Type 2 diabetes accounts for 90 % of cases of diabetes around the world, afflicting 2.5 million Canadians and costing over 15 billion dollars a year in Canada. It is a severe health condition which makes body cells incapable of taking up and using sugar. Dr. Alexey Pshezhetsky of the Sainte-Justine University Hospital Research Center, affiliated with the University of Montreal, has discovered that the resistance to insulin seen in type 2 diabetics is caused partly by the lack of a protein that has not previously been associated with diabetes. This breakthrough could potentially help to prevent diabetes.
‘We discovered that Neu1, a protein nicknamed after ‘neuraminidase 1’, turns the absorption of sugar ‘on’ or ‘off’ in body cells, by regulating the amount of sialic acid on the surface of cells’, Dr. Pshezhetsky explains.
‘We are now trying to find a way to restore Neu1 levels and function in diabetes. If we can remove sialic acid residues from the cell surface, this will force the insulin receptor do its job of absorbing blood sugar properly. This could give doctors an opportunity to reduce the use of insulin therapy, and might help to reduce the diabetes epidemic, says Dr. Pshezhetsky.

Although type 2 diabetes is initially treated with diet, exercise and tobacco avoidance, doctors try to restore normal levels of insulin by prescribing it when this fails. The number of cases diagnosed around the world continues to grow incredibly quickly: according to the United States Center Disease Control, cases in that country grew on average by 82% between 1995 and 2010. In Oklahoma, the number increased by 226%. The disease accounts for 90% of diabetes cases around the world, and its prevalence has increased in parallel with the obesity epidemic. Obesity is in fact thought to cause this disease which can in turn lead to heart disease, strokes and even limb amputation due to poor circulation. University of Montreal

Deposits of a hormone called amylin in the brain may indicate risk for developing dementia and type 2 diabetes. The analysis by researchers at the NIA-funded Alzheimer’s Disease Center at the University of California, Davis, is the first to identify amylin deposits in post-mortem brain tissue from older people who had been diagnosed with Alzheimer’s disease or vascular dementia and diabetes. The findings also indicated that amylin may play a similar role in the Alzheimer’s disease process as amyloid protein, a hallmark of the disorder. Amylin (also known as islet amyloid polypeptide) is a hormone expressed and secreted with insulin. It influences blood sugar levels; when too much is secreted, risk for developing diabetes increases. These new findings show that amylin deposits can also build up and form plaques in the brain, similar to amyloid plaques found in Alzheimer’s disease. The researchers examined post-mortem brain tissue from three groups of volunteers older than 70 years: those who had diabetes and dementia (vascular dementia or Alzheimer’s), those who had Alzheimer’s but no diabetes, and those free of these disorders. Investigators found significant amylin deposits in the brain tissue of people with both dementia and diabetes. Surprisingly, they also found amylin in people with Alzheimer’s but without diabetes—perhaps because these individuals had undiagnosed insulin resistance. The healthy controls had few amylin deposits. The study, led by Dr. Florin Despa, may explain why people with diabetes are at risk for dementia. Like amyloid, amylin circulates in the blood and, during the disease process, is overproduced and not cleared normally, building up in the brain. Over time, both proteins lead to the loss of brain cells and brain damage. Amylin buildup in the brain’s blood vessels may also play a role in amyloid buildup and contribute to risk for Alzheimer’s, the study found. National Institute on Ageing

New Northwestern Medicine research on the genetics of diabetes could one day help women know their risk for developing gestational diabetes before they become pregnant — and lead to preventive measures to protect the health of offspring.

Gestational diabetes affects 18 percent of pregnancies but usually disappears when a pregnancy is over. Babies born to women with gestational diabetes are typically larger at birth, which can lead to complications during delivery. They are at an increased risk of developing metabolic diseases, such as diabetes, in childhood and adulthood.

This is the first study to suggest differences between the underlying genetic architecture of diabetes in and outside of pregnancy.

Gestational diabetes has been associated with type 2 diabetes, because, during pregnancy, resistance to insulin increases, similar to the effect of weight gain during a lifetime in a non-pregnant state.

But researchers found variants in two genes — HKDC1 and BACE2 — that were associated with measures of glucose and insulin levels of pregnant women but not associated with these measures in the rest of the population, including people with type 2 diabetes.

