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 28th early edition of PNAS.
Mast cells are best known for their role in allergic responses but a new study by researchers at Brigham and Women’s Hospital and colleagues has now shown a link with diet-induced obesity and type 2 diabetes. Writing in the July edition of Nature Medicine, they show that mast cells are far more abundant in white adipose tissue from obese humans and mice than in tissue from normal weight individuals.
In mice on a high calorie diet, treatment for two months with either of the allergy treatments, ketotifen fumarate or cromolyn, led to significant weight loss and improvement in diabetic markers compared with control animals. More dramatic improvements were seen if the animals were also switched to a reduced fat diet.
In further studies, the team showed that mice which lack mature mast cells neither became obese nor developed diabetes over a three month period, despite being fed a Western diet rich in sugars and fats. As a next step towards possible testing in humans, the researchers plan to study the effect of the compounds on obese and diabetic non-human primates.
Ketotifen fumarate and cromolyn are both used in anti-allergy eye drops, and to prevent asthma attacks. Although both stabilise mast cells, the exact mechanisms by which they achieve this are somewhat different.
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.
Type-2 diabetes is a metabolic disorder that is increasing rapidly in the developed world. The disease is caused by reduced production of insulin by the pancreas and /or reduced responsiveness to insulin by cells in the body, particularly fat, muscle and liver cells. Reduced insulin activity causes higher blood glucose levels as well as other complex metabolic changes, leading eventually to organ damage with increased morbidity and mortality.
A number of medicines are used to treat type-2 diabetes; these include metformin, sulphonyl ureas, and thiazolidinediones. More recently, inhibitors of dipeptidyl peptidase-4 (DPP-4) have emerged as an alternative method of treatment. DPP-4 inhibitors act by increasing levels of the gastrointestinal hormones, incretins, which increase the amount of insulin released by the pancreas, inhibit glucagon release and also slow gastric emptying.
New data has been presented showing that Januvia™ (sitagliptin), in combination with metformin, provided significant glucose lowering over two years. In separate studies, addition of Januvia™ to regimens based on thiazolidinediones also led to improved blood sugar control. Januvia™ was the first DPP-4 inhibitor to be approved for the treatment of diabetes in the US and Europe although several other inhibitors are in varying stages of development.
Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease, diabetes and obesity. A 39-residue synthetic peptide, Exenatide, which is approved for the treatment of type 2 diabetes, acts by mimicking the action of endogenous glucagon-like peptide-1 (GLP-1), a regulator of glucose metabolism and insulin secretion.
Researchers have now shown that chronic administration of a non-peptide molecule, Boc5, can induce weight loss and increase insulin sensitivity in a mouse model of diabetes and obesity by binding to the receptor for GLP-1. Boc5 is the only non-peptide molecule reported so far that behaves as a full GLP-1 mimetic in vitro and in vivo. Although Boc5 itself does not have the properties of a ‘drug-like’ molecule, it may represent a starting point for the discovery of orally bioavailable agents with the potential to treat metabolic disorders.
Researchers at the Salk Institute have shown that agonists of both AMP-activated protein kinase (AMPK ) and a peroxisome proliferator-activated receptor (PPAR) can mimic some of the beneficial effects of exercise in mice. In a treadmill running test, the PPAR-β/δ agonist, GW 1516 (GW 501516), acted synergistically with exercise to increase running endurance after 4 weeks. The AMPK agonist, AICAR, surprisingly enhanced running endurance even in sedentary mice, also after 4 weeks dosing. PPAR-δ and AMPK agonists have the potential to treat diseases such as diabetes, where exercise has been shown to be beneficial and to offer protection against obesity, but also have the more controversial potential to increase endurance in athletes.
Like exercise, AICAR and GW1516 trigger a variety of changes that contribute improved endurance and the ability of muscle cells to burn fat. A phase II clinical trial of GW1516 for the potential treatment of dyslipidemia has been completed.
Researchers at the University of Warwick have suggested that eating broccoli could undo the damage caused to heart blood vessels by diabetes. They found that sulforaphane, a compound found in broccoli, can prevent biochemical dysfunction induced by hyperglycemia in cultured endothelial cells. People with diabetes have a particularly high risk of heart disease and stroke, which are linked to damaged blood vessels.
Sulforaphane may also trigger production of thioredoxin, which protects against cell damage in the heart.
Studies have also linked consumption of cruciferous vegetables, such as broccoli, with decreased incidence of ischemic stroke.
It has also been reported that 3,3′-diindolylmethane and indole-3-carbinol, other compounds found in cruciferous vegetables, may have anticancer, antiviral, antibacterial and antioxidant properties.