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Morahan G.,University of Western Australia | Mehta M.,University of Western Australia | James I.,Murdoch University | Chen W.-M.,University of Virginia | And 10 more authors.
Diabetes | Year: 2011

OBJECTIVE - Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1 diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions. RESEARCH DESIGN AND METHODS - To address this issue, the Type 1 Diabetes Genetics Consortium recruited 3,892 families, including 4,422 affected sib-pairs. After genotyping 6,090 markers, linkage analyses of these families were performed, using a novel method and taking into account factors such as genotype at known susceptibility loci. RESULTS - Evidence for linkage was robust at the HLA and INS loci, with logarithm of odds (LOD) scores of 398.6 and 5.5, respectively. There was suggestive support for five other loci. Stratification by other risk factors (including HLA and age at diagnosis) identified one convincing region on chromosome 6q14 showing linkage in male subjects (corrected LOD = 4.49; replication P = 0.0002), a locus on chromosome 19q in HLA identical siblings (replication P = 0.006), and four other suggestive loci. CONCLUSIONS - This is the largest linkage study reported for any disease. Our data indicate there are no major type 1 diabetes subtypes definable by linkage analyses; susceptibility is caused by actions of HLA and an apparently random selection from a large number of modest-effect loci; and apart from HLA and INS, there is no important susceptibility factor discoverable by linkage methods. © 2011 by the American Diabetes Association.

Rhodes E.T.,Childrens Hospital Boston | Rhodes E.T.,Harvard University | Pawlak D.B.,Childrens Hospital Boston | Pawlak D.B.,Juvenile Diabetes Research Foundation | And 11 more authors.
American Journal of Clinical Nutrition | Year: 2010

Background: The optimal diet for pregnancy that is complicated by excessive weight is unknown. Objective: We aimed to examine the effects of a low-glycemic load (low-GL) diet in overweight and obese pregnant women. Design: We randomly assigned 46 overweight or obese pregnant women to receive a low-GL or a low-fat diet. Participants received carbohydrate-rich foods, fats, and snack foods through home delivery or study visits. The primary outcome was birth weight z score. Other endpoints included infant anthropometric measurements, gestational duration, maternal weight gain, and maternal metabolic parameters. Results: There were no significant differences in birth weight z score or other measures of infant adiposity between groups. However, in the low-GL compared with the low-fat group, gestational duration was longer (mean ± SD: 39.3 ± 1.1 compared with 37.9 ± 3.1 wk; P = 0.05) and fewer deliveries occurred at ≤38.0 wk (13% compared with 48%, P = 0.02; with exclusion of planned cesarean deliveries: 5% compared with 53%; P = 0.002). Adjusted head circumference was greater in the low-GL group (35.0 ± 0.8 compared with 34.2 ± 1.3 cm, P = 0.01). Women in the low-GL group had smaller increases in triglycerides [median (interquartile range): 49 (19, 70) compared with 93 (34, 129) mg/dL; P = 0.03] and total cholesterol [13 (0, 36) compared with 33 (22, 56) mg/dL, P = 0.04] and a greater decrease in C-reactive protein [-2.5 (-5.5, 20.7) compared with -0.4 (-1.4, 1.5) mg/dL, P = 0.007]. Conclusions: A low-GL diet resulted in longer pregnancy duration, greater infant head circumference, and improved maternal cardiovascular risk factors. Large-scale studies are warranted to evaluate whether dietary intervention during pregnancy aimed at lowering GL may be useful in the prevention of prematurity and other adverse maternal and infant outcomes. This trial is registered at clinicaltrials. gov as NCT00364403. © 2010 American Society for Nutrition.

Kordowich S.,Max Planck Institute for Biophysical Chemistry | Mansouri A.,Max Planck Institute for Biophysical Chemistry | Collombat P.,Max Planck Institute for Biophysical Chemistry | Collombat P.,French Institute of Health and Medical Research | Collombat P.,Juvenile Diabetes Research Foundation
Molecular and Cellular Endocrinology | Year: 2010

Due to the increasing prevalence of type 1 diabetes and the complications arising from actual therapies, alternative treatments need to be established. In order to compensate the beta-cell deficiency associated with type 1 diabetes, current research focuses on new strategies to generate insulin-producing beta-cells for transplantation purpose, including the differentiation of stem or progenitor cells, as well as the transdifferentiation of dispensable mature cell types. However, to successfully force specific cells to adopt a functional beta-cell fate or phenotype, a better understanding of the molecular mechanisms underlying beta-cell genesis is required. The present short review summarizes the hitherto known functions and interplays of several key factors involved in the development of the different endocrine cell lineages during pancreas morphogenesis, as well as their potential to direct the generation of beta-cells. Furthermore, an emphasis is made on beta-cell regeneration and the determinants implicated. © 2009 Elsevier Ireland Ltd. All rights reserved.

