August 4, 2008

C-Peptide and Your Nerves

When a beta cell synthesizes insulin it creates a substance called "proinsulin" which splits into the actual insulin molecule and another substance--a chain of proteins called C-peptide. Details of this process are described in this Wikipedia article:

Most of us learn about C-peptide because testing its concentration in our blood is useful for determining if a person's beta cells are making insulin. This is especially true if a person is injecting insulin. That is because injected insulin only contains the actual insulin molecule not C-peptide. So the only way you get C-peptide in your blood is if your beta cells are making proinsulin, which then is presumed to turn into insulin.

For years C-peptide was considered to be inert, but it now turns out that C-peptide may play an important role in our body. There is some evidence that it is actively involved in the processes that fight oxidation in our blood vessels. This is important because damage to our blood vessels is what causes neuropathy. When tiny capillaries are damaged they do not supply blood to our nerves. Damage to blood vessels also leads to kidney damage.

A recently published study found one mechanism which may explain the effects of C-peptide on blood vessels. You can read the abstract HERE:

Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-κB pathway

How important this could be is suggested by a very small controlled study where for three months human C-peptide was injected in people with Type 1 diabetes who produce no C-peptide of their own. Improvements were seen in neuropathy and kidney function in the group who received the C-peptide.

Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus

Another very similar study that lasted 6 months found a similar effect on nerves:

C-Peptide Replacement Therapy and Sensory Nerve Function in Type 1 Diabetic Neuropathy

It is important to understand that the process by which synthetic insulin is manufactured never produces C-peptide. There is a false belief floating around the internet that insulin manufacturers "throw out" the C-peptide. In fact, what they do is get genetically modified microbes to spit out copies of the final insulin molecule. Pro-insulin is never produced in the insulin manufacturing process. Pro-insulin was present in the old animal insulins but the process of purifying those animal insulins which was necessary to eliminate substances that caused serious allergic reactions in some people also eliminated the C-peptide, so you will not find C-peptide in any animal insulins sold today as they too contain only the actual insulin molecule.

The good news for those of us who are lacking C-peptide is that it appears that drug companies are working on producing synthetic C-peptide. If the initial, admittedly very small scale, research on the ability of C-peptide to prevent complications holds up, in a few years you might be able to inject synthetic C-peptide and lower your chances of developing microvascular complications.

But that said, it is very important to realize that there is just as much--if not more--research that suggests that you can also reverse and prevent microvascular complications by keeping your blood sugar within truly normal limits, and avoiding highs that go over 140 mg/dl for any significant amount of time. That level appears to be the level at which neuropathy first appears. You can read the research that shows this on this page:

Research Connecting Organ Damage with Blood Sugar Level.

One thing that makes me question whether C-peptide is a truly magical elixir is how many people with Type 2 who still produce insulin--often a lot of it--develop neuropathy and early kidney damage before they have blood sugars high enough to give them a diabetes diagnosis. Since these people are secreting proinsulin and often test with very high levels of C-peptide since they are primarily insulin resistant, not insulin deficient, one has to wonder how potent the effects of C-peptide really are. Clearly the presence of C-peptide in these people's blood streams does not prevent the microvascular complications.

Another question that rises in the minds of those of us who still can produce some insulin is whether we are suppressing our C-peptide secretion by injecting insulin and if we are, if this might make complications more rather than less likely.

The evidence, such as it is, suggests that injecting insulin early rather than late lowers the rate of microvascular complications--mostly because, as stated before, the benefits of lowering blood sugar to normal levels appear to outweigh any possibly helpful impact of C-peptide.

So if your own native--produced insulin is not able to keep your blood sugar in normal limits, any benefits you get from producing C-peptide are outweighed by the damage caused by the high blood sugars your inadequate insulin production creates. In any event, it appears that even when you inject insulin your body still produces some insulin. That is why doctors will give C-peptide tests to people with Type 2 who inject insulin and use the results to rule out Type 1 diabetes. Even when people with Type 2 diabetes are injecting large amounts of insulin, if some beta cells are still alive they will secrete detectable amounts of C-peptide.

Since there is clearly another big-selling diabetes product in the works here, if you start seeing a lot of studies promoting the value of C-peptide in the journals you should assume that some company is about to launch a blockbuster new, and of course expensive, synthetic C-peptide.