‘With additional study and verification of these and other risk genes, we could one day have genetic risk profiles to identify individuals at elevated risk for developing gestational diabetes,’ said M. Geoffrey Hayes, first author of the study.

Hayes is an assistant professor of medicine-endocrinology at Northwestern University Feinberg School of Medicine and assistant professor of anthropology at Northwestern’s Weinberg College of Arts and Sciences.

The findings suggest that the roles of the gene HKDC1 in glucose metabolism and BACE2 in insulin secretion are more important during pregnancy versus the non-pregnant state — across all ethnicities studied.

Researchers used DNA and phenotype data of more than 4,000 participants of four different ancestry backgrounds (Hispanic, Thai, Afro-Caribbean and European) from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. HAPO is a multicenter, international study of pregnant women of varied geographic, ethnic and socio-demographic backgrounds.

This study’s findings could one day help pinpoint quantitative genetic traits that predict which women may develop gestational diabetes. North Western University

A large-scale, international study on the genes involved in epilepsy has uncovered 25 new mutations on nine key genes behind a devastating form of the disorder during childhood.
Among those were two genes never before associated with this form of epilepsy, one of which previously had been linked to autism and a rare neurological disorder, for which an effective therapy already has been developed.
The findings suggest a new direction for developing genome-wide diagnostic screens for new-borns to identify who is at risk for epilepsy and potentially to develop precise therapies for the condition.
The results are the first to emerge from a set of epilepsy-genetics projects known as EPGP and Epi4K, which were launched by the National Institutes of Health in 2007 and 2012, respectively, and involve more than 40 institutions on three continents. While UC San Francisco and Duke University serve as the administrative hubs, the projects involve a team of nearly 150 scientists across 25 specialities, in the hopes of generating this type of advance on the intractable disease.
‘The limitations of what we currently can do for epilepsy patients are completely overwhelming,’ said Daniel Lowenstein, MD, a UCSF neuroscientist and renowned epilepsy expert who, along with Ruben Kuzniecky, MD, from New York University, is overseeing the Epilepsy Phenome/Genome Project (EPGP). ‘More than a third of our patients are not treatable with any medication, so the idea of finding specific drug targets, instead of a drug that just bathes the brain and may cause problems with normal brain function, is very appealing.’
The global team started with the most severe forms of the disorder, known as epileptic encephalopathies (EE), which affect roughly one in 2,000 children, often before their first birthdays. Many of these children also experience other severe disabilities, including autism or cognitive dysfunction. Whether the epilepsy contributes to those, or vice versa, is being addressed in a parallel study.
‘We knew there was something happening that was unique to these kids, but we had no idea what that was,’ said Elliott Sherr, MD, PhD, a UCSF physician-scientist who is the principal investigator of the Epi4K Epileptic Encephalopathy project and who developed this group of patients within EPGP. ‘In a common disease like cystic fibrosis, you’re likely to see more than one child in a family affected. In this case, it is very rare to have more than one person in the entire family with this condition.’
That lack of clear, inherited links to the disease led them to propose that the condition was being caused by de novo, or brand new, mutations on certain genes.
They set out to test that hypothesis.
The team identified children with two classic forms of EE – infantile spasms and Lennox-Gastaut Syndrome – in which no other family member was affected. They excluded children who had identifiable causes of epilepsy, such as strokes at birth, which are a known risk for this group of disorders. Of the 4,000 patients whose genomes are being analysed in the Epi4K, 264 children fit that description.
The Epi4K sequencing team, led by David Goldstein, PhD, at Duke, ran a genetic scan on the children and their parents, which they compared to thousands of people of similar heritage without epilepsy. They used a cutting-edge new technique called exome sequencing to focus on the exome – the 2 percent of our genetic code that represents active, protein-making genes. Those 25,000 genes are considered to be the code for what makes us unique, including disease mutations.
The genetic analysis revealed 439 new mutations in the children, with 181 of the children having at least one. Nine of the genes that hosted those mutations appeared in at least two children with EE and five of those had shown up in previous, smaller EE studies. Of the four others, two may have been coincidental, the researchers found. But two new genes never before associated with EE – known scientifically as GABRB3 and ALG13 – each appeared with less than a one-in-40-billion statistical chance (p = 4.1×10-10) of being connected to EE by coincidence.
The findings implicated GABRB3, for the first time, as a single-gene cause of EE, and offered the strongest evidence to date for the gene’s role in any form of epilepsy, Sherr said. Knowing this about GABRB3, which is also involved with Angelman’s Syndrome, also offers the possibility that children with mutations only in this gene might benefit from the existing therapy for Angelman’s.
Another new gene, ALG13, is key to putting sugars on proteins, which points to a new way of thinking about the causes of and treatment for epilepsy.
‘The take-home is that a lot of these kids have genetic changes that are unique to them,’ Sherr said. ‘Most of these genes have been implicated in these or other epilepsies – others were genes that have never been seen before – but many of the kids have one of these smoking guns.’ University of California – San Francisco

