A New Tune For Middle C

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Insulin, like all other proteins, must undergo a bit of shaping before it is ready for business. Proteins are really just chains of amino acids (sometimes called polypeptide chains) that are arranged like beads on a string. Incredibly, these polypeptide chains simply fold in upon themselves to form the complex molecular machines that make everything happen within us. The biophysics of this process is under intense study. Sometimes that folding process is enough but sometimes it needs to be helped along with a bit of snipping. Insulin is one of those proteins that need some snipping. This snipping is performed by yet another string of amino acid beads that have folded in upon themselves to form an enzyme called a protease. The polypeptide chain gets cut in two very specific places to make three approximately equal pieces. The front and back piece get put together with some special chemical bonds (disulphide bonds) to help keep things folded properly while the middle piece gets tossed. We call the two pieces that get put together to make insulin the A chain and the B chain. The middle piece that gets tossed is called the C peptide. For years we considered the C peptide to be of no physiological use however that song is now changing its tune.

I was alerted to this by Bob Fenton, another diabetes blogger (http://bobsdiabetes. blogspot.com/). He sent me a piece from the Telegraph, a newspaper published in Briton which described the work of Dr. Karen Porter. I pulled up the research paper and found it to be quite interesting. Dr. Porter is looking at why patients with diabetes fare so poorly with heart disease. Not only do they need more procedures such as bypass surgery but the outcomes of these surgeries are often quite poor. For example, the saphenous vein (a big vein found in the thigh) is often used for coronary artery bypass grafts. The graft gets plugged surprisingly quickly when the patient has diabetes and is taking insulin; a process that gets the fancy name “intimal hyperplasia”. The plugging of the graft is not due to atherosclerotic plaque but rather due to the proliferation of the cells of the graft itself (hence the word, hyperplasia). The new cells can only grow inward and so the hole gets plugged and heart disease returns.

It is possible to examine theses cells in a tissue culture dish and this is what the research team did. They obtained bits of saphenous vein from non diabetic patients who had heart disease and were getting a coronary bypass graft (and volunteered for the study). These bits of tissue were placed into tissue culture dishes containing a liquid maintenance medium in the presence of either insulin or C-peptide or neither or both. Now it has been known for some time that insulin can act as a growth factor for some cells and others had demonstrated that insulin will promote the growth of the cells of the saphenous vein. What this group found was that C-peptide reversed the effect.

Insulin is cleaved within the secretory granule from which it will be released. Thus upon release, not only is insulin entering the blood stream but also an equal amount of C-peptide. Diabetes patients who do not make their own insulin do not get any C-peptide since it is not included in synthetic human insulin preparations. This leads to a lot of interesting and important questions. Would heart disease decrease for diabetes patients taking insulin if C-peptide was present? The present work suggests that after a saphenous vein graft cardiac bypass graft, C peptide might have a positive effect but we do not know how it will work for a patient whose heart is still healthy. As a pharmacologist, I would like to know how C-peptide works. Is there a separate receptor for C-peptide? Does C-peptide bind to some part of the insulin receptor and modify its function? Would the addition of C-peptide improve other diabetes complications?

At least some of these questions have been answered. A company called “Creative Peptides” is promoting the use of C-peptide in diabetes and has funded a clinical trial. The results were published in 2007 by Drs Karin Ekberg and colleagues from the Karolinska Institute in Stockholm. They found that a replacement dose of C-peptide resulted in an improvement in diabetic neuropathy. Others have shown that C-peptide can bind to membranes from endothelial cells, kidney cells, and nerve cells, indicating that a receptor for C-peptide exists and is probably different from the insulin receptor (which is found on many if not all cells). While the receptor has not yet been identified researchers have identified several signaling pathways that are altered when C-peptide is present. These result in the production of a chemical called nitric oxide (NO) which helps with blood flow as well as an increase in the activity of the pump that keeps the electrical gradient that powers neurons. C-peptide has also been shown to increase the secretion of neurotrophic factors which function to protect neurons. Within the symphony of the body, this is not a trivial part.

Can we expect to see C-peptide on the market any time soon? After mucking around on the web I found the beginnings of an answer in good old Wikipedia. A US company called Cebix has secured patents for the manufacture of C-peptide. According to the Cebix website they will be performing another phase II clinical trial which will start in 2011. Should you be interested in seeing if you qualify for this trial, keep an eye on the clinical trial web site www.clinicaltrials.gov. If indeed, insulin alone promotes a degree of discord, it is satisfying to know that harmony will be restored.

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C-peptide (C part of the A, B and C polypeptide chains of proinsulin) is an important part of insulin that protects people from diabetes complications. How did Big Pharma justify removing it without putting it back? In spite of better blood sugar control – this missing piece of insulin may explain the rise in diabetes complications.

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