Endocrine III - diabetes

Question 1

What are the areas and cells in the pancreas that secrete substances - and which substances?

Answer 1

Islets of Langerhans
A cell: Glucagon
B cell: Insulin
D cell: Somatostatin
F cell: pancreatic polypeptide

Question 2

What is the structure of insulin?

Answer 2

• Three disulphide bonds
• Two disulfide bonds connect chain A and B
• Third disulfide bond is an intrachain bond in chain A

Question 3

How is insulin synthesised?

Answer 3

Transcription and translation of gene and mRNA forms preproinsulin -> forms proinsulin, ammonia group and signal sequence in the endoplasmic reticulum
Proinsulin forms insulin and C-peptide in the golgi apparatus
Insulin and C-peptide stored in granules, to be secreted by exocytosis

Question 4

How does high glucose lead to insulin release?

Answer 4

1) B cells take up glucose by GLUT2, and glucokinase forms glucose 6-P which is used in oxidative metabolism for ATP formation
2) Blood glucose >5mM produce high ATP -> leads to closing of ATP-sensitive K+ channels
3) Membrane depolarisation results in calcium influx via VG calcium channel
4) High intracellular Ca triggers release of granules of insulin and C-peptide

Question 5

What are the effects of insulin on adipose, striated muscle and liver?

Answer 5

Adipose tissue:
- Increased glucose uptake
- Increased lipogenesis
- Decreased lipolysis
Striated muscle:
- Increased glucose uptake
- Increased glycogen synthesis
- Increased protein synthesis
Liver:
- Decreased gluconeogenesis
- Increased glycogen synthesis
- Increased lipogenesis

Question 6

What are the stimulating factors for insulin release from B cells?

Answer 6

• Elevated blood glucose - major activator
  Enhancement of glucose-induced insulin release:
  > Amino acids: arginine, leucine and glutamate
  > Gut hormones: incretins
  > Neural input: parasympathetic stimulation after a meal - ACh

Question 7

What inhibits insulin secretion from B cells?

Answer 7

Epinephrine and norepinephrine

Question 8

What happens once insulin binds to IRs?

Answer 8

Activates MAP kinase signalling pathway > cell growth, proliferation, gene expression
Also
Activates PI-3K signalling pathway >
- synthesis of lipids protein and glycogen ,
- cell survival and proliferation , and
- fusing of GLUT4 vesicles with cell surface membrane

Question 9

What is the fasted state?

Answer 9

• Limited glucose availability
• Constant supply from the liver
• Other tissues switch to alternative fuels: FFA, ketones

Question 10

What is the fed state?

Answer 10

• Glucose abundant
• Hepatic glucose production no longer required
• Alternative fuels not required
• Excess glucose diverted to energy storage

Question 11

What is diabetes mellitus?

Answer 11

Deficient secretion or action of insulin
Two types

Question 12

What is type 1 vs type 2 DM?

Answer 12

Type 1: atrophy or destruction of b cells of pancreas due to an immune response or viral infection
Type 2: insulin resistance - more insulin than normal is needed for the insulin receptors to repsond > b cell failure

Question 13

What other forms of DM?

Answer 13

Maturity-onset diabetes of the young
Secondary diabetes
Gestational DM

Question 14

Type 1 DM
Cause, signs, onset, complications, treatment

Answer 14

Autoimmune destruction of B cells
Very low or absent levels of insulin, very low C-peptide
Starts in childhood/adolescence
Osmolar symptoms
Complication: DKA
Treatment: lifelong insulin

Question 15

Type 2 DM
Risk factors
Onset
Cause
Treatment

Answer 15

Risk factors: obesity, sedentary lifestyle, strong familial tendency, ageing
Gradual onset
Target tissues have insulin resistance, and decreased insulin secretion
Treatment: lifestyle > medications > insulins

Question 16

What are the symptoms of DM?

Answer 16

Classic triad: 3 P’s - Polyphagia, polydipsia, polyuria
-Extreme fatigue
- Blurry vision
- Repeated infection
- Slow wound healing
- Weight loss
- Numbness in hands and feet

Question 17

What are microvascular complications of DM?

Answer 17

Eye: damage blood vessels in eye > retinopathy, cataracts, glaucoma
Kidney: damage of small vessels > nephropathy
Neuropathy: damages peripheral nerves > pain/numbness. Feet wounds undetected > infected

Question 18

What are the macrovascular complications of DM?

Answer 18

Brain: increased risk of stroke, cerebrovascular disease e.g. ischaemic attack
Heart: increased risk of CHD
Extremities: peripheral vascular disease reduced blood flow to legs > gangrene

Question 19

What is required to diagnose diabetes?

Answer 19

• Fasting plasma glucose - 8 hours after meal
• Random plasma glucose
• Elevated HbA1c levels
• OGTT (gold standard)
• 2 hour plasma glucose - after glucose dose

Question 20

What is HbA1c and its significance to DM?

Answer 20

Non-enzymatic glycation of haemoglobin
Indicator of long term glucose control over last 2-3 months
Poor glucose control, higher risk of complications
Used to diagnose DM

Question 21

What is glucagon, how is it synthesised?

Answer 21

Peptide hormone with 29 amino acids in single pp chain
Proglucagon is a tissue specifically modified precursor
In A-cells proglucagon converted to glucagon by selective proteolytic cleavages in secretory granules

Question 22

What are stimulating factors for glucagon secretion from a-cells

Answer 22

• Low blood glucose level - major activator
  Enhancement of release:
• Amino acids: arginine and alanine
• Stress hormones: epinephrine and norepinephrine
• Neural input: sympathetic stimulation during stress

Question 23

What are inhibiting factors for glucagon secretion from a-cells?

Answer 23

Glucose
Insulin

Question 24

How does glucagon bind to receptors and what does this cause?

Answer 24

• Glucagon binds to specific high-affinity G protein-coupled receptor (GPCR) on plasma membrane > activates adenylyl cyclase
• The formed cAMP binds to 2 regulatory subunits of cAMP-dependent protein kinase (PKA)
• Separates subunits and activates protein kinase A (PKA) > phosphorylates target enzymes using C-subunit

Question 25

What are the actions of glucagon in the liver?

Answer 25

Liver:
- Activation of glycogenolysis and inhibition of glycogen synthesis
- Activation of gluconeogenesis and inhibition of glycolysis
- Activation of synthesis of fatty acids and cholesterol

Question 26

What are the actions of glucagon in the renal cortex and fat cells?

Answer 26

Renal cortex:
- Gluconeogenesis and inhibition of glycolysis
Fat cells:
- Activation of TAG degradation