Identifying the mechanism behind a genetic susceptibility to type 2 diabetes

Type 2 diabetes is reaching epidemic proportions in the developed world. Determining if and how certain genes predispose individuals to type 2 diabetes is likely to lead to the development of new treatment strategies for individuals with the disease.

In a study appearing in the August issue of the Journal of Clinical Investigation Valeriya Lyssenko and colleagues from Lund University in Sweden show that certain variants of the gene TCF7L2 make individuals more susceptible to type 2 diabetes. The susceptibility variants were associated with increased expression of TCF7L2 in pancreatic islet cells and decreased islet cell secretion of insulin. Consistent with this, ectopic overexpression of TCF7L2 in human islet cells decreased insulin secretion in response to exposure to glucose. This study identifies TCF7L2 type 2 diabetes susceptibility variants and provides a mechanism by which these genetic variants might cause susceptibility to the disease. As discussed by the authors and in the accompanying commentary by Andrew Hattersley from Peninsula Medical School in the United Kingdom, future studies are likely to investigate the potential for manipulating the signaling pathways controlled by TCF7L2 for the development of new therapeutics for type 2 diabetes.

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TITLE: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes

AUTHOR CONTACT:
Valeriya Lyssenko
Lund University, University Hospital Malma, Malma, Sweden.
Phone: 46-40-391214; Fax: 46-40-391222; E-mail: Valeri.Lyssenko@med.lu.se.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30706

ACCOMPANYING COMMENTARY
TITLE: Prime suspect: the TCF7L2 gene and type 2 diabetes risk

AUTHOR CONTACT:
Andrew T. Hattersley
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.
Phone: 44-1392-406806; Fax: 44-1392-406767; E-mail: Andrew.Hattersley@pms.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33077

Contact: Karen Honey
press_releases@the-jci.org
215-573-1850
Journal of Clinical Investigation

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Huntington’s disease study shows animal models on target

This release is available in French.

An international team of researchers has published a benchmark study showing that gene expression in several animal models of Huntington’s Disease (HD) closely resembles that of human HD patients.

The results, published August 1, 2007, in the , validate the applicability of using animal models to study human disease and will have important consequences for the pertinence of these models in preclinical drug testing.

Huntington’s disease is an incurable and fatal hereditary neurodegenerative disorder caused by a mutation in the gene that encodes the huntingtin protein. Neurons in certain regions of the brain succumb to the effects of the altered protein, leading to severe motor, psychiatric, and cognitive decline. Several recent studies have shown that the mutant huntingtin protein modifies the transcriptional activity of genes in affected neurons. This disease mechanism is a promising new avenue for research into the causes of neuronal death and a novel potential approach for treatment.

Led by EPFL professor Ruth Luthi-Carter, and involving collaborators from six countries, the current study found a marked resemblance between the molecular etiology of neurons in animal models and neurons in patients with HD. This implies that animal models are relevant for studying human HD and testing potential treatments.

To come to this conclusion, the scientists measured the gene expression profile of seven different transgenic mouse models of HD, representing different conditions and disease stages. These profiles clarified the role of different forms and dosages of the protein hungtintin in the transcriptional activity of neurons. They then designed and implemented novel computational methods for quantifying similarities between RNA profiles that would allow for comparisons between the gene expression in mice and in human patients. “Interestingly, results of different testing strategies converged to show that several available models accurately recapitulate the molecular changes observed in human HD,” explains Luthi-Carter. “It underlines the suitability of these animal models for preclinical testing of drugs that affect gene transcription in Huntington’s Disease.”

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More Information:

EPFL Laboratory of functional neurogenomics, http://lngf.epfl.ch/

Alexandre Kuhn ; +41 21 693 1731
alexandre.kuhn@epfl.ch

Professor Ruth Luthi-Carter; +41 21 693 9533
ruth.luthi-carter@epfl.ch

Contact: Alexandre Kuhn
alexandre.kuhn@epfl.ch
41-216-931-731
Ecole Polytechnique Fédérale de Lausanne

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Flip of genetic switch causes cancers in mice to self-destruct, Stanford researchers find

STANFORD, Calif. – Killing cancerous tumors isn’t easy, as anyone who has suffered through chemotherapy can attest. But a new study in mice shows that switching off a single malfunctioning gene can halt the limitless division of tumor cells and turn them back to the path of their own planned obsolescence.

