In the space below, explain in detail how insulin and glucagon regulate blood glucose

during an 8 hour fast and after eating a high carbohydrate meal. Next discuss the
similarities and differences between type I vs. type II diabetes. Lastly compare the
physiological consequences of "insulin shock" vs. a type I diabetic who has forgotten
to take their insulin for several days.

Insulin and glucagon are two hormones that are secreted by the pancreas in an attempt to
regulate blood glucose levels. During an 8 hour fast, blood glucose levels are extremely
low because you are not receiving glucose from consuming carbohydrates. There are
alpha cells located in the pancreas, which detect when these blood glucose levels have
dropped. The alpha cells then secrete the hormone glucagon, which then acts on the liver.
In the liver there is a high level of glycogen, which is repeating units of glucose hooked
together by alpha 1-4 bonds. The glucagon reaches the liver and binds to a receptor on the
liver, which activates the enzyme phosphorylase. This enzyme breaks the alpha 1-4
bonds between glycogen to form glucose units. These glucose molecules can then leave
the liver and enter our blood stream, which raises the BG level to normal. On the
contrary, when our blood glucose levels rise after eating a high carbohydrate meal
insulin, from the pancreas, is secreted to bring these levels back down to normal. The
beta cells in our pancreas can detect when our blood glucose levels rise and then secrete
insulin into our bloodstream. The insulin in our bloodstream binds to muscle cells and
then signals the insulin binding receptor to intracellularly signal GLUT-4 transport
proteins to move up and insert into the skeletal muscle phospholipid bilayer. The bilayer
of the vesicle and the bilayer of the SM blend together and the GLUT-4 transport proteins
are now inserted into the cell membrane. The glucose now gets transported into the SM
cell, which causes the BG levels to decrease back to normal range and the creation of
alpha 1-4 bonds between each of the glucose molecules so it can be stored as glycogen.

Type 1 diabetes, also referred to as insulin-dependent diabetes mellitus, is a case in which

a person builds antibodies against beta cells so they dont recognize their own beta cells
therefore, the antibodies destroy them and no longer can produce insulin. Victims have to
use other methods to bring their blood glucose levels back down to normal, usually by an
insulin injection. This disease typically occurs in children and its symptoms usually
include polyuria, polydipsia, bedwetting, and failure to thrive due to the urination of
glucose. Type 2 diabetes, also referred to as non-insulin dependent diabetes, is not
characterized by the destruction of beta cells, but rather the problem arises in the insulin
signaling transduction pathway. Normally, insulin binds to the receptors and causes
GLUT-4 to transport. There is a signal between the insulin binding and causing the
GLUT-4 transporters to insert/move to fuse with the phospholipid bilayer of the skeletal
muscle so that glucose can be transported to the cell. Type 2 diabetics produce insulin
but it loses its ability to have its glucose transporter to insert and fuse with the
phospholipid bilayer, making them insulin resistant. This causes the BG level to keep
rising.

Insulin shock occurs after injecting too much insulin into the bloodstream so that the
alpha cells don't have the time to get activated quickly enough to release glucose to
counteract this. In response to this, the glucose transporters get inserted all over skeletal
muscles and glucose starts being taken up really fast and BG drops really low. On the
contrary, if a type 1 diabetic fails to take their insulin their BG quickly rises and exceeds
the tmax (transport maximum) of 200mg/100ml of blood. This causes the diueresis of
the extra glucose, which causes endothileal damage. This can result in retinoapathy,
neuropathy, and/or circulatory hypoxia.

In the space below draw a typical nephron making sure to identify the important
physiological structures. Next explain in detail where and how water is reabsorbed,
making sure to differentiate between mandatory and facilitated reabsorption and
how these are regulated during dehydration and following consumption of a gallon
of water. Lastly, explain in detail how loop diuretics and anti - ADH diuretics
works.

