Insulin Mechanism and Action Flashcards
What is insulin?
Hormone responsible for regulation of blood glucose levels in fed, post-prandial conditions
Why can’t glucose levels get too low? What happens when it gets too low?
- 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
What are the symptoms of mild, moderate and severe hypoglycaemia?
- 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
Why can’t glucose concentration in the blood be too high?
- 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
What does glucose homeostasis involve? What is the normal fasting blood concentration?
- 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
What is post-prandial metabolism?
- Glucose can be converted into molecules that can be stored in specific tissues
o Insulin takes care of this!
What type of gland is the pancreas? What is the Islet of Langerhans?
- 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
What are the main cell types in the Islets of Langerhans and what are their functions?
- 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)
What are the steps in which endogenous insulin production is moderated?
- Synthesis:
- Transcription from the insulin gene
- mRNA stability
- mRNA translation
- Post-translational modifications
What is the process of insulin production from preproinsulin?
- 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
What is the structure of insulin?
- 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)
When does secretion of insulin occur? How does this relate to insulin synthesis?
- Secretion of insulin happens after post-translational modifications
- Insulin synthesis and insulin secretion are largely independent
What is the main mechanism of insulin secretion - which transporters, enzymes and channels are involved?
- 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
What are the physiological roles of insulin?
- 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
How is the insulin receptor activated?
- 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
What are the limitations of glucose transport?
- Glucose cannot cross the membrane freely
- Glucose transporters GLUT4 are stored intracellularly
- Glucose cannot be removed from the bloodstream and cannot be stored in the muscle cell
What can the IRS adaptor protein only bind to?
Phosphorylated receptor
What happens when insulin binds to its receptor?
GLUT4 are inserted into the membrane and glucose can cross the membrane to be stored in the cell
How does insulin stimulate glucose uptake muscles in muscles and adipocytes?
- Glucose cannot cross the plasma membrane: its uptake requires specific glucose transporters
- The glucose transporter GLUT4 is contained in intracellular vesicles in the absence of insulin
- Insulin-induced Akt activation stimulates GLUT4 translocation to (and insertion into) the plasma membrane and ultimately glucose uptake
How does insulin stimulate glycogen synthesis in muscles?
Akt phosphorylates and inactivates glycogen synthase kinase (GSK): this allows activation of glycogen synthase (GS)
How does insulin stimulate lipogenesis in adipocytes?
- Increased glucose uptake
- Activation of AcetylCoA carboxylase
- Increased expression of lipogenic genes
How does inhibit lipolysis in adipocytes?
Insulin inhibits hormone sensitive lipase.
Inhibition of hydrolysis of triglycerides.
It inhibits fatty acids beta oxidation via synthesis of malonyl CoA
What does insulin do in the liver?
- … enhances glucose uptake o No effect on the glucose transporter (liver expresses GLUT2 mainly) – effect on glucokinase - … increases glycogen synthesis o Glycogen can increase to up to 5-6% of the liver mass (~100 grams of stored glycogen) - … increases lipogenesis o Lipids are exported as lipoproteins - ... INHIBITS GLUCONEOGENESIS o Synthesis of new glucose
What are the additional functions of insulin in the cells?
- Insulin promotes protein synthesis and storage
- It stimulates transport of amino acids into the cells
o Valine, leucine, isoleucine, tyrosine, phenylalanine - It increases translation of mRNAs
o Synthesis of new proteins - It inhibits catabolism of proteins
o It decreases amino acids release from cells (muscle) - Insulin promotes K+ intracellular uptake
Summarise the function of insulin in the liver, muscles and adipose cells.
Liver: - Increases glycogen synthesis - Increases lipogenesis - Decreases gluconeogenesis Muscles: - Increases glucose uptake (through GLUT4 translocation) - Increases glycogen synthesis - Decreases protein catabolism Adipose cells: - Increases glucose uptake (GLUT4 translocation) - Increases lipogenesis - Decreases lipolysis
What happens in type 1 and 2 diabetes in terms of insulin?
- Type 1 Diabetes o Disruption of pancreatic β cells o Very reduced/no insulin production o Hyperglycaemia and Dyslipidaemia - Type 2 Diabetes o Muscle/adipose/liver cells (etc) do not respond to insulin properly (INSULIN RESISTANCE) + pancreatic β cells do not produce enough insulin to compensate for it o Hyperglycaemia and Dyslipidaemia
