Is Injecting C-Peptide Also Necessary?

C-peptide is naturally produced whenever the body produces insulin, so, since type 1 diabetics produce either no or very little insulin, they also don’t produce c-peptide. C-peptide was long thought to be a useless metabolic by-product of insulin, but research over the last 20 years has shown that its absence may be essential to causing diabetic complications. It would seem logical, then, that type 1 diabetics should be treated not just by injecting insulin, but also by injecting c-peptide. Unfortunately, however, there have been conflicting results about the benefits of injecting c-peptide in diabetics, but I think it is worth to resolve questions about its therapeutic value and side-effects, especially if we are developing complications not just because of hyperglycemia, but because of a lack of c-peptide.

The following article, whose edited introduction is reproduced here, discusses some of these issues:

John Wahren, et al., “The Clinical Potential of C-Peptide Replacement in Type 1 Diabetes,” Diabetes, 61 (4) 761-772 (2012):

“Several studies demonstrate that patients with type 1 diabetes who show a degree of remaining β-cell activity are considerably less prone to develop microvascular complications than those who are totally C-peptide deficient. A series of studies was undertaken involving administration of the peptide to patients with type 1 diabetes, who lack C-peptide. This approach gave positive results, and it became apparent that replacement of C-peptide in physiological concentrations resulted in significant improvements in several diabetes-induced functional abnormalities In vivo studies in animal models of type 1 diabetes have defined a beneficial influence of C-peptide on diabetes-induced functional and structural abnormalities of the kidney, peripheral nerves, and central nervous system. In addition, several studies in type 1 diabetic patients describing positive effects of C-peptide replacement therapy on nerve and kidney function have appeared The wealth of information now available supports the notion that C-peptide administration, together with regular insulin therapy, may be beneficial in the prevention and treatment of microvascular complications. The purpose of this review is to focus on C-peptide physiology and its potential role in the treatment of type 1 diabetes complications.”

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The question is if the lack of C-peptide is the cause of the complications, or just a side-affect of lack of insulin.

Like saying diabetics are more likely to have insulin syringes. Do insulin syringes cause complications?

If it works that’s great, but I haven’t seen anything convincing yet for C-pep therapy.


Yeah, the Ersatta trial failed to show the expected results so further efforts to develop the drug were discontinued in 2015, but they were just looking at its effects in nerves, so it is still unclear whether it might not work for other complications. In real patients with diabetes, the complications will either already be en route to appearing or shall have already appeared, so it might be difficult to interrupt the established processes or the existing complications, even by a treatment that would have stopped them from even starting if given sooner. Also, if hyperglycemic memory is operating in patients, it will continue to produce complications on its own regardless of what is done. Finally, it’s difficult to say how much c-peptide is required to have a therapeutic action, since it may well be higher than the normal amounts produced in the body.

I have reservations about the drug, especially since some studies have even shown harm from it, but still, I think it has a lot of potential promise, at least from the evidence of animal studies, so the good in it should be teased out from further research.

I wrote something on this topic a while ago, which I reproduce below:

C-peptide is a natural hormone involved in insulin synthesis. It has long been known that administration of c-peptide to type 1 diabetics up to the normal levels found in healthy individuals can be beneficial in ameliorating characteristic diabetic complications, yet c-peptide accomplishes this without improving glucose utilization in any significant, long-term way, and also without reducing the amount of insulin the patient has to inject. (1) This suggests that its ameliorative action operates independently of both glucose control and insulin dose. Among other positive effects, c-peptide improves the deformability of red blood cells, allowing them to pass through narrow capillaries more readily, thus improving microcirculation; and it promotes vasodilation; it improves the low nitric oxide production in the diabetic endothelium, making the blood vessels healthier; c-peptide promotes renal function. (2) Since patients who either cannot produce any insulin or are producing lower than normal amounts of insulin also necessarily produce correspondingly less c-peptide, it is possible that at least some or perhaps all of the typical complications of diabetes result from a lack of c-peptide. Since c-peptide could be replaced without changing the insulin dose or long-term glucose utilization, it could also be added to a diabetic treatment program without creating its own hypoglycemia risk.

