Electronic letters to:

Research:
Gary T.C. Ko, Wing-Yee So, Peter C. Tong, Wing-Bun Chan, Xilin Yang, Ronald C. Ma, Alice P. Kong, Risa Ozaki, Chun-Yip Yeung, Chun-Chung Chow, and Juliana C. Chan
Effect of interactions between C peptide levels and insulin treatment on clinical outcomes among patients with type 2 diabetes mellitus
CMAJ 2009; 180: 919-926 [Abstract] [Full text] [PDF]
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[Read eLetter] Does C-peptide provide the link to prevention of complications in type 2 diabetes mellitus?
Sujoy Khan   (8 May 2009)
[Read eLetter] Without CAD Inherited Real Risk no diabetic is involved by coronary disorder.
Sergio Stagnaro   (6 May 2009)

Does C-peptide provide the link to prevention of complications in type 2 diabetes mellitus? 8 May 2009
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Sujoy Khan
Scunthorpe General Hospital, Scunthorpe, DN15 7BH, UK

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Re: Does C-peptide provide the link to prevention of complications in type 2 diabetes mellitus?

sujoykhan{at}gmail.com Sujoy Khan

Gary Ko and colleagues recent report on the increased risk of cardiovascular events with normal or raised C-peptide levels in type 2 diabetes mellitus [1], confirms previous findings that C-peptide is not merely a surrogate marker of pancreatic beta-cell reserve, but a biologically active cleavage product of the proinsulin molecule [2, 3]. There is emerging evidence that C-peptide acts via a specific G-protein coupled receptor activating the phosphatidyl-inositol-3 kinase (PI3-K) pathway that is implicated in endothelial dysfunction leading to smooth muscle cell proliferation and atherosclerosis [2, 3]. C-peptide co- localizes with macrophages and monocytes in arterial walls of diabetics [4] and promotes CD4+ T cell recruitment in early atherosclerotic lesions that induces the proliferation of vascular smooth muscle cells [5].

Plasma C-peptide levels correlate with high serum TNF-alpha levels and has been associated with progressive retinopathy and nephropathy of type 2 diabetes mellitus. Larger differentiating adipocytes release more of the pro-inflammatory cytokine TNF-alpha that can inhibit signal transmission via the insulin receptor, which provides the link between obesity and insulin resistance [6]. However, C-peptide administration was shown to protect against the cytopathic effects of TNF-alpha in renal tubular cells, by increasing TRAF2 expression (via PI3-K), a NF-kappaB- dependent survival gene that antagonizes TNF-alpha mediated apoptosis [7]. It seems obvious that C-peptide and TNF-alpha interact at multiple levels with different outcomes in different settings.

Future long-term studies will be able to establish the safety and efficacy of C- peptide in type 2 diabetes mellitus, as various interrelated mechanisms such as hyperglycemia, hyperinsulinemia, advanced glycation end products, and dyslipidemia lead to inevitable complications. Until then, clinicians will need to consider early treatment with insulin and simultaneously address cardiovascular risk factors to manage this complex disease.

Conflict of interest: None declared.

Yours sincerely, Sujoy Khan [1], Maneesh Udiawar [2]

[1] Path Links Immunology, Scunthorpe General Hospital, Scunthorpe, UK

[2] Centre for Endocrine and Diabetes Sciences, University Hospital of Wales, Cardiff, UK

References:

1. Ko GT, So WY, Tong PC, et al. Effect of interactions between C peptide levels and insulin treatment on clinical outcomes among patients with type 2 diabetes mellitus. CMAJ. 2009;180:919-26.

2. Hills CE, Brunskill NJ. Intracellular signalling by C-peptide. Exp Diabetes Res. 2008; 2008:635158.

3. Bruemmer D. C-Peptide in insulin resistance and vascular complications: teaching an old dog new tricks. Circ Res. 2006;99:1149-51.

4. Marx N, Walcher D, Raichle C, et al. C-peptide colocalizes wih macrophages in early arteriosclerotic lesions of diabetic subjects and induces monocyte chemotaxis in vitro. Arterioscler Thromb Vasc Biol 2004; 24: 540-5.

5. Walcher D, Aleksic M, Jerg V, et al. C-peptide induces chemotaxis of human CD4-positive cells: involvement of pertussis toxin-sensitive G- proteins and phosphoinositide 3-kinase. Diabetes 2004; 53: 1664-70.

6. Nieto-Vazquez I, Fernández-Veledo S, et al. Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem. 2008;114:183-94.

7. Al-Rasheed NM, Willars GB, Brunskill NJ. C-peptide signals via Galpha i to protect against TNF-alpha-mediated apoptosis of opossum kidney proximal tubular cells. J Am Soc Nephrol. 2006;17:986-95.

Conflict of Interest:

None declared
Without CAD Inherited Real Risk no diabetic is involved by coronary disorder. 6 May 2009
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Sergio Stagnaro,
!6039 Riva Trigoso (Genoa) Italy
Quantum Biophysical Semeiotics Research Laboratory

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Re: Without CAD Inherited Real Risk no diabetic is involved by coronary disorder.

dottsergio{at}semeioticabiofisica.it Sergio Stagnaro

Editors, as I illustrate in two Commentaries, now-a-days posted on www.athero.com (1-2),CAD Inherited Real Risk, characterized by newborn-pathological, type I, subtype b) aspecific Endoarteriolar Blocking Devices, coronary microvessel remodelling is based on, represents the conditio sine qua non of CAD. Neither diabetic nor non-diabetic patients can suffer from acute coronary disorders, in absence of such as inherited real risk (3-6). Notoriously, coronary inherited real risk, as well as subclinical, and consequently very dangerous, coronary heart disease is very prevalent among older individuals, independently associated with atually known risk of CAD , and substantially increases the risk (presence of newborn, pathological, type I, subtype b) aspecific, Endoarterial Blocking Devices in coronary small arteries, according to Hammersen), among individuals with hypertension or diabetes mellitus (5,6). The knowledge of such as CAD real risk, until now ignored or sometime overlooked, will pay a central role in future, efficacious primary prevention of acute heart disorder, a severe today's epidaemics.

Referenes. 1)Stagnaro Sergio. Pre-Metabolic Syndrome and Metabolic Syndrome: Biophysical-Semeiotic Viewpoint. www.athero.org, 29 April, 2009. http://www.athero.org/commentaries/comm904.asp 2)Stagnaro Sergio. CAD Inherited Real Risk, Based on Newborn-Pathological, Type I, Subtype B, Aspecific, Coronary Endoarteriolar Blocking Devices. Diagnostic Role of Myocardial Oxigenation and Biophysical-Semeiotic Preconditioning. www.athero.org, 29 April, 2009 http://www.athero.org/commentaries/comm907.asp. 3) Stagnaro-Neri M., Stagnaro S. Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of Ischaeemic Heart Disease even silent. Acta Medica Mediterranea 13, 109-116, 1997. 4) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology, 2007. http://www.fac.org.ar/qcvc/llave/c007i/stagnaros.php 5)Stagnaro Sergio. New bedside way in Reducing mortality in diabetic men and women. Ann. Int. Med.2007. http://www.annals.org/cgi/eletters/0000605- 200708070-00167v1 6) Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1; and especially in www.fce.it, Semeiotica Biofisica

Conflict of Interest:

None declared