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Synthesis: Insulin is synthesised and secreted by Beta cells of islets of Langerhans.
Adult human pancreas contain 2,00,000 to 18,00,000 islets. Islet constitute 1.5 % of total weight of pancreas and weight about 1 gm. Islet cells contain A,B,C,D,cells. Surrounded by acini which produce digestive enzymes. Through Paracrine effect A,B,C,D, cells influence each other. A cell secrete Glucagon, B cell -Insulin, C-cell Gastrin and D-cell Somato Statin.
Initially Pro Insulin is produced which is a larger polypeptide. Pro-insulin contains 81
amino acids with a molecular weight of 9000 dalton. Synthesis of pro-insulin molecule starts at ribosomes of rough endoplasmic reticulum and gets transported in microvescicles to Golgi complex where it is condensed into membrane bound granules (beta granules). Cleavage of Pro Insulin by Protease Splits this polypeptide into insulin and C Peptide. Insulin is stored with a minute quantity of zinc. Beta granules enclosed in smooth membranous sacs are released into cytoplasm and are taken up by contractile microtubular filaments which go into action following influx of calcium into beta cells during periods of stimulation. Insulin is released into extracellular fluid by the process of Emiocytosis. This secretion from beta cells mostly contains Equirnolar concentration of insulin and C. peptide (94%) and a small amount of Pro-insulin and other intermediaries. Around 200 units of insulin is usually stored in healthy pancreas.
Healthy adults need around 40 units of insulin per day. Insulin has 51 aminoacids in its
structure. It has 2 separate A & B Straight chains linked by disulfide bridges between and within the chain.
Insulin secretion from beta cells has two phases. The first phase solely contributed by
stored insulin inside beta cells and occurs within half a minute of rise of glucose. The second phase starts about 15 minutes later and continues for more than an hour. The phase comprises mostly of newly synthesized insulin. In diabetics the first phase is abolished and second phase is delayed and pronounced.
Glucose is a stimulus for insulin secretion. Glucose acts in the beta cells by activating
gluco receptors. Situated on the surface and stimulating intracellular mechanism after entry into the cells. Prompt and immediate response depends on release of second signal. C-A MR Thus glucose stimulated insulin release is biphasic in nature.
Factors which increase insulin release
Physiological stimuli
Glucose, Mannose Aminoacids-Leucine, Arginine Ketone bodies (especially in
starvation) Appetising food -GI hormones
* Cholecystokinin (CCK)
* Gastrin
* GIP(Gastrin Inhibitory Peptide)
* Secretin *GLP - 1
VIP
* Acetylcholine
* Glucose dependent insulinotropic polypeptide
* Glucagonlike insulinotropic polypeptide (CLIP)
* Growth hormone
* Glucagon
* Parasympathetic stimulation (Vagal)
* Betaadrenergic stimulation
Pharmacologic & Experimental
* C-AMP
* Theophylline
* Calcium
* Sulphonylureas
* Mebendazole
* Pentamidine
Factors which blunt insulin release
* Physiologic
* Somatostain
* Hypothermia
* Exercise
* Infections
* Sympathetic stimulation
* (Epinephrine and Nor Epinephrine)
Pharmacological & Experimental
* Manno heptulose
* Diazoxide
* Prostaglandins
* Diphenyl hydantoin
* Beta cell poisons - Alloxan, Streptozotocin
* Diuretics
* Oral contraceptives
* Morphine
* H2 receptor blocker
* Ca++ channel blocker
* Clonidine
* B2 receptor agonists
* Atropine
Physiologic Action of Insulin on carbohydrate metabolism
Insulin facilitates glucose transfer across cell membranes in tissues. Insulin stimulates the
intracellular enzyme gluco-kinase and accelerates phosphorylation of glucose and enhance glucose oxidation. It promotes glycogen formation and its deposition in liver and muscles by activating Glycogen synthetase and prevents Glycogenolysis by inhibiting Phosphorylase. Insulin promotes preferential oxidation of glucose to provide energy and spares fat and protein breakdown.
Insulin stimulates transfer of aminoacids at cell membrane level and acting on ribosomes it
increases protein synthesis. It is an anabolic hormone. It counteracts the effect of Catabolic hormones like adrenaline, Cortico steroid, glucagon, growth hormone. It inhibits gluconeogenesis.
