April 10, 2009

Research That's Been Ignored: C-Peptide May Cause Thickened Arteries

I was rooting around looking for studies addressing the question of whether or not high insulin levels including those caused by injecting insulin causes heart attack when I stumbled on a very interesting article published in 2007 the journal Circulation Research that raised the possibility that it is not insulin, but the C-peptide which is produced as a byproduct of natural insulin production that causes cardiovascular disease.

C-Peptide in Insulin Resistance and Vascular Complications: Teaching an Old Dog New Tricks Dennis Bruemmer. Circ Res 2006 November 24; 99(11): 1149–1151. doi: 10.1161/01.RES.0000251785.83860.3b.

This article points to several other studies including:

C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2.
Walcher D et al. Circ Res 2006;99:1181.

In this study they examined
"postmortem thoracic artery specimens ... As previously described, C-peptide deposition was detectable in the intima of all diabetic subjects included in this recent study. In addition, 8 of these 21 individuals with diabetes exhibited C-peptide deposition in the media, where C-peptide colocalized with VSMCs [vascular smooth muscle cells].
This shows that C-peptide is deposited in early vascular lesions and appears to stimulate the overgrowth that leads to clogged arteries.

The researchers then went on to examine whether C-peptide could cause smooth muscle proliferation:
To assess the effect of C-peptide on VSMC proliferation, thymidine incorporation assays were performed. Twenty-four hour stimulation of human aortic smooth muscle cells (HASMCs) with human C-peptide increased cell proliferation in a concentration-dependent manner with a maximal 2.6±0.8-fold induction at 10 nmol/L C-peptide (P<0.05 compared with unstimulated cells; n=9). The extent of C-peptide induced HASMC proliferation was similar to the effect of the well established VSMC mitogen platelet-derived growth factor (PDGF) at 10 ng/mL. Scrambled C-peptide (at 10 nmol/L), containing similar amino acids in a random order, had no such effect, underscoring the specificity of C-peptide’s mitogenic action (Figure 1A). In addition, heat-inactived C-peptide did not induce cell proliferation, thus ruling out endotoxin contamination
They found that it did and double checked that it was the C-peptide causing the proliferation not something else.

If this is true, it is is an extremely interesting finding that may answer the question that all of us have who inject insulin: are we raising our heart attack risk by using insulin to lower our blood sugar?

The reason that this is so important is that most studies which have linked insulin levels to cardiovascular risk have not distinguished between the effects of high levels of naturally secreted insulin and the effects of high levels of injected insulin. If C-peptide rather than circulating insulin is the problem, injected insulin may be much safer than high levels of naturally secreted insulin because injected insulin does not contain C-peptide.

People with Type 2 diabetes may be producing a lot of insulin because severe insulin resistance multiplies by a factor of ten how much insulin they need. For example, a young person with Type 1 who produces no insulin at all might need only 20 units a day of insulin to attain a 6% A1c while a person with Type 2 might need 200 units to achieve the same blood sugar level. I have heard from people with extreme forms of diabetes who are injecting as much as 500 units a day.

Because insulin is a growth hormone, it is a valid concern to ask whether injecting huge quantities of insulin might be promoting heart disease even as it lowers blood sugar in people with Type 2. It is the fear that this is the case that has driven the latest retreat from the idea that people with Type 2 should strive for lower A1cs.

But if it turns out that it is C-peptide causing the thickening of arteries, not insulin, things get very interesting indeed, because injected insulin contains no C-peptide.

This lack of C-peptide has become a huge issue to some members of the Type 1 community because there is other research that suggests that C-peptide might help counteract the nerve damage seen with diabetes. So some people with Type 1 diabetes have launched a campaign to demand that insulin manufacturers add C-peptide to injected insulin to make it more "natural."

But if it turns out that "natural" C-peptide is what causes clogged arteries, this might not be such a good idea.

And if that is true, it might also explain why sulfonylurea drugs that stimulate beta cells to produce even more insulin are associated with a higher risk of heart attack. It might also suggest that using drugs to sensitize Type 2s to their own very high levels of secreted insulin (with the accompanying high levels of C-peptide) might be more dangerous than using Metformin with injected insulin.

A more recent review of the research on C-peptide--available in full text and worth reading in its entirety--also cites findings that:
"C-peptide has been shown to induce pro-inflammatory mediators, such as nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2, indicating that C-peptide treatment could be associated with side-effects that may accelerate the development of diabetes-associated complications.
Proinsulin C-peptide: Friend or foe in the development of diabetes-associated complications? Lina Nordquist and M Johansson. Vasc Health Risk Manag. 2008 December; 4(6): 1283–1288.

Yet another recent discussion of the relationship of C-peptide and clogged arteries is found here:

C-Peptide and Atherogenesis: C-Peptide as a Mediator of Lesion Development in Patients with Type 2 Diabetes Mellitus? Nikolaus Marx and Daniel Walcher, Exp Diabetes Res 2008; 2008: 385108. Published online 2008 April 1. doi: 10.1155/2008/385108.

There's a lot more to the diabetes-heart disease story than C-peptide of course, including the fact that people with Type 1 diabetes who have no circulating C-peptide at all still develop heart disease after long-term exposure to high blood sugars.

And because we know of the oft-demonstrated straight line relationship between A1c and heart attack in everyone, not just people with diabetes or who are using diabetic medications, it is very likely that high glucose levels themselves, rather than insulin, may play just as important a role in producing cardiovascular disease.

But this finding about C-peptide may point to why insulin resistance is such a problem for people with Type 2 diabetes. It may also encourage you to follow strategies that not only lower blood sugar but ower the amount of insulin your body produces and along with that the amount of C-peptide that might be deposited in your arteries.