This evidence that diabetic complications have at least two separate causes, insulin deficiency and c-peptide deficiency, with insulin only controlling the long-term glucose utilization, may explain some of the disconnect observed between diabetic complications and glucose control. For example, while patients who have survived 50 years or more with type 1 diabetes have been reported to have an HbA1c value above 10% in some studies, they often have only very mild complications. (3) Significantly, the Joslin Clinic Report on its Gold Medalist survivors (50 years disease duration and more) notes that 66% of them still have residual c-peptide production, which is undetectable in the majority of type 1 diabetics 5 years post-diagnosis or longer. (4) Since there is independent evidence that inflammation in diabetics correlates with their degree of complications, it could be that the same persisting immunological response to pancreatic beta cells which causes this inflammation also causes patients to have a lower c-peptide production from their correspondingly small number of surviving beta cells, so that what inflammation apparently causes might in fact be caused by a lack of c-peptide. (5)

A recent study has interestingly shown that even a very small amount of residual c-peptide production in a patient can have enormous benefits with respect to the development and progress of complications. Even though, in healthy individuals, the normal c-peptide level is, on average, around 0.5 nmol/L, with fasting levels at 0.42 nmol/L and glucose challenge levels at 0.6 nmol/L, this study has shown that in type 1 diabetics a c-peptide level of even just 0.04 nmol/L, a mere 8.4% of normal levels, can have dramatic benefit. (6) Even improvements to this level from extremely small to merely very small levels showed real clinical benefit to the patients, as long as they were above a lower threshold of 0.08 nmol/L. (7) Benefits included reduced risk of severe hypoglycemia, lower HbA1c values, lower risk of retinopathy, and reduced nephropathy risk. (8)

  1. J. Wahren, et al, “Role of C-Peptide in Human Physiology,” American Journal of Endocrinology and Metabolism (2000) v. 278, pp. E762, E766.
  2. Ibid., pp. E762-E765.
  3. G. Gill, et al, “Insulin Dependent Diabetes of Over 50 Years Duration,” Practical Diabetes International (2005) v. 10, n. 2, p. 60; S. Bain, et al, “Characteristics of Type 1 Diabetes of Over 50 Years Duration,” Diabetes Medicine (2003) v. 20, n. 10, p. 808; J. Sun, et al, “Protection from Retinopathy and Other Complications in Patients with Type 1 Diabetes of Extreme Duration,” Diabetes Care (2011) v. 34, n. 4, p. 968.
  4. Joslin Clinic Gold Medalists Report (online); J. Lachin, et al, “Impact of C-Peptide Preservation on Metabolic and Clinical Outcomes in the Diabetes Control and Complications Trial,” Diabetes, publication ahead of print, October 2, 2013, p. 5.
  5. W. Zhang, et al, “Inflammation and Diabetic Retinal Microvascular Complications,” Journal of Cardiovascular Disease Research (2011) v. 2, n. 2, p. 96; D. Luis-Rodriguez, et al, “Pathophysiological Role and Therapeutic Implications of Inflammation in Diabetic Nephropathy,” World Journal of Diabetes (2012) v. 3, n. 1, p. 7.
  6. J. Lachin, et al (note 4), pp. 3-4.
  7. Ibid., p. 15.
  8. Ibid., pp. 14-16.
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I would like to point out that those with diabetes for 50 years or more all used animal insulins during their early diabetic years. Animal insulins contain a whole array of hormones that are not found in the fabricated insulins of later years and today. What other hormones are produced by the pancreatic beta cells that we don’t even know about that have protective effects upon our vascular and nervous systems? Very little research is being done in that direction today. The manufacturers of insulins thought it too expensive to add c-peptide to the insulins they make. I guess it was more profitable for them to invest in gadgetry for the “control” of diabetes that is also saleable to the vast T2 market.

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It was almost certainly a mistake to ‘purify’ insulin by omitting c-peptide when they started making new insulins in the late 1970s. I remember at the time there was great excitement that these new insulins would solve a lot of diabetic problems, since they would not cause immunological reactions to it, as the old, animal-sourced insulins did. Well, it turned out, they didn’t provide any significant benefit in this regard.

In that connection, it is also interesting that diabetic complications only first started to be noticed as a major problem after the development of long-acting insulins. One theory is that in the first phase of insulin therapy, when only fast-acting insulin was available, patients had to inject themselves all day with it to maintain a semblance of normal metabolic status, so they were having repeated hypoglycemic episodes every day. These repeated hypoglycemic episodes may have interrupted the process by which complications develop. As one endocrinology professor of my acquaintance put it: “As long as you clean the house once a day, it can’t get too messy.”

