BICD150, Lecture 7 Notes

8/11/2019 BICD150, Lecture 7 Notes

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Lecture 7

Topics covered:

- Puberty- Endocrinology of pregnancy

- Pancreatic hormone- Insulin Fed state - Glucagon Fasting state - Stimuli for secretion- Receptor transduction mechanism- Actions- Hypo and hyper glycemia- Diabetes mellitus and metabolic syndrome

Puberty:

Puberty begins with the beginning of the release of GnRH which stimulates the sexual organs.

The age of the onset of puberty is decreasing and is attributed to better nutrition. Secondary sexualcharacteristics develop under the influence of sex steroids during puberty in both males and females.

- Height spurt- Penis growth- Testicular growth- Pubic hair and axillary hair- Increased muscle and lean mass in males- Increased fat in females (it is relative to males)- Body odor- Menarche in females- Breast size and changes in the body shape- Lubrication of the vagina- Sperm production

There has been a correlation between the body weight and the onset of puberty. Overweight kids tendto undergo puberty earlier than lean children. This could relate to the storage of the sex hormones inthe adipose tissue present in the overweight people.

- Adipocytes secrete a hormone called Leptin which was discovered in rodents which were obeseand had mutation in the OB/OB gen e. Leptos=thin

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OB/OB mutants did not undergo puberty and it is now believed that Leptin is involved intriggering the signal for puberty.- The size of the Adipocyte is related to the secretion of this hormone; bigger the size of

adipocytes, more the production and secretion of Leptin.

High levels of Leptin leads to increased appetite.


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Fertilization:

Once the secondary oocyte is ovulated, it remains viable for fertilization for only about 24 hours.Nevertheless, viable sperm may remain in the female reproductive tract for about 3-5 days afterejaculation. It is hypothesized that the ovulated secondary oocyte may attract the sperm via chemotaxis.Of the 100 million sperm ejaculated, only 100 reach the oocyte, and only one sperm will inducefertilization. How is polyspermy prevented? In order to fertilize the egg, the sperm must penetratethrough the corona radiata, a layer of granulosa cells, as well as through the zona pellucida, a protectivemucopolysaccharide coat. In order to achieve this task, capacitated sperm undergo the acrosomalreaction, which can only occur if the sperm undergo capacitation. The acrosomal reaction involves the

exocytosis of the acrosome, which contains enzymes that dissolve the corona radiata and the zonapellucida, allowing the sperm to reach the egg and find the sperm binding receptors on the vitellinelayer, which is the outer layer of the ovum. The binding of the sperm to its receptor triggers ferti lizationand the completion of Meiosis II by the ovum. Additionally, fertilization triggers the cortical reaction,which is the main mammalian mechanism that safeguards against polyspermy. Before fertilization, theegg plasma membrane is tightly connected to an outer membrane, called the vitelline layer. The eggcontains numerous vesicles filled with mucopolysaccharides, called cortical granules, along its peripheryin the cytosol. Upon sperm entry and fertilization, there is a sudden spike in calcium levels that starts atthe point of sperm entry and spreads through the entire surface of the egg. The increased calcium levelstrigger the exocytosis of the cortical granules into the intermembrane space between the vitelline layerand the egg plasma membrane. The increased concentration of the cortical granules in theintermembrane space results in a sharp osmotic gradient that serves to draw large volumes of waterinto the intermembrane space, and thus, leads to the separation of the plasma membrane from thevitelline layer, inhibiting sperm entry into the ovum.

Fertilization occurs in the ampulla, which is the portion of the oviduct closest to the fimbriae. Theembryo takes four to five days to traverse the oviduct and to reach the uterine cavity. About two daysafter reaching the uterus and seven days after fertilization, the embryo implants in the endometrium.During this time, the embryo undergoes rapid mitotic divisions so that the embryo exists as a blastula by


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the time it reaches and implants in the uterus. The blastocyst consists of a hollow spherical structurecomposed of approximately 100 cells. The trophoblast, or the cells in the outer layer of the blastocyst,will form the chorion and placenta, whereas the cells of the inner cell mass will give rise to the fetus, theamnion, which secretes amniotic fluid, and the allantois, which produces the umbilical cord.