The best way to cut down on your native insulin production is to cut down on the amount of carbohydrate you eat. Metformin also has been shown to lower native insulin production without sacrificing blood sugar control, as I blogged a few days ago. This C-peptide factor may explain why Metformin has often been found to have a positive effect on cardiovascular disease.

If your insulin production is dropping and you are insulin resistant, this data suggests you might better off injecting insulin rather than using a drug like Glyburide, Amaryl, or Prandin to stimulate more native insulin--and C-peptide-- production. The explanation for why these insulin stimulating drugs appear to raise the incidence of heart attack has focused on their ability to stimulate receptors on the heart. And since newer drugs in these families don't target the heart receptor, it has been argued they are safer. But this new finding about C-peptide makes me wonder if it is the C-peptide they stimulate causing heart problems too.


Anonymous said...

great find I think you are on to something here. You mentioned the supposed safety of new generation sulfonylureas but this c peptide effect may explain all the poor data on new gen sulfs and coronary plaque increase. By the way, TZDs decrease c peptide levels better than any drugs on the market right now by their effects on peripheral insulin resistance vs insulin resistance of the liver as shown with metformin

Jenny said...

Forget the TZDs. Avandia has been definitely linked to much worse cardiac outcomes and Actos also has been found to cause congestive heart failure in younger people who did not have it before taking the drug.

To say nothing of the fact both drugs cause osteoporosis and retinal edema which can lead to blindness.

Anonymous said...

well pick your poison. Sulfs increase c peptide and destroy the pancreas, metformin is the gold standard- a great drug but fails after 3 years by itself, Dpp4i may prevent tumor suppression. Isn't it weighing the risk/benefit? As you said you have to reduce c-peptide and the only way to do it substantially is to treat insulin resistance.

Jenny said...

Metformin works very well for much longer than 3 years in people who eat carb controlled diets.

No oral drug works well if you eat a lot of carbs.

I have heard from many people with Type 2 who have made dramatic drops in their blood sugars long term eating a low carb diet with or without exercise.

Trinkwasser said...

This is fascinating stuff, the Insulin Hypothesis seems to be overtaking the Lipid Hypothesis as an explanation for cardiovascular disease and this adds an extra twist

Jenny said...


After a lot of thought, I'm thinking the problem may be that I've been using quite a bit of Prandin this month.

Prandin is much like a Sulf and I respond very strongly to it. When I went back I remembered that the first time I tried it I gained a pound in little more than a week. I'd forgotten that.

Prandin gives me hypos and then I end up with rebounds and those modify hunger. But it's also possible that the insulin stimulated by prandin is hyper efficient at storing fat. The Prescribing Info for Prandin makes it clear it does cause weight gain and I appear to be at least 3 times more sensitive to it than normal (which turns out to be typical for MODY people according to a study I just found.)

Too bad, as it was nice to take a pill when I was out and didn't want to have to contend with a shot. But not nice to gain what turned out to be 8 lbs in 6 weeks!

Anonymous said...

Hi Jenny,
I'm a big fan and an avid reader of your blog. This article really hit home with me and it struck a fearful nerve--I'll tell you why. I am, and have been, and always will be a low-carbohydrate eater--I find it keeps my weight in check (otherwise I'd gain mercilessly whilst ingesting ANY carbs) while allowing me to actually EAT.
Here's my fear, based on what I think I understand from this article--it's our own naturally secreted insulin that contains these allegedly bad c-peptides; that part I got; now, I don't use sugar, but I still haven't beaten my addiction to things sweet--like Splenda and even Truvia, for instance. I'm sure by now you know where I'm going with this--despite keeping my blood sugar in what 'they' call the 'normal' range (my last blood test showed 82, not that a standard test is really thorough--I got that notion from you, by the way...)I'm concerned that my consistent ingestion of these sugar-free substitutes in my coffee, diet sodas (you simply cannot avoid them unless you go all purist...)is indeed causing an excess of insuling secretion, and thus c-peptide overflow, and thereby I'm screwing up my arteries. Do you have any data or personal thoughts on this one?
Thanks for all your wonderful writing!

Jenny said...


I have seen no evidence that artificial sweeteners cause insulin secretion.

Nothing to worry about here.

Trinkwasser said...

Looking at the papers it seems there's a U curve or a J curve for c-peptide, much as with LDL cholesterol. That makes it very plausible that the Prandin as opposed to pure insulin is pushing the level over your tipping point. Unless of course it has an effect elsewhere in your system, like leptin.

Pity, because some MODYs respond well to sulfs. :(

ISTR a paper suggesting that for some individuals a sweet taste may induce insulin secretion, but at a much lower level than actual carbs or even protein. I wouldn't think this was anything to worry about for someone who is otherwise doing well

Jenny said...

Every person with MODY I've talked to who has tried sulfs or prandin has run into hunger and weight gain issues. Not sure why, but its a known thing. And you have to eat them with significant carbs or you hypo.

Trinkwasser said...

Interesting, I know the doses need to be very low


very likely then that the fear of insulin is placed above the fear of complications, as so often :(

Jenny said...

I was told that Dr. Hattersley believes MODY patients do better long term with sulfs rather than insulin. OTOH, since this is an English clinic, I have to wonder what kind of insulin regimens they were using and what kind of control their patients attained with insulin. They are very fond of 70/30 twice a day and recommend high carb low fat diets. So sulfs might give better blood sugars and less complications in that case, but not when insulin is being titrated to food correctly.

The girl from 132 Queen Street said...

Jenny do you have any updates on this issue.

Jenny said...

I haven't seen anything more on this. That is the case with so much diabetes-related research, especially if it isn't about a drug or device being promoted by a huge, predatory drug company.