Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
Circulation Research. 2006;99:1149-1151
doi: 10.1161/01.RES.0000251785.83860.3b
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bruemmer, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bruemmer, D.
Related Collections
Right arrowRelated Article
(Circulation Research. 2006;99:1149.)
© 2006 American Heart Association, Inc.


Editorials

C-Peptide in Insulin Resistance and Vascular Complications

Teaching an Old Dog New Tricks

Dennis Bruemmer

From the Division of Endocrinology and Molecular Medicine, University of Kentucky College of Medicine, Lexington.

Correspondence to Dennis Bruemmer, MD, University of Kentucky College of Medicine, Department of Internal Medicine, Division of Endocrinology and Molecular Medicine, Wethington Health Sciences Building Room 575, 900 South Limestone Street, Lexington, KY 40536-0200. E-mail Dennis.Bruemmer{at}uky.edu



See related article, pages 1181–1187


Key Words: insulin resistance • C-peptide • smooth muscle cell • proliferation


*    Clinical Evidence Linking Insulin Resistance, Hyperinsulinemia, and Cardiovascular Disease
up arrowTop
*Clinical Evidence Linking...
down arrowInsulin Resistance and Smooth...
down arrowC-Peptide: The Old Dog...
down arrowSources of Funding
down arrowDisclosures
down arrowReferences
 
Based on the recent evidence that patients with type 2 diabetes have the same risk of myocardial infarction as nondiabetic subjects with a history of infarction, diabetes has been designated as an atherosclerosis equivalent.1 Insulin resistance plays a primary role in the development of type 2 diabetes and considerable evidence supports the association between insulin resistance, hyperinsulinemia, and vascular disease.2,3 Although the molecular mechanisms are incompletely understood, this association is supported by several large clinical studies showing a direct relationship between insulin levels and cardiovascular risk. The Paris Prospective Study4 and the Multiple Risk Factor Intervention Trial (MRFIT)5 reported positive relationships between insulin levels and atherosclerotic events. In addition, the Veterans Affairs High Density Lipoprotein Intervention Trial (VA-HIT)6 demonstrated the highest incidence of cardiovascular events in the subgroups with highest levels of insulin. Finally, the landmark Insulin Resistance Atherosclerosis Study (IRAS) provided further evidence for an inverse relationship between carotid intima-medial thickness and insulin sensitivity.7


*    Insulin Resistance and Smooth Muscle Cell Proliferation
up arrowTop
up arrowClinical Evidence Linking...
*Insulin Resistance and Smooth...
down arrowC-Peptide: The Old Dog...
down arrowSources of Funding
down arrowDisclosures
down arrowReferences
 
Controversy exists regarding the cellular mechanisms leading to atherosclerosis in insulin resistance and type 2 diabetes. Because of the observed numerical increases and functional abnormalities in intimal smooth muscle cells (SMC) in diabetes, this cell type has received intensive attention. In advanced lesions, SMC and their secreted products are a major component of the lesion comprising up to 70 to 80% of the total content of advanced human lesions.8 In particular, diabetes accelerates SMC accumulation in atherosclerotic lesions and SMC proliferation directly correlates with insulin levels.9,10 SMC proliferation is also the primary mechanism leading to the failure of procedures used to treat occlusive atherosclerotic diseases in patients with diabetes.11 Restenosis following coronary revascularization in patients with type 2 diabetes results from excessive neointima formation because of SMC proliferation.12 In addition, compensatory hyperinsulinemia associated with insulin resistance in patients with type 2 diabetes strongly predicts neointimal SMC proliferation.13

Despite more than 3 decades of intensive investigations, the detailed molecular mechanisms underlying the association between insulin resistance, SMC proliferation and accelerated atherosclerosis are still unclear. Hyperglycemia, hyperinsulinemia, advanced glycation endproducts, and dyslipidemia have each been suggested to stimulate SMC proliferation. Although hyperglycemia has been demonstrated to stimulate SMC proliferation in vitro and is thought to contribute to neointima formation, this concept has been challenged by recent reports demonstrating no mitogenic activity of high glucose.9,14 In addition, hyperglycemia in streptozotocin-induced diabetic rats is not associated with increased neointima formation.15 Instead, it is becoming increasingly evident that insulin resistance and resulting hyperinsulinemia play key roles in promoting SMC proliferation and vascular neointima formation.14,15 Insulin signaling in SMC results in phosphorylation of tyrosine residues on the insulin receptor substrates which activates downstream PI-3 kinase/Akt or ERK1/2-MAPK signaling pathways. However, insulin resistance and compensatory hyperinsulinemia result in a selective impairment of the PI 3-kinase pathway with intact signaling along the ERK1/2-MAPK pathway.3,16 Consistent with this concept, the proliferative ERK1/2-MAP kinase signaling pathway is activated in the arterial wall under insulin resistant conditions and induces the expression of c-Fos, Egr-1 and other early growth response genes that control the transition from SMC quiescence to proliferation and migration.17 Insulin alone is a rather weak mitogen and because insulin potentates the effects of other mitogens such PDGF, angiotensin II, and thrombin, increased neointima formation in insulin resistance may not be exclusively explained by hyperinsulinemia but rather by a complex interplay between several mitogens and their downstream activation of the ERK1/2-MAPK signaling pathway.


