Endocrinology

Question 1

What are the three types of pancreatic cells?

Answer 1

ß Cells that produce insulin → anabolic hormone
that promotes storage of glucose, fatty acids and amino
acids in cells.

α Cells that produce glucagon → catabolic hormone
that mobilises glucose, fatty acids and amino acids for
energy production.

δ Cells that produce somatostatin → acts locally
(paracrine role) within pancreas to inhibit both insulin
and glucagon secretion.

Question 2

What causes diabetes mellitus?

Answer 2

Impaired insulin secretion or insulin action results in the
metabolic disease

Insulin is the only blood glucose lowering hormone in the body, which explains why diabetes mellitus is such a significant and common disease.

In contrast, a lack of glucagon secretion and/or action can be compensated for by other hormones, and no disease state exists for glucagon insufficiency.

Question 3

What causes glucagonoma

Answer 3

Excess glucagon production occurs, where a tumour of the pancreatic alpha cells that hypersecretes glucagon.

Question 4

Insulin Synthesis

Answer 4

Linear pre-proinsulin in nucleus –>
Signal peptide removed folded “proinsulin” in ER –>
C peptide cleaved in Golgi mature insulin is 51 amino acids –>
Stored in secretary granules for secretion (exocytosis)

Question 5

Insulin Mechanism

Answer 5

Insulin binds to tyrosine kinase receptors, binding causes autophosphorylation of the receptor, activating tyrosine kinase activity, the activated receptor then phosphorylates intracellular proteins, initiating a cascade (PI3K/PKB pathway) that promotes GLUT4 translocation to the membrane.

Question 6

Summarise the major signaling pathways and outcomes

Answer 6

MAPK pathway → promotes cell growth.

PI3K/PKB pathway → activated through IRS; promotes glucose transporters (GLUT4) translocation to cell surface. Also glucose storage and oxidation.

PI3K/mTOR pathway → activated through IRS; promotes protein synthesis, inhibits proteolysis, cell growth.

multiple (other) pathways → activated through IRS; promotes triglyceride synthesis, inhibits lipolysis.

Question 7

What are the metabolic actions of insulin?

Answer 7

Liver: Enhances glycogen synthesis, glycolysis, and inhibits glucose production (gluconeogenesis).

Muscle: Promotes glucose uptake via GLUT4, glycogen storage, and protein synthesis by increasing amino acid uptake.

Adipose Tissue: Facilitates glucose uptake, triglyceride synthesis (lipogenesis), and inhibits lipolysis.

Question 8

Insulin and Glucagon

Answer 8

Insulin (from ß cells) promotes glucose uptake and storage in muscle, adipose tissue, and the liver.

Glucagon (from α cells) opposes insulin, increasing blood glucose levels by promoting glycogen breakdown (glycogenolysis) and glucose production (gluconeogenesis).

Question 9

Primary function of Glucagon

Answer 9

Maintains adequate blood glucose levels i.e. prevents blood glucose from falling too low. Important in post-absorptive (& fasting) state. Opposite effects to insulin – counter regulatory. Major site of action is liver. Promotes catabolism and an increase blood glucose.

Question 10

How is glucagon regulated?

Answer 10

Stimulated by hypoglycemia, high amino acids, and stress signals, and inhibited by somatostatin and insulin.

Question 11

Metabolic action of glucagon

Answer 11

Liver: Glucagon’s main target is the liver, where it promotes glycogenolysis (breakdown of glycogen) and gluconeogenesis (synthesis of glucose), increasing blood glucose levels during fasting or between meals.

Adipose Tissue: Although less direct, glucagon can stimulate lipolysis in adipose tissue, providing fatty acids as an alternative energy source.

Question 12

Explain the process of glucagon synthesis

Answer 12

Location: Glucagon is synthesized in the alpha (α) cells of the pancreatic islets of Langerhans.

Precursor Molecule: Glucagon synthesis begins with preproglucagon, a larger precursor protein produced in the endoplasmic reticulum (ER). This precursor is then cleaved to form proglucagon.

Processing of Proglucagon: Proglucagon undergoes further processing, primarily within pancreatic α-cells, where it is cleaved by specific enzymes to produce glucagon, a 29-amino acid polypeptide.

Alternative Processing: In other tissues, such as the intestinal L cells, proglucagon can be processed into glucagon-like peptide-1 (GLP-1) and GLP-2, which are incretins (hormones that enhance insulin secretion). This tissue-specific processing allows the same precursor to produce different peptides with distinct functions.

Question 13

How is glucagon released?

