NPB 101 MT3 (Endocrine)

Organs that function specifically for the endocrine system

• pituitary

• thyroid

• parathyroid

• adrenal gland

How do endocrine cells communicate?

Endocrine signaling

Hormone

an extracellular signaling molecule that is released into the blood and acts at its receptors in distal tissues in order to elicit a physiological response

Diffusion is “pathetic” but efficient, how?

Strong propulsion causes fast blood flow in the body (makes up for the slow speed of diffusion)

Nervous system

Anatomic Arrangement: A “wired” system: a structural arrangement exists between neurons and their target cells, with structural continuity in the system

Type of chemical messenger: neurotransmitters released into the synaptic cleft

Distance of action of the chemical messenger: short distance (diffuses across the synaptic cleft)

Specificity of action on the target cell: dependent on the close anatomic relationship between neurons and their target cells

Speed of response: rapid (milliseconds)

Duration of action: brief (milliseconds)

Major functions: coordinates rapid, precise responses

Endocrine system

Anatomic Arrangement: A “wireless” system: glands are widely dispersed and not structurally related to one another or to their target cells

Type of chemical messenger: hormones released into the blood

Distance of action of the chemical messenger: long distance (carried by the blood)

Specificity of action on the target cell: dependent on the specificity of target cell binding and responsiveness to a particular hormone

Speed of response: slow (minutes to hours)

Duration of action: long (minutes to days or longer)

Major functions: controls activities that require long duration rather than speed

Hydrophilic hormones

• High water solubility: Low lipid solubility (cannot pass through a lipid membrane well

• Water-loving

• Stored in secretory vesicles post-synthesis until recception of stimulus for secretion

Lipophilic hormones

• High lipid solubility: Low water solubility

• Lipid-loving

Hydrophilic hormone types

• AA derivatives (amines)

• Peptide hormones

AA derivative hormones

• Amines

• Hydrophilic

• Include:

  • dopamine

  • norepinephrine

  • epinephrine

  • melatonin

Peptide hormones

• Majority of hormones fit this subcategory

• Short to medium length chains of AAs (3 AA to 200AA)

• Hydrophilic

• Include:

  • All pancreatic hormones (e.g., insulin, glucagon)

  • All digestive tract hormones (e.g., secretin, gastrin, CCK, GLP-1, GIP)

  • All Hypothalamic releasing or inhibiting hormones (except dopamine, see above)

  • All anterior and posterior pituitary hormones

  • Various others: angiotensin II, insulin-like growth factor I, erythropoeitin, atrial natriuetic peptide, calcitonin

Amine synthesis benefit

Different hormones derived from each other allows conservation of energy

Dopamine

• The only hypothalamic releasing/inhibiting hormone that is not considered to be a peptide hormone

  • Smaller than an AA, making it the smallest second set of biologically active molecules (compounds) in the body (after gasses)

Peptide hormone synthesis

• Produced from mRNA, which creates inactive hormones

  • Activated upon enzyme cutting activity

• mRNA → pre-hormone → pro-pre-hormone → hormone

Lipophilic hormone types

• Thyroid hormones

• Steroid hormones

Thyroid hormones

• Derived from 2 tyrosines + iodide (added)

• Lipophilic

  • Note: both lipid and water soluble yet still works like a typical “highly lipid soluble” hormone

• Types:

  • Thyroxine (T4)

  • Triiodothyronine (T3)

• Activate thyroid hormone receptor

• Complicated synthesis in thyroid gland

Steroid hormones

• Derived from cholesterol

• Lipophilic

  • Note: highly lipid soluble but have a little bit of water solubility

• Types:

  • Estrogens

  • Androgens

  • Progestins

  • Glucocorticoids

  • Mineralocorticoids

  • Vitamin D

  • Receptors for these hormones are variable in amount with respect to time

Steroidogenesis

The particular steroid hormone produced by a cell depends on the expression and activity of a specific set of “steroidogenic enzymes”

The chemical (soluble) properties of a hormone impact its

• Storage: If it can be stored in cells before release into the bloodstream

• Transport: How the hormone is carried throughout the bloodstream

• Metabolism and Excretion

• Mode of action at target cells

Hydrophilic hormone storage

Kept in secretory vesicles after synthesis, thus secretion gets regulated separately from synthesis

