Tag: diabetes

In people with diabetes, damage to peripheral nerves and blood vessels means that wounds can initially go unnoticed, leading to infection, poor healing and, in extreme cases, the need for amputation. Globally, diabetes is one of the leading causes of lower limb amputation and foot problems are one of the most common reasons for hospitalisation of diabetic patients. One of the reasons for poor healing is that diabetic tissue fails to form new blood vessels to reconnect ischemic areas to a blood supply, and researchers at Stanford University School of Medicine and the Albert Einstein College of Medicine have been investigating the reasons for this.

They found that whereas normal fibroblasts – cells that play a critical role in wound healing – increase production of vascular endothelial growth factor (VEGF) in response to low oxygen levels, fibroblasts from diabetic patients did not increase production. They went on to grow healthy fibroblasts in either a low or high glucose environment for four weeks and then subjected the cells to low oxygen levels for 24 hours. The cells that had been growing in the high glucose environment increased VEGF production by only 20%, compared with 200% for the cells grown in the low glucose environment. Production of VEGF is triggered by hypoxia-inducible factor-1α (HIF-1α) acting in concert with the co-activator, p300, and the team further showed that HIF-1α- p300 binding was reduced by 50% in a high glucose environment. High glucose levels initiate a cascade of radical reactions leading to dysfunctional p300 and, since release of protein-bound iron is involved in this cascade, the team reasoned that treatment with an iron-chelating agent should interrupt the chain of reactions. They showed that deferoxamine was able to restore HIF-1α – p300 binding in cell culture experiments and, when they treated small wounds in diabetic mice with topical deferoxamine, the treated mice produced three times more VEGF than untreated animals and their wounds healed in 13 days compared with 23 days for the control group.

Deferoxamine is an iron chelating agent that is administered, usually intravenously, to treat acute iron poisoning, especially in small children. The researchers hope that they will soon be able to determine whether topical deferoxamine promotes healing of wounds in diabetic patients.

The report is published in the July 28^th early edition of PNAS.

During the development of type 2 diabetes, uptake of glucose from the blood by muscle and fat cells in response to insulin is reduced. The pathways involved in the insulin-stimulated uptake of glucose were believed to be similar in all mammals, but US scientists have now highlighted a key difference between mice and humans. Glucose is taken up by fat and muscle cells via the GLUT4 glucose transporter, thus removing glucose from the bloodstream. When blood glucose is low, the receptor is sequestered away from the cell surface and is released from the intracellular compartment in response to insulin stimulation when blood glucose rises. In type 2 diabetes, however, the GLUT4 compartment is abnormal and the transporter is not mobilised to the cell surface in response to insulin stimulation. The muscle isoform of clathrin heavy chain, CHC22, was found to be involved in formation of the intracellular GLUT 4 components in human muscle cells and adipocytes and was also found to be associated with the abnormal GLUT4 compartments in muscle cells from people with type 2 diabetes. Mice also have an insulin-responsive GLU4 compartment but lack the CHC22 protein – mice engineered to express CHC22 in fat and muscle tissue had defects in their GLUT4 transport pathway and showed features of diabetes, including high blood sugar and reduced responses to insulin. As well as suggesting that faulty vesicle trafficking, as well as problems with insulin signalling, may play a role in the development of type 2 diabetes, the study highlights the importance of being aware of differences between animals used in model studies and humans.

The study is published in the journal Science.

The increasing incidence of type I diabetes underlines the importance of securing affordable sources of insulin. The first insulins to be used therapeutically were extracted from the pancreases of pigs and cattle but, since the 1980s, most of the insulin used has the human sequence and is produced by genetically modified bacteria or yeasts. In December, SemBioSys Genetics Inc announced that it had begun a phase I//II clinical trial designed to demonstrate the bioequivalence of its SBS-1000 insulin and two commercially available insulins. The trial, involving up to 30 healthy volunteers and taking place in the UK, will compare both insulin concentrations and effects on blood glucose levels. SBS-1000 insulin is prepared from proinsulin produced by genetically modified safflower plants and has been shown to be physically, structurally and functionally indistinguishable from pharmaceutical-grade human insulin by analytical testing and in pre-clinical studies. The trial is the first in which insulin produced by plants has been administered to humans, and full results are expected to be available during the first half of 2009.

Some critics oppose the growing of genetically modified crops and believe that these pose a threat to livestock, wildlife and human health. If, however, the safflower-derived insulin is cheaper to purify – purification represents a significant proportion of the cost in manufacturing insulin by fermentation – the new technology could provide better access to insulin, especially for children in the developing world with type 1 diabetes.