Answer 13

Stimulated by Low Blood Glucose: Hypoglycemia (low blood glucose) is a primary trigger for glucagon release, as the body seeks to raise blood sugar to maintain homeostasis.

Other Triggers: High levels of amino acids, exercise, and sympathetic nervous system activation (through catecholamines like epinephrine) also stimulate glucagon release.

Inhibition: High blood glucose levels and insulin inhibit glucagon secretion.

Question 14

Does glucagon influence blood AA levels?

Answer 14

No, it has a limited protein metabolic effect.

Question 15

Insulin acts on adipocytes to…

Answer 15

promote G uptake via GLUT4
stimulate Hexokinase expression (G to G-6-P), which maintains downhill

glucose concentration gradient for G entry promote glycolysis to provide precursors for lipogenesis inhibit hormone sensitive lipase, an important enzyme required for the

breakdown of fat (triacyglycerides).

Question 16

Insulin acts on myocytes to …..

Answer 16

Promote G uptake, storage and utilisation - similar to hepatocytes with some exceptions:

Insulin stimulates movement of GLUT4 to the cell membrane, as the main GLUT expressed in muscle.

Hexokinase expression [1]: muscle express hexokinase not glucokinase, but the phosphorylation reaction is the same that they facilitate is the same (Glucose → Glucose-6-P).

Insulin also has an important protein anabolic effect in muscle by promoting amino acid uptake.

Question 17

Insulin acts on hepatocytes to ….

Answer 17

Stimulate G protein uptake

Promote glycogen synthesis and inhibits its breakdown

Promote glycolysis

Inhibit gluconeogenesis (glucose output)

Promote synthesis and storage of fats and inhibit breakdown

Promote protein synthesis and inhibit breakdown

Question 18

Summarise the actions of insulin.

Answer 18

CHOs. Insulin decreases blood G by promoting uptake by cells (utilization & storage), whilst blocking two mechanisms by which liver increases G into blood (gluconeogenesis and glycogenolysis).

Fats. Insulin lowers blood G & FAs, promoting storage as triglycerides. It prevents lipolysis.

Proteins. Insulin has a protein anabolic, lowering blood AAs & enhancing protein synthesis. It prevents protein breakdown.

Question 19

What is gestational diabetes mellitus?

Answer 19

Occurs during pregnancy, similar to T2DM in causing insulin resistance. While often resolving postpartum, it increases future T2DM risk for both mother and child.

Question 20

What is Type II Diabetes Mellitus (T2DM)?

Answer 20

Characterized by insulin resistance and eventual β-cell dysfunction. Early stages may involve hyperinsulinemia, with later progression to hypoinsulinemia as β-cells fail.

Question 21

What is Type I Diabetes Mellitus (T1DM)?

Answer 21

An autoimmune condition where β-cells are destroyed, leading to insulin deficiency.

Question 22

Key receptors in hormone signaling.

Answer 22

G-protein coupled receptors (GPCRs)
eg. oxytocin, GHRH, somatostatin, dopamine

Tyrosine kinase receptors (RTKs)
eg. Insulin, IGF-1

Cytokine receptors, tyrosine kinase associated receptors
e.g. EPO, leptin, prolactin and GH

Steroid receptors
e.g. oestrogen-receptor

Question 23

What are incretins (GLP-1 and GIP)?

Answer 23

Hormones from the gut that stimulate insulin release and promote satiety, aiding in glucose homeostasis and appetite suppression.

Question 24

Classes of steroid hormone

Answer 24

Gonadal or sex steroids
e.g. progesterone, testosterone, oestradiol

Glucocorticoids
e.g. cortisol, corticosterone

Mineralocorticoids
e.g. aldosterone

Question 25

Outline the pathway of steroid hormone synthesis.

Answer 25

Cholesterol → Progestagen → Androgen → Glucocorticoid → Oestrogen → Mineralocorticoid. or Cholesterol → Progestagen → Androgen → Oestrogen

Question 26

Describe the regulation of glucocorticoid production.

Answer 26

Hypothalamo-Pituitary-Adrenal (HPA) axis: CRH from the hypothalamus → ACTH from anterior pituitary → cortisol release from adrenal cortex.

ACTH = adrenocorticotrophic hormone
* Binds to plasma membrane receptors on cortical cells
* ACTH-receptor is “melanocortin type 2 receptor” (MC2-R)
-> Increases cholesterol uptake and trafficking
-> Increases pregnenolone production
-> Increases expression key enzymes
- P-450scc (side chain cleavage)
- P-450c11 (11-beta hydroxylase)

Question 27

What effects do glucocorticoids have on the body?

