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Journal of Cell and Animal Biology Vol. 6(8), pp. 123-128, 30 April, 2012 Available online at http://www.academicjournals.org/JCAB DOI: xxx ISSN 1996-0867 ©2012 Academic Journals Review Insulin: A review M. Akram*, Khan Usmanghani, H. M. Asif Department of Basic Medical Sciences, Faculty of Eastern Medicine, Hamdard University, Karachi, Madinat-al-Hikmah, Muhammad Bin Qasim Avenue, Karachi, Pakistan-74600, Pakistan. Accepted 25 April, 2012 Insulin is anabolic hormone that is secreted from beta cells of pancreas and is involved in various cellular functions of body insulin is a polypeptide hormone produced by the beta cells of islets of langerhans of pancreas. It has profound influence on the metabolism of carbohydrate, fat and protein. Insulin is considered as anabolic hormone, as it promotes the synthesis of glycogen, triacylglycerols and proteins. This hormone has been implicated in the development of diabetes mellitus. Insulin occupies a special place in the history of biochemistry as well as medicine. Insulin was the first hormone to be isolated, purified and synthesized; first hormone to be sequenced; first hormone to be produced by recombinant DNA technology. Its deficiency results in diabetes mellitus. Key words: Insulin, effect of insulin on body organ, insulin related metabolic disorders. INTRODUCTION Insulin plays a key role in the regulation of carbohydrates, lipid and protein metabolism. Insulin exerts anabolic and anticatabolic influences on the body metabolism. In a normal individual, about half of the individual glucose is utilized to meet the energy needs of the body (mainly through glycolysis). The other half is converted to fat (40%) and glycogen (10%). Insulin is required for the uptake of glucose by muscle (skeletal, cardiac and smooth), adipose tissue, leucocytes and mammary glands (Kahn, 1994). Insulin increases glucose utilization in muscle and liver. The net effect of insulin on lipid metabolism is to reduce the release of fatty acids from the stored fat and decrease the production of ketone bodies. Insulin favors the synthesis of triacylglycerols from glucose by providing more glycerol 3 – phosphate (from glycolysis) and NADP (from HMP shunt). Insulin decreases the activity of hormone – sensitive lipase and thus reduces the release of fatty acids from stored fat in adipose tissue. The mobilization of fatty acids from liver is also decreased by insulin. Insulin reduces ketogenesis by decreasing the activity of HMG Co-A synthetase. Further, *Corresponding author. E-mail: [email protected]. Tel: 92-021-6440083. Fax: 92-021-6440079. insulin promotes the utilization of acetyl Co-A for oxidation (Krebs cycle). Insulin promotes cell growth and replication. It increases protein synthesis. Xi et al. (2005) has studied that Crocetin prevents dexamethasoneinduced insulin resistance in rats. STRUCTURE OF INSULIN Human insulin (mol. Wt. 5,734) contains 51 amino acids arranged in two polypeptides chains. The chain A contains 21 amino acids while B has 30 amino acids. Both are held together by two interchain disulfide bridges, connecting A7 to B7 and A20 to B19. In addition, there is an intercahain disulfide link in chain A between the amino acids 6 and 11(Bell et al., 1980). BIOSYNTHESIS OF INSULIN Insulin is produced by the beta cells of the islets of langerhans of pancreas. The gene for this protein synthesis is located on chromosome 11. The synthesis of insulin involves two precursors, namely preproinsulin with 108 amino acids (mol. Wt. 11,500) and proinsulin with 86 amino acids (mol. Wt. 9, 000). They are sequentially degraded to form the active hormone insulin and a connecting peptide (C-peptide). Insulin and C-peptide are produced in equimolar concentration. C-peptide has no biological activity; however, its estimation in the plasma serves as a useful index for the endogenous production of insulin. In the beta cells, insulin and also (proinsulin) combines with zinc to form complexes. In this form, insulin is stored in the granules of the cytosole which is released in response to various stimuli by exocytosis (Froguel et al., 1994). REGULATION OF INSULIN SECRETION About 40-50 units of insulin are secreted daily by human pancreas. The normal insulin concentration in plasma is 20-30µU/ml(Gartner et al., 2007). This short life permits rapid metabolic changes in accordance to the alteration in the circulating levels of insulin. This is advantageous for the therapeutic purposes. A protease enzyme, namely insulinase (mainly found in liver and kidney), degrades insulin (Bowerman, 2007). Metabolic effects of insulin Insulin plays an important role in regulating the metabolism of carbohydrates, lipid and proteins. Insulin has anabolic effects on body metabolism (Madi son et al ., 1960). Insulin receptors GLUCOSE Glucose is the most important stimulus for insulin release. The effect is more pronounced when glucose is administered orally (either direct or through a carbohydrate rich meal). A rise in blood glucose level is a signal for insulin secretion (Alberti et al., 1998). It is found on target tissue for insulin. It is a tetramer of two alpha and two beta subunit. The beta subunits span the cell membrane and have tyrosine kinase activity. The phosphorylated receptor then phosphorylates intracellular proteins. The insulin receptor complexes enter the target cells. Insulin down regulates its own receptors in target tissues (Abbasi et al., 2002). AMINO ACIDS Effects on carbohydrate metabolism