Ectopic pregnancies refer to the implantation of the blastocyst in a site other than the uterus, forexample in the oviduct, or in the abdominal cavity external to the uterus. Ectopic pregnancies are verydangerous and often fatal. A tubal pregnancy refers to the implantation of the blastocyst into theoviduct. Because the embryo is the fastest growing tumor that grows at an exponential rate and theoviduct cannot stretch like the uterus, a tubal pregnancy often results in fallopian tube rupture and


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internal bleeding. The treatment for tubal pregnancy is the surgical removal of the affected oviduct; thisprocedure does not render the patient infertile as the remaining oviduct may capture and propel anovulated secondary oocyte toward the uterus and result in conception.

The blastocyst secretes enzymes that break down and form a hole in the endometrium where theembryo inserts itself. Soon after implantation, the endometrial layer grows back over the blastocyst, andin doing so, completely covers the blastocyst within itself. As the blastocyst further grows and matures,the chorion forms fingerlike projections called chorionic villi, which contain enzymes at their tips. Thechorionic villi further penetrate and breakdown the innermost layer of the endometrium, which is highlyvascularized. The breakdown of the vascularized endometrium forms pools of maternal blood thatsurround the villi, which contain the embryonic blood vessels. The fetal circulation is structured in amanner similar to that found in the pulmonary circulation in that the umbilical vein contains nutrientsand high oxygenated blood whereas the umbilical artery contains poorly oxygenated blood andmetabolic wastes. The chorionic villi are the sites of exchange between the maternal and fetalcirculations. Nutrients, gases, hormones, and antibodies are transferred from the maternal blood intothe fetal circulation via diffusion and facilitated transport, while fetal hormones and waste products

from the fetal circulation are transferred into the maternal circulation. Although the villi allow for theexchange of nutrients and wastes, they do not allow for the mixing of maternal and fetal blood as thevilli membrane is impermeable to red blood cells.

Hormones during pregnancy

- hCG: Mainly substitutes for LH- hPL: Stimulates the breast and also, more importantly, is similar to GH in its metabolic effect.


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- Relaxin: it decreases the contractility of the uterus and is called so because it relaxes the pelvicligaments (connective tissue binding different bones together), leading to be able to have thebirth canal open up for the delivery of the baby.

- Fetus and mother both can provide androgens and estrogens (by conversion of theseandrogens).

- 17-hydroxy progesterone: Secreted by the corpus luteum only and is used as a measure ofCorpus Luteum function by the physicians.

- Estrogen: Though the placenta can synthesize peptide hormones de novo, the placenta needssteroid precursors in order to synthesize steroid hormones. Thus, the placenta uses DHEA-Sulfate from the maternal and fetal adrenal cortex to synthesize estrogen. The placenta has asulfatase, which cleaves the sulfate from the DHEA, allowing DHEA to be converted to thevarious estrogens.

Elevated levels of estrogen contribute to the development of the mammary glandularstructure as well as activating the nauseatory reflex of the medulla oblongata. Estrogen is alsobelieved to play a crucial role in the induction of labor. Estrogen promotes uterine contractilityby stimulating oxytocin upregulation on the myometrium thereby increasing the sensitivity ofthe myometrium to oxytocin. Also, estrogen increases the number of gap junctions between themyometrial cells. This latter effect results in consistent, unidirectional contractions that occur inunison. Toward the end of the third trimester, the estrogen to progesterone ratio increases,either by progesterone receptor downregulation, increased estrogen secretion, upregulation ofestrogen receptors, or a combination of these three effects.