The surprising possibility that a cell’s own natural mechanism for ensuring its mortality could be used to vanquish tumors opens the door to a new approach to developing drugs to treat cancer patients, according to Dean Felsher, MD, PhD, associate professor of medicine (oncology) and of pathology at the Stanford University School of Medicine. Felsher is the senior author of the study to be published July 30 in the advance online version of the Proceedings of the National Academy of Sciences.

“Our research implies that by shutting off a critical cancer gene, tumor cells can realize that they are broken and restore this physiologic fail-safe program,” said Felsher.

Cancer can be notoriously resistant to medical treatment. Not only do cancer cells proliferate uncontrollably, they somehow circumvent the mechanism that causes normal cells to die when they get old or malfunction. That makes cancer cells effectively immortal unless doctors manage to squelch them.

The gene Felsher’s team studied produces a protein called Myc (pronounced “mick”), which promotes cell division. A mutation of the gene causes cells to overproduce the protein, prompting perpetual cell division and tumor growth. By turning off the mutated gene, the researchers found that not only did uncontrolled cell division cease, but the cells also reactivated a normal physiological mechanism, called senescence, which makes it possible for a cell to eventually die.

“What was unexpected was just the fact that cancer cells had retained the ability to undergo senescence at all,” said Felsher. Cancer researchers had long thought the senescence process had to be irreversibly disrupted for a tumor to develop.

The researchers worked with a series of mice engineered to have Myc-triggered cancers of either the liver, blood or bones, along with a specially constructed version of the Myc gene that they could switch off by feeding the mice antibiotics. When the mice dined on doses of the drugs, invariably, the tumors ceased growing and then diminished, with some disappearing over the course of just a few days.

Although Felsher’s lab had previously shown that mouse tumors diminished and disappeared when Myc was switched off, they hadn’t been sure how the process actually worked. Historically, most research involving genetic methods of battling cancer cells has focused on reactivating genes called tumor-suppressor genes, which are generally overcome by a proliferating cancer. No one had explored the idea that senescence might play a key role in diminishing tumors.

Felsher described senescence as acting like a fail-safe mechanism to stop cancer. When a cell detects a deleterious mutation, it launches the senescence process, resulting in the permanent loss of the cell’s ability to proliferate, thus halting any cancer.

“In order to become tumor cells, those cells have to overcome senescence,” said Chi-Hwa Wu, PhD, postdoctoral researcher in Felsher’s lab and first author of the study. Wu had the inspiration to explore whether the sudden diminishment they had observed in the tumors might be due to the reactivation of some latent remnant of the trigger for senescence.

Through a series of experiments looking at enzymes associated with the senescence process, as well as some molecular markers, Wu confirmed her suspicion. And not only was senescence occurring in cells that had been thought to be incapable of it, the process was reactivated in all the different tumors they studied.

Consider it a cell version of the Jekyll-and-Hyde transformation. “It’s sort of like Mr. Hyde realizing that there’s something wrong with him and then being able to put himself back into his normal state as Dr. Jekyll,” Felsher said.

In addition to the deepened understanding of how the process of senescence works, Felsher and Wu see a lot of potential for new approaches to treating cancer, beyond the traditional tactic of trying to kill cancer cells directly. “This work implies that maybe part of the strategy should involve figuring out how to get the cancer cells to just be allowed to do what they originally wanted to do anyway, which is to not be proliferating endlessly and growing uncontrolled,” said Felsher.

The next step for the team is to see how well the approach works in human cancer cells. “And we’re also trying to figure out what the mechanism is,” Felsher said. “What are the molecular mechanisms of this, so that we can figure out how to better treat cancer””

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Other authors on the research paper are Jan van Riggelen, PhD, postdoctoral researcher; Alper Yetil, graduate student in cancer biology; Alice Fan, MD, instructor in medicine (oncology), and medical student Pavan Bachireddy.

The study was funded by the National Cancer Institute, the National Institutes of Health, the Leukemia and Lymphoma Society, the Burroughs Wellcome Fund, the Damon Runyon Lilly Clinical Investigator Award, the Lymphoma Research Foundation and the Howard Hughes Medical Institute.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions – Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at http://mednews.stanford.edu.