Lipophilic hormone storage

None: hormones diffuse out of cells as soon as they are synthesized

Hydrophilic hormone transportation

Completely soluble in plasma; travel where they need to go easily and freely

Lipophilic hormone transportation

Insoluble in plasma, so hormones bind weakly onto carrier proteins circulating in the blood

• Weak binding permits them to “jump on and off” [of carrier proteins] at will

Hydrophilic hormone metabolism

• Chemical modification to become less active: hormones cleaved by circulating general proteases (enzymes that cut proteins or peptides at many different peptide bonds)

• Chemical modification to become more active: hormones cleaved by specific proteolytic enzymes (cut at a specific peptide bond)

  • these activating enzymes all come from different places in the body to increase efficiency of production

(specifically in reference to peptide hormones)

Lipophilic hormone metabolism

• Chemical modification to become less active: hormones modified by liver enzymes to be more water-soluble and therefore can’t enter cells, and are also more easily excreted in urine

• Chemical modification to become more active: enzymes in target cells chemically modify one version of a hormone to produce a more active version of the hormone

Hormone receptor properties

Expressed in target tissues and upon hormone binding initiate biochemical chain of events that alters cell function

Hydrophilic hormone mode of action (@ target cells)

Act via receptors in target cell membrane (i.e., membrane receptors) and activate receptor-enzyme complexes, or recruit second-messenger systems to produce their physiological response

Lipophilic hormone mode of action (@ target cells)

Act via intracellular receptors that act in the cell nucleus (i.e. nuclear receptors) to induce gene transcription, producing their long-term physiological response

• These hormones can simply pass through the lipid membrane without external help, so getting to the location of action is the easy/fast part

• Their function of inducing gene transcription is the natural goal; from there, the time-consuming part (to cause long-term effects)

Time-consuming → high reward

Which signaling strategy might affect cells the fastest?

Hydrophilic

Which signaling strategy might have effects that last the longest?

Lipophilic

Hydrophilic hormones’ Second Messenger Pathway (specific example)

1. Binding of extra-cellular messenger (hormone) to receptor activates a G protein

   1. G protein α-subunit shuttles to adenylyl cyclase to activate it

2. Adenyl cyclase converts ATP to cAMP

3. cAMP activates protein kinase A

4. Protein kinase A phosphorylates inactive designated protein, activating it. This is done through the targeting of:

   1. Ion channels (& other transporters)

   2. Enzymes

   3. Transcription factors (alter gene transcription, so this response takes longer)

5. Active designated protein brings about desired response

G-receptor role in Hydrophilic second-messenger cascade

Targeted by over 40% of all prescription drugs because they're so frequent in plasma membranes

Hydrophilic hormones’ Second Messenger Pathway (general description)

one hormone molecule binds to the exterior surface of the cells → activation of hundreds or thousands of enzyme molecules inside the cell → catalyze many rounds of reaction → produced amplification of signal

Phosphorylation in Hydrophilic second-messenger cascade

• Can either have no effect, increase, or decrease activity — depends on the kinase and protein

• A single kinase can act upon thousands of proteins

  • It's stopped by an esterase eventually

Lipophilic hormones’ Regulation of Gene Transcription Pathway (specific example using a nuclear receptor)

1. Free lipophilic hormone diffuses through plasma membrane

2. Hormone binds with its respective specific intracellular receptor

3. Hormone receptor complex binds with DNA’s hormone response element

4. Binding activates gene

5. Activated gene transcribes mRNA

6. New mRNA leaves nucleus

7. Ribosomes read "mRNA to synthesize new proteins

8. New protein is released from ribosome and processed into its final folded form

9. New protein brings about desired response

Nuclear receptors in Lipophilic gene-transcription pathway

Intracellular receptors that regulate specific gene transcription

How is endocrine function regulated?