Answer 27

1. Fuel metabolism
   Increase hepatic glucose output & peripheral catabolism
2. Permissive effects
   required for metabolic reactions & vascular reactivity
3. Water Excretion
   necessary normal water excretion
4. Resistance adaptation to stress
   preserves blood glucose
5. Reduce response to inflammatory stimuli &
   immunosuppression – a pharmacological effect.

Question 28

What are the three stages of ACTH action?

Answer 28

Immediate Effects:
- Increase in cholesterol esterase and cholesterol ester synthetase.
- Enhanced transport of cholesterol into mitochondria.
- Increased binding of cholesterol to P-450scc (cholesterol side-chain cleavage enzyme).
- Production of pregnenolone (a precursor for steroid hormones).
Subsequent Effects:
- Increased gene transcription for enzymes involved in steroidogenesis:
- P-450scc (cholesterol side-chain cleavage enzyme).
- P-450c17 (17α-hydroxylase).
- P-450c11 (11β-hydroxylase).
- Adrenoxin and LDL receptor (low-density
lipoprotein receptor), which are important for
cholesterol uptake.

Long-term Effects:
- Increase in size and functional complexity of cellular organelles.
- Increase in the size and number of adrenocortical cells.

Question 29

What are the primary actions of GH on growth?

Answer 29

Its actions are generally anabolic
* increases number & size of cells in soft tissues
* increases thickness & length of long bones

Question 30

How does GH affect muscle, adipose tissue, and liver?

Answer 30

Muscle
< stimulates AA uptake
< decreases glucose uptake,
< inhibits protein breakdown
–> increases muscle mass

Adipose tissue
< decreases glucose uptake
< increases fat breakdown (lipolysis)
–> decrease in fat deposits

Liver
< increase protein synthesis,
< increase gluconeogenesis
–>Overall increase blood glucose

Question 31

What metabolic roles does GH play in children versus adults?

Answer 31

In children, it promotes true growth and metabolic effects. In adults, it maintains muscle mass and manages metabolic functions.

Question 32

What are the metabolic effects of growth hormone?

Answer 32

Counteracts the actions of insulin
That is, causes insulin insensitivity - is “diabetogenic”
leads to hyperglycaemia.

Role
* defense against hypoglycemia i.e. maintain blood glucose (ignores
insulin signal to lower blood glucose)
* development of “stress” diabetes during fasting and inflammatory
illness

BUT in relation to glucose homeostasis…..
* Normally plasma GH does not cause such metabolic effects.
* But is critical in starvation response & exercise (next slide).
* Also important in patients under hGH treatment.

During fasting
* GH is the only “anabolic hormone” to increase
(insulin and IGF-I levels decrease)
* GH acts together with increased levels of the catabolic hormones
(glucagon, adrenaline and cortisol)
* Thought that key role of GH is to preserve muscle mass

During moderate exercise
* protein and glucose metabolism remain unaffected
* GH stimulates of lipolysis - FA as alternative energy source

Question 33

List the types of energy sources used by muscles based on duration of activity.

Answer 33

Immediate e.g. power events
* source ATP or
* phosphocreatine (PCr)
* ADP + PCr ATP + Cr

Non-oxidative e.g. sprint
* anaerobic glycolysis
* glycogenolysis provides glucose
* fastest pathway

Oxidative (e.g. >2 min)
* oxidation of glucose & fat
* most efficient pathway

Question 34

How does endocrine control adjust during exercise?

Answer 34

Increased cortisol, GH, adrenaline, and glucagon; decreased insulin.

Question 35

Explain the role of lactate in exercise.

Answer 35

Lactate is produced by type IIb muscle fibers and converted to pyruvate for oxidation. It can also be converted back to glucose by the liver (Cori cycle).

Question 36

What metabolic changes occur during prolonged exercise?

Answer 36

Increased fat mobilization and gluconeogenesis; decreased plasma glucose regulated by glucagon and other hormones.

Question 37

Describe how the body stores energy after meals.

Answer 37

Carbohydrates are stored as glycogen, proteins are synthesized into tissue, and fats are stored in adipose tissue.

Question 38

What are the metabolic priorities during an overnight fast?

Answer 38

Maintain blood glucose through glycogenolysis and gluconeogenesis, primarily supported by glucagon and cortisol.

Question 39

How does the body’s metabolism shift during prolonged fasting?

Answer 39

Moves from gluconeogenesis to ketogenesis, using fat stores to produce ketone bodies as alternative energy for the brain and muscles.

Question 40

Explain the stages of starvation and energy sources used.