We won't know how effective it really is until we can see the results of some large trails with thousands rather than tens of subjects. My guess is that it will have some value, as does Symlin, another drug that replaces a hormone destroyed when the pancreas is the subject of immune attack. But is the case with Symlin, the value of an artificial C-peptide will be enormously enhanced if it is used in conjunction with a diet that cuts way, way down on the carbohydrates that raise blood sugar.

No magic bullet is going to prevent complications when your blood sugar is well over 200 mg/dl for hours at a time. And fortunately, we already know how to prevent that from happening. Cut back on the carbs!


Scott S said...

One of the key distinctions here is that we should consider that the source of inflammation differs in type 1 and type 2 diabetes, therefore the benefits of C-Peptide therapy may also be very different in these two distinct patient groups. Only time will tell, of course, but we do know from earlier studies that treatment of patients with proinsulin had pretty disasterous outcomes, dramatically increasing cardiovascular disease and providing less in the way of glycemic control vs. the insulin molecule itself. It would appear that should a therapy come from this research being done in Sweden, it will likely be a supplement to insulin therapy, and may mainly benefit patients with type 1 diabetes, not necessarily those with type 2, largely because the source of inflammation in both diseases are very different.

Jenny said...


If the earlier research attempted to substitute proinsulin for insulin, I can see where the results would be disastrous since it might not be possible to duplicate the situation in which the enzymes that cleave the proinsulin would kick in and do their job.

But the damage in that case might be mostly due to the poor blood sugar control. Given the very slow adoption of the understanding that high blood sugars themselves seem to be enough promote cardiovascular disease it is possible they did not factor that into their conclusions.

I see so many studies where people with very high blood sugars who get complications have the complication blamed on something like "eating fat" when the blood sugar level alone is enough to produce the complication.

Anonymous said...

This subject brings to mind a question I have, because I am going to finally have a C-peptide level test the next time I have blood drawn before my appt with the endocrinologist. My diagnosis is "prediabetes" because I run high BG numbers in response to a 3hr GTT, but I can maintain relatively low BG numbers (high normal range & 5.5% A1c) and normal weight with a LC diet and no meds.

When my insulin levels were drawn during the GTT, the thought was inadequate insulin during first phase insulin response. I had more questions about that last time with endo (but my visit was primarily about my hypothyroid condition), so he suggested the C-peptide test before next visit.

Is it a good idea to have the test drawn in a fasting condition, when supposedly the insulin level would be low, or can I do it randomly, or after a meal, etc? Or would I even want to make sure some insulin is cranking, and consume some more carbs than usual before the test?

Any thoughts?

Jenny said...


All the data about C-peptide relates to its values in the fasting state. So your doctor will not be able to interpret a non-fasting test.

The most significant thing such a test could tell you would be if the fasting level is low--which shows failing beta cells, normal, which might mean that your problem is only after meals, or high which suggests high insulin resistance of the sort that is typical in the kind of pre-diabetes that is characterized by hypoglycemia and which eventually turns into insulin resistant type 2.

Beyond that, the test is not that helpful. Call and double check with your doctor if he wants the test to be fasting. Most probably he would.

I have had both fasting and non fasting tests but the nonfasting test was only useful because of the fasting information I had--which revealed that the fasting and nonfasting levels were identical (which is not usual and points to my not secreting any extra post-meal insulin. But my kind of diabetes is pretty rare.)

Anonymous said...

Let’s consider a way to settle this debate about new insulins, old (natural) insulins, C-peptides and a good diet plan. You are correct—after 1972, when purification methodology improved, proinsulin (C-peptide) levels were essentially non-existent in any commercially available insulin. Since the advent of synthetic, artificial insulin—which mate the A and B strands, rather than complete the proinsulin molecule—the modern insulins also do not have any C-peptide.

I would like to suggest that the insulin cartel, through a cooperative research effort at many “independent” universities, track three groups of diabetics in order to discover the effect on C-peptide levels within each group. The groups would be divided into a control group (managed with lifestyle choice and best diet), 2nd group (treated with basal and bolus modern insulins), and 3rd group (prediabetic, based on current “numbers,” treated according to guidelines related to early treatment with insulin to PREVENT diabetes). [This last group has been studied by the pharmaceutical industry ONLY to promote the early use of insulin and other diabusiness products.]

All three groups would have initial C-peptide level determination. The hypothesis to be proven or disproved: Does continuous use of synthetic/artificial foreign hormones result in attack on pancreatic beta cells and subsequent loss of C-peptide production.