*    C-Peptide: The Old Dog With a New Trick
up arrowTop
up arrowClinical Evidence Linking...
up arrowInsulin Resistance and Smooth...
*C-Peptide: The Old Dog...
down arrowSources of Funding
down arrowDisclosures
down arrowReferences
 
In this issue of Circulation Research, Walcher and colleagues extend our current knowledge on mechanisms promoting SMC proliferation under conditions of hyperinsulinemia by adding C-peptide to the list of mitogens.18 C-peptide, the 31 amino-acid residue formed during cleavage of insulin from proinsulin, is released by the pancreatic ß cell in equimolar amounts with insulin and has long been thought to be biologically inert. Recent evidence indicates that C-peptide may not merely be an inactive by-product of insulin biosynthesis but act as hormonally active peptide.19 Early studies have suggested that C-peptide may have beneficial vascular effects by attenuating vascular and neural dysfunction in tissues of diabetic rats.20 However, recent experiments identified the presence of C-peptide specifically in atherosclerotic lesions from diabetic patients and revealed that C-peptide may also have proathergenic effects such as stimulation of monocytes and T-cell chemotaxis.21,22 In their present study, Walcher and colleagues demonstrate colocalization of C-peptide with SMC in early human atherosclerotic lesions of diabetic subjects. In vitro, stimulation of SMC with C-peptide resulted in a dose-dependent induction of cell proliferation evidenced by [3H] thymidine incorporation and nuclear KI-67 staining. These studies outline a previously unrecognized role for C-peptide to act as mitogen for SMC.

Of course, these results require further characterization of the related mechanisms by which C-peptide exerts its effect to induce SMC proliferation. Notably, C-peptide induces several signaling pathways including the ERK1/2-MAPK and PI-3 kinase pathways.23 Although C-peptide specifically binds to the plasma membrane24 and activation of these signaling pathways suggest the involvement of a G-protein-coupled receptor, a specific receptor has yet to be identified. In their studies, Walcher and coauthors demonstrate that C-peptide–induced SMC proliferation is mediated through phosphorylation of the protein tyrosine kinase Src which has been implicated as intermediate in signaling networks that couple G-protein-coupled receptors with downstream signaling cascades such as the PI-3 kinase/Akt and the Ras/MAP kinase pathway.25 Consistent with this concept, both the PI-3 kinase/Akt and the ERK1/2-MAPK are considered to be important signaling pathways regulating SMC proliferation and pharmacological inhibition of these pathways prevented C-peptide–induced SMC proliferation. As the final common pathway activated by PI-3 kinase and ERK1/2 MAPK signaling is the cell cycle, C-peptide increased cyclin D1 expression and subsequently phosphorylation of the retinoblastoma protein as the gatekeeper of G1->S phase cell cycle progression. Based on these observations, C-peptide stimulates SMC proliferation through a Src->PI-3 kinase/ERK1/2-MAPK-dependent progression of the cell cycle (Figure 1).


Figure 1
View larger version (35K):
[in this window]
[in a new window]

 
Regulation of SMC Proliferation in Insulin Resistance. The sine qua non of insulin resistance in adipose tissue, liver, and muscle is compensatory hyperinsulinemia. In the insulin resistant state, tyrosine phosphorylation of the insulin receptor and signaling via the insulin receptor substrate (IRS)-1/2/PI-3 kinase/Akt pathway is impaired resulting in diminished metabolic effects. In contrast, tyrosine phosphorylation of ERK1/2 MAPK by insulin is maintained and perpetuated by other growth factors resulting in SMC proliferation and migration. As demonstrated by Walcher et al18 C-peptide, secreted in equimolar amounts to insulin, activates both the PI-3 kinase/Akt and ERK1/2 MAPK pathways via upstream activation of the Src kinase. Activation of these pathways results in SMC proliferation through phosphorylation of the retinoblastoma protein and cell cycle progression.

