THE ENDOCRINE SYSTEM

MACRO TO MICROMOLECULES

Digestion breaks down macromolecules into micromolecules.

Carbs → protein

Proteins → amino acids

Lipids → fatty acids

CATABOLIC AND ANABOLIC

Catabolic = breakdown to small molecules

Anabolic = build-up and storage

Our metabolism is build for intermittent eating, not constant snacking.

GLUCOSE VS GLYCOGEN

Glucose = utility (fuel)

Glycogen = storage (skeletal muscle + liver)

KETONE BODIES

Glycogen cannot be stored in the neurons so they need a constant glucose supply

BUT

when glucose is limited, ketone bodies are a back-up fuel after days of prolonged fasting.

HYPOGLYCEMIA

• blood glucose < 4mM (acute < 3mM)

• Possible brain dysfunction, seizures, loss of consciousness, coma

• defended by glucagon, cortisol, adrenaline, GH

HYPERGLYCEMIA

• Blood glucose > 10mM (persistent > 20mM)

• Osmotic diuresis, thirst, long-term vascular and neural damage

• defended by insulin

THE PANCREAS (EXOCRINE)

• 98%

• Acinar cells in lobules secrete digestive enzymes, bicarbonate, and electrolytes via the pancreatic duct to the duodenum

• Bicarbonate neutralises stomach acid so pH suits the enzyme = better digestion + absorption

THE PANCREAS (ENDOCRINE)

• 2%

• Islets of langerhans secrete hormones into systemic blood

• Leaf-like gland posterior to the stomach

ISLETS OF LANGERHANS - B CELLS

• Produce insulin

• anabolic

• promotes storage of glucose, fatty acids and amino acids in cells

ISLETS OF LANGERHANS - A CELLS

• produce glucagon

• catabolic

• mobilises glucose, fatty acids and amino acids for energy

ISLETS OF LANGERHANS - DELTA CELLS

• produce somatostatin

• paracrine

• acts on neighbouring cells to inhibit insulin and glucagon

INSULIN AND GLUCAGON

in the context of glucose homeostasis, they are stated to be ‘functional antagonists’ (they act opposite to each other and are reciprocally secreted in most circumstances).

• They are not antagonists in the pharmacological sense

• The opposition is not strict

  • It is not always glucose ←> insulin relationship

DIABETES AND GLUCAGON DEFICIENCY

• Insulin is the only blood glucose-lowering hormone, so failure of synthesis/secretion = diabetes mellitus

• But there is no disease from glucagon deficiency as other hormones compensate

INSULIN SYNTHESIS

Pro-insulin in nucleus → signal peptide removed in ER → folded proinsulin → c-peptide cleaved in golgi → mature insulin (51aa) in secretory glands → exocytosis.

*measuring c-peptide indicates the secretory capacity of B cells

INSULIN RECEPTOR

• Tyrosine kinase receptor (RTK)

• Receptors highest in the liver, skeletal muscle, adipose tissue

Insulin binds → activates receptor → autophosphorylation of intracellular RTK domain → activates tyrosine kinase → phosphorylates proteins → glucose homeostasis + metabolic functions

INSULIN EFFECTS PER ORGAN SUMMARY

GLUT FAMILY

Glucose is too big/polar to cross the membrane freely, so it needs carriers (GLUT).

• move glucose via facilitated diffusion

• 14 in human genome

GLUT 1

• In many cells, blood brain barrier, erythrocytes

• role in basal glucose uptake

• insulin independent

GLUT 2

• in liver hepatocytes, pancreatic b cells

• role in hepatic glucose uptake + glucose sensing in b cells

• insulin independent

GLUT 3

• in most cells, high in CNS neurons

• role in basal uptake + keeps neurons supplied

• insulin independent

GLUT 4

• in skeletal/cardiac myocytes, adipocytes

• role in regulating glucose uptake

• insulin dependent

GLUT 5

• in intestinal epithelium

• role in fructose transport

• insulin independent

INSULIN AND GLUT4

Insulin stimulated:

• vesicles undergo exocytosis, inserting GLUT 4 into the cell membrane

Insulin unstimulated:

• GLUT4 sits in the cytoplasmic vesicles

*only GLUT4 regulated this way, other gLUTS already on the membrane

DEFINITIONS

Glycogenesis = forming glycogen

Glycogenolysis = breaking down glycogen

Gluconeogenesis = forming new glucose

Glycolysis = breaking down glucose

Lipogenesis = forming fat

Lipolysis = breaking down fat

INSULIN IN THE LIVER (Hepatocytes)

Nutrient-rich blood passes via hepatic portal vein, insulin is secreted in response to nutrients and acts immediately at the liver.