- Thyroid Gland : Although TSH secretion does not increase during pregnancy, the production ofthe thyroid hormones rises, especially during the first trimester. Human chorionic gonadotropinacts as a weak TSH receptor agonist; thus, during the first trimester, when hCG levels arehighest, the mother may develop transient hyperthyroidism and the thyroid gland may undergo


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slight hypertrophy. Specifically, early gestation is marked by increased T4 synthesis, whereaslate gestation is marked by increased T3 levels. Furthermore, increased estrogen levelsstimulate the increased synthesis of thyroglobulin, thus, increasing the half-life and serum levelsof the thyroid hormones.

- Adrenal Cortex: During pregnancy, the maternal adrenal cortex demonstrates increased activity

and hormone synthesis in all three zones. Glucocorticoid synthesis increases due to theexceptionally high levels of pregnancy hormones, especially estrogen, which also stimulatesincreased production of corticosteroid binding globulin, the carrier protein for cortisol. Thus,both the synthesis and half-life of cortisol is increased during pregnancy. It is interesting to notethat pregnant women do not develop s ymptoms of Cushings disease and it has been suggestedthat progesterone may be responsible for this effect by selectively antagonizing the action of thecorticosteroids. Thus, the main effect of cortisol during pregnancy is to increase insulinresistance, in order to reserve glucose stores for the developing fetus. Also, increased cortisolsecretion may contribute to the development of striae, or stretch marks, commonlyassociated with pregnancy.

Aldosterone secretion demonstrated eight times more secretion during pregnancy.However, pregnant women do not commonly develop hypertension because progesterone is acompetitive inhibitor of the mineralcorticoid receptor, thus ensuring normal blood pressureduring pregnancy.

Androgen secretion, especially DHEA-Sulfate, increases during pregnancy in order tosupport placental secretion of estrogens.

- Insulin: During gestational diabetes, high glucose will travels to the fetus and stimulates thesecretion of insulin. This can lead to the collection of water in the babies, leading to big size ofthe babies.

- Oxytocin: By 12-18 weeks of gestation, the fetal posterior pituitary begins to secretevasopressin and oxytocin and the levels of both hormones progressively increase in the fetal

circulation throughout pregnancy. It has been suggested that fetal secretion of oxytocin maycontribute to the maintenance of labor because levels of oxytocin in the umbilical artery aregreater than oxytocin levels found in the fetal umbilical vein. In other words, the oxytocin levelsthat the fetus secretes into the maternal circulation exceed the oxytocin levels the fetusreceives from the maternal circulation. Note, however, that this increase in oxytocin occurs onlyafter the induction of labor. Towards the end of the third trimester and prior to the induction oflabor, oxytocin levels are constant; however, increased estrogen action leads to an upregulationof oxytocin receptors in the myometrium, increasing the effectiveness of oxytocin. It is onlyafter the fetus descends into the cervix, that the oxytocin positive feedback loop is triggered andoxytocin levels rise exponentially. Thus, although fetal oxytocin probably does not induce labor,it may play a significant role in maintaining labor by giving rise to consistent contractions.

Pancreas and its hormones

The pancreas is a dual function organ as it acts to maintain homeostatic control of digestion andmetabolism. About 98% of the pancreas is composed of exocrine cells, which secrete bicarbonate rich juice and synthesize all of the digestive enzyme precursors. The remaining 2% of the total mass of thepancreas is composed of small clusters of endocrine cells, called the islets of Langerhans that containthree distinct cells types. About 75% of the islet of Langerhans are composed of beta cells, which secrete


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insulin, 20% is composed of the alpha cells, which secrete glucagon, and about 4% are delta cells (or Dcells), which secrete somatostatin. Like all endocrine glands, the islets of Langerhans, are highlyvascularized and surrounded by capillary beds. In addition, they are closely associated with synapses ofautonomic neurons. Insulin and glucagon are antagonistic hormones in that insulin decreases bloodglucose levels whereas glucagon increases blood glucose. Somatostatin, which is also found in the

hypothalamus and stomach, plays a regulatory role by inhibiting glucagon and insulin secretion.Moreover, these pancreatic peptide hormones, have a short half-life and they therefore must becontinuously secreted in order to exert sustained action. Importantly, because insulin and glucagon areantagonistic hormones, it is the insulin to glucagon ratio that dictates the direction of metabolism.


