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.