• mainly GLUT 2

• insulin maintains concentration gradient to promote further glucose entry

INSULIN EFFECTS ON LIVER CELL

• increase glucose uptake, glycogen synthesis, fat synthesis/storage, protein synthesis

• decrease glycogenolysis, gluconeogenesis, breakdown

INSULIN IN THE SKELETAL MUSCLE (Myocytes)

• Glucose uptake via GLUT4

• Important protein anabolic effects in muscle by promoting amino acid uptake

• Muscle holds the largest glycogen store

• Promotes increased glucose uptake, glycogen synthesis, glycolysis, oxidation

• Hexokinase (Enzyme) expression

INSULIN IN ADIPOSE TISSUE (Adipocytes)

• Glucose uptake via GLUT4

• Promotes glucose uptake + glycolysis to give precursors for lipogenesis

• Inhibits hormone-sensitive lipase (enzyme required for breakdown of fats)

• Hexokinase expression

HOW B CELLS SENSE GLUCOSE

Increase blood glucose → GLUT2 uptake (no insulin needed) → glucokinase = glucose → GGp → glycolysis + oxidation → increased ATP → ATP-sensitive K+ channels close → K+ builds up → depolarisation → voltage-gated Ca2+ channels open → Ca2+ influx → granule fusion → insulin exocytosis

STIMULATES INSULIN SECRETION

• increased glucose, amino acids, fatty acids

• Parasymp NS stimulation (acetylcholine)

• Glucagon-like peptide (GLP-1)

• Gastric inhibitory polypeptide

• gastrin, secretin, CCK

• Glucagon

INHIBITS INSULIN SECRETION

• Sympathetic NS stimulation (noradrenaline)

• somatostatin

GLUCAGON

• prevents blood glucose from falling too low

• important in post-absorptive and fasting state

• opposite effects to insulin

• major action site is the liver

• promotes catabolism and increased blood glucose

GLUCAGON SYNTHESIS

Glucagon is a 29-residue peptide cleaved from proglucagon in pancreatic a-cells.

Glucagon-like peptide (GLP-1) is secreted by intestinal L-cells.

STIMULATES GLUCAGON SECRETION

• decreased glucose

• increase amino acids

• SNS stimulation (noradrenaline/adrenaline)

• cortisol

• infection

• exercise

INHIBITS GLUCAGON SECRETION

• insulin

• PSNS stimulation (acetylcholine)

• somatostatin

AMINO ACID PARADOX

Why does a protein meal raise both insulin and glucagon?

Amino acids stimulate insulin → insulin drives amino acid uptake into muscle but also lowers blood glucose. Glucagon rises at the same time → liver output of glucose replaces what insulin removed → blood glucose stays flat.

GLUCAGON ACTIONS

• Lipolysis effects more in liver than adipose tissue

• no effect on amino acids blood levels

• Key hormone in post-absorptive state, but not the only one in starvation

• Liver (and kidney)

  • increase glucose production via glycogenolysis + gluconeogenesis = increased blood glucose

DIABETES MELLITUS

• Disease of impaired carbohydrate, fat + protein metabolism

• Characterised by persistent hyperglycemia

• urine is sweet, causing osmotic diuresis

• polyuria (increased urination)

• polydipsia (increased drinking, dehydration)

• polyphagia (increased eating)

• vascular and peripheral nerve damage

TYPE 1 DIABETES

• Insulin dependent

• juvenile onset

• destruction of beta cells

• inadequate insulin production

• abrupt/rapid

• treatment = insulin injections, dietary management

TYPE 2

• Non-insulin dependent

• adult-onset

• insulin resistance/insensitivity

• inability of b-cells to produce adequate insulin quantities

• slow/gradual

• treatment = dietary management, exercise, oral medication

TYPE 2 PROGRESS

Early stages:

• Insulin insensitivity → hyperglycemia → increased signals to B cells → increased pancreatic mass and hyperinsulinema

Later stages:

• Hyperinsulinema + hyperglycemia → increased FFA → B-cell failure and hypoinsulinema

INSULIN INSENSITIVITY

Is a lack of insulin signal transduction, a rightward shift in sensitivity, not a loss of maximal capacity.