In concert, these studies demonstrate the presence of C-peptide in atherosclerotic lesions from diabetic patients and it is tempting to speculate that C-peptide–induced proliferation of SMC in the setting of insulin resistance and hyperinsulinemia could provide a previously unrecognized mechanism leading to accelerated atherosclerosis and its complications in patients with type 2 diabetes. The results by Walcher et al substantially improve our understanding of the role of the previously thought to be inactive C-peptide. This study together with the mentioned evidence supporting biological activity of C-peptide may require revising the recent view of C-peptide as an inert by-product of insulin synthesis. However, they also raise many new questions and leave room for further studies. For example, is there a specific cellular C-peptide receptor or a G-protein-coupled receptor activated by C-peptide? Does C-peptide induce neointimal SMC proliferation in vivo? May C-peptide promote macrovascular disease whereas having potentially beneficial effects on blood flow and microvascular disease as suggested by other evidence?20 These questions certainly deserve further molecular studies and in particular in vivo experiments using infusion or injection of C-peptide in animal models of atherosclerosis or neointimal SMC proliferation to further exploit the contribution of C-peptide to cardiovascular disease in type 2 diabetes.


*    Sources of Funding
up arrowTop
up arrowClinical Evidence Linking...
up arrowInsulin Resistance and Smooth...
up arrowC-Peptide: The Old Dog...
*Sources of Funding
down arrowDisclosures
down arrowReferences
 
D.B. is supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (RO1 HL084611–01 to D. B.), the American Diabetes Association (Research Award 1–06-RA-17 to D.B.), and the American Heart Association (Scientist Development Grant 0435239N to D.B.).


*    Disclosures
up arrowTop
up arrowClinical Evidence Linking...
up arrowInsulin Resistance and Smooth...
up arrowC-Peptide: The Old Dog...
up arrowSources of Funding
*Disclosures
down arrowReferences
 
None.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
up arrowClinical Evidence Linking...
up arrowInsulin Resistance and Smooth...
up arrowC-Peptide: The Old Dog...
up arrowSources of Funding
up arrowDisclosures
*References
 

