Insulin Mechanism and Action Flashcards
1
Q
What is insulin?
A
Hormone responsible for regulation of blood glucose levels in fed, post-prandial conditions
2
Q
Why can’t glucose levels get too low? What happens when it gets too low?
A
- Brain is highly dependent on extracellular glucose concentration
- ATP is used to power cellular functions
- Concentration of glucose in blood cannot be too low
o Hypoglycaemia
3
Q
What are the symptoms of mild, moderate and severe hypoglycaemia?
A
- Autonomic Symptoms: (mild hypo)
o Including: Trembling, palpitation, sweating, anxiety, hunger, tingling - Neuroglycopaenic Symptoms: (moderate hypo)
o Including difficulty concentrating, confusion, weakness, drowsiness, vision changes, difficulty speaking, dizziness, tiredness - Severe hypo:
o Confusion, disorientation, convulsion, fitting, seizures, loss of consciousness, coma
4
Q
Why can’t glucose concentration in the blood be too high?
A
- Concentration of glucose in the blood cannot be too high
o Hyperglycaemia - Macrovascular:
o atherosclerosis - cardiovascular events - Microvascular:
o Kidney and nerve disease, blindness, amputation
5
Q
What does glucose homeostasis involve? What is the normal fasting blood concentration?
A
- In healthy humans, blood glucose is tightly maintained despite wide fluctuations in glucose consumption, utilisation and production
- Apart from the first few days of life, normal fasting blood glucose concentrations are kept within a narrow physiological range of 3.5–5.5 mmol/L
6
Q
What is post-prandial metabolism?
A
- Glucose can be converted into molecules that can be stored in specific tissues
o Insulin takes care of this!
7
Q
What type of gland is the pancreas? What is the Islet of Langerhans?
A
- Pancreas is primarily an EXOCRINE gland, comprising acinar and ductal cells
- Islets of Langerhans form the ENDOCRINE part of the pancreas - a recent study indicated an average of 3.2 million islets in a human pancreas
8
Q
What are the main cell types in the Islets of Langerhans and what are their functions?
A
- Alpha (α) cells producing glucagon
o account for ~30% of human islet cells* - Beta (β) cells producing insulin
o ~ 60% of human islet cells* - Delta (δ) cells producing somatostatin
- PP (or γ) cells producing pancreatic
- polypeptide
- Epsilon (ε) cells producing ghrelin
(delta, PP and epsilon cells together make up about 10% of the Islet cells)
9
Q
What are the steps in which endogenous insulin production is moderated?
A
- Synthesis:
- Transcription from the insulin gene
- mRNA stability
- mRNA translation
- Post-translational modifications
10
Q
What is the process of insulin production from preproinsulin?
A
- Insulin is initially synthesised as preproinsulin in pancreatic β-cells
- About 5–10 min after its assembly in the endoplasmic reticulum, preproinsulin is processed into proinsulin
- Proinsulin undergoes maturation into active insulin through the action of cellular endopeptidases within the Golgi apparatus
- Endopeptidases cleave off C peptide from insulin by breaking the bonds between lysine 64 and arginine 65, and between arginine 31 and 32
- Insulin and C-peptide are then stored awaiting secretion
11
Q
What is the structure of insulin?
A
- Two chains linked by three disulfide linkages
- Monomers tend to form dimers when insulin concentration increases
- In the presence of Zn2+ and at specific pH dimers form hexamers (storage form of insulin)
- Once hexamers are secreted, insulin dissociates into its monomeric form (active form of insulin)
12
Q
When does secretion of insulin occur? How does this relate to insulin synthesis?
A
- Secretion of insulin happens after post-translational modifications
- Insulin synthesis and insulin secretion are largely independent
13
Q
What is the main mechanism of insulin secretion - which transporters, enzymes and channels are involved?
A
- Glucose enters the β-cells through the glucose transporter (GLUT2 in rodents; GLUT1&3 in human islets)
- Glucokinase (that converts glucose into glucose 6-phosphate) acts as the glucose sensor for insulin secretion
- The high Km of glucokinase ensures that initiation of insulin secretion by glucose occurs only when blood glucose levels are high
- Glucose is converted to glucose-6 phosphate and to pyruvate (glycolysis)
- Pyruvate, through Krebs cycle and electron transport chain, generates ATP, leading to a rise in the ATP:ADP ratio within the cell
- At sub-stimulatory glucose concentrations, KATP channels are open. The resting membrane potential is maintained at a hyperpolarised level (~ −70 mV)
- Increased ATP/ADP ratio results in closure of the KATP channels and membrane depolarisation
- Voltage-gated Ca2+ channels open, intracellular concentration of Ca2+ increases and this triggers insulin secretion
- Pancreatic β cells release insulin in two phases
- The first phase release is rapidly triggered in response to increased blood glucose levels
- The second phase is a sustained, slow release of newly formed vesicles
14
Q
What are the physiological roles of insulin?
A
- Insulin-responsive cells express a specific receptor at the plasma membrane
- The insulin receptor is a transmembrane receptor that belongs to the large family of Tyrosine kinase receptors
15
Q
How is the insulin receptor activated?
A
- Insulin binds to the α subunits within the receptor. This causes a conformational change that activates the Tyrosine kinase domain residing on the intracellular portion of the β subunits