GESTATIONAL DIABETES MELLITUS

• Hyperglycemia first detected in pregnancy

• most common in 3rd trimester

• similar to type 2

• stabilises after birth but long term risk for mother + child.

ADRENAL GLAND

Zona Glomerulosa

• adrenal cortex

• hormone = aldersterone

Zona Fasciculata & Reticularis

• adrenal cortex

• hormone = cortisol, corticosterone, androgens

Medulla

• adrenal medulla

• hormone = adrenaline, noradrenaline

STEROID HORMONES

1. Sex steroids

• progesterone, testosterone, oestradiol

2. Glucocorticoids

• cortisol, corticosterone

3. Mineralocorticoids

• aldersterone

• All are made from cholesterol

• lipophilic

• synthesis = secretion

STEROID HORMONE SYNTHESIS

Cholesterol moves along the line and gets edited at each step by enzymes. The enzyme a layer has, determines what it makes.

STEROID SYNTH - OUTER LAYER

• Zona glomerulosa

• enzyme aldersterone synthase

• makes aldersterone

STEROID SYNTH - MIDDLE/INNER LAYER

• zona fasciculata + reticularis

• enzymes make cortisol, corticosterone, androgens

ENZYME P450scc

• first edit of cholesterol → pregnenolone

• rate-limiting step (like a speed limit for the whole line)

ENZYME 11B-Hydroxylase

• last edit of precursor → active cortisol

HPA AXIS

1. Stressor occurs

2. Hypothalamus releases CRH

3. CRH travels to anterior pituitary which releases ACTH

4. ACTH travels in blood to adrenal cortex

5. Adrenal makes cortisol

6. Negative feedback

IMMEDIATE ACTH EFFECTS IN ADRENAL CELL

• Brings in more cholesterol and moves it to the mitochondria

• Boosts first edit of cholesterol → pregnenolone

LATER ACTH EFFECTS IN ADRENAL CELL

Hours later:

• Turns on genes for key enzymes (P450scc, 11B-hydroxylase) and LDL receptor = more cholesterol uptake

Long-term:

• Cells grow in size and number

CORTISOL EFFECTS

1. Fuel metabolism

• Liver = makes new glucose

• Muscle = breaks proteins into aa which helps get more glucose

• Fat = break down into fatty acids which become alternative fuel source to save glucose for brain

2. Permissive

• Helps noradrenaline and GH work properly

3. Water excretion

• Needed for normal water excretion

4. Stress adaptation

• So the system can ‘switch off’ and preserve glucose

5. Anti-inflammatory and immunosuppressive

CORTISOL EFFECT SUMMARY

Make sugar, burn muscle and fat

GH MAIN EFFECT SUMMARY

Make sugar, keep muscle, burn fat

GH METABOLIC ACTIONS IN MUSCLE

• Stimulate amino acid uptake

• Decrease glucose uptake

• Inhibit protein breakdown

Overall, inhibit muscle mass.

GH METABOLIC ACTIONS IN ADIPOSE TISSUE

• Decrease glucose uptake

• Increase fat breakdown

Overall, decrease in fat deposits.

GH METABOLIC ACTIONS IN LIVER

• Increase protein synthesis

• Increase gluconeogenesis

Overall, increase blood glucose.

GH AND GLUCOSE

GH causes an overall blood glucose rise as it acts against insulin (diabetogenic).

• Matters most in fasting/starvation/exercise

  • GH teams up with glucagon, adrenaline and cortisol to keep glucose high and shift body to burning fat and protecting muscle

• Triggered by:

  • low glucose and fatty acids, high amino acids, stress/exercise/deep sleep

EXERCISE AND IMMEDIATE ENERGY

• Ex. power lift

• stored ATP and phosphocreatine

• ADP + PCr → ATP + Cr

EXERCISE AND NON-OXIDATIVE ENERGY

• Ex. 100m sprint

• glucogenolysis + anaerobic glycolysis

• fastest pathway

EXERCISE AND OXIDATIVE PATHWAY

• Ex. 10km run

• Oxidation of glucose and fat

• needs liver and adipose tissue

• most efficient

EXERCISE AND HORMONES

• Increased:

  • adrenaline, glucagon, cortisol, GH

• Decreased:

  • insulin

With greater exercise intensity/duration.