Insulin is a lipogenic hormone. It enhances synthesis of free fatty acids from glucose born
in liver and adipose tissue. Acting on hormone sensitive lipase it inhibits lipolysis. Lipogenesis is promoted through free fatty acids and glycerol. This action leads to lowering of blood sugar and decrease in free fatty acid levels in serum.
Insulin receptors are found over cell membrane of hepatocytes, adipocytes, myocyte and
monocytes. Molecules of insulin are bound at the receptor sites and facilitates transfer of metabolites through cell membrane. It not only helps in membrane transport of metabolites but also influences intracellular mechanism of cells.
Metabolic effects of Insulin deficiency: Insulin lack in mild form may show fasting
normoglycemia and post meal hyperglycemia because normally after a carbohydrate meal 70% of glucose is trapped in liver. This occurs due to prompt release of insulin. Failure of this mechanism leads to postmeal hyperglycemia. In moderate deficiency fasting hyperglycemia occurs and blood glucose remains high even 4-5 hours after a meal. This is because of production of glucose by gluconeogeneis and glycogenolysis and diminished peripheral utilisation of glucose due to insulin definciency. Severe insulin deficient states produce hyperglycemia, hyperlipidemia and hyper amino acidemia due to lack of utilisation of glucose free fatty acids and amino acids derived from adipose tissue and muscles. These are utilised to provide alternative fuels when excess of fatty acids are exceeding more than the peripheral utilisation. Liver takes it up and produce ketone bodies.
Insulin profile in different types of diabetics: In Type-I diabetics serum insulin is negligible
in fasting state and very little or no response after carbohydrate load.
Type-II diabetics fasting serum insulin is either normal or elevated. Release of insulin in
response to glucose load is sluggish and attains the peak later than normal but remains higher for long time. Thus hyperinsulinaemia depends on state of adiposity.
In lean Typer-II diabetes mellitus serum insulin levels are lower than normal and response
to stimulus is less.
In resistant diabetes mellitus there is insulopenia at fasting as well as in response to
meals. Thus, in this typer of patients and in young diabetes mellitus patients with pancreatic calculi and fibrosis quantity of plasma insulin is higher than Typer-I diabetes mellitus.
Structural difference between Human, Bovine and Porcine Insulin
A Chain B Chain
8 10 30
Human Threonine Isoleucine Threonine
Porcine Threonine Isoleucine Alanine
Bovine Alanine Valine Alanine
Thus porcine insulin differs only in one aminoacid at position 30 of B chain, while bovine
differs at 3 positions.
Insulin antigenecity: Insulin antigenecity was first discovered in 1928. While the
occurrence of insulin resistance after insulin treatment was first observed in 1938. There are minor differences in the aminoacid composition of the molecules from species to species. The differences are generally not sufficient to affect the biological activity of particular insulin in heterologous species but are sufficient to make the insulin antigenic. Almost all humans who have received commercial beef insulin for more than 2 months have antibodies against beef insulin, but the titer is usually low. Porcine insulin differs from human insulin by only one aminoacid residue and has low antigenecity. However homologous insulin was also found to be antigenic. Thus this suggests the presence of another undefined difference between crystalline insulin extracted from the pancreas and the circulating hormone. In a study it was found that antibodies formed against insulin of another species may react to a considerable extent with the endogenous insulin of the organism in which they were produced. It is likely that insulins similar with respect to their aminoacid composition are more closely related antigens than or insulins with very different compositions, this does not necessarily imply that they are also less antigenic. Thus more than one feature of the insulin molecule in responsible for its antigenecity such as its structural and spatial configuation.
It is not known whether the antigenic components of the insulin lies on A or B chain.
Human insulin produced by recombinant DNA technology is used to avoid problems of antibody formation.
Insulin Antibodies: Atleast 5 classes of insulin antibodies may be produced during the
course of insulin, interferes with its activity. In patients with insulin resistance due to antibody production the degree of insulin resistance can be correlated roughly with the capacity of the serum to bind insulin. More than one type of antibody can arise in response to insulin administration.
