 Treatment of Addison’s Disease
Treatment involves hormone replacement therapy
to correct the levels of steroid hormones your body
isn't producing:

1. Hydrocortisone (Cortef), prednisone or

methylprednisolone to replace cortisol. These
hormones are given on a schedule to mimic the normal
24-hour fluctuation of cortisol levels.

2. Fludrocortisone acetate to replace aldosterone.

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What is Cushing’s syndrome?
 Cushing’s syndrome
- Hypersecretion of cortisol, androgens, aldosterone
- Adiposity:
Deposits of adipose tissue in the face, neck & trunk, Moon
shaped face, Buffalo hump, weight gain
Adverse effects of
Glucocorticosteroids
• Cushing’s syndrome
• Osteoporosis
• Tendency to hyperglycaemia
• Negative nitrogen balance
• Increased appetite
• Increased susceptibility
to infections
• Obesity, etc.
 It’s not always Cushing’s
• Other common conditions associated with high
cortisol levels
– Pregnancy
– Alcohol dependence
– Morbid Obesity (100 pounds over his/her ideal body weight, has a BMI of 40 or
more)
– Depression
– Poorly controlled Diabetes
– Physical stress/Malnutrition/Chronic Exercise

• Bottom line: There are many other causes of Cushing’s

(Best to test in the outpatient setting)
 Diagnosis of Cushing’s Syndrome
• Obtain a careful history to exclude exogenous
glucocorticoid use.

• Perform at least two first-line biochemical tests to

obtain the diagnosis:
– Urine free cortisol (UFC) (at least two measurements)
– Late-night salivary cortisol (two measurements)
– 1-mg overnight Dexamethasone Suppression Test
– Longer low-dose Dexamethasone Suppression Test (2 mg/d for
48 h)

NB. Dexamethasone suppression test measures whether adrenocorticotrophic

hormone (ACTH) secretion by the pituitary can be suppressed
Algorithm for
testing Cushing’s
Next lecture

GI tract hormones

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