1. Negative feedback control of hormone secretion

2. Neuroendocrine reflexes can promote hormone secretion

3. Circadian rhythms can control hormone secretion

4. Changes in hormone receptor activity, often by expression or availability

5. In relation to other hormones: permissiveness, synergy, or antagonism

Endocrine function regulation via Negative feedback control

Can be driven by either:

1. Direct sensing of changes in the controlled variable (ie: control of blood glucose, Karen can see that the TP is back on the shelf and will stop shouting at the manager)

2. The endocrine axis itself, where one of the hormones in the control system provides feedback. [ie: hypothalamic-pituitary-(thyroid/adrenal, gonad)- axes, Karen could hear the manager talking to the store clerk]

Endocrine function regulation via Neuroendocrine reflexes

Result in a sudden increase in hormone secretion in response to a specific stimulus

(ie: secretion of epinephrine from the adrenal medulla in response to increased sympathetic nervous system output, or vasopressin secretion from the posterior pituitary when blood pressure drops)

Endocrine function regulation via Circadian rhythms

• Rate of secretion of many hormones fluctuates up and down as a function of time.

• Most commonly, this is characterized by repetitive oscillations occurring every 24h, responsive to light (and dark).

• This is an example of “feed-forward” control.

  • Advantage: preparation for future events

  • Ie: one job of cortisol is to increase blood glucose in the morning so we have energy to start the day — making it a glucocorticoid

Endocrine function regulation via Receptor activity (number, availability, or responsiveness)

A target cell’s response to a hormone is correlated to the number of that cell’s receptors that are occupied by the hormone, therefore endocrine function can be regulated by both the concentration of the hormone and the number of available receptors

Endocrine function regulation via other hormones

• Permissiveness = one hormone must be present in sufficient amounts to ‘permit’ another hormone to have its full effects (think of E for progesterone)

• Synergy = the combined actions of several hormones are greater than the sum of their separate effects.

• Antagonism = one hormone causes the loss of another hormone’s receptors. Opposite of permissiveness

Effective concentration of a hormone in the bloodstream is influenced by:

Primarily, rate of secretion, but also:

• Regulated metabolism by conversion or activation– sometimes the secreted hormone needs to be “activated” before it can bind to its receptor. 

• Transport– lipophilic hormones may circulate mostly in a carrier protein bound form, but only the unbound “free” form can enter cells and activate a receptor. 

• Metabolic inactivation and excretion (feces and urine) (lowers the amount)

Hyposecretion

Too few hormone secreted by endocrine gland

Hypersecretion

Too much hormone secreted by the endocrine gland

Two major ways of hormone secretion regulation

• 1) Physiological changes (including reproduction) or developmental cues are sensed within or relayed to the brain (specifically, the hypothalamus), where the information is integrated (which then allows either -/+ feedback)

  • This results in changes in pituitary hormone secretion that act directly on target cells and/or regulate the secretion of other hormones. 

  • Negative feedback often works here to maintain hormone levels in blood within predetermined high and low set points, but as we will see, positive feedback can occur as well, but that’s mostly involved in reproduction (vs the more common negative feedback in regulating homeostasis)

• 2) The hormone-secreting cell directly senses a change in a controlled variable and responds by increasing or decreasing the secretion of hormones that correct that change back to a set point, in a classical negative feedback fashion

  • This is how blood glucose levels are controlled

Pancreas Hormones

Don’t receive as much blood supply because they don’t require a lot of energy (not like they need it to incite contractions or anything)

Pancreas Islets of Langerhans

Endocrine control of nutrient (especially glucose) levels after digestion

Pancreas Duct Cells

Neutralize the enzymes from the stomach, allowing the pH to increase so they can function better

Pancreas Acinar Cells

• Secrete enzymes that break things down

• Function best around 7.2 pH → located next to duct cells

Endocrine portion of pancreas

Islets of Langerhans

Exocrine portion of pancreas

Acinar & Duct cells

Homeostatic regulation of blood glucose involves…

The shuttling of energy stores between ingested nutrients and their stored forms to maintain a relatively constant supply of glucose for all the cells of the body — especially for the brain

Anabolic reactions

Build storages of fuel from food

Catabolic reactions

Break down storages of fuel from food

The food we eat is derived from several macronutrient forms:

1. PRO — protein

2. CHO — carbohydrates

3. FAT

AAs are derived from what macronutrient?

Proteins

Simple sugars, including glucose, are derived from what macronutrient?

Carbohydrates

Fatty acids and monoglycerides are derived from what macronutrient?

Fats

Macronutrient derivations

AAs, simple sugars, fatty acids, and monoglycerides can be used immediately as fuel when created or can be stored for future use

Sugars get stored where in the body?