Insulin allergy: There is a substantial decrease in the incidence of allergic reactions to
insulin which is mainly attributable to the availability of highly purified preparations of the hormone, but still these reactions are inevitable as a result of small amounts of denatured or aggregated insulin in all preparations and to the presence of minor cantaminants or components added to insulin in its formulation (Protamine, Zinc and Phenol). The most frequent allergic manifestations are IgE, mediated local cutaneous reactions although very rarely patients may develop life threatening systemic anaphylactic reactions due to IgG antibodies. Immediate type of hypersensivity is a rare condition with local or systemic urticaria. A subcutaneous nodule appearing several hours or later at the site of insulin injection and lasting for upto 24 hours has been attributed to IgG mediated complement binding Arthus reaction. The cause of allergy is due to histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies. Appropriate steps for diagnosing underline cause by measuring insulin specific IgE antibodies should be undertaken. Skin testing is also useful however many patients exhibit positive reaction to intradermal insulin without experiencing any adverse effect from subcutaneous insulin. Allergy to insulin is treated by desensitization it is found to be successful in 50% cases. Antihistamines are useful in patients with cutaneous manifestations. Glucocortioids are useful in very severe systemic reactions.
Insulin resistance: This is often self limited condition and may clear spontaneously after
several months. Insulin resistance is defined as a status when the absolute insulin requirement exceeds more than 200 units per day. It is attributed mainly to circulating IgG antibodies in the blood. When a patient is maintained on bovine insulin and the level of resistance is very high and the circulating antibody is specifically more reactive with bovine insulin, switching over to a less potent antigenic porcine insulin or human insulin may cause a dramatic reduction in insulin doses or may atleast shorten the duration of human resistance. Other forms of therapy include sulphated beef insulin ( a chemically modified form of beef insulin containing an average of 6 sulphated groups per molecule). Immunosupression and glucocorticodis also play a vital role.
Insulin degradation : Half life of insulin in plasma is adoubt 5-6 minutes in normal
subjects. Insulin degradation primarily occurs in liver, kidney and muscle. Peripheral tissue such as fat also inactivate insulin but this is of less significance quantitatively. 50% of the insulin that reaches the liver via the portal vein is destroyed and never reaches the systemic circulation. Several enzymes have been implicated in insulin degradation. The major step in insulin degradation involves hydrolysis of the disulphide bonds between A and B chains through the action of glutathione insulin transhydrogenase (insulinase). After this reductive cleavage further degradation by proteolysis occurs. Liver approximately clears 60% of insulin released from pancreas and kidney remove 35-40% of endogenous hormone. However in insulin treated diabetics receiving subcutaneous insulin, 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 primary insulin degrading enzyme is a thiol metallo proteinase. This enzyme is localised in hepatocytes but immunologically related molecules also have been found in muscle, kidney and brain. Hepatic degradation of insulin operates near its maximal capacity and cannot compensate for diminished renal breakdown of insulin. Insulin is filtered by renal glomeruli and is reabsorbed by the tubules which is also degrade it. Severe impairment of renal function appears to affect the rate of disappearance of circulating insulin to a greater extent than does hepatic disease. The oral administration of glucose appears to reduce hepatic extraction of insulin. Proteolytic degradation of insulin in the liver occurs primarily after internalisation of the hormone and its receptors and to a lesser extent at the cells surface. The primary pathway for internalisation is receptor mediated endocytosis. The complex of insulin and its receptor is internalised into small vesicles and termed endosomes, where degradation is initiated. Some insulin is also degraded by the lysosomes.
REFERENCES
1. Insulin Relation to Diabetes: M.M.S. Ahuja: Practice of Diabetes Mellitus 1983.
Vikas Publishing House Pvt.Ltd.Page 26- 30.
2. Pathophysiology of Diabetes Mellitus in Joslin Diabetes Mellitus. Alexander Marble,
Priscilla White, Robert F. Bradly and Leo P.Krall: Lea* Febiger Publishers 1972: 2nd
Ed.Page 40-45.
3. Insulin, oral hypoglycemic agents and pharmacology of endocrine pancreas:
Stephen N. Davis, Daryl K.Granner; Chapter 60, page 1487 to 1513- Goodmans
and Gilmans; The Pharmacological Basis of Therapeutics 9th Ed. 1996.
4. Basic and clinical pharmacology: Pancreatic hormones and antidiabetic drugs; John
H.Karam; 1989 Appleton Lange Medical Publication 4th Ed.
5. Endocrine functions of the pancreas and regulation of carbohydrate metabolism:
Chapter 19; Review of medical physiology 18th Ed.; William F. Ganong; A Lange
Publication page 312-315.
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