180L/day of fluid are filtered through the kidneys and 179L of the 180L/day are
reabsorbed back into the bloodstream. There are two types of ways in which water is
reabsorbed back into the bloodstream after it is filtered through the glomerulus of the
nephron. 144L of the 179 that are reabsorbed per day, which is about 80%, is reabsorbed
by mandatory re-absorption. The other 35L (19.5%) are reabsorbed through facilitated
reabsorption. 99% of water that is filtered is reabsorbed and the other 1% is what is
filtered, not reabsorbed, and urinated out. Mandatory reabsorption occurs in the proximal
convoluted tubule of the nephron. There are Na/K pumps located in the basal membrane
of the PCT, which pump sodium out of the cells into the vasa recta. Since there is no
Na/K pump on the apical membrane it makes it so they cannot be pumped back into the
PCT. 80% of the sodium that is filtered is immediately reabsorbed in the PCT therefore,
water follow the sodium via osmosis (water moving toward the higher concentration of
particles). As soon as 80% sodium is taken up into the bloodstream then 80% of the
water follows. Facilitated reabsorption absorbs the sodium and water in different places
on the nephron. The sodium is reabsorbed in the ascending limb of the loop of henle
while the water gets reabsorbed in the collecting duct. There are sodium pumps located
on the ascending limb of LOH, however the sodium is not pumped out evenly. The Na
pumps that pump out the most sodium are the first pumps where the ultra filtrate enters.
As the fluid travels up the ascending limb of LOH the sodium concentration decreases
because sodium is being pumped out as it ascends creating as osmotic gradient to be used
in the collecting ducts if ADH is present. The osmotic gradient refers to the amount of
water reabsorbed and how concentrated the urine is. There is a high sodium
concentration at the lower end because more sodium is pumped out here and the number
of sodium particles decreases because less is being pumped out as the ultra filtrate
ascends. No water is reabsorbed here because the wall of the ascending limb is too think
and impermeable to water. As the blood becomes more concentrated with ions the
osmoreceptors in the hypothalamus of the brain sense this and release ADH. The filtrate
now enters the collecting duct and the ADH released binds to receptors on the collecting
duct making the collecting duct wall permeable to water and the water is then reabsorbed
toward the osmotic gradient by osmosis.

During dehydration and over consumption of water the reabsorbtion methods are
affected. During dehydration mandatory reabsorption still absorbs 80% of the fluid that
is filtered because it is a fixed variable. Facilitated reaborption during dehydration is
dependent on the ADH production. When we get dehydrated we lose water and the ions
that are left behind get more concentrated which increases the osmolarity in the blood.
The blood passes by the osmoreceptors and they start producing action potentials and
release ADH. The ADH gets in the bloodstream to collecting duct and the wall becomes
permeable to water, but since very little water is present due to dehydration we reabsorb
almost all of it thus we urinate very little and the urine is highly concentrated with
sodium ions. If we were to consume a gallon of water, the mandatory reabsorption would
still stay fixed, reabsorbing 80% of the water. However, the excess water would cause
the osmolarity levels to decrease because the blood is less concentrated with sodium ions
(more water present). The osmorecptors sense this and stop sending action potentials and
stop releasing ADH. This then causes the collecting ducts to not be permeable to water,
therefore water isnt reabsorbed and you urinate it out.

Anti-ADH diuretics slow the production of ADH in the pituitary gland so less ADH is
produced. This causes less water to be reabsorbed because it inhibits the collecting ducts
from being permeable to water, thus, we urinate more (affect only facilitated water
reabsorption). Loop diuretics work in the loop of henle. They slow down the sodium
reabsorption of the ascending think limb of LOH and therefore, reduce the osmostic
gradient.

In the space below draw how the blood concentrations of LH, FSH, estradiol, and
progesterone respond during a typical 28-day menstrual cycle. Next, explain in
detail the 3 phases of the ovarian cycle and how they influence the 3 phases of the
uterine cycle. Lastly, explain how birth control pills work to prevent pregnancy.

LH: low and then spikes at day 14 then is low the rest of the time (high only ONE day)
FSH: high on day one, drops when estradiol starts to be produced from granulosa cells
and remains low until about day 14. Little spike at day 14 because of the positive
feedback from the high levels of estradiol; by day 27 it starts to increase back up again
because if a women is NOT prego then she needs to start another cycle. The corpus
luteum has died and there is no progesterone, which allows FSH to go back up.
PROGESTERONE: low through day 1-15 because NOT made by follicle; the corpus
luteum makes this so it starts increasing on day 15 and peaks at day 21 (corpus luteum is
largest); drops to low level at day 28 (not prego); this removes the break for the inhibition
on pituitary gland, then the pituitary gland starts to produce FSH again to start next cycle;
low progesterone stops inhibition on pituitary via negative feedback
ESTRADIOL: low on day 1; day 5 estradiol increases exponentially; day 15 it decreases
rapidly because the granulosa cells have turned into the corpus lutem; rises rapidly during
follicular phase, drops during formation of the corpus luteum

