Transcript Jan 15 - Winona State University

Endocrine functions of the pancreas,
pituitary and pineal glands 1/15
Remember: no class or labs Monday for Martin Luther King
observance. Monday lab students make-it-up T, W or Thur
• How do the three types of diabetes differ?
• Why do hormonal responses change?
• How does the hypothalmus regulate hormone release?
• What two hormones are created by the
neurohypophysis?
• What six hormones are created by the
adenohypophysis?
• How are hormones synthesized?
• What hormones are produced by the gonads?
• How does the pineal gland determine wakefulness?
Blood glucose (mg/dL) values from lab for subject #1, #2
and #3 after overnight fast (pre-meal) and after a
glucose challenge (meal). Can you explain what
happened in each condition based on these values?
Trial #
Person #1
Person#2
Person#3
Fasting Blood Glucose
1
2
75
57
113
121
175
190
Trial #
Person #1
Person#2
Person#3
Post Challenge Glucose
1
2
127
121
133
129
188
220
Fasting Average
3
57
118
184
63.0
117.3
183.0
Post-Meal Average
2
123
127
194
123.7
129.7
200.7
Practice Quiz for Monday and Wednesday’snotes
1) _______is a second messenger that increases intracellular
calcium and is produced by the enzyme phospholipase-C.
a) IP3 b) cyclicAMP c) Diacylglycerol
d) Sodium
2) Aldosterone is a steroid produced in what specific part of the
adrenal gland?
a) Medulla b) Cortex c) Zona glomerulosa d) Kidney
3) Which receptor for epinephrine in causes fatty acids to be
released from adipocytes as part of the Fight-or-Flight
response?
a) Alpha-1 b) Alpha-2 c) Beta-1 d) Beta-2 e) Beta-3
4) Cholesterol is not a precursor to what adrenal hormone?
a) Cortisol b) Aldosterone c) DHEA d) Epinephrine e) Insulin
There are three types of diabetes mellitus that are all
characterized by pathogenically high blood glucose.
Diabetes is the epidemic of our generation! MN and WI counties,
within 25 miles of Winona State University based on 2008 Census data and
the national Type 2 Diabetes estimate of 8.3% affliction. (CDC 2010).
Winona Houston Fillmore Wabasha Buffalo Trempeleau TOTAL
County
13,425 27,754
Population 49,879 19,244 20,838 21,884
153,024
• Type I or Juvenile onset: Characterized by a lack of (or
insufficient) insulin secretion after a meal (no beta cells)
• Type II or Adult Onset: Characterized by the inability of cells in
the body to response to insulin released from the pancreas.
Insulin produced but does not function properly at target cells,
eventually results in failure of beta-cells and insulin
dependence
• Gestational Diabetes: Characterized by a transitory insulin
resistance during pregnancy. Abberation of an intent by mom’s
endocrine system so save nutrients for the fetus (poorly understood etiology)
• These three diseases are very different and cause very
different problems.
Current criteria for the diagnosis of diabetes
ADA 2011 Standard of Care, Diabetes Care, 2011:34, S4-S10
Any One of Following Defines Person as Being Clinically Diabetic
• Hemoglobin A1c Glycosylation Value: A1C 6.5%- measures long-term
glycemic control.
• Fasting plasma glucose (FPG) of 126 mg/dl (7.0 mmol/l) or more with
no caloric intake for at least 8 hours
• 2-hour plasma glucose of 200 mg/dl (11.1 mmol/l) or more during an
oral glucose tolerance test (OGTT) with load of 75 glucose in water
• Classic symptoms of hyperglycemia or hyperglycemic crisis, and
random plasma glucose of 200 mg/dl (11.1 mmol/l) or more
• In the absence of unequivocal hyperglycemia, result should be confirmed
by repeat testing.
• Testing for diabetes in asymptomatic (means one need not be aware of
having disease symptoms-potentially silent)
THE THREE TYPES OF DIABETES MELLITUS RESULT
FROM EITHER AN INABILITY TO SECRETE INSULIN OR
THE INABILITY OF SENSITIVE CELLS TO DETECT INSULIN.
• Type I, IDDM: B-cells destroyed by autoimmune disease, reflux from
bile duct, infection, or exocrine digestion
• Sensitive cells like heart, liver, adipocytes, muscle need insulin and
insulin receptors to let glucose enter the cytosol!
• See tutorial: http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/pancreas/index.html
• IDEA: save glucose for the brain during fasting: glucose dependent
• COST: Without insulin, the glucose stays in bloodHyperglycemia
• Why is Hyperglycemia a Problem?
• Hemes and proteins glycosylated = loss of function!
• Blindness, Oxidative stress and Vasoconstriction due to glycosylation!
• Glucose is normally reabsorbed by the PCT of the nephron, if too
much goes to the kidney it is not reabsorbed and it stays in the
filtrate/urine
• Diabetes Insipidus no ADH release from posterior pituitary! (no
glucose in urine)
IDDM (type-I) is usually juvenile in onset, and requires
insulin injections for life because beta cells can’t grow back!
