Endocrinology: Endocrine Pancreas and Diabetes

Question 1

Fuel metabolism

Answer 1

Biochemical processes by which organisms utilise energy-containing molecules (glucose, fatty acids, amino acids) to generate ATP
These processes involve the breakdown (catabolism) and synthesis (anabolism) of molecules to either release or store energy

Question 2

Anabolism

Answer 2

Set of metabolic pathways that build larger molecules from smaller ones, requiring energy input. Involves the synthesis of complex molecules such as proteins, carbohydrates, lipids and nucleic acids from simpler precursors.

Question 3

Catabolism

Answer 3

Metabolic processes that break down complex molecules into simpler ones, releasing energy in the process, typically used to generate ATP. Involve breakdown of carbohydrates, fats and proteins into smaller molecules like glucose, fatty acids and amino acids. These smaller molecules can enter metabolic pathways to produce energy or be used as building blocks for anabolic reactions.

Question 4

What does fuel metabolism involve?

Answer 4

Fuel metabolism involves a series of biochemical reactions that regulate the breakdown and synthesis of energy-containing molecules

Question 5

Reactions of fuel metabolism

Answer 5

Glycolysis
Pyruvate oxidation
Citric acid (Krebs) cycle
Electron transport chain and oxidative phosphorylation
Beta oxidation
Gluconeogenesis
Glycogenesis
Glycogenolysis

Question 6

Glycolysis

Answer 6

• Initial step of glucose metabolism, occurs in the cytoplasm
• Glucose –> 2x pyruvate, generate 2ATP adn NADH (electron carrier)
  Anaerobic process

Question 7

Pyruvate oxidation

Answer 7

• Aerobic
• Pyruvate enters mitochondria, undergoes oxidative decarboxylation
• Each pyruvate loses CO2 and is converted into acetyl-CoA

Question 8

Citric acid (Krebs cycle)

Answer 8

• Acetyl-coA enters
• Undergoes enzymatic reactions that result in release of CO2, ATP, NADH and FADH2
• Occurs in mitochondrial matrix

Question 9

Electron transport chain and oxidative phosphorylation

Answer 9

• NADH and FADH2 donate electrons to electrons to the electron transport chain
• Occurs in inner mitochondrial membrane
• As electrons move through the chain, energy is released and used to pump protons across the membrane, creating an electrochemical gradient
• Gradient drives synthesis of ATP from ADP + P in oxidative phosphorylation
• 34-36 ATP produced

Question 10

Beta-oxidation

Answer 10

• Metabolic pathway for fatty acid catabolism
  Fatty acids broken into acetyl-coA to enter Krebs

Question 11

Gluconeogenesis

Answer 11

• Synthesis of glucose from non-carbohydrate precursors, e.g., amino acids, glycerol, lactate
• Mainly occurs in liver, lesser extent in kidneys during periods of fasting/ low blood glucose levels

Question 12

Glycogenesis

Answer 12

• Synthesis of glycogen from excess glucose
• Liver and skeletal muscles

Question 13

Glycogenolysis

Answer 13

• Breakdown of glycogen into glucose

Question 14

Importance of cellular ATP

Answer 14

ATP is the primary energy carrier in cells. Important for:
Energy transfer
- Stores chemical energy in high-energy phosphate bonds
- Energy released from hydrolysis drives cellular processes
Universal energy currency
- Source of energy in all living organisms
Immediate energy source
- Provides readily available source of energy for cellular processes
- Constantly regenerated through metabolic pathways, ensures cells have a continuous supply of energy to meet demands
Coupling reactions
- ATP hydrolysis drives endergonic reactions forwarded by transferring phosphate groups to substrates, activating them for further chemical transformations
Regulation of cellular processes
- Indicator of cellular energy status
- High ATP trigger energy storage pathways
- Low ATP prompt ATP production and energy conservation

Question 15

Fuel metabolism is regulated via insulin and glucagon secretion. What is released in what state, and what are the metabolic effects each hormone?