Jennifer Cochran and Matthew Scott have created a bioengineered peptide that has been shown in mice to provide better imaging of a type of brain tumour known as medulloblastoma.
In a breakthrough that could have wide-ranging applications in molecular medicine, Stanford University researchers have created a bioengineered peptide that enables imaging of medulloblastomas, among the most devastating of malignant childhood brain tumours, in lab mice.
The researchers altered the amino acid sequence of a cystine knot peptide — or knottin — derived from the seeds of the squirting cucumber, a plant native to Europe, North Africa and parts of Asia. Peptides are short chains of amino acids that are integral to cellular processes; knottin peptides are notable for their stability and resistance to breakdown.
The team used their invention as a ‘molecular flashlight’ to distinguish tumours from surrounding healthy tissue. After injecting their bioengineered knottin into the bloodstreams of mice with medulloblastomas, the researchers found that the peptide stuck tightly to the tumours and could be detected using a high-sensitivity digital camera.
‘Researchers have been interested in this class of peptides for some time,’ said Jennifer Cochran, PhD, an associate professor of bioengineering and a senior author of the study. ‘They’re extremely stable. For example, you can boil some of these peptides or expose them to harsh chemicals, and they’ll remain intact.’
That makes them potentially valuable in molecular medicine. Knottins could be used to deliver drugs to specific sites in the body or, as Cochran and her colleagues have demonstrated, as a means of illuminating tumours.
For treatment purposes, it’s critical to obtain accurate images of medulloblastomas. In conjunction with chemotherapy and radiation therapy, the tumours are often treated by surgical resection, and it can be difficult to remove them while leaving healthy tissue intact because their margins are often indistinct.
‘With brain tumours, you really need to get the entire tumour and leave as much unaffected tissue as possible,’ Cochran said. ‘These tumours can come back very aggressively if not completely removed, and their location makes cognitive impairment a possibility if healthy tissue is taken.’
The researchers’ molecular flashlight works by recognising a biomarker on human tumours. The bioengineered knottin is conjugated to a near-infrared imaging dye. When injected into the bloodstreams of a strain of mice that develop tumours similar to human medullublastomas, the peptide attaches to the brain tumours’ integrin receptors — sticky molecules that aid in adhesion to other cells.
But while the knottins stuck like glue to tumours, they were rapidly expelled from healthy tissue. ‘So the mouse brain tumors are readily apparent,’ Cochran said. ‘They differentiate beautifully from the surrounding brain tissue.’
The new peptide represents a major advance in tumour-imaging technology, said Melanie Hayden Gephart, MD, neurosurgery chief resident at the Stanford Brain Tumor Center and a lead author of the paper.
‘The most common technique to identify brain tumours relies on preoperative, intravenous injection of a contrast agent, enabling most tumours to be visualised on a magnetic resonance imaging scan,’ Gephart said. These MRI scans are used like in a computer program much like an intraoperative GPS system to locate and resect the tumors.
‘But that has limitations,’ she added. ‘When you’re using the contrast in an MRI scan to define the tumour margins, you’re basically working off a preoperative snapshot. The brain can sometimes shift during an operation, so there’s always the possibility you may not be as precise or accurate as you want to be. The great potential advantage of this new approach would be to illuminate the tumour in real time — you could see it directly under your microscope instead of relying on an image that was taken before surgery.’
Though the team’s research focused on medulloblastomas, Gephart said it’s likely the new knottins could prove useful in addressing other cancers. Stanford University