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3. GI Hormones: The entry of nutrients into the intestine triggers the secretion of a wide variety ofGI homones, and especially the secretion of one class of GI hormones called the incretins,namely glucagon like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). These hormonesstimulate insulin secretion in a feed-forward manner, that is, the GI tract anticipates an increasein plasma glucose and opts for the secretion of insulin before plasma glucose levels become too

high. This action prevents a sudden surge of plasma glucose and ensures homeostaticmaintenance during the digestion and absorption of nutrients. Notably, somatostatin inhibitsthe secretion of these GI hormones and thus inhibits this feed-forward effect.

4. Parasympathetic Activity (Acetylcholine): Because the parasympathetic branch of the autonomicnervous system dominates during situations of rest and digest, the ingestion of a mealstimulates the vagus nerve, which contains neural circuits that innervate the pancreas directly,thus stimulating insulin secretion.

5. Sympathetic Activity (Epinephrine, only): The stimulation of beta adrenergic receptors byepinephrine also acts as a stimulator of insulin secretion. Beta adrenergicreceptors stimulatory effects and Alpha 2 receptors Inhibitory effect (main stimulus).

6. Glucagon: Though glucagon is antagonistic to insulin, it weakly stimulates for insulin secretionfor two main reasons. First, the co-secretion of glucagon and insulin helps to fine-tune plasmaglucose levels in order to ensure that glucagon does not result in excess increase in plasmaglucose. The pancreatic alpha cells require insulin stimulation in order to take up glucose, whichinhibits glucagon secretion in a negative feedback manner. Insulin stimulation of alpha cellsresults in the upregulation of glucose transporters (GLUT4) in the plasma membrane, whichallows for glucose entry into the cell. Thus, in order to maintain adequate levels of blood glucoseand to prevent glucagon-induced hyperglycemia, the pancreatic alpha cells need insulin in orderto take up glucose and to inhibit glucagon secretion as needed. Similarly, adipose tissue andskeletal muscle, also require insulin stimulation in order to become capable of taking up glucose.During times of stress or exercise, glucose needs to be transported to the active skeletal musclein order to maintain ATP production.

Mechanism of Insulin Secretion: Recall that increased plasma glucose levels stimulate insulinsecretion. Glucose diffuses into the pancreatic beta cell via the GLUT2 transporter when bloodglucose levels are high. The glucose is converted into ATP via oxidative phosphorylation. Pancreaticbeta cells contain special potassium leak channels that become blocked by ATP (K ATP channel). Thus,a high plasma glucose concentration translates into a high ATP concentration inside the pancreaticbeta cell, and thus, blockage of the K ATP channel. When the K ATP channel is not blocked by ATP, itallows for potassium ions to diffuse out of the cell, maintain the hyperpolarized membranepotential. However, when ATP blocks the K ATP channel, potassium accumulates inside the pancreaticbeta cell, thus depolarizing the membrane potential (since potassium ions carry a positive charge).This depolarization triggers the activation and opening of voltage gated calcium channels, thusleading to net influx of calcium into the pancreatic beta cell. The increased cytosolic calcium levelstriggers the exocytosis of docked insulin filled vesicles, thus leading to increased plasma insulinlevels. However, measurement of insulin secretion rates shows that after reaching a maximal rate,insulin secretion falls and remains steady at a diminished rate then subsequently rises once again.This trend in insulin secretion represents the exhaustion of the docked insulin stores. The steady,


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Receptor and transduction pathways of insulin:

Depending on the receptors activated, insulin results in one of two anabolic pathways: 1) thecarbohydrate metabolism pathway or 2) the mitogenic pathway. Insulin mainly targets the liver, adiposetissue, and skeletal muscle. Insulin stimulates a Growth Factor Receptor, and the proteins that thereceptor activates are called Insulin Receptor Substrates (IRSs), which set off the appropriate signaltransduction pathway.