As glycogen in liver and muscle

Fatty acids are stored where in the body?

As triglycerides in adipose tissue

AAs are stored where in the body?

They’re actually used to build structural and functional proteins for the body instead

What fuel is the brain able to use?

Glucose, with the exception of ketoacids produced by the liver during starvation

Why does the brain use ketoacids for fuel during starvation?

It is unable to store glucose reserves for later use

Most abundant metabolic fuel in the body

Adipose tissue (storage site for fat)

If the body wants to access protein for fuel, what has to be done?

Structural proteins (such as those within our skeletal muscle being used for skeletal muscle things) have to be broken down and removed from their system.

This is so inconvenient that it’s only used for energy as a last resort; death often results long before the capacity is fully used (structural and functional impairment results)

Anabolism

• The buildup or synthesis of larger organic molecules from small organic molecular subunits

• Dominates the absorptive/fed state

• Glucose is plentiful and serves as the major energy source

Catabolism

• Breakdown or degradation of large energy-rich molecules within cells

• Dominates the post-absorptive/fasting state

“Genesis” root

= building up

“Genolysis” root

= breaking down

Fuel metabolism Anabolic reactions

• Glycogenesis: glucose → glycogen → ↓blood glucose

• Protein synthesis: AAs → protein → ↓blood AAs

• Fat synthesis (lipogenesis or triglyceride synthesis): fatty acids & glycerol → triglycerides → ↓blood fatty acids

Fuel metabolism Catabolic reactions

• Glycogenolysis: glycogen → glucose → ↑blood glucose

• Gluconeogenesis: glycerol & AAs → glucose → ↑blood glucose

  • technically just an “interconversion” reaction that is most active in the post-absorptive state

• Protein degradation: protein → AAs → ↑blood AAs

• Fat breakdown (lipolysis or triglyceride degradation): triglycerides → fatty acids & glycerol → ↑blood fatty acids

Hormone(s) that increase blood glucose

• Glucagon – Released by alpha cells in the pancreas when blood glucose is low. It stimulates the liver to break down glycogen into glucose (glycogenolysis) and produce new glucose from non-carbohydrate sources (gluconeogenesis), raising blood sugar 

• Epinephrine (adrenaline) – Released by the adrenal medulla during stress, exercise, or low blood sugar. It promotes glycogen breakdown in the liver and muscle, and increases glucose production in the liver, thus raising blood glucose 

• Cortisol – Released by the adrenal cortex in response to stress or low glucose. It increases gluconeogenesis in the liver and reduces glucose uptake by peripheral tissues, elevating blood sugar 

• Growth hormone (GH) – Secreted by the anterior pituitary. It promotes lipolysis (fat breakdown) and gluconeogenesis, and reduces insulin sensitivity, leading to higher blood glucose

Hormone(s) that decrease blood glucose

Insulin – Released by beta cells in the pancreas when blood glucose is high (e.g., after a meal). It stimulates cells (especially liver, muscle, and fat) to take up glucose from the blood, store it as glycogen, and reduce glucose production by the liver, thereby lowering blood sugar

Insulin

• Major absorptive state hormone: It travels through the blood to facilitate uptake and storage of glucose (and storage of other fuels) in target organs

• Primary goal: enhance glucose uptake via the transporter protein GLUT4, in many tissues of the body (especially fat cells and resting skeletal muscle)

• Released by beta cells in the pancreas’ Islets of Langerhans when blood glucose is high (e.g., after a meal). It stimulates cells (especially liver, muscle, and fat) to take up glucose from the blood, store it as glycogen, and reduce glucose production by the liver, thereby lowering blood sugar

GLP-1

• Originally developed to increase insulin secretion in TII Diabetes

• + Parasympathetic stimulation onto Islet β cells for insulin production

Insulin mediated GLUT transportation

• To the liver: insulin-independent transport via GLUT2, but insulin is required (dependent!) for glycogenesis

• To the skeletal muscles: GLUT4 transport, stored as glycogen

• To fat cells: GLUT4 transport, stored as triglycerides (via new triglyceride synthesis)

• To the brain: insulin-independent transport via GLUT2, no storage

When is insulin required for glucose uptake in skeletal muscles?

