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Cellular effects of C-peptide:FunctionCellular effects of C-peptide: C-peptide has been shown to bind to the surface of a number of cell types such as neuronal, endothelial, fibroblast and renal tubular, at nanomolar concentrations to a receptor that is likely G-protein coupled. The signal activates Ca2+ dependent intracellular signaling pathways such as MAPK, PLCγ and PKC, leading to upregulation of a range of transcription factors as well as eNOS and Na+K+ATPase activities ^[3]. The latter two enzymes are known to have reduced activities in patients with type I diabetes and have been implicated in the development of long-terms complications of type I diabetes such as peripheral and autonomic neuropathy.In vivo studies in animal models of type 1 diabetes have established that C-peptide administration results in significant improvements in nerve and kidney function. Thus, in animals with early signs of diabetes-induced neuropathy, C peptide treatment in replacement dosage results in improved peripheral nerve function, as evidenced by increased nerve conduction velocity, increased nerve Na+,K+ ATPase activity, and significant amelioration of nerve structural changes^[4]. Likewise, C-peptide administration in animals that had C-peptide deficiency (type 1 model) with nephropathy improves renal function and structure; it decreases urinary albumin excretion and prevents or decreases diabetes-induced glomerular changes secondary to mesangial matrix expansion ^[5][6][7][8]. C-peptide also has been reported to have anti-inflammatory effects as well as aid repair of smooth muscle cells^{[9] [10]}.

• Newly diagnosed diabetes patients often get their C-peptide levels measured as a means of distinguishing type 1 diabetes and type 2 diabetes. C-peptide levels are measured instead of insulin levels because insulin concentration in the portal vein ranges from two to ten times higher than in the peripheral circulation. The liver extracts about half the insulin reaching it in the plasma, but this varies with the nutritional state. The pancreas of patients with type 1 diabetes is unable to produce insulin and therefore they will usually have a decreased level of C-peptide, whereas C-peptide levels in type 2 patients are normal or higher than normal. Measuring C-peptide in patients injecting insulin can help to determine how much of their own natural insulin these patients are still producing. C-peptide is easily detected because antibodies that are sensitive to it are readily available, whereas antibodies to insulin are much more difficult to obtain.

• C-peptide is also used for determining the possibility of gastrinomas associated with Multiple Endocrine Neoplasm syndromes (MEN 1). Since a significant amount of gastrinomas also include men that include pancreatic, parathyroid, and pituitary adenomas, higher levels of C-peptide together with the presence of a gastrinoma suggest that organs besides the stomach may harbor neoplasms.
• C-peptide levels are checked in women with Polycystic Ovarian Syndrome (PCOS) to determine degree of insulin resistance.

Both excess body weight and a high plasma concentration of C-peptide predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of the disease, according to the results of a long-term survival analysis reported in the October 6, 2008 Online First issue of Lancet Oncology.

Several physiological effects have been observed in several Phase 1 and exploratory Phase 2 studies in almost 300 type 1 diabetes patients, who lacked endogenous C-peptide. Improvements were seen on diabetic peripheral neuropathy, nephropathy and other decrements associated with long-term complications of type I diabetes. ^{[11][12][13][14][15][16][17][18][19]}. Dosing with C-peptide has shown to be safe to dose to patients and there were no effects of C-peptide demonstrated in healthy subjects (who make their own C-peptide).

A company based in La Jolla, California called Cebix Incorporated has secured manufacturing and other patents in a number of countries for C-peptide, and aims to commercialize it as a therapeutic for diabetic neuropathy, retinopathy and nephropathy. The peptide is currently being formulated into a once-weekly subcutaneous use and a pivotal phase 2b study in diabetic neuropathy will be initiated late 2011.

www.cebix.com [1]