Answer 40

Initial: Glycogen. Intermediate: Muscle sparing, use of fatty acids. Long-term: Reliance on ketone bodies, up to 70% of brain energy after 40 days.

Question 41

What happens in ketogenesis, and how are ketone bodies used?

Answer 41

Fatty acids are broken down to acetyl-CoA, which forms ketone bodies (acetoacetate, β-hydroxybutyrate, acetone). These are utilized by muscles and the CNS for energy.

Question 42

What does the first law of thermodynamics state about energy balance?

Answer 42

Energy balance follows the rule: energy in = energy out.

Question 43

What are the types of energy balance?

Answer 43

Positive (intake > expenditure), neutral, and negative (expenditure > intake).

Question 44

Give an example of positive energy balance over time.

Answer 44

A positive balance of 20 kcal/day can lead to a gain of 1 kg per year or 20 kg over two decades.

Question 45

Which hypothalamic centers regulate hunger and satiety?

Answer 45

The ventromedial nucleus (satiety center) stops eating when stimulated, and the lateral hypothalamus (hunger center) induces eating when stimulated.

Question 46

What are the main functions of the hypothalamus?

Answer 46

Regulates behaviors like feeding, rage, and reproductive behavior, and maintains homeostasis for body temperature, metabolism, water balance, growth, stress, and reproduction.

Question 47

What types of inputs and outputs does the hypothalamus process for feeding regulation?

Answer 47

Inputs: Neural and humoral signals. Outputs: Neural and humoral responses.

Question 48

What are the sources of short-term feeding signals to the hypothalamus?

Answer 48

Central neural inputs (from brain), mechanical/chemical signals (from gut), and peripheral neural and endocrine inputs.

Question 49

How does the hypothalamus integrate short-term and long-term feeding signals?

Answer 49

Short-term signals influence immediate feeding behavior, while long-term signals regulate metabolic and endocrine processes.

Question 50

What did parabiosis experiments with Ob/Ob and Db/Db mice suggest?

Answer 50

They indicated a circulating factor regulating food intake, as the Ob mouse lost weight when paired with a wild-type mouse.

Question 51

Describe the key findings from the Db/Db mouse in parabiosis experiments.

Answer 51

The Db mouse overproduces a factor (leptin) that it cannot respond to due to the lack of a functional receptor, leading to obesity and type 2 diabetes.

Question 52

What is the significance of the Ob/Ob mouse model?

Answer 52

The Ob mouse lacks leptin, leading to hyperphagia (excessive eating) and morbid obesity.

Question 53

What is leptin, and where is it produced?

Answer 53

Leptin is a polypeptide hormone (146 amino acids) produced by adipocytes, with plasma levels proportional to body fat.

Question 54

What is the role of leptin in the body?

Answer 54

Leptin signals the brain about total body fat stores, reducing appetite (anorexigenic effect) and helping maintain energy balance.

Question 55

What type of receptor is the leptin receptor, and where is it primarily located?

Answer 55

The leptin receptor is a Class 1 cytokine receptor (tyrosine kinase-associated) and is primarily found in the hypothalamus.

Question 56

What are the roles of anorexigenic neurons and orexigenic neurons in appetite regulation?

Answer 56

Anorexigenic neurons (produce POMC, CART) inhibit food intake, while orexigenic neurons (produce NPY, AGRP) stimulate food intake.

Question 57

What effect does leptin have on anorexigenic and orexigenic neurons?

Answer 57

Leptin stimulates anorexigenic neurons to suppress appetite and inhibits orexigenic neurons to reduce food intake.

Question 58

How is POMC processed differently in various cells?

Answer 58

In arcuate neurons, POMC produces α-MSH to inhibit feeding, while in pituitary corticotrophs, POMC is processed to produce ACTH.

Question 59

What are some orexigenic signals (appetite-stimulating) released during fasting?

Answer 59

Ghrelin and hypoglycemia stimulate appetite.

Question 60

List anorexigenic signals (satiety-inducing) released during digestion.

Answer 60

Insulin, vagal inputs, cholecystokinin (CCK), peptide YY (PYY), and incretins (GLP-1 and GIP).

Question 61

What are incretins, and name two examples.

Answer 61

Incretins are gastrointestinal hormones that stimulate insulin secretion in a glucose-dependent manner. Examples are GLP-1 and GIP.

Question 62

How do incretin mimetics (GLP-1 and GIP agonists) help treat type 2 diabetes?

Answer 62

They increase insulin secretion, slow gastric emptying (enhancing satiety), and suppress appetite through hypothalamic effects, aiding in glycemic control and weight loss.