Resting skeletal muscles need GLUT4 to be inserted into their membrane

When is insulin not required for glucose uptake in skeletal muscles?

Contracting skeletal muscles already have GLUT4 inserted into their membrane whilst contracting

Insulin effects on Carbohydrate Metabolism

1. Enhances glucose uptake via GLUT4

2. Increases liver and skeletal muscle glycogenesis

3. Inhibits liver and muscle glycogenolysis

4. Inhibits liver gluconeogenesis

↑ α ↓[Blood Glucose]

Insulin effects on Fat Metabolism

1. Enhances glucose uptake in adipocytes for triglyceride synthesis

2. Increases adipocyte triglyceride synthesis

3. Inhibits adipocyte lipolysis

↑ α ↓[Blood Fatty Acids]

Insulin effects on Protein Metabolism

1. Enhances AA uptake into muscle and liver

2. Increases protein synthesis

3. Inhibits proteolysis

↑ α ↓[Blood AAs]

Which statement about blood glucose levels is TRUE?

It must remain within a normal range because the brain needs a constant supply of glucose.

Which statement is TRUE for insulin but FALSE for glucagon?

It stimulates glucose uptake by resting skeletal muscle

Glucagon

• Major post-absorptive state hormone

• Facilitates the maintenance of fasting blood glucose

• Produced by the Islets of Langerhans’ α-cells

Glucagon in Adipose tissue

Increases lipolysis and inhibits triglyceride synthesis

Glucagon in the Liver

• Decreases glycogen synthesis

• Increases glycogenolysis

• Increases gluconeogenesis (uses amino acids, glycerol)

• Mildly increases ketogenesis (byproduct of FA metabolism) (in prep for worst-case scenario where the brain needs ketones for energy)

How to remember the order of Anabolism/Catabolism in the body?

A comes before C

Glucagon in Skeletal muscle

No direct effects of glucagon on skeletal muscle, but: the absence of insulin (or minimal levels) leads to reduced glucose uptake and increased protein degradation

Glucagon in the Brain

No direct effects of glucagon on the brain but: its action in peripheral tissues helps maintain blood glucose to keep the brain happy.

Glucagon effects on Carbohydrate Metabolism

1. Inhibits liver glycogenesis

2. Increases liver glycogenolysis

3. Increases liver glucogenesis

↑ α ↑[Blood Glucose]

Glucagon effects on Fat Metabolism

1. Decreases triglyceride synthesis

2. Increases lipolysis

3. Mildly increases liver ketogenesis

↑ α ↑[Blood Fatty Acids]

Glucagon effects on Protein Metabolism

Minimal/No effect

Stimulation of Glucagon via ↓[Fatty acids]

Recognition that body is “running low on fuel from fat”

• Breaks down more glycogen.

• Makes more glucose from amino acids and glycerol.

• Increases fat breakdown to restore fatty acids in the blood

Stimulation of Glucagon via ↑[AAs]

Prevention of the typical insulin-only response post-meal

• Gluconeogenesis performed instead/additionally

• Glucose then released into the blood

Diabetes Mellitus

• It is a group of metabolic disorders sharing the common underlying feature of hyperglycemia.

• In diabetes, hyperglycemia results from

  • Defects in insulin secretion

  • Defects in insulin action

  • Defects in both insulin action and secretion

• Chronic hyperglycemia can result in multiple organ damage

• 11-12% of the population in the US suffers from diabetes (2021) (it is the most common of all endocrine system related diseases). 

• 3X that number suffers from “pre-diabetes” (some evidence for dysregulated glucose homeostasis)

Hyperglycemia in diabetics results from

• Defects in insulin secretion

• Defects in insulin action

• Defects in both insulin action and secretion

RBC Glycosylation

• When glucose concentration in the blood becomes excessive, glucose molecules stick to the hemoglobin of the blood

• The attachment of glucose to hemoglobin is permanent; the two remain stuck until the end of the 3-4 blood cell lifespan

• Thus, remains unaffected by whether or not someone is fasting when blood glucose is tested

What makes the A1C such an efficient test for diabetes?

It’s not affected by fasting vs. non‑fasting — results reflect long term patterns instead of short-term ones.

• The score specifically represents the average blood glucose over the past 3–4 months [which is also lifespan of RBCs (with glycosylated hemoglobin)]