EXERCISE AND MUSCLE CONTRACTION

• Moves GLUT4 to the membrane without insulin

• Uses plasma glucose once glycogen is depleted

EXERCISE AND LACTATE

• Type 11b muscle fibres converted to pyruvate and oxidised

• Lactate taken up by liver and converted to glucose

CARBOHYDRATE STORAGE AFTER MEAL

• First pass through liver takes 20-30% of glucose (insulin-independent)

• Rest enters circulation, RBCs and brain (insulin-independent)

• Muscle and fats use GLUT4 (insulin-dependent)

PROTEIN STORAGE AFTER MEAL

• Some amino acids taken up/oxidised by liver

• Insulin drives amino acid uptake into muscle → protein

FAT STORAGE AFTER MEAL

• Insulin stores lipoprotein lipase

• Inhibits hormone-sensitive lipase and prevents lipolysis

OVERNIGHT FASTING

Priorities:

• Maintain blood glucose for the brain

• Maintain protein reserves

Done by:

• Endocrine control (increased glucagon, decreased insulin)

• Metabolism (decreased glucose uptake, glycogenolysis, gluconeogenesis, lipolysis)

FASTING TO STARVING

After a few days of not eating, metabolism shifts from enhanced gluconeogenesis to ketogenesis.

GLUCOGENEOSIS VS KETOGENESIS

Glucogeneosis:

Precursors = glycerol, amino acids, lactate

Site = liver, kidney in prolonged starvation

Ketogenesis:

Precursors = fatty acids → B-oxidation → acetyl-CoA

Site = liver only

KETOGENESIS

• Acetoacetate, B-hydroxybutyrate and acetone produced by the liver enter circulation and can be used as an alternative energy store

• Muscle and CNS can do reverse action, liver can’t

• Brain gets 30% of energy from ketones after 3 days and 70% after 40days

• Fruity smelling breath due to acetone

STARVATION DURATION

Circulating glucose ~ 1.4hr survival

Liver glycogen ~ 4.2 hr survival

Muscle glycogen ~ 8.4hr survival

Muscle protein ~ 14 days survival

Adipose TAG ~ 83 days survival

ENERGY BALANCE

Law of thermodynamics: energy in = energy out + storage

A surplus of 20kcal per day = +1kg a year = +20kg in two years… yet most adult weights remain relatively constant. Suggesting other factors like appetite and body composition.

LATERAL HYPOTHALAMUS

• Hunger/feeding

• Stimulation causes eating

VENTROMEDIAL NUCLEUS

• Satiety centre

• stimulation reduces eating

HUNGER AND SATIETY

Also influenced by cortex (willpower), senses (smell), environment (stress), memory, hedonics and genetics.

DISCOVERY OF LEPTIN

Ob/Ob = obese mouse

Db/Db = diabetic mouse

1. Db makes an excess of a signal that cures Ob mouse

2. Db lacks the receptor for its signal

3. Absence of receptor and feedback leads to higher levels of the signal in Db mouse

Signal/factor = leptin

LEPTIN

• Polypeptide hormone

• produced by apidocytes

• Plasma levels proportional to total body adipose tissue

• Provides brain info about fatness

Receptor:

• Class 1 cytokine receptor

• present in many tissues

• main target = neurons in hypothalamus

WHY LEPTIN DIDNT CURE OBESITY

It was thought that leptin injections would cure obesity but:

• many obese people already have high leptin but not the receptor

• leptin resistance

LEPTIN IN BRAIN (ARCUATE NUCLEUS)

Anorexigenic neurons

• ‘brake’

• transmitter = POMC, CART

• reduce food intake, feel full

• leptin stimulates these neurons

Orexigenic neurons

• ‘accelerator’

• transmitter = NPY, AGRP

• increase food intake, feel hungry

• leptin inhibits these neurons

FULLNESS SIGNALS (ANOREXIGENIC)

1. Stomach stretch

2. CCK

3. Peptide YY

4. Insulin

5. GLP-1 and GIP

Switch on ‘brake’, switch off ‘accelerator’

HUNGER SIGNAL (OREXIGENIC)

1. Ghrelin (stomach grumble)

2. Low blood glucose

Switch off ‘brake’, switch on ‘accelerator’

INCRETIN DRUGS

Incretin = gut hormones that boost insulin release when glucose present

Drugs = ozempic

• Are agonists of GLP-1, GIP

• Treat type 2 diabetes, cause weight loss

• 3 actions:

  • pancreas = more insulin

  • Stomach = slows gastric emptying, feel full longer

  • Hypothalamus = acts on brain to cut appetite