  1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; 339: 229–234.[Abstract/Free Full Text]
  2. Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest. 2006; 116: 1813–1822.[CrossRef][Medline] [Order article via Infotrieve]
  3. Nigro J, Osman N, Dart AM, Little PJ. Insulin resistance and atherosclerosis. Endocr Rev. 2006; 27: 242–259.[Abstract/Free Full Text]
  4. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia. 1980; 19: 205–210.[CrossRef][Medline] [Order article via Infotrieve]
  5. Orchard TJ, Eichner J, Kuller LH, Becker DJ, McCallum LM, Grandits GA. Insulin as a predictor of coronary heart disease: interaction with apolipoprotein E phenotype. A report from the Multiple Risk Factor Intervention Trial. Ann Epidemiol. 1994; 4: 40–45.[Medline] [Order article via Infotrieve]
  6. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study G. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999; 341: 410–418.[Abstract/Free Full Text]
  7. Howard G, O’Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R. Insulin sensitivity and atherosclerosis. Circulation. 1996; 93: 1809–1817.[Abstract/Free Full Text]
  8. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Jr., Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis : a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, Am Heart Association. Circulation. 1995; 92: 1355–1374.[Abstract/Free Full Text]
  9. Suzuki LA, Poot M, Gerrity RG, Bornfeldt KE. Diabetes accelerates smooth muscle accumulation in lesions of atherosclerosis: lack of direct growth-promoting effects of high glucose levels. Diabetes. 2001; 50: 851–860.[Abstract/Free Full Text]
  10. Absher PM, Schneider DJ, Baldor LC, Russell JC, Sobel BE. The retardation of vasculopathy induced by attenuation of insulin resistance in the corpulent JCR:LA-cp rat is reflected by decreased vascular smooth muscle cell proliferation in vivo. Atherosclerosis. 1999; 143: 245–251.[CrossRef][Medline] [Order article via Infotrieve]
  11. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med. 2002; 8: 1249–1256.[CrossRef][Medline] [Order article via Infotrieve]
  12. Kornowski R, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA, Hong MK, Popma JJ, Leon MB. Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia: a serial intravascular ultrasound study. Circulation. 1997; 95: 1366–1369.[Abstract/Free Full Text]
  13. Takagi T, Akasaka T, Yamamuro A, Honda Y, Hozumi T, Morioka S, Yoshida K. Impact of insulin resistance on neointimal tissue proliferation after coronary stent implantation: Intravascular ultrasound studies. J Diabetes Complications. 2002; 16: 50–55.[CrossRef][Medline] [Order article via Infotrieve]
  14. Indolfi C, Torella D, Cavuto L, Davalli AM, Coppola C, Esposito G, Carriero MV, Rapacciuolo A, Di Lorenzo E, Stabile E, Perrino C, Chieffo A, Pardo F, Chiariello M. Effects of balloon injury on neointimal hyperplasia in streptozotocin-induced diabetes and in hyperinsulinemic nondiabetic pancreatic islet-transplanted rats. Circulation. 2001; 103: 2980–2986.[Abstract/Free Full Text]
  15. Park S-H, Marso SP, Zhou Z, Foroudi F, Topol EJ, Lincoff AM. Neointimal hyperplasia after arterial injury is increased in a rat model of non-insulin-dependent diabetes mellitus. Circulation. 2001; 104: 815–819.[Abstract/Free Full Text]
  16. Wang CCL, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes. 2004; 53: 2735–2740.[Abstract/Free Full Text]
  17. Jonas M, Edelman ER, Groothuis A, Baker AB, Seifert P, Rogers C. Vascular neointimal formation and signaling pathway activation in response to stent injury in insulin-resistant and diabetic animals. Circ Res. 2005; 97: 725–733.[Abstract/Free Full Text]
  18. Walcher D, Babiak C, Poletek P, Rosenkranz S, Bach H, Betz S, Durst R, Grüb M, Hombach V, Strong J, Marx N. C-peptide induces smooth muscle cell proliferation - involvement of Src-kinase, phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2. Circ Res. 2006; 99: 1181–1187.[Abstract/Free Full Text]
  19. Johansson J, Ekberg K, Shafqat J, Henriksson M, Chibalin A, Wahren J, Jornvall H. Molecular effects of proinsulin C-peptide. Biochem and Biophys Res Commun. 2002; 295: 1035–1040.
  20. Ido Y, Vindigni A, Chang K, Stramm L, Chance R, Heath WF, DiMarchi RD, Di Cera E, Williamson JR. Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. Science. 1997; 277: 563–566.[Abstract/Free Full Text]
  21. Marx N, Walcher D, Raichle C, Aleksic M, Bach H, Grub M, Hombach V, Libby P, Zieske A, Homma S, Strong J. C-peptide colocalizes with macrophages in early arteriosclerotic lesions of diabetic subjects and induces monocyte chemotaxis in vitro. Arterioscler Thromb Vasc Biol. 2004; 24: 540–545.[Abstract/Free Full Text]
  22. Walcher D, Aleksic M, Jerg V, Hombach V, Zieske A, Homma S, Strong J, Marx N. C-peptide induces chemotaxis of human CD4-positive cells: involvement of pertussis toxin-sensitive G-proteins and phosphoinositide 3-kinase. Diabetes. 2004; 53: 1664–1670.[Abstract/Free Full Text]
  23. Kitamura T, Kimura K, Jung BD, Makondo K, Okamoto S, Canas X, Sakane N, Yoshida T, Saito M. Proinsulin C-peptide rapidly stimulates mitogen-activated protein kinases in Swiss 3T3 fibroblasts: requirement of protein kinase C, phosphoinositide 3-kinase and pertussis toxin-sensitive G-protein. Biochem J. 2001; 355: 123–129.[CrossRef][Medline] [Order article via Infotrieve]
  24. Rigler R, Pramanik A, Jonasson P, Kratz G, Jansson OT, Nygren PA, Stahl S, Ekberg K, Johansson BL, Uhlen S, Uhlen M, Jornvall H, Wahren J. Specific binding of proinsulin C-peptide to human cell membranes. Proc Natl Acad Sci U S A. 1999; 96: 13318–13323.[Abstract/Free Full Text]
  25. Schlessinger J. New roles for Src kinases in control of cell survival and angiogenesis. Cell. 2000; 100: 293–296.[CrossRef][Medline] [Order article via Infotrieve]

Related Article:

C-Peptide Induces Vascular Smooth Muscle Cell Proliferation: Involvement of Src-Kinase, Phosphatidylinositol 3-Kinase, and Extracellular Signal-Regulated Kinase 1/2
Daniel Walcher, Christina Babiak, Paulina Poletek, Stephan Rosenkranz, Helga Bach, Susanne Betz, Renate Durst, Miriam Grüb, Vinzenz Hombach, Jack Strong, and Nikolaus Marx
Circ. Res. 2006 99: 1181-1187. [Abstract] [Full Text] [PDF]




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bruemmer, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bruemmer, D.
Related Collections
Right arrowRelated Article