Answer 15

• Absorptive (fed) state: insulin bigger influence: increase in glucose oxidation, glycogen synthesis, fat synthesis, protein synthesis
• Post-absorptive state: glucagon bigger influence: increase in glycogenolysis, gluconeogenesis, ketogenesis, protein breakdown (longer term)

Question 16

What stimulate insulin secretion?

Answer 16

• Stimulatory: stimulates beta cells of the pancreas to release insulin
  o High plasma glucose
  o Parasympathetic stimulation
  o High free fatty acids, amino acids
  o Gastrointestinal hormones, e.g., glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP1)
• Inhibitory: inhibits beta cells and prevents insulin secretion
  o Low plasma glucose
  o Sympathetic stimulation/ adrenaline: stress
  o Cortisol
  o Low blood fatty acids
  o Somatostatin

Question 17

What inhibits insulin secretion?

Answer 17

• Inhibitory: inhibits beta cells and prevents insulin secretion
  o Low plasma glucose
  o Sympathetic stimulation/ adrenaline: stress
  o Cortisol
  o Low blood fatty acids
  o Somatostatin

Question 18

What type of hormone is insulin?

Answer 18

Peptide hormone

Question 19

What type of hormone is glucagon?

Answer 19

Peptide hormone

Question 20

What types of receptors does insulin bind to?

Answer 20

Cell surface enzyme-linked receptors

Question 21

What happens when insulin binds with a cell surface receptor?

Answer 21

Insulin receptors are cell surface enzyme-linked receptors
1. Translocation of proteins into cell membranes: within seconds
2. Phosphorylation of metabolic enzymes  altered activity: 10-15 mins
3. Effects on mRNA translation and DNA transcription: hours-days

Question 22

Actions of insulin on carbohydrates

Answer 22

o Facilitates glucose uptake and utilisation (most cells)
o Stimulates glycogenesis and inhibits glycogenolysis (liver and muscles)
o Increases conversion of glucose to fatty acids (and ultimately triglycerides) in adipose cells
o Inhibits gluconeogenesis (decreasing availability of amino acids and inhibiting hepatic enzymes

Question 23

Actions of insulin on fats

Answer 23

o Increases fatty acidd uptake into adipose
o Increases fatty acid synthesis from glucose in adipose
o Decreases lipolysis in adipose

Question 24

Actions of insulin on proteins

Answer 24

o Promotes the active transport of amino acids into muscle increases protein synthesis

Question 25

What stimulates glucagon secretion?

Answer 25

• Stimulatory: stimulates alpha cells of the pancreas to release glucagon
  o Low plasma glucose
  o Sympathetic stimulation/ adrenaline
  o GI hormones (CCK, gastrin, GIP)
  o High free amino acids

Question 26

What inhibits glucagon secretion?

Answer 26

• Inhibitory: inhibits alpha cells and prevents glucagon secretion
  o High plasma glucose
  o Insulin, somatostatin (paracrine actions)
  o High free fatty acids

Question 27

Actions of glucagon on the liver

Answer 27

o Decrease glycogen synthesis
o Increase glycogenolysis
o Increase gluconeogenesis
o Increase ketogenesis
o Increase in glucose and ketones in blood results

Question 28

Actions of glucagon on adipose tissue

Answer 28

o Increase lipolysis
o Decrease triglyceride synthesis
o Increases circulation of free fatty acids results

Question 29

Features of the pancreas

Answer 29

• About 6 inches long, shaped like a finger
• Head of pancreas is on RHS of the pancreas
• Located back of abdomen, behind the stomach
• Exocrine pancreas: comprised of acini – secrete digestive enzymes and bicarbonate into duodenum (via the pancreatic duct)
• Endocrine pancreas: comprised of islets of Langerhans (<2% of total cellular mass) – comprised primarily of alpha, beta (70%) and delta cells, secrete insulin and glucagon into the blood

Question 30

Fate of metabolic fuels during absorptive and post-absorptive states

Answer 30

• The brain must be continuously supplied with glucose (no carbohydrate storage)
• After a meal, nutrients are ingested and are entering the blood – causing high glucose levels
• Food intake is intermittent, therefore nutrients must be stored
• In post-absorptive (fasted) state, stored substrates (carbohydrates, fats, protein) are degraded to release utilisable units (glucose, fatty acids, amino acids etc)

Question 31

What is diabetes mellitus?