We are actually trying to start a company based upon this. Cebix clinical design and product were flawed. We are pursuing a different approach for patents. Very promising but getting funding is tough…2 profs ageeed to do research for 3 studies and found a cmo to do a critical experimental piece, pending funding. Over 170 references and just started to enter the rabbit hole. hopefully more to follow…

C-peptide treatment for diabetics has been studied since the early 1990s without any clinical advances having resulted, so it is a very brave thing to try to found a company on the hope of advancing it from bench to bedside. I am concerned about the studies that have found that c-peptide can be harmful, such as that by D. Vasic and D. Walcher, “Proinflammatory Effects of C-Peptide in Different Tissues,” International Journal of Inflammation, ID 932725 (2012), which suggested it might play a role even in the development of the worst of the diabetic complications, diabetic nephropathy.

If you are looking for an expert for your team the best person to contact would be John Wahren in Sweden, who is the premier advocate for and expert in c-peptide treatment for diabetics.

Are you saying that frequent hypos were helpful in some way ? Also why do you say, newer insulins didn’t reduce insulin allergies ?

I know this is old. But I just read this.

This is a riot.

It is sad how often you do see faulty logic used in this manner. I know I studied this in some college class. I think it might have been part of some math course where you take a statement and formally prove/disprove things about the the converse, the inverse, things like that. It was like 350 years ago so hard to remember.

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Actually, I was dx’d in the 80’s, and animal insulin–porcine–was what I used for my first couple of years. Pretty sure I was switched to humulin as soon as it became available. But it doesn’t detract from your overall point.

I was present for the hype about the new insulin in the 1970s. My endocrinologist in 1976 predicted that I could use much less insulin because it would be so great with all the allergic effects removed. As it turned out, there was no improvement, except in the profits of Big Pharma, since the price went up.

My friend, who was professor of endocrinology, theorized that since complications take time to form, if their formation process is frequently interrupted by hypoglycemia episodes, they will not develop, even if the patient does spend some time in hyperglycemia. That was the source of his phrase, “It doesn’t matter how messy you are, as long as you completely clean the house once a day, it can’t get too dirty.” It is true that diabetic complications in the post-insulin era only became a great topic of concern after Hagedorn had introduced long-acting insulins, but of course, since many truths of medicine are only known as correlations, we can’t be sure that it was therapy with long-term acting insulins not producing frequent hypoglycemic episodes that caused the complications to increase or whether the problem was only first noticed at that time.

It is worth keeping in mind, though, that the harmfulness of hyperglycemia is still known only because it correlates with a higher level of complications, not because the exact mechanism by which it does so is known. So you have what philosophers of science refer to as Hume’s problem, which is that correlation is not causality, so the fact the train from Edinburgh comes into the station every day when the hand of the clock strikes four does not mean that the hand of the clock striking four is what actually causes the train to move, pulling it into the station rather than just coinciding with its arrival. Kant attempted a solution to this problem by suggesting that the concepts used to construct the continuum of our experience of the world at its most basic level were validated by this use and had some greater authority from this for re-use to explain scientific phenomena. These concepts were his famous ‘categories.’ But the problem still remains that correlation is not causality, so if we find that everyone who has hyperglycemia has more complications, that could just be due to something else that ties the two phenomena together rather than to one being the cause of the other.

Of course there was a lively debate for a long time as to whether tight control was necessary to avoid complications. You and I have both been dx’d long enough to have bridged that period. I remember the triumphal expression on my dr’s face when the DCCT study came out in 1993, showing that tight control correlated with better outcomes, and that seems to have settled it as far as the physicians are concerned. But you’re right that the exact mechanism of how hyperg. produces the observed effects isn’t known. By the same token, though, neither is the mechanism whereby cigarettes cause lung cancer. The tobacco industry was fighting on that line for a long time–maybe still is, for all I know–but the correlation was in the end too strong to ignore. Not to mention a lot of other things (not all of them diseases) that are surmised because of strong correlation when actual mechanisms can’t be determined. In pragmatic terms, the evidence suggests not smoking is a much better bet than smoking if you want to avoid lung cancer, even if some smokers never get it and some non-smokers do. I think the point of the DCCT was the same: you can take your chances, but tighter control is where the smart money is.

His examples are hardly equivalent. Long-acting insulins first became available in the 30s, when injectable insulin had only been in use for 15 years or less. It’s not surprising it wasn’t until then that complications started to be recognized.