• Dependent Cells Can Starve without insulin!>>So they must
metabolize fatty acids and ketones because these are less insulin
dependent.
• Non-sugar metabolites cause metabolic acidosis!
• Fatty acid metabolism and excess blood glucose result in
hepatic/heart/renal disease
• These individuals often BECOME obese because their brain thinks
they are starving, when they just cant use the food that’s there!
• Hyperinsulinemia: overdose of replacement insulin causing
hypoglycemia and neural tissue starvation. What would happen to
your blood glucose if too much insulin was administered? Why do
diabetics often “carry a candy bar”?
Type II or Non-insulin Dependent Diabetes Mellitus
occurs when adipoctyes (mostly) stop responding to
insulin, often as a result of energy excess.
• Same Symptoms: polyuria, polydipsia, polyphagia.
•
+urine +thirst
+eating
•
why? why?
why?
• Risk Factors: Age, Heredity(family/cultural), Obesity
• Onset typically after age 40, now days it is often seen in
obese college-age and younger persons.
– Traditionally Adult onset, but not any more (how about insulin
resistance in child with a BMI of 80?)
• Adipocytes and other cells fail to respond to insulin and
glucose influx after a meal becomes very slow, so
glucose has nowhere to go….it accumulates in the blood
causing hyperglycemia.
• Treat with exercise and better diet.
Gestational Diabetes is the “third” type- it occurs in
transitory nature during pregnancy
Test with an OGTT-oral glucose tolerance test
Cellular responses to hormones/drugs can change.
WHY IS THIS IMPORTANT????
• Up Regulation: exposure improves future sensitivity!
– Oxytocin and increasing numbers of receptors as birth
approachesMore receptors More contractile force!
• Down Regulation: exposure decreases future sensitivity
– Insulin/Obesity: reduced receptors causes Type II diabetes
– Fewer hormone receptors Less ability to remove glucose
from blood!
• How does receptor up/down regulation explain why a drug
may work at first, but not later?
• Hormone/Second Messenger Destruction: Cells can also
learn to destroy hormones and 2nd messengers more rapidly.
– Phosphodiesterase: stops cAMP activity
– If a cell makes more PDE, you need to use more hormone
to get effect!
The pituitary gland is composed to two parts:
1) Neurohypophysis: connected to hypothalamus by axons.
2) Adenohypophysis: a portal system of fenestrated capillaries
supplies it with hypothalamic releasing hormones.
Fenestration make these 1st
capillaries very permeable to
the releasing hormones!!!
The neurohypophysis
consists of a set of nerve
endings that release their
hormones directly into the
blood. These hormones
are synthesized in the
hypothalamus and travel
via axonal TX.
Fenestrations also make this second set permeable too!
HOW DOES THE HYPOTHALMUS REGULATE
PITUITARY FUNCTION?
• Hypothalamus location: floor and walls of 3rd Ventricle
• Hypophysis (pituitary) sits in the sella turica of the
sphenoid below the hypothalamus.
• Hypothalamus and Hypophysis are connected by the
infundibulum or stalk.
• Posterior Pituitary (Neurohypophysis): Direct release of
hormones made in hypothalamus into fenestrated
capillaries.
• Anterior Pituitary (Adenohypophysis): Hypothalamic
releasing/inhibiting hormones required to promote release
a second hormone from Ant. Pit (REQ=> Portal Circulatory
Structure!)
Posterior Pituitary: What pituitary hormones regulate
child birth and water homeostasis/blood pressure?
Two hypothalamic nuclei create two sets of hormones that are
released into the blood stream at the neurophypophysis:
• Paraventricular Nucleus: Oxytocin:child birth/milk
• Saladin claims importance questionable: Be Careful!
• Days before birth OT receptors in uterus increase!
• Increased receptorsstronger SMC contractionsDelivery!
• OT>PL>>IP3>>Ca++>>Contraction and Prostaglandins
• Supraventricular Nucleus: Anti-Diuretic Hormone (ADH or
Vasopressin) Maintains blood pressure!
• +Water Reabsorption in kidney+Blood Volume+Blood Pressure
• Constrictor effect only at very high levels +Blood Pressure.
• Adjusts plasma volume and osmolarity.
• Diabetes Insipidus often occurs when lesions form in tracts
– Note: no glucose in the urine!
THE HYPOTHALMUS CONTROLS ANTERIOR PITUITARY
FUNCTION WITH RELEASING/INHIBITING HORMONES
THAT ONLY WORK IF THE PORTAL SYSTEM IS INTACT!
• Releasing/Inhibiting hormones released to blood/capillaries in
hypothalamus (portal system #1) and pulled out at second
capillary bed in anterior pituitary.