Answer 31

Syndrome of impaired metabolism
Primary metabolic disturbance in diabetes
- Decreased glucose uptake, and utilisation, increased hepatic glucose production  increase blood glucose concentration
- Increased utilisation of fat and proteins, decrease lipogenesis in adipose tissue  blood free fatty acid and ketone concentration

Question 32

Type 1 diabetes mellitus: prevalence, aetiology and issue

Answer 32

• Less than 10% of all diabetes mellitus cases
• Characterised by failure of beta cells to secrete insulin
• Usual age of onset ~14 years
• Rapid onset
• Aetiology
  o Largely caused by an autoimmune attack of beta cells (following infection, environmental insult)
  o Minor genetic influence; may influence susceptibility to autoimmune attack
• Issue
  o Absence of circulating insulin
  o Elevated glucagon levels
  o Ketosis
  o Chronic ‘fasted’ state

Question 33

Clinical manifestations of type 1 diabetes mellitus

Answer 33

o Polyuria + thirst
o Dehydration (osmotic diuresis
o Glycosuria
o Weakness and fatigue
o Weight loss (protein and fat loss)
o Hypercholesterolemia
o Blurred vision
o Ketone breath (ketonemia)
o Metabolic acidosis –> coma

Question 34

Type 2 diabetes mellitus: prevalence, aetiology and issue

Answer 34

• More than 90% of all diabetes mellitus cases
• Characterised by gradual development of insulin resistance and attenuation of meal-induced insulin secretion
• More common in older people (>40) particularly if overweight and sedentary
• Aetiology
  o Strong genetic influence
  o May develop as a result of other genetic and endocrine diseases, pregnancy
  o Lifestyle and diet are important contributors (e.g., inactivity, alcohol consumption, obesity)
• Issue
  o Tissue insensitivity to insulin
  o Reduced response of pancreatic cells to glucose
  o Reduced production of insulin (due to pancreatic cell ‘burnout’ and damage)

Question 35

Clinical manifestations of type 2 diabetes mellitus

Answer 35

o Tends to be mild early in disease and thus condition can go undiagnosed for some time
o Ketone production typically less evident than T1DM, or as with T1DM
- Typically, a progressive condition that requires escalating levels of therapy
- Glucotoxicity
o Chronic hyperglycaemia may further densities beta cells to glucose stimulation
o Chronic hyperglycaemia may block GLUT4 mobilisation and worsen insulin resistance
- Lipotoxicity
o High levels of circulating free fatty acids can inhibit insulin secretion and insulin signalling
o Excess fatty acids inhibit glucose utilisation and may stimulate gluconeogenesis in liver

Question 36

Complications of diabetes mellitus

Answer 36

• Micro- and macrovascular damage
  o Increased risk for heart attack, stroke, nephropathy and end-stage kidney disease, retinopathy and blindness, ischemia and gangrene of limbs
  o Hypertension (second degree to renal injury)
  o Atherosclerosis (due to endothelial damage and abnormal lipid metabolism)
• Peripheral neuropathies and ANS dysfunction
  o Impaired cardiovascular reflexes
  o Impaired bladder control
  o Distal sensory neuropathy (reduced sensation in extremities)
  o Gastroenteropathy (gastroparesis, constipation with episodes of diarrhoea)

Question 37

Oral complications of diabetes

Answer 37

• Diabetes, particularly with poor glycaemic control, associated with increased risk of dental caries, gingivitis, periodontal disease and alveolar bone loss
• Reduced salivary flow, decreased pH, and lower salivary calcium concentration are all thought to contribute
• Reduced blood supply to the gums (due to microvascular damage) can slow healing and increase infection
• Diabetics more susceptible to developing oral mucosal diseases (e.g., aphthous ulceration) and fungal infections (e.g., thrush), due to compromised immune function
• Taste disturbances and neurosensory disorders may affect diet and oral hygiene
• Some studies suggest that oral infections can contribute to higher blood glucose levels (two-way interaction)