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Highlights in Chemical Biology

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Blood cells get active


24 July 2009

American scientists have shown that a peptide produced in the body could potentially be used to treat type 2 diabetes. 
 
C-peptide is released into the bloodstream at the same time as insulin and is often measured in diabetic patients to determine the levels of insulin that they produce. Recently, C-peptide treatment has been found to have beneficial effects for type 1 diabetes; however it doesn't affect type 2 blood cells as it cannot bind to their membranes. Now, a team led by Dana Spence at Michigan State University, East Lansing, US, has found that C-peptide can be activated with zinc to increase binding. 

Red blood cells

Peptide treatment could make diabetic blood cells healthier

Spence explains that the membranes of the diabetic red blood cells are more negatively charged than healthy ones as negative phosphatidyl serine groups flip from the inner to the outer cell membrane. 'At physiological pH, C-peptide is negatively charged as well so they're probably not going to interact very much,' he says. 'We think that the positively charged metal facilitates the interactions between peptide and the membrane.' 

"These findings pave the way for the development of novel therapeutics in the field of type 2 diabetes."
- Claus Jacob
Spence's team found that the zinc-peptide species improved type 2 blood cells' activity, which is typically lower than that of normal cells. They measured the activity by monitoring the adenosine triphosphate (ATP) released from the red blood cells as they deform on travelling through small blood vessels. The group also explored the effect of metformin, a drug often prescribed to type 2 diabetic patients, on C-peptide. They found that, when they administered zinc-activated C-peptide with metformin, the type 2 diabetic red blood cells released ATP at levels comparable to healthy ones. Diabetic red blood cells are more rigid and so normally release less ATP than normal cells.

As metformin is positively charged at physiological pH, Spence suggests the metformin neutralises the phosphatidyl serine groups on the outer cell membrane, making it less negative and more able to interact with the C-peptide.

Claus Jacob, an expert in metalloproteins and drug design, from Saarland State University, Germany, says the findings 'provide a fine explanation of the modes of action of C-peptide and metformin towards these [red blood] cells. They also pave the way for the development of novel therapeutics in the field of type 2 diabetes.'

Elizabeth Davies

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Link to journal article

Zinc-activated C-peptide resistance to the type 2 diabetic erythrocyte is associated with hyperglycemia-induced phosphatidylserine externalization and reversed by metformin
Jennifer A. Meyer, Wasanthi Subasinghe, Anders A. F. Sima, Zachary Keltner, Gavin E. Reid, David Daleke and Dana M. Spence, Mol. BioSyst., 2009, 5, 1157
DOI: 10.1039/b908241g

Also of interest

A perspective on the role of metals in diabetes: past findings and possible future directions
Jennifer A. Meyer and Dana M. Spence, Metallomics, 2009, 1, 32
DOI: 10.1039/b817203j

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