INSULIN : "Hey wake up Mr. GLUT-4, it's getting sugary allover"
GLUT-4 : "Oh noo... not again, Why doesn't he stop eating so much".
Insulin is the glucose controller that is produced by the Beta cells of pancreas and stored as a pack of secretary granule along with C- peptide in equimolar amounts. It has a A chain (21AA) and B chain (30AA) connected by C - peptide.
History says :
Insulin is discovered by Banting with the help of his assistant Charles Best. Prof John MacLeod and Banting are awarded with Noble prize for the discovery of insulin.
Why is it secreted? :
Increased glucose in the blood should be controlled before it plays all bad in the body. Excess glucose can call upon bacteria to have a meet, makes the cells go mad and they start to make terrible mistakes like producing excess ketone bodies (toxic acids). So it is a need to maintain the glucose in a normal range. Pancreas takes stand and starts producing both Insulin (B cells) and Glucagon (A cells) that maintain glucose levels.
How's it secreted? :
When we are still in making - in fetus, the pancreatic islets are formed in the 3rd month and insulin secretion begins at about 5th month of fetal life.
GLP -1 and GIP are called incretins and are potent stimulators of insulin secretion. They also inhibit Glucagon secretion. They are released in the GI tract after a person eats a meal.
When the glucose level increases in the blood, it goes into the cell through the transporter GLUT-2 (All glucose transporters are independent of insulin except GLUT-4) in the surface of pancreatic Beta cells and metabolises to form ATP. These ATP act on and close the K+ channels (ATP dependent) causing depolarisation. It activates the voltage gated Calcium channels and release calcium that act on the secretary vesicles or granules with insulin stored in them. Insulin is secreted from those secretary granules into the blood via exocytosis.
How does it act ? :
Insulin bind to the insulin receptor which is a tetramer made up of two Alpha (A) and two Beta (B) subunits.
A - it is extracellular part that binds to insulin
B - it penetrate through the cell membrane into the cytoplasm (intracellular). - it activates tyrosine kinase which causes phosphorylation of many enzymes.
What increases or stimulates the insulin secretion? :
✅ Increased ATP - due to more glucose, fatty acids, keto acids, amino acids (Arginine, leucine).
✅ Harmones - GLP-1 ( Glucagon like peptide -1), GIP ( Gastric Inhibitory peptide), Gastrin, Secretin, Cholecystokinin.
✅ Drugs - Theophylline, Beta adrenergic stimulators,
sulfonylureas (close ATP sensitive K+ channels)
✅ Acetylcholine
What Inhibits the insulin secretion? :
❌ Potassium depletion: In Hypokalemia due to decrease in potassium, Insulin secretion is effected. Infact, in cases of hyperkalemia insulin is used to decrease potassium level as it promotes glucose uptake by cells along with potassium.
❌Somatostatin - universal Inhibitor.
❌Drugs - Diazoxide (potassium channel opener - used in cases of Insulinoma - high C - peptide), Phenytoin, Thiazides, Alloxan, Microtubule inhibitors ( Taxanes, Vinca alkaloids ), Beta blockers (Propranolol), Alpha agonists (Epinephrine and Nor Epinephrine)
❌ Sympathetic stimulation
Hormones that can cause Hyperglycemia antagonising the effect of insulin :
🔸Glucagon
🔸 Epinephrine
🔸Cortisol
🔸 Growth harmone
🔸Thyroid harmone
What does insulin do ? :
🔺 Increased glucose entry into cells ( by increasing the number of insulin dependant GLUT-4 transporter in the cell membrane)
1. Of adipose tissue for fatty acid, glycerol phosphate, synthesis increasing their levels and increase also triglyceride deposition.
2. Of skeletal muscle for Glycogen and protein synthesis ( also increases uptake of amino acid and ketone).
3. In liver glucose uptake is Increased by increasing the activity of glucokinase and inactivating glycogen phosphorylase. Synthesis of glycogen occurs and it's breakdown is decreased.
🔺Increased potassium uptake in cells leading to Hypokalemia.
🔺 Increased protein, lipid and glycogen synthesis in the liver. (Glycolysis is also increased). Gluconeogenesis is inhibited.
🔺Increase in cell growth.
🔺 Lipoprotein lipase is activated where as 🔻Harmone sensitive lipase is inhibited.
What happens when insulin is low or ineffective ? :
When the insulin is low due to any cause in the synthesis or secretion of glucose or when the insulin is ineffective due to increased insulin resistance (down regulation of GLUT-4) in the cells, the levels of glucose raise in the blood which is termed as Hyperglycemia.
🔹Diabetes Mellitus is one such condition of Hyperglycemia where the Insulin is low (Type-1 DM) or ineffective due to low level or increased resistance ( Type -2 DM ). Hypoglycemic drugs can serve the purpose of initial lowering of glucose level but when it is not controlled insulin is the only management of choice.
🔹In cases of uncontrolled Hyperglycemia as in a diabetic patient, metabolic acidosis with ketosis develops which is termed as Diabetic-ketoacidosis. Insulin as an Intravenous continuous infusion stays as the main stay of treatment in that case.
💠In addition to Type 2 diabetes, insulin resistance is associated with several other conditions, including:
🔹Obesity,
🔹Cardiovascular disease,
🔹Nonalcoholic fatty liver disease,
🔹Metabolic syndrome,
🔹Polycystic ovary syndrome (PCOS).
Types of Insulin :
Individual insulin products are numerous, but insulin may be divided into four major types.
✅ Rapid-acting insulin – Soluble insulin acts quickly (30-60 minutes) and lasts for between 3 and 5 hours. - Lispro (Humalog), Glulisine (Apidra), Aspart (NovoRapid).
✅ Intermediate-acting – Isophane insulin acts slightly slower (1-3 hours) and lasts for between 10 and 18 hours - NPH (Humulin -N, Nivolin NPH).
✅ Long-acting insulin – These insulin types Determir(Levimir), Glargine, protamine zinc, zinc suspension) act slowly (1-2 hours) and last much longer, for up to 24 hours.
Uses of insulin :
🔸Diabetis Mellitus - in divided doses given as a subcutaneous injection.
🔸 Gestational Diabetes - in divided doses as subcutaneous injection.
🔸Diabetic-ketoacidosis (common in Type -1 Diabetics) - as IV drip along with correction of acidosis and treating the cause.
🔸Hyperosmolar Hyperglycemia syndrome - Controlled rehydration is the main stay of treatment along with insulin.
🔸Hyperkalemia - Insulin increases the activity of Na-K ATPase in the cell membrane so that potassium is pumped into cells and it's levels decreases in the blood. Insulin is given along with dextrose to prevent hypoglycemia.
That's all with the controller of glucose.
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