Contact: Lou Bergeron
louisb3@stanford.edu
650-723-3900
Stanford University Medical Center

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New studies on goat milk show it is more beneficial to health than cow milk

-It helps to prevent diseases such as anaemia and bone demineralisation
-UGR researchers have carried out a comparative study on the properties of goat milk compared to those of cow milk. Rats with induced nutritional ferropenic anaemia have been used in the study
-Goat milk helps digestive and metabolic utilisation of minerals such as iron, calcium, phosphorus and magnesium
-Part of the results of this research have been published in the prestigious scientific journals International Dairy Journal and Journal Dairy Science

C@MPUS DIGITAL Research carried out at the Department of Physiology of the University of Granada has revealed that goat milk has more beneficial properties to health than cow milk. Among these properties it helps to prevent ferropenic anaemia (iron deficiency) and bone demineralisation (softening of the bones).

This project, conducted by Doctor Javier Díaz Castro and directed by professors Margarita Sánchez Campos, Mª Inmaculada López Aliaga and Mª José Muñoz Alférez, focuses on the comparison between the nutritional properties of goat milk and cow milk, both with normal calcium content and calcium enriched, against the bioavailability of iron, calcium, phosphorus and magnesium. To carry out this study, the metabolic balance technique has been used both in rats with experimentally induced nutritional ferropenic anaemia and in a control group of rats.

In order to know how the nutritive utilisation of these minerals may affect their metabolic distribution and destination, the UGR researcher has determined the concentration of these minerals in the different organs involved in their homeostatic regulation and different haematological parameters in relation to the metabolism of the minerals.

Better results with goat milk
Results obtained in the study reveal that ferropenic anaemia and bone demineralisation caused by this pathology have a better recovery with goat milk. Due to the higher bioavailability of iron, calcium, phosphorus and magnesium, the restoration of altered haematological parameters and the better levels of parathyroid hormone (PTH), a hormone that regulates the calcium balance in the organism was found in the rats that consumed this food.

Javier Díaz Castro points out that the inclusion of goat milk with normal or double calcium content in the diet “favours digestive and metabolic utilisation of iron, calcium and phosphorus and their deposit in target organs – parts of the organism to which these minerals are preferably sent – involved in their homeostatic regulation”.

According to this researcher, all these conclusions reveal that regular consumption of goat milk – a natural food with highly beneficial nutritional characteristics – “has positive effects on mineral metabolism, recovery from ferropenic anaemia and bone mineralisation in rats. In addition, and unlike observations in cow milk, its calcium enrichment does not interfere in the bioavailability of the minerals studied”.

Although there is no doubt that these findings may be a base for further in depth study of the multiple health benefits of goat milk, the UGR researcher warns that “studies in humans are still required in order to confirm the findings obtained in rats and to promote goat milk consumption both in the general population and in the population affected by nutritional ferropenic anaemia and pathologies related to bone demineralisation”. Part of the results of this research has been published in the prestigious scientific journals International Dairy Journal and Journal Dairy Science.

Reference: Dr Javier Díaz Castro. Department of Physiology of the University of Granada.
Tel.: +34 958248319. Mobile: +34 654574434. Email: javierdc@ugr.es

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Research links genetic mutations to lupus

WINSTON-SALEM, N.C. – A gene discovered by scientists at Wake Forest University School of Medicine has been linked to lupus and related autoimmune diseases. The finding, reported in the current issue of Nature Genetics, is the latest in a series of revelations that shed new light on what goes wrong in human cells to cause the diseases.

“This research is a huge leap toward understanding the cause of lupus and related autoimmune diseases,” said Fred Perrino, Ph.D., a co-author on the paper and a professor of biochemistry at Wake Forest. “There had been few clues before now.”

Perrino, who discovered the gene in 1998, said he suspected it was involved in human disease, but it took a group of researchers from around the world collaborating to put the puzzle together.

“We’ve known that lupus was a complex disease, but now we have a specific protein and a particular cellular process that appears to be one of the causes,” said Perrino. “We’re connecting the dots to understand the biology of what’s going on with the disease.”

In Nature Genetics, lead author Min Ae Lee-Kirsch, M.D., from the Technische Universität Dresden in Dresden, Germany, and colleagues report finding variations of the TREX1 gene discovered by Perrino in patients with systemic lupus erythematosus. The study involved 417 lupus patients from the United Kingdom and Germany. Mutations were found in nine patients with lupus and were absent in 1,712 people without lupus.

“Our data identify a stronger risk for developing lupus in patients that carry variants of the gene,” said Lee-Kirsch.