The Carbohydrate Metabolism Pathway:

In this route, insulin triggers a series of signal transduction pathways that ultimately result in increasedglucose metabolism. First, insulin increases glucose transport into adipocytes and resting muscle cells.Insulin accomplishes this task by increasing the insertion of GLUT4 transporters into the plasmamembrane of these cells. The family of GLUT transporters are glucose channels that allow for thepassive diffusion of glucose across the cell membrane as dictated by its concentration gradient. TheGLUT4 transporter is inserted in the membrane only in the presence of specific cellular cues. In theabsence of such cues, the GLUT4 transporter resides in a storage pool in the cytosol. In contrast, theliver cells have GLUT2 transporters that are always present in the plasma membrane; regardless ofinsulin stimulation. Thus, glucose transport is independent of insulin in hepatocytes. When bloodglucose levels are high, hepatocytes maintain a concentration gradient for glucose diffusion into the cellby activating hexokinase, which phosphorylates the glucose converting it to glucose 6-phosphate (G6P).This allows for steady glucose diffusion into the hepatocyte because G6P is not the same molecule as

glucose. When blood sugar levels are low, the GLUT2 transporters allow for glucose diffusion in thereverse direction into the extracellular fluid in order to maintain glucose homeostasis. Noteworthy,glucose transport in exercising skeletal muscle is also independent of insulin secretion. An unknownpathway is activated during skeletal muscle contraction that results in increased GLUT4 insertion in theskeletal muscle plasma membrane. Secondly, insulin enhances cellular utilization and storage of glucose.This effect is coupled to the first one Insulin increases glucose uptake in order to drive glucosemetabolic and storage processes. Insulin activates enzymes necessary for glycolysis, as well as those


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necessary for glycogenesis and lipogenesis. Insulin also promotes fat synthesis by blocking -oxidation,which breaks down fats. Thus, insulin increases fat stores in two ways: by activating the enzymesnecessary for fat storage and by inhibiting the enzymes necessary for fat degradation.

The Mitogenic Pathway: Insulin promotes mitosis and therefore increases the number of cell productionand tissue growth. The mitogenic responses work through a series of different proteins involved in aseparate signal transduction pathway.

Metabolic actions of Insulin:

- Increased glycogen synthesis- Increased glycolysis- Increase protein synthesis- Decrease glycogen breakdown by inhibiting glycogen phosphorylase- Increase lipoprotein lipase- Increase lipogenesis- Decrease hormone sensitive lipase

- Inhibit gluconeogenesis- Adenylate kinase: ADP+ADP ATP+AMP. When energy levels are high, the energy levels of AMP

levels are low and vice versa. The levels of AMP regulates AMP kinase (low AMP activates AMPkinase and vice versa). AMPK will stimulate the formation of more mitochondria which leads tohigher formation of ATP. AMPK also stimulates glycolysis, stimulates fatty acid oxidation, inhibitsgluconeogenesis, inhibits fatty acid synthesis, etc. Insulin via AKT inhibits this AMPK which willlead to the metabolic effects of Insulin. Check figure 17-8 from our textbook.

- Adipocytes secrete: Leptin, Resistin, TNF-a, IL-6 which increase insulin resistance whereasadiponectin decreases insulin resistance.

- Metformin is a drug used to treat Type-II diabetes. This drug stimulates AMPK and inhibitsgluconeogenesis.

The mitogenic pathway involves the effects of insulin as a growth factor and affects all cells. Thus,insulin leads to the general growth of all cells.

Inhibition of insulin signaling:

- Remove insulin- Increase phosphatases- Down-regulation of the receptors

BICD150, Lecture 7 Notes

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