Amino acids induce the secretion of insulin. This is particularly observed after the ingestion of protein rich meal that causes transient rise in plasma amino acid concentration. Among the amino acids, arginine and leucine are potent stimulators of insulin release (John et al., 1966). Insulin influences glucose metabolism in many ways. The net effect is that insulin lowers blood glucose level (hypoglycemic effect) by promoting its utilization and storage and by inhibiting its production (Hanson et al., 2000). GASTROINTESTINAL HORMONES Effect on glucose uptake by tissues Gastrointestinal hormones (secretin, gastrin, and pancreozymin) enhance the secretion of insulin. The GIT hormones are released after the ingestion of food (Capella, 1995). Insulin is necessary for the absorption of glucose by muscle (skeletal, cardiac and smooth), adipose tissue, white blood cells and mammary glands. Surprisingly, 80% of glucose uptake in the body is not dependent on insulin (Ohkubo et al., 1995). Regarding the liver, the entry of glucose into hepatocytes does not require insulin. However, insulin stimulates utilization of glucose in the liver and therefore indirectly promotes uptake (Atkin et al., 1994). FACTORS AFFECTING INSULIN SECRETION Epinephrine is the most potent inhibitor of insulin release. In emergency situations like stress, extreme exercise and trauma in the nervous system stimulates adrenal medulla to release epinephrine. Epinephrine suppresses insulin release and promotes energy metabolism by mobilizing energy yielding compounds –glucose from liver and fatty acids from adipose tissue (Bach, 1994). Degradation of insulin In the plasma, insulin has a normal half life of 4-5 min. Effect on glucose utilization Insulin increases glucose utilization in muscle and liver. The activation and the quantities of certain key enzymes of glycolysis that is, glucokinase (not hexokinae) phosphofructokinase and pyruvate kinase are increased by insulin, increasing the activity of glycogen synthetase (Cherri ngt on et al ., 1978). Effect on glucose production Insulin decreases gluconeogenesis by suppressing enzymes pyruvate carboxylase, phosphoenolpyruvate carboxykinase and glucose 6 phosphatase. Insulin also inhibits glycogenolysis by glycogen phosphorylase inactivation (Edgert on et al. , 2001). iii) Increased glycerol phosphate synthesis iv) Increased triglyceride deposition v) Activation of lipoprotein lipase vi) Inhibition of hormone-sensitive lipase vii) Increased K+ uptake (Si ndel ar et al ., 1997). Muscle Effect on lipid metabolism The net effect of insulin on lipid metabolism is to reduce the release of fatty acids from the stored fat and reduce the production of ketone bodies. Among the tissues, adipose tissue is more sensitive to insulin (Gosch et al., 1996). i) Increased glucose entry ii) Increased glycogen synthesis iii) Increased amino acid uptake iv) Increased protein synthesis in ribosomes v) Decreased protein catabolism vi) Decreased release of gluconeogenic amino acids vii) Increased ketone uptake viii) Increased K+ uptake Effect on lipogenesis Liver Insulin promotes the synthesis of triglycerides from glucose through more glycerol -3- phosphate (from glycolysis) and NADP (from HMP shunt). Insulin increases the activity of acetyl Co-A carboxylase, a key enzyme in synthesis of fatty acids (Rosdahl et a l ., 1998). i) Decreased ketogenesis ii) Increased protein synthesis iii) Increased lipid synthesis iv) Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis. Effect on lipolysis General Insulin decreases the activity of the hormone - sensitive lipase and thus reduces the release of fatty acids from fat stored in adipose tissue. The mobilization of fatty acids by the liver is also decreased by insulin (Choudhury et al., 2004). Increased cell growth. Insulinoma Insulin reduces ketogenesis by reducing the activity of HMG Co-A synthetase. Furthermore, insulin promotes the utilization of acetyl Co-A for oxidation (Krebs cycle). Insulinoma must be considered as one possible cause of spontaneous hypoglycemia. This is arbitrarily defined as a blood-glucose concentration below 2.2 mmo1/1 (40 mg/100 ml). It may be many years before it is realized that the patient, commonly in the care of the neurologist or psychiatrist, has this rare condition (Iskra et al., 2011). Effects on protein metabolism RESEARCH STUDY Insulin causes the entry of amino acids into cells. Insulin promotes cell growth and replication. It also increases protein synthesis. Effect of Zingiber officinale on insulin and diabetic patient Effect on ketogenesis Effects of insulin on various tissues Adipose tissue i) Increased glucose entry ii) Increased fatty acid synthesis Z. officinale produces a significant increase in insulin levels and a decrease in fasting glucose levels in diabetic rats. In an oral glucose tolerance test, treatment with Z. officinale was found to decrease significantly the area under the curve of glucose and to increase the area under the curve of insulin in STZ-diabetic rats. Z. officinale is effective in hypercholestrolemia, hypertriglyceridemia and blood blood pressure in diabetic rats. This study suggest a potential antidiabetic activity of the juice of Z. officinale in type I diabetic rats, possibly involving 5-HT receptors (Sanjay et al., 2004). CONCLUSION Insulin is secreted by the beta cells of pancreas. Insulin deficiency results in diabetes mellitus. Insulin is involved in metabolism of carbohydrate, protein and lipids. 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