Insulin is the polypeptide hormone secreted from the pancreas. The word insulin was derived from the Latin word, "Insula" which means "Island" as it is produced in the islets of Langerhans in pancreas. At least four polypeptides with regulatory activity are secreted by the islets of Langerhans in the pancreas. Two of these are hormones insulin and glucagon and have important functions in the regulation of the intermediary metabolism of carbohydrates, proteins, and fats.
Insulin in anabolic, increasing the storage of glucose, fatty acids and amino acids. Glucagon is catabolic, mobilizing glucose, fatty acids and the amino acids from stores into the bloodstream. The two hormones are thus reciprocal in their overall action and are reciprocally secreted in most circumstances. Insulin excess causes hypoglycemia, which leads to convulsions and coma. Insulin deficiency, either absolute or relative, causes diabetes mellitus (chronic elevated blood glucose), a complex or debilitating disease that if untreated is eventually fatal.
Discovery & Production:-
In 1889, Oskar Minkowski, a young assistant at the Medical College of Strasbourg, and Joseph Von Mering, at the Hoppe-Seyler Institute in Strasbourg, had a friendly disagreement about weather the pancreas, known to contain lipases, was important in fat digestion in dogs. To resolve the issue, they began an experiment on the digestion of fats. They surgically removed the pancreas from a dog, but before their experiment got any further, Minkowski noticed that the dog was now producing far more urine than normal. Also, the dog’s urine had glucose levels far above normal. These findings suggested that lack of some pancreatic product caused diabetes.
Minkowski tried unsuccessfully to prepare an extract of dog pancreas that would reverse the effect of removing the pancreas-that is, would lower the urinary or blood glucose level. Now, we know that insulin is a protein, and that the pancreas is very rich in proteases (trypsin and chymotrypsin), normally released directly into the small intestine to aid in digestion. These proteases doubtless degraded the insulin in the pancreatic extracts in Minkowski’s experiments.
Despite considerable effort, no significant progress was made in the isolation or characterization of the "anti-diabetic factor". Until the summer of 1921, when Frederick.G.Banting, a young scientist working in the laboratory of J.J.R. Macleod at the University of Toronto, and a student assistant, Charles Best, took up the problem. By that time, several lines of evidence pointed to a group of specialized cells in the pancreas as the source of the anti- diabetic factor, which came to be called insulin.
Taking precautions to prevent proteolysis, Banting and Best succeeded in December 1921 in preparing a purified pancreatic extract that cured the symptoms of experimental diabetes in dogs. On January 25, 1922, their insulin preparation was injected into Leonard Thompson, a 14-years old boy severely ill with diabetes mellitus within days, the levels of ketone bodies and glucose in Thompson’s urine dropped dramatically, the extract saved his life, in 1923, Banting and Macleod won the Nobel Prize for their isolation of insulin.
By 1923, pharmaceutical companies were supplying thousands of patients throughout the world with insulin extracted from porcine pancreas. With the development of genetic engineering technique in 1980’s, it becomes possible to produce unlimited quantities of human insulin by inserting the coloned human gens of insulin into micro-organisms which were than cultured on the industrial scale.
Chemistry & Species Specificity:-
Insulin is a small protein with a molecular weight in humans of 5808. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges, there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of our amino acids.
Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues; a small quantity of unprocessed or partially hydrolyzed proinsulin is released as well. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the beta cells store the insulin in the form of crystals consisting of two atoms or zinc and six molecules of insulin, the entire human pancreas contains up to 8mg of insulin, representing approximately 200 biologic units. Originally, the unit was defined on the basis of the hypoglycemic activity of insulin in rabbits. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay purposes contain 28 units per mg.
Biosynthesis & Secretion:-
Insulin is synthesized in the rough endoplasmic reticulum of the B cells. It is then transported to the Golgi apparatus, where it is packaged into membrane-bound granules. These granules move to the plasma membrane by a process involving microtubules, their contents are expelled by exocytosis. The insulin then crosses the basal lamina of the B cell and a neighboring capillary and the fenestrated endothelium of the capillary to reach the bloodstream.
Like other polypeptide hormones and related proteins that enter the endoplasmic reticulum, insulin is synthesized as part of a larger preprohormone. The gene for insulin is located on the short arm of chromosome 11 in humans. It has tow introns and three exons. PreProinsulin has a 23-amino acid signal peptide removed as it enters the endoplasmic reticulum. The remainder of the molecule is then folded, and the disulfide bonds are formed to make proinsulin. The peptide segment connecting the A and B chains, the connecting peptide, facilitates the folding and then is detached in the granules before secretion. Two proteases are involved in processing the proinsulin; to date it has no other established physiologic activity. Normally, 90-97% of the product released from the B cells is insulin along with equimolar amounts or C peptide. The rest is mostly proinsulin. C peptide can be measured by RIA, and its level in blood provides an index of B cell function in patients receiving exogenous insulin.
Degradation:-
The liver and kidney are the tow main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35-40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30-40%. The half life of circulating insulin is 3-5 minutes.
Circulating Insulin:-
Basal insulin values of 5-15µU/mL (30-90 pmol/L) are found in normal humans, with a peak rise to 60-90µU/mL (360-540pmol/mL) during meals.
Principal actions of Insulin:-
Rapid (Seconds)
- Increased transport of glucose, amino acids and K+ into insulin-sensitive cells.
- Intermediate (Minutes)
- Stimulation of protein synthesis
- Inhibition of protein degradation
- Activation of glycolytic enzymes and glycogen synthase
- Inhibition of phosphorylase and gluconeogenic enzymes
Delayed (Hours)
- Increase in mRNAs for lipogenic and other enzymes
Effects of Insulin on Various Tissues:-
- Adipose Tissues
- Increased glucose entry
- Increased fatty acid synthesis
- Increased glycerol phosphate synthesis
- Increased triglyceride deposition
- Activation of lipoprotein lipase
- Inhibition of hormone-sensitive lipase
- Increased K+ uptake
Muscle
- Increased glucose entry
- Increased glycogen synthesis
- Increased amino acid uptake
- Increased protein synthesis in ribosomes
- Decreased protein catabolism
- Decreased release of gluconeogenic amino acids
- Increased ketone uptake
- Increased K+ uptake
Liver
- Decreased ketogenesis
- Increased protein synthesis
- Increased lipid synthesis
- Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis and increased glucolysis
General
- Increased cell growth
Diabetes Mellitus:-
Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose) levels that result from defects in insulin secretion, or action, or both. Diabetes mellitus, commonly referred to as diabetes was first identified as a disease associated with \"sweet urine,\" and excessive muscle loss in the ancient world. Elevated levels of blood glucose (hyperglycemia) lead to spillage of glucose into the urine, hence the term sweet urine.
Normally, blood glucose levels are tightly controlled by insulin, a hormone produced by the pancreas. Insulin lowers the blood glucose level as we discussed earlier. When the blood glucose elevates (for example, after eating food), insulin is released from the pancreas to normalize the glucose level. In patients with diabetes, the absence or insufficient production of insulin causes hyperglycemia. Diabetes is a chronic medical condition, meaning that although it can be controlled, it lasts a lifetime.
Types of Diabetes Mellitus:-
There are two types of diabetes.
- Type I or Insulin dependent Diabetes
- Type II or Insulin non-dependent Diabetes
BY
Muhammad Asif Mahmood
Department Of Pharmacy
University Of Lahore