What does that C-peptide test result mean?

PLEASE READ THIS ARTICLE CAREFULLY BEFORE COMMENTING OR EMAILING ME QUESTIONS ABOUT YOUR C-PEPTIDE TEST! The point of this article is that the C-peptide test tells you only if you are making some amount of insulin, but not how much. It cannot be used to diagnose ANYTHING unless it is very close to 0. People keep emailing me asking me questions that could be answered by reading this post in full.

Now back to the post:
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One of the common questions I get from readers of my web site is what the result of a C-peptide test might mean and whether it can identify the kind of diabetes they have.

Unfortunately, in many cases, the answer is, that it cannot.

C-peptide is a chain of proteins that is spun off in the process by which the beta cell makes insulin. During this process, a precursor molecule, proinsulin is split into insulin and C-peptide. So for every molecule of insulin your beta cells produce, they also produce a molecule of C-peptide.

C-peptide is removed from the bloodstream by your kidneys while insulin is removed by the liver. This makes a difference in how long these peptides stay in the bloodstream. It takes half an hour until C-peptide is removed, while insulin is gone in five minutes. This means that there should be five times as much C-peptide in your blood at any given time as there is insulin and the longer activity period should smooth out the effects of testing at any one particular moment.

However, if there is something wrong with your kidneys they may not remove C-peptide in a normal manner and the result of a C-peptide test may be misleading.

If a person is injecting insulin, measuring C-peptide is the only way doctors can determine whether they are also making insulin on their own since lab tests do not distinguish between injected insulin and homemade.

Some doctors prefer to measure C-peptide even in people not injecting insulin because of its longer life in the bloodstream which means you won't see as much fluctuation from moment to moment in C-peptide levels as you may find with insulin levels.

The main thing a C-peptide test tells you is whether or not your body is making C-peptide. This sounds like a "duh" kind of statement. But in fact, that really is all that the test tells us. This can be useful in itself--if there is no C-peptide in a blood sample, your beta cells are not making any insulin. A very low C-peptide result is the definitive way to diagnose severe Type 1 diabetes--though many people with Type 1 will continue to have a low level of C-peptide in their blood for years after diagnosis as good control started soon after at Type 1 diagnosis appears to keep a small number of their beta cells alive.

To derive more meaning for the results of a C-peptide test the lab must know whether it was taken fasting or not fasting and what the blood glucose level was at the moment it was taken. In theory, a high fasting blood sugar with a high C-peptide value should point to Type 2 diabetes primarily caused by insulin resistance. That is because the high C-peptide value would suggest a lot of insulin was being produced but insulin resistance was keeping it from lowering blood sugar. In contrast, a C-peptide value that was normal or below normal taken at the same time as a high fasting glucose would suggest a form of Type 2 where failing beta cells rather than insulin resistance was the primary thing raising blood sugar.

In theory, testing C-peptide very few years should also give you some idea of whether or not your beta cells are slowly failing.

Unfortunately, it is here that things start breaking down. The problem is that there is no standardization in the way that labs measure C-peptide or in the reference ranges they provide. A recent study that sent 40 different samples out to 15 laboratories found nine different techniques being used. The study found that "Within- and between-run CVs [coefficient of variation (CV) equals the standard deviation divided by the mean (expressed as a percent).It is used to measure consistency across a range of results] ranged from <2% to >10% and from <2% to >18%,respectively."

In short, if you sent the same sample to a different lab, you could get a very different result. This study concluded this inconsistency was greatest, "...especially at higher C-peptide concentrations. Within-laboratory imprecision also varied, with some methods giving much more consistent results than others."

It is usually suggested that because of the different test protocols and reference ranges in use, you use the same lab to compare C-peptide values, when trying to determine if your C-peptide levels are dropping. But the results of the study above suggest that "within laboratory imprecision" is significant enough to make this a questionable strategy, too.

Labs may also not provide on a reference range for fasting C-peptide test results since most doctors order only fasting C-peptide tests. This can be a problem for those of us who have forms of diabetes where our beta cells are able to secrete basal insulin (the slow steady drip of insulin that keeps our blood sugar normal in the fasting state) but are unable to secrete insulin in response to the rising blood glucose that happens at meal time.

