What are high peptides

The Importance of C-Peptide in Vascular Wall Damage - A New Hypothesis for Lesion Formation in People with Diabetes

Before the hormone insulin is released from the pancreas, it takes a complex route: First, a chain, preproinsulin, is synthesized in the beta cells, which are located in the so-called islets of Langerhans in the pancreas. One end of it is separated enzymatically and the result is proinsulin, a single-chain precursor of insulin. This is folded and linked in two places. The two-chain biologically active insulin molecule is released through renewed cleavage.

Structure of proinsulin before insulin is released
(Arrows indicate C-peptide)
Photo: Pschyrembel Dictionary Diabetology

A piece called the C-peptide remains. This cleavage product, C-peptide, is released in a ratio of 1: 1 to insulin. In patients with insulin resistance and the onset of type 2 diabetes mellitus, both high-risk populations for the development of arteriosclerotic vascular changes, C-peptide is typically found in high levels in the blood. C-peptide has long been considered a biologically inert (inactive) substance, but more recent data suggest that C-peptide binds to a surface receptor that has not yet been identified. B. can activate in tubular cells of the kidney. With regard to insulin, various experimental studies have shown that hyperinsulinemia itself has no direct effect on damage to the blood vessel walls in diabetics, but the meaning of C-peptide in this context is still largely unclear. New work investigated the importance of C-peptide in early atherogenesis, the inflammatory damage to the inner walls of the arteries. This phase of lesion formation is characterized by the so-called endothelial dysfunction present in patients with insulin resistance and diabetes. Here, the vascular cell layer lining the arteries from the inside (the endothelium) is increasingly permeable, so that plasma substances can seep into the vascular wall and be deposited there.

Due to the fact that patients with insulin resistance and type 2 diabetes have both high C-peptide levels and endothelial dysfunction, the question was first investigated whether C-peptide is deposited in these patients in early arteriosclerotic changes below the inner vessel wall cells (subendothelial). Immunohistochemical staining of early arteriosclerotic lesions in diabetics showed clear C-peptide deposits in the area of ​​the inner vessel wall. Such changes could not be found in the vessels of people without diabetes. A second crucial step in the phase of endothelial dysfunction is that monocytes and CD4-positive T cells immigrate. Interestingly, in individuals with diabetes, C-peptide occurs in early arteriosclerotic lesions along with immigrated monocytes and CD4-positive lymphocytes. Quantitative image analyzes were able to show in a study that deposited C-peptide was found in all examined diabetic individuals, whereas an immigration of monocytes and T cells was only found in some of the patients. This suggested the hypothesis that C-peptide is first deposited in the vessel wall and that the influx of inflammatory cells then follows this deposition.

Against this background, it was investigated whether C-peptide has a chemotactic effect on inflammatory cells, that is, "attracts" inflammatory cells with chemical signals and promotes their migration into the vessel wall. In vitro chemotaxis assays in were able to show that C-peptide induces the directed migration of monocytes and CD4-positive cells in a concentration-dependent manner. The extent of the effect of C-peptide on cell migration was comparable to that of already known chemotactically active agents such as in MCP1 or RANTES. Interestingly, C-peptide has no chemotactic activity on the inflammatory cell group of neutrophils, which are not found in atherosclerotic lesions. Further investigations into intracellular signaling were able to show that C-peptide in CD4-positive lymphocytes activates a special receptor via a special path and consequently structural proteins are solidified in a cascade of reactions and, on the other hand, the cells also contract.

On the basis of these data, the hypothesis was developed that C-peptide is deposited subendothelially in the context of endothelial dysfunction in insulin-resistant patients and those with early type 2 diabetes and that its chemotactic activity on monocytes and T cells could promote the immigration of these cells into the vascular wall (Illustration). Such a mechanism could help explain the extensive and diffuse pattern in which blood vessels are atherosclerotically damaged in this high-risk population. Animal experimental data must now further investigate the in vivo relevance of this hypothesis.

Legend: Hypothesis on the importance of C-peptide for early atherogenesis.

In patients with type 2 diabetes and high levels of C-peptide, C-peptide is deposited in the vessel wall due to the changed permeability of the inner vessel wall cells (subendothelial) and, through its chemotactic activity, promotes the immigration of monocytes and CD4-positive lymphocytes into the resulting lesions .

Prof. Dr. med. Nikolaus Marx, Ulm University Hospital, Internal Medicine II