• 6 Ant. Pit. Hormones: FSH,LH,TSH,ACTH,PRL,GH
Respective Hypothalamic Hormones Control Release:
• 1) Thyrotropin Releasing Hormone (TRH)+TSH and PRL
• 2) Prolactin Releasing Factor (PRF)+PRL
• 3) Prolactin Inhibitory Factor (PIF)-PRL
• 4) Corticotropin Releasing Factor(CRH)++ACTH
• 5) Growth Hormone Releasing Hormone (GHRH)+GH
• 6) Gonadotropin Releasing Hormone(GnRH)+FSH/LH
• 6) Somatostatin (GNIH)  -GH AND -TSH
FOUR TROPHIC HORMONES ARE RELEASED FROM THE
ANTERIOR PITUITARY: ACTH, PRL,TSH AND GH
• Adrenocorticotrophic hormone (ACTH)-Stimulates adrenal
cortex and glucocorticoid secretion for stress
management.
• Prolactin (PRL)-Stimulates milk synthesis following birth.
• Thyroid stimulating Hormone (TSH)-Stimulates thyroid
gland to release T3/T4 and create a calorigenic state in
body>>>HEAT or growth dung infancy
• Growth Hormone (GH)-Stimulates cell division, protein
synthesis and bone growth
Promotes FA metabolism: saves glucose for
glycogen synthesis and storage.
Related to Gigantism, Acromegally and Dwarfism
• Pituitary tumors can occur in a pituitary cell line for anyone
of these hormones, this type of cancer is very tough to
treat with radiation of surgery! WHY???
How does Prolactin play a role in making the
cows come home?
THE TWO ANTERIOR PITUITARY GONADOTROPHIC
HORMONES PROMOTE SEX STEROID SYNTHESIS.
LH is Luteinizing Hormone:
LH (not FSH) Stimulates testosterone production by Leydig cells
in testes
Stimulates initial estrogen secretion from follicle and corpus
luteum
FSH is Follicle Stimulating Hormone:
FSH (not LH) Stimulates sperm maturation at testes
-Stimulates egg maturation/ovulation
Classic Feedback Loop in Women leading to Ovulation:
• GnRH FSH and LH + follicle/estradiol+GnRH LH Surge
OvulationCorpus luteum makes progesterone and some
estradiol to maintain endometrium
GONADS RESPOND TO FSH/LH AND SECRETE MANY SEX
STEROIDS WITH TWO IMPORTANT ONES BEING:
ESTRADIOL AND TESTOSTERONE.
• Males: produce testosterone in response to LH
Promotes Protein Synthesis, Stops growth plate
DHEA (dehydroxyepandiosterone) is a precursor
for testosterone synthesis
– FSH release is inhibited because high levels of testosterone
inhibit GnRH release from hypothalamus
• Females: produce estrogen in response to FSH
Estradiol causes follicular maturation/release
Newly formed corpus luteum makes progestrone in
addition to continued estrogen
• Menopause occurs later in life when even extremely high levels of
FSH are unable to increase estradiol secretion and follicular
maturation.
Sex Steroid Synthesis in gonads of males and females is very
similar, difference is that in females testosterone is further
metabolized to make estradiol. Smaller amounts of synthesis also
occurs in the zona reticularis of the adrenal cortex.
THE PINEAL GLAND IS OUR BIOLOGICAL CLOCK:
IT CONTROLS CIRCADIAN AND SEASONAL RHYTHMS.
• Located in back/bottom area of brain of “mammals” on roof
of third ventricle.
• “Circadian Rhythms” are daily cycles of hormone production.
– Rhythms can also occur on a monthly and yearly cycle.
• During the day a modified amino acid called serotonin is
released (wakefulness).
– “Wakefulness” is the opposite of “depression”
– Many antidepressant drugs work by reducing serotonin
destruction/removal improve “mood” and
• At night serotonin is converted into melatonin which is a
hormone that causes drowsiness and sleep.
• Why does honey on toast help you wake up or dream?
• This is source of “jet-lag” symptoms!
HORMONAL CIRCADIAN RHYTHMS CAN BE VERY IMPORTANT IN EXPLAINING WHY
ASTHMA OR HEART ATTACKS ARE MORE COMMON AT CERTAIN TIMES OF THE DAY.
• 1) Remember that EPI and NE can dilate cardiac blood vessels
and airways by relaxing smooth muscle!
*How does this help during exercise?
• 3) Remember that cortisol can helps constrict airways!
• How does this help clean air when you sleep?
• 4) When are asthma/heart attacks more common?
• When is cortisol or EPI/NE more prominent?
• Many anti-depressive drugs mimic serotonin/melatonin
• Many anti-depressive drugs prevent the destruction or
removal of serotonin (PROZAC blocks pumps).
• Seasonal Affective Disorder and PreMenstrual Syndrome
are two classic examples of disorders that may respond to
modified serotonin release, uptake or destruction.