 FOLDER 18.3  FOLDER 18.4 Functional Considerations: Insulin Synthesis, an Example of Posttranslational Processing chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas PANCR EAS 655 655 Recently, researchers identified expression of insulin and insulin growth factors (IGF I and IGF II) in nerve cells in several regions of the brain. It is known that insulin resis-tance characteristic of diabetes mellitus is linked to neural degeneration, cognitive dysfunction, and dementia. The reduced rate of insulin and IGF production in the brain contributes to the degeneration of brain cells, an early symptom of Alzheimer’s disease (AD). Postmortem ex-amination of the brain tissue from individuals diagnosed with AD confirmed that levels of insulin and IGFs were sig-nificantly reduced in the hippocampus (the part of the brain responsible for memory), frontal lobes, and hypothalamus. In contrast, in the cerebellum (which is generally not af-fected by AD), researchers noted normal levels of these hormones. Abnormalities in insulin production in the brain do not present symptoms typical to type 1 or type 2 dia-betes mellitus, but they may indicate that AD could be a manifestation of type 3 diabetes. If these new observations are confirmed in the future, it might be possible to develop a targeted treatment for AD that is not available today. Insulin is produced within B cells in the pancreas. It is a small protein consisting of two polypeptide chains joined by disulfide bridges. Its biosynthesis presents a clear ex-ample of the importance of posttranslational processing in the achievement of the final, active structure of a protein. Insulin is originally synthesized as a single 110–amino acid polypeptide chain with a molecular weight of about 12,000 daltons. This polypeptide is called preproinsulin. Preproinsulin contains an amino-terminus signal sequence (24 amino acids in length) that is required for the precursor hormone to enter rER. As the molecule is inserted into the cisternae of the rER, the preproinsulin signal sequence is proteolytically cleaved to form proinsulin. Post translational processing reduces the preproinsulin to a polypeptide with a molecular weight of about 9,000 daltons. Proinsulin is a single polypeptide chain of 81 to 86 amino acids that has the approximate shape of the letter G (Fig. F18.4.1). Two disulfide bonds connect the bar of the G to the top loop. During packaging and storage of proinsulin in the Golgi apparatus, a cathepsin-like enzyme cleaves most of the side of the loop, leaving the bar of the G as an A chain of 21 amino acids cross-linked by the disulfide bridges to the top of the loop, which becomes the B chain of 30 amino acids. The 35–amino acid peptide removed from the loop is called a C peptide (connecting peptide). It is stored in the secretory vesicles and released with the insulin in equimolar amounts. No physiologic function has been identified for the C peptide. Because C peptide has a longer half-life than insulin, higher concentrations of C peptides are detected in the peripheral blood. For these reasons, measurement of cir-culating levels of C peptides provides important clinical information about the secretory activity of B cells. Be-cause C peptide is cleared from the body by the kidney, measurement of its urinary excretion provides a useful in-formation about B cell insulin secretion. C peptide mea-surements are frequently used to assess the residual B cell function in patients treated with insulin, to distinguish between types 1 and 2 diabetes and in the diagnosis and monitoring therapy of insulinoma (tumor of B cells). C peptide may also be used to monitor the progress of pan-creas or islet cell transplantation. FIGURE F18.4.1 • Posttranslational processing of insulin. Insulin is synthesized as the preproinsulin, a single polypeptide chain that undergoes posttranslational modifications. Initially, the signal sequence is removed within cysternae of the rER. Resulted shorter polypeptide chain know as proinsulin is transported to Golgi apparatus where is further modified by formation of internal disulfide bonds and removal of C chain that produces biologically active insulin. signal sequence chain B chain A chain C H2N C peptide preproinsulin proinsulin insulin COOH S H2N H2N H2N COOH COOH COOH S S S S S chain B chain A chain C S S S S S S chain B chain A S S S S S S