OVARIAN CYCLE:
Phase 1 (Follicular Phase):
The follicular phase occurs between day 1 and 13 in the ovarian cycle. FSH is secreted
by the pituitary gland because the estradiol level is very low (no granulosa cells). The
FSH gets into the bloodstream and stimulates one primary follicle to grow, called the
graafian cell, which is made up of an ovum surrounded by granulosa cells. There are few
granulosa cells between days 1 and 5. By day 6 the graafian follicle has started to grow
and the amount of granulosa cells have increased, however, the ovum does not change in
size. These granulosa cells secrete estradiol, which now exponentially increases due to
granulosa cell growth. These increasing levels of estradiol have a negative feedback on
the pituitary gland, which stops the production of FSH. By day 13 the graafian follicle
has grown 20x its original size, which means there is 20x the amount of estradiol than in
resting state. Estradiol now switches from having a negative feedback to having a
positive feedback on the pituitary causing it to secrete LH.
Phase 2:
Phase 2 occurs on day 14, ovulation day. There is a spike in LH here because the
estradiol turned on the pituitary. LH is released for one day only! This activates an
enzyme that causes the graafian cell to fuse to the outside of the ovary. The ovum then
leaves the ovary and goes into the ova duct, which leads from the ovary to the uterus.
The ovum is now ovulated out of the ovary and will travel down the ova duct to the
uterus (5 days). The high levels of LH also cause the granulosa cells that were produced
from the graafian cells to form into the corpus luteum.
Phase 3:
Phase 3 occurs between day 15 and 28 and is called the luteal phase. The first part of this
phase is the early luteal phase. By day 15 there are no granulosa cells because they turn
into the corpus luteum. The formation of the corpus luteum causes the secretion of the
hormone progesterone and the corpus luteum grows for 7 days. The late luteal phase
occurs from day 21 to day 28 and the progesterone levels start to decrease. By day 21 if a
women is not pregnant then her body needs to get ready to start a new cycle. Between
day 21 and 28 the corpus luteum dies off and now becomes a small structure called the
corpus albican (if not pregnant). This causes the progesterone levels to decrease rapidly
which has a negative feedback effect on the pituitary gland causing to start releasing FSH
allowing the start of a new cycle.
All of the phases of the ovarian cycle are directly connected to the Uteran Cycle
The first phase of the uteran cycle is called the menstrual phase and occurs between day 1
and 5. Since the levels of estradiol are low during these days in the ovarian cycle it
causes the endometrial lining of the uterus to remain very thing (~1mm). The second
phase of the uteran cycle occurs between day 6 and day 14 and is called the proliferation
phase. During these days in the follicular phase of the ovarian cycle estradiol levels
increase due to the increase in number of granulosa cells. These increased levels of
estradiol cause the endometrial lining of the uterus to proliferate and go from 1mm of
thickness to 10mm of thickness. The third and final phase of the uteran cycle is called
the secretory phase and occurs between day 14 and day 28. From day 15-21 in the
ovarian cycle levels of progesterone are rising due to the formation of the corpus luteum.
The endometrial lining remains thick during this phase and the high progesterone levels
cause the formation of spiral capillaries in the endometrial lining, which provide blood
supply. Progesterone also allows the formation and storage of glycogen (food supply).
On day 21 the endometrial lining is proliferated, spiral capillaries and glycogen are all
present. If the woman is not pregnant, the estradial and progesterone levels are so low by
day 28 that the capillaries, glycogen, and thickness of the endometrial lining begin to
disappear. The levels are low because they decrease as the corpus luteum turns into the
corpus albican. This leads into the next menstrual phase because these low levels cause
FSH to climb back up for another primary follicle to start turning into a graafian cycle.
*takes 5 days for ovum to pass alone the ova duct and usually arrives around day 20/21

Birth control works by negative feedback. They give low levels of estradiol and
progesterone to give a negative feedback on the pituitary to shut off LH (no ovulation)
and FSH (no graafian follicle) production. Without LH and FSH a primary follicle will
not develop into the graafian follicle and she cannot get pregnant. The ovums are still
secreted even though this cycle isnt happening. A women taking contraceptives does not
have an LH spike because the pills keep estradiol levels low = no ovulation. The 7
placebo pills are taken when the estradiol and progesterone levels decrease mimicking the
ate luteal phase and this brings on a menstrual phase