In recent years, the gene was also linked to Aicardi-Goutieres syndrome, a rare neurological disease that causes death in infants, and to chilblain lupus, an inherited disease associated with painful bluish-red skin lesions that occur during cold weather and usually improve in summer. The current research also links it to Sjogren’s syndrome, a form of lupus.

The diseases are all autoimmuine diseases, which means that the body makes antibodies against itself. In lupus, these antibodies cause pain and inflammation in various parts of the body, including the skin, joints, heart, lungs, blood, kidneys and brain. The disease is characterized by pain, heat, redness, swelling and loss of function.

Perrino began studying the protein made by the gene more than 14 years ago.

“We basically cracked open cells to locate the protein and find the gene,” said Perrino. “In the 14 years since, we’ve learned a lot about the protein and how it functions.”

The gene manufactures a protein, also known as TREX1, whose function is to “disassemble” or “unravel” DNA, the strand of genetic material that controls processes within cells. The “unraveling” occurs during the natural process of cells dying and being replaced by new cells. If a cell’s DNA isn’t degraded or unraveled during cell death, the body develops antibodies against it.

“If the TREX1 protein isn’t working to disassemble the DNA, you make antibodies to your own DNA and can end up with a disease like lupus,” said Perrino.

Perrino and colleagues at Wake Forest have been studying the gene and its protein since 1993. Thomas Hollis, Ph.D., an assistant professor of biochemistry at Wake Forest, is credited with solving the structure of both TREX1 and a similar protein, TREX2. Perrino has also developed a way to measure the function of the proteins.

In a study reported in April in the Journal of Biological Chemistry, Hollis and Perrino found that three variations of the gene reduced the activity of the protein by four- to 35,000-fold.

“Now that we have the structure, we can understand how it disassembles DNA and how mutations in the gene may affect that process,” said Hollis.

The researchers hope that understanding more about the gene’s mutations and the structure of the protein may lead to drug treatments to help ensure that mutant copies of the gene are inactive.

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Media Contacts: Karen Richardson, krchrdsn@wfubmc.edu; Shannon Koontz, shkoontz@wfubmc.edu; at 336-716-4587.

Wake Forest University Baptist Medical Center is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university’s School of Medicine. U.S. News & World Report ranks Wake Forest University School of Medicine 18th in primary care and 44th in research among the nation’s medical schools. It ranks 35th in research funding by the National Institutes of Health. Almost 150 members of the medical school faculty are listed in Best Doctors in America.

Contact: Karen Richardson
krchrdsn@wfubmc.edu
336-716-4453
Wake Forest University Baptist Medical Center

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Children and young people show elevated leukaemia rates near nuclear facilities

Review covers 136 countries in US, Canada, UK, France, Germany, Japan and Spain

Leukaemia rates in children and young people are elevated near nuclear facilities, but no clear explanation exists to explain the rise, according to a research review published in the July issue of European Journal of Cancer Care.

Researchers at the Medical University of South Carolina carried out a sophisticated meta-analysis of 17 research papers covering 136 nuclear sites in the UK, Canada, France, the USA, Germany, Japan and Spain.

They found that death rates for children up to the age of nine were elevated by between five and 24 per cent, depending on their proximity to nuclear facilities, and by two to 18 per cent in children and young people up to the age of 25.

Incidence rates were increased by 14 to 21 per cent in zero to nine year olds and seven to ten percent in zero to 25 year-olds.

“Childhood leukaemia is a rare disease and nuclear sites are commonly found in rural areas, which means that sample sizes tend to be small” says lead author Dr Peter J Baker.

“The advantage of carrying out a meta-analysis is that it enables us to draw together a number of studies that have employed common methods and draw wider conclusions.”

Eight separate analyses were performed – including unadjusted, random and fixed effect models – and the figures they produced showed considerable consistency.

But the authors point out that dose-response studies they looked at – which describe how an organism is affected by different levels of exposure – did not show excess rates near nuclear facilities.

“Several difficulties arise when conducting dose-response studies in an epidemiological setting as they rely on a wide range of factors that are often hard to quantify” explains Dr Baker. “It is also possible that there are environmental issues involved that we don’t yet understand.

“If the amount of exposure were too low to cause the excess risk, we would expect leukaemia rates to remain consistent before and after the start-up of a nuclear facility. However, our meta-analysis, consistently showed elevated illness and death rates for children and young people living near nuclear facilities.”

The research review looked at studies carried out between 1984 and 1999, focusing on research that provided statistics for individual sites on children and young people aged from zero to 25.