This pattern is characteristic of some forms of MODY diabetes, and explains why a person with MODY-1 or MODY-3 may have completely normal fasting C-peptide while experiencing extremely high blood sugars after meals. You can see an example of this in this MODY case history where the young patient whose genetic testing diagnoses MODY-1 has a normal C-peptide along with a 9.2% A1c.

With this in mind, here's what your C-peptide can tell you:

1. Very Low C-peptide test results.If your CC-peptide is significantly below the normal fasting range given by your lab no matter when your blood sugar was tested your beta cells are likely to be dead or dying. If you are young or very recently diagnosed with diabetes of any type, a very low C-peptide value is a good way of diagnosing Type 1 (autoimmune) rather than Type 2 diabetes.

But if you have had Type 2 for decades, and have not kept your blood sugars at normal levels, you may also have a very low C-peptide test value because over the years the very high blood sugars you have been exposed to may have killed off your insulin-producing beta cells.

Some insurers require a C-peptide test result below .5 nanograms/ml before they will cover the costs of an insulin pump.

2. High Fasting C-peptide Test Results. A high fasting C-peptide test value taken at the same time as a high fasting blood glucose test value suggests that you are insulin resistant though still making lots of insulin. (Unless you have kidney disease, in which case this test result may not reflect your actual insulin levels.)

If your fasting C-peptide level is high, it is very likely that you will be able to control your blood sugar by cutting way down on the amount of carbohydrate you eat.

It also means that you should first try strategies that lower insulin resistance before trying drugs that stimulate more insulin release, such as Amaryl, Glipizide, Januvia or Byetta.

If you have high fasting C-peptide levels, the drug Metformin, which increases insulin sensitivity, should be helpful in lowering your blood sugar. Exercise may also be very helpful as many people (though not all) find it temporarily reduces insulin resistance.

Weight loss may or may not help, depending on what is causing your insulin resistance. There are normal weight people who are very insulin resistant, but some people who are obese are able to reduce insulin resistance by losing weight--though of course, there is some circular logic here, since high levels of insulin resistance make weight loss very difficult!

3. Nonfasting C-peptide test results. If your non-fasting C-peptide test is not abnormally low (pointing to completely dead beta cells) there is no accurate way to interpret a non-fasting C-peptide test result. There are research studies where nonfasting C-peptide measurements are taken and studied, but given the nonstandarization of this test across labs and the fact that most labs do not give any lab reference range for nonfasting values, the meaning of a nonfasting C-peptide test that is normal or high (compared to a fasting reference range) is impossible to interpret.

If you have a normal C-peptide, very high post-meal blood sugars, normal or near normal weight, and a family history of thin people diagnosed with Type 2 diabetes or Type 1 diabetes that stayed relatively easy to control, you may have MODY but a C-peptide test will not be able to diagnose it.

Normal or High C-Peptide Test Results May Be Good News.

There is some recent research that suggests that C-peptide rather than being an inert byproduct of insulin synthesis is, in fact, important for preventing diabetic complications. This research is in its infancy. You can read about it in this earlier blog post.

If in fact it turns out that C-peptide is able to prevent complications, those of us who have secretory defects that respond to beta cell stimulation may have to reconsider whether or not to stimulate our beta cells with drugs like Byetta or sulfonylureas or whether to supplement with injected insulin that does not contain C-peptide.

I have been informed by correspondents diagnosed with MODY that they have been told by Dr. Hattersley who is one of the world's authorities on MODY, that he prefers to stimulate insulin secretion with gliclazide (Diamicron), a sulfonylurea drug that is unfortunately not available in the U.S., rather than use injected insulin because he believes it gives better long term results. If, in fact, C-peptide turns out to be beneficial, that might explain this finding. Unfortunately I have not been able to find any published research supporting the advantages of beta cell stimulation over insulin supplementation for people with MODY. The sulfonylurea drugs available in the U.S. often cause dramatic hunger and blood sugar swings that make them unpleasant to use and which lead to weight gain.

For people who do not have genetic secretory defects, the disadvantages of stimulating insulin secretion with drugs may be made clear by the most recent follow up to the UKPDS study, where people who used metformin to lower blood sugar had a far better long term outcome in terms of heart attack as those who used sufonylurea drugs. (Though all groups in this study had many more complications than necessary since they started out with A1cs of 7% or higher and allowed them to deteriorate over subsequent decades.) I'll be discussing this study in detail in a future blog post.

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: http://en.wikipedia.org/wiki/Proinsulin

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!