Until now, the insulin cartel has been allowed to suggest that C-peptide loss in Type 2’s, over time, is a direct result of the DISEASE, only. I would suggest that all three groups be maintained on identical diet/exercise protocols. Other ancillary results that might prove interesting would be the number of heart attacks, dead-in-bed victims, automobile accident victims, and other disease complication development throughout the course of the study. All of the enrolled patients would be newly diagnosed—thus precluding any former use of T2 medications. If you really want to make this kind of study interesting, a 4th group could be added, that is comprised of individuals incorporating a balanced supplement program to enhance their dietary regime.

The conclusion I would expect from a study like this is that “good diet” would come out a winner, with maintained or improved C-peptide levels. Those taking synthetic insulin, I suspect, would be the losers—over time—with C-peptide production reduced. I would also expect the death rate from ancillary causes to be rampant in the group given insulin analogs.

In your case—when you take a miniscule amount of insulin daily—you cannot appreciate the hazards related to insulin and unexpected outcomes. Someone on another site reflected that she felt insulin—because of its long history—was one of the safest drugs on the market. This sort of naiveté will kill. Insulin is the 8th most-reported drug on the adverse events list of dangerous drugs. This is astounding when you consider that it is “consumed” by only 5 percent of the population. T2’s, in many cases, are firmly set in lifestyle routines, and unexpected results can be devastating. I have had two T2 friends die in the past year from heart attacks, solely related to going “low” while the heart rate and blood pressure increased, causing death.


Anonymous said...

You say that Pro-insulin never is produced in insulin production. But is this true?

I am i student of biotechnology, and I'm pretty sure that when rekombinant insulin is produced in for example yeast or E. Coli, then you get proinsulin out of it. There isn't a way to sepperate the incorperated genes exact enough to make them produce ONLY human insulin.

So the pharmaceutical companies like Novo Nordisk and Eli Lilly do "throw out" the C-peptide, although I think they use it for studies.

The reason why Proinsulin can't be injected dirrectly is because the sepperation of C-peptide from proinsulin happens in the Golgi Apparatus, which is inside the cells (ie. the enzymes that cleave proinsulin does not flow around in our bloodstream). When we inject inslun we inject into our bloodstream and it never actually enters our cells. Thus the sepperation will never happen. But I see no problem in injekting C-peptides and human insulin together, of course not in type 2 diabetics who already have a abnormally high level of c-peptides.

Jenny said...

I am not well enough informed about the actual process to know if this is true. Since they go in and change the protein chains that are produced--which is how you get the analog insulins which have different amino acids in them than human at points, I'd imagine they could split out the whole insulin chain.

But if someone who has definitive knowledge of this would like to comment, please do.

PRIVATE said...

I cannot believe what my endo said to me today. I take Metformin and without it my blood sugar goes up and stays up, and although I'm still told that I'm "pre-diabetic", they refuse to listen to my concerns. I told her that after working out my blood sugar goes up and I get boils all over my skin and this is immediately after exercise or any stressful situation. My most recent tests showed low C-peptide and low fasting insulin. So I said that I believe my beta cells are dying and I could possibly benefit from taking some insulin at this point, she said that I need to come off of Metformin and just "let my sugars go up." She said that I need to put on weight and that I should stop checking my blood sugar so often as it's unnecessary. I could not believe what I was hearing. Then she ordered some other tests, which she said I didn't need to fast for, another c-peptide (she didn't order the first one I had done previously), and insulin and pro-insulin. My guess is the results won't tell me much as I wasn't fasting. She said I also need at least 100 grams of carbs a day and that letting my blood sugar go higher for a while won't harm me. I feel like I just landed on Mars and I'm surrounded by a bunch of Aliens....what is wrong with doctors !?!?!?!?

Unknown said...

Most of us learn about C-peptide because testing its concentration because injected insulin only contains the actual insulin molecule not C-peptide. So the only way you get C-peptide in your blood is if your beta cells are making proinsulin, which then is presumed to turn into insulin.

Really confused by this above comment Jenny, as I am on Bovine Insulin and have been for 30 years with no complications. I learnt recently that animal insulin does infact still contain C-peptide, whereas Human insulin has the C-peptide removed? so not sure your above comment is strictly true?

Jenny said...

I'm curious where you learned that there is c-peptide in the bovine insulin sold for use by people with diabetes.

It appears that testing for c-peptide levels in people with Type 1 diabetes to assess beta cell function goes back to the 1980s, a time when all injected insulin was animal insulin. (There's a study of the history of C-peptide research HERE).

Isn't the bovine insulin used today for humans purified?