Four studies covered the UK, with a further three covering just Scotland. Three covered France, two looked at Canada and there was one study each from the USA, Japan, Spain, the former East Germany and the former West Germany.

“Although our meta-analysis found consistently elevated rates of leukaemia near nuclear facilities, it is important to note that there are still many questions to be answered, not least about why these rates increase” concludes Dr Baker.

“Several hypotheses have been proposed to explain the excess of childhood leukaemia in the vicinity of nuclear facilities, including environmental exposure and parental exposure. Professor Kinlen from Oxford University has also put forward a hypothesis that viral transmission, caused by mixing populations in a new rural location, could be responsible.

“It is clear that further research is needed into this important subject.”

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Notes to editors

Meta-analysis of standardized incidence and mortality rates of childhood leukaemia in proximity to nuclear facilities. Baker PJ and Hoel D. European Journal of Cancer Care. 16, pages 355-363. July 2007.

The European Journal of Cancer Care provides a medium for communicating multi-professional cancer care across Europe and internationally. The Journal publishes peer-reviewed papers, reviews, reports, features and news, and provides a means of recording lively debate and an exchange of ideas. It is published six times a year by Blackwell Publishing.
Blackwell Publishing is the world’s leading society publisher, partnering with 665 medical, academic, and professional societies. Blackwell publishes over 800 journals and has over 6,000 books in print. The company employs over 1,000 staff members in offices in the US, UK, Australia, China, Singapore, Denmark, Germany and Japan and officially merged with John Wiley & Sons, Inc’s Scientific, Technical and Medical business in February 2007. Blackwell’s mission as an expert publisher is to create long-term partnerships with our clients that enhance learning, disseminate research, and improve the quality of professional practice. For more information on Blackwell Publishing, please visit http://www.blackwellpublishing.com or http://www.blackwell-synergy.com

Contact: Annette Whibley
wizard.media@virgin.net
Blackwell Publishing Ltd.

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CMAJ – Press Release

Embargo: Monday, July 16th, 2007 at 5 pm

Poor ventilation and crowding in Nunavut homes associated with lung infections in Inuit children

Inadequate ventilation and overcrowding may contribute to the high incidence of lower respiratory tract lung infections in young Inuit children. Dr. Tom Kovesi and colleagues collected data on respiratory health and indoor air quality for 49 Inuit children under 5 years of age in the Baffin Region of Nunavut. They found that lower respiratory tract infection was significantly associated with indoor carbon dioxide levels and occupancy. On average, there were 6.1 occupants per house (as compared with 3.3–4.4 in southern Canada). Ventilation rates were below the recommended Canadian standard in 80% of the houses, with carbon dioxide levels often exceeding recommended concentrations. Elevated carbon dioxide is an indication of crowding and reduced ventilation. Smokers were present in 93% of the homes.

In a related commentary, Dr. Pamela Orr notes that the results of this research come as no surprise to those who live, work and study in the Canadian North. However, it is not clear whether crowded housing and inadequate ventilation are risk markers (reflecting an association with other risks, for example poverty) or risk factors (reflecting causation, for example exposure to infection) for lung infections in children. She notes that Kovesi’s study raises several questions, including the appropriateness of current housing designs in the North, which reflect Euro-Canadian designs for single nuclear family life rather than the extended communal family life of Inuit.

Inuit infants in the Baffin Region of Nunavut have the highest reported rate of hospital admission because of severe respiratory syncytial virus lung infection in the world, with annualized rates of up to 306 per 1000 infants. The infections are unusually severe in these infants: 12% of those admitted to hospital in Iqaluit require intubation and intensive care, necessitating costly and difficult air transport to tertiary care hospitals in southern Canada. Inuit infants also have disproportionately high rates of permanent chronic lung disease following a lower respiratory tract infection.

Contact for research: Dr. Tom Kovesi, Pediatric Respirologist, Children’s Hospital of Eastern Ontario. To arrange an interview, contact Julie Leblanc, CHEO Sr. Communications Advisor; 613 737-7600, ext. 3586, JLeblanc@cheo.on.ca

Contact for commentary: Pamela Orr, professor, Departments of Medicine, Medical Microbiology and Community Health Sciences, and consultant, J.A. Hildes Northern Medical Unit, University of Manitoba, Winnipeg, Man., is available on July 16 only; 204 787-3391 or 204 787-7772

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