Cooper J.D.,University of Cambridge | Howson J.M.M.,University of Cambridge | Smyth D.,University of Cambridge | Walker N.M.,University of Cambridge | And 16 more authors.
Diabetologia | Year: 2012

Aims/hypothesis Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1Diabetes Genetics Consortium(T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. Methods We genotyped the most disease-predicting singlenucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. Results Seventeen of the 18 susceptibility loci reached nominal levels of significance (p<0.05) in the expanded family collection, with 14q24.1 just falling short (p=0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p< 2.8×10 -3). All susceptibility loci had consistent direction of effects with the original study. Conclusions/interpretation The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed. © 2012 Springer-Verlag.

News Article
Site: news.mit.edu

Biomedical devices that can be implanted in the body for drug delivery, tissue engineering, or sensing can help improve treatment for many diseases. However, such devices are often susceptible to attack by the immune system, which can render them useless. A team of MIT researchers has come up with a way to reduce that immune-system rejection. In a study appearing in the May 18 issue of Nature Materials, they found that the geometry of implantable devices has a significant impact on how well the body will tolerate them. Although the researchers expected that smaller devices might be better able to evade the immune system, they discovered that larger spherical devices are actually better able to maintain their function and avoid scar-tissue buildup. “We were surprised by how much the size and shape of an implant can affect its triggering of an immune response. What it’s made of is still an important piece of the puzzle, but it turns out if you really want to have the least amount of scar tissue you need to pick the right size and shape,” says Daniel Anderson, the Samuel A. Goldblith Associate Professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the paper’s senior author. The researchers hope to use this insight to further develop an implantable device that could mimic the function of the pancreas, potentially offering a long-term treatment for diabetes patients. It could also be applicable to devices used to treat many other diseases. “I believe the understanding achieved here will help scientists not only move forward on creating better implants to someday treat diabetes, but will also aid in the design of any type of human or animal implant to treat or diagnose disease,” says study author Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, IMES, and the Department of Chemical Engineering. Lead authors of the paper are Koch Institute postdocs Omid Veiseh and Joshua Doloff, and Minglin Ma, a former Koch Institute postdoc who is now an assistant professor at Cornell University. This study grew out of the researchers’ efforts to build an artificial pancreas, which began several years ago. The goal is to deliver pancreatic islet cells encapsulated within a particle made of alginate — a polysaccharide naturally found in algae — or another material. These implanted cells could replace patients’ pancreatic islet cells, which are nonfunctional in Type I diabetes. Just like normal islet cells, these cells would sense sugar levels in the blood and secrete the appropriate amount of insulin to absorb the sugar, eliminating the need for insulin injections. However, if scar tissue surrounds the implanted cells, they can’t do their job. “The purpose of these implantable devices is to protect the cells from the immune system, but allow them to stay alive and continue to function,” Anderson says. The researchers tested spheres in two sizes — 0.5 and 1.5 millimeters in diameter. In tests of diabetic mice, the spheres were implanted within the abdominal cavity and the researchers tracked their ability to accurately respond to changes in glucose levels. The devices prepared with the smaller spheres were completely surrounded by scar tissue and failed after about a month, while the larger ones were not rejected and continued to function for more than six months. The larger spheres also evaded the immune response in tests in nonhuman primates. Smaller spheres implanted under the skin were engulfed by scar tissue after only two weeks, while the larger ones remained clear for up to four weeks. “We observed over an order of magnitude fewer immune cells on all surfaces of larger diameter spheres,” Doloff says. “When we first got this data it was counterintuitive,” Anderson says. “There was reason to think when you have these little small beads they would elicit less of a response, but it just wasn’t the case.” This effect was seen not only with alginate, but also with spheres made of stainless steel, glass, polystyrene, and polycaprolactone, a type of polyester. “We realized that regardless of what the composition of the material is, this effect still persists, and that made it a lot more exciting because it’s a lot more generalizable,” Veiseh says. “What is impressive is that this is a very systematic study,” says Douglas Melton, chair of Harvard University’s Department of Stem Cell and Regenerative Biology, who was not involved in the research. “They compared sizes and shapes and materials in a very systematic way, so it’s very thorough. They came to a nice, simple, and interesting conclusion that one should make spheres of at least 1.5 millimeters in diameter.” The researchers believe this finding could be applicable to any other type of implantable device, including drug-delivery vehicles and sensors for glucose and insulin, which could also help improve diabetes treatment. Optimizing particle size and shape could also help guide scientists in developing other types of implantable cells for treating diseases other than diabetes. “For any of these devices that people want to make, it may be important to think carefully about the size and shape of them,” Anderson says. The research was funded by the Juvenile Diabetes Research Foundation, the Leona M. and Harry B. Helmsley Charitable Trust Foundation, the National Institutes of Health, the Koch Institute Support Grant from the National Cancer Institute, and the Tayebati Family Foundation. Veiseh was also supported by the Department of Defense.

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