Insulin
Insulin, a protein hormone with 51 amino acids contains two polypeptide chains (A & B) with 21 and 30 amino acids respectively connected by two di-sulphide bridges with a third di-sulphide bridge in the A-chain. Insulin is synthesized as pre-proinsulin, processed in the endoplasmic reticulum and released.
During processing of proinsulin, along with insulin another polypeptide called C peptide is produced which also enters the plasma along with insulin.
Levels of C peptide in plasma indicate beta cell function in insulin deficient patients. It has a half-life of 5 minutes.
Structurally insulin of dogs, cats and pigs is identical. Insulin from cattle, sheep, horse, pig and dog differs only in positions 8th, 9th and 10th in A chain, hence the biological actions of insulin are not highly species specific. Insulin from one species is mildly antigenic when injected into another.
Biological effects of insulin
Liver, skeletal muscle and adipose tissue are the principal target organs of insulin where it enhances the entrance of glucose, amino acids, fatty acids, K+ and Na+ ions.
It stimulates glycogenesis, lipogenesis, glycolysis and protein synthesis, whereas it inhibits gluconeogeneis, lipolysis and ketogenesis.
It lowers blood glucose, fatty acids and amino-acids levels and promotes intra cellular conversion of these compounds to glycogen, triglycerides and protein respectively.
Effects of insulin on Carbohydrate Metabolism-
Glucose does not readily penetrate the cell membranes except in neurons, liver, intestinal epithelium, RBCand WBC, renal tubular epithelium and retina.
Presence of insulin causes more amount of glucose entry (2 to 5 fold more) through the plasma membrane into the muscle and adipose cells.
Glucose can be transported down their concentration gradient across the cell membrane by transport proteins called glucose transport proteins (GLUTs) which are present in the cell membrane of all cells. Detection of plasma glucose by pancreatic islet cells as well as uptake/ release of glucose from cells involve GLUT. GLUT is present in many isoforms
When insulin concentration rises in the plasma, number of GLUT-4 molecules increases in the cell membrane and glucose transport into the cell is increased
In liver, insulin activates the enzyme glucokinase to initiate phosphorylation of glucose, thus the glucose is trapped inside the liver cells.
Insulin promotes the activities of glycogen synthase to favour glycogenesis, while it inhibits phosphorylase and prevents the split of glycogen into glucose.
Liver can store glycogen up to 10 to 15% of its mass.
The normal resting muscle membrane is almost impermeable to glucose. In the presence of insulin, glucose permeability is increased and muscle glycogen synthase activity is enhanced.
However during heavy exercise the muscle membrane becomes highly permeable to glucose even in the absence of insulin. Much of the glucose in the muscle is stored in the form of muscle glycogen instead of being used for energy. Approximately 75% of the glucose is converted into glycogen and only 20 to 30% undergo glycolysis.
In many cells, insulin facilitates glycolysis by activating glycolytic enzymes.
Insulin inhibits proteolysis in the peripheral tissues, thereby reducing amino acid availability for gluconeogenesis.
Effects of insulin on Fat Metabolism-
Insulin by increasing rate of utilization of glucose in many body tissues functions as fat sparer.
In the liver when the liver glycogen level goes above 15%, insulin promotes the conversion of glucose to fatty acid and their transport to the adipose cells for triglyceride synthesis and storage. Insulin increases acetyl‑CoA formation from pyruvate, the substrate for fatty acids synthesis. Glycolytic break down of glucose by insulin supplies large quantities of a ‑glycerophosphate which is the source of glycerol. Binding of glycerol with fatty acids forms triglycerides; the triglycerides are transported to adipose tissue and stored as fat.
Insulin also promotes glucose transport into adipose cells, where they are converted to a- glycerophosphate and to glycerol for triglyceride synthesis.
Insulin inhibits the action of hormone‑sensitive lipase and prevents hydrolysis of the triglycerides in adipose tissue and release of fatty acids into the circulating blood.
Insulin diminishes beta oxidation of fat, thus inhibits ketone body production. In adipose tissue, insulin induces the synthesis of lipoprotein lipase, (promotes movement of fatty acids into adipose tissue) inhibits intracellular lipase and enhances fatty acid esterification. Cholesterol synthesis is also enhanced by insulin.
Ketogenic and Acidotic Effects of lack of Insulin-
Lack of insulin promotes the activation of hormone ‑sensitive lipase and rapid breakdown of fatty acids from the liver and adipose cells and excessive production of acetyl ‑ CoA.
Portion of acetyl‑CoA utilized for energy in the liver; excess is condensed to form acetoacetic acid, beta hydroxy butyric acid and acetone, which are the ketone bodies and their presence in large quantities in the body fluids is called as ketosis.
Effects of insulin on Protein Metabolism-
Insulin acts along with growth hormone and cause active transport of amino acids into the cells and increases the rate of transcription of DNA in the cell uncles, thus affects the ribosomes to increase the translation of messenger RNA forming new proteins.
Insulin greatly enhances the rate of protein synthesis and prevents the degradation of proteins for gluconeogenesis and promotes positive nitrogen balance.
Due to its effects on protein metabolism, insulin is required for growth of the animal; GH and insulin act synergistically to promote growth.
Regulation of insulin secretion
The most important factor in the control of insulin secretion is the concentration of blood glucose. Increased concentration of blood glucose initiates the synthesis and release of insulin by positive feedback mechanism.
Gastrin, secretin, CCK, gastric inhibitory peptides, ACTH, cortisol, estrodiol, GH, glucagon, progesterone, thyroxine and acetylcholine, amino acids (arginine and lysine are the most potent) and fatty acids in plasma stimulate insulin secretion.
In sheep the short chain fatty acid butyrate and propionate stimulates the release of insulin, whereas in dog the long chain fatty acids stimulate insulin release.
Glucagon has direct stimulatory effect on beta cells and insulin secretion, whereas somatostatin and adrenergics inhibit the secretion of insulin.
Calcium is the final triggering step in the release of insulin from the islet cells; hence hypocalcemic condition in cows and pigs depresses insulin secretion.