Synthesis, Storage and Secretion of Insulin

 

The information regarding synthesis, storage and secretion of Insulin was given by D.F. Steiner and his colleagues. The origin goal was to determine regarding the synthesis of A and B chains of insulin and the construction of disulfide cross linkages. The incubation of radioactive substances such as lucine and phenylalanine is done with islet tissues of rat pancreas or human pancreatic tumors and tumors of this type produce excessively large amount of insulin. Production of two radioactive proteins occurs from the pancreatic tumor and is capable of combining with a specific antibody to pure insulin. One was established to be insulin itself. The other one is closely related resembled to insulin itself because it has reacted to anti-insulin antibody and is substantially having larger molecular weight than insulin. Treatment of the second product with trypsin and carboxypeptidase causes cleavage of a number of peptide bonds and the formation of a compound that was proved to be identical with native insulin.

            Chemical and enzymatic degradation studies on pancreas showed that large insulin like molecule formed by the pancreas. The molecule is known as proinsulin and it consists of a single polypeptide chain having from 81 to 86 residues, depending on the origin of the species. Both A and B chains are present in proinsulin. The A chain constitutes the carboxyl-terminal end of the proinsulin chain and B chain the amino-terminal end. Between the A and B chains is the connecting C chain. Two pairs of basic amino acids separate the A and B chains from the C chains.

            Proinsulin, which has only a small amount of insulin like activity itself, is the biosynthetic precursor of insulin. The transformation of proinsulin into insulin is apparently accomplished by the action of peptidases in the islet tissue. The conversion of proinsulin to insulin is another example of the pattern of synthesis and activation of a number of proteins whose biological function is largely extracellular.

            Insulin is first made on the ribosomes in the form of proinsulin, which is translocated via the cisternae of the endoplasmic reticulum to the Golgi apparatus. The proinsulin is cleaved to form insulin and C-peptide, which are packaged in Golgi vesicles, where the insulin and C-peptide crystallize with Zn2+ in an ordered array. Ultimately, on receipt of certain signals triggered by an increase in the blood glucose level, the contents of these vesicles are released by exocytosis through the plasma membrane into the blood. Ca2+ plays an important role in insulin release.

            The normal human pancreas contains about 10 mg of insulin, but the amount secreted into the blood daily is only about 1 to 2 mg. Free C-peptide and a small amount of proinsulin also circulate in the blood; they are apparently released together with insulin. Depending on the glucose concentration and certain other factors, the release of insulin from the pancreas occurs. When the blood glucose increases significantly above its normal level of about 80-90 mg per 100 ml, after a meal, the contents of the secretion vesicles closest to the plasma membrane of the β cells are ejected into the blood. The insulin concentration then declines to the normal level in an hour or two after a meal. The half-life of insulin molecules in the blood is only about 3 to 4 min; the release of insulin from the pancreas therefore is very responsive to fluctuations in the blood glucose concentration. The release of insulin is also stimulated by increased level of certain amino acids and by specific factors secreted by the stomach and intestine.

Source:- Biochemistry Second Edition, The Molecular Basis of Cell Structure and Function, Albert L. Lehninger, The Johns Hopkins University School of Medicine, Page number 417-420.

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