A variant within a gene family involved in the expression of type 1 diabetes may offer some protection against conditions caused by the disease, such as diabetic retinopathy, a new study suggests. The findings, which appear in the May issue of the journal Human Immunology, raise some interesting questions about whether these variants—called alleles—could be exploited to block some of the more devastating long-term complications of type 1 diabetes, which usually develops during childhood or adolescence.
“If we could find the mechanism for that protection, we might be able to block the specific effects of these alleles on the susceptible tissue before it takes effect,” says neurogeneticist David Greenberg, PhD, senior author of the new study, which was coauthored by William Stewart, PhD. Both are principal investigators in the Battelle Center for Mathematical Medicine in The Research Institute at Nationwide Children’s Hospital.
Scientists have long wondered why complications involving the body’s microvascular system, such as retinopathy, affect some people with type 1 diabetes, but not others. One explanation is an underlying genetic susceptibility to microvascular problems, a possibility Greenberg and his colleagues wanted to explore.
The team began by looking at the Human Leukocyte Antigen (HLA) gene family, an extremely diverse set of genes that helps the immune system recognize proteins made by disease-causing invaders such as viruses and bacteria. HLA genes have hundreds of variations, called alleles, some of which cause type 1 diabetes and other autoimmune diseases. The question is: Do they also affect the microvascular system? In many diabetics, this network of capillaries and tiny blood vessels becomes faulty, leading to such problems as kidney disease, nerve damage and retinopathy—the number one cause of adult blindness in the U.S.
“HLA is the single most important genetic influence on the expression of type 1 diabetes, so it made sense to ask if it was also a factor in complications,” says Greenberg, who also is a professor of pediatrics in The Ohio State University College of Medicine.
Drawing on the Human Biological Data Interchange, a national repository of DNA and cell lines collected from families with type 1 diabetes, Greenberg and his colleagues identified 425 individuals from families in which at least one person was diagnosed before the age of 30 and required insulin treatment. They then divided participants into two groups, those who had experienced at least one microvascular problem and those who had no complications, even after living with diabetes for most of their lives.
The researchers analyzed the tissues, looking for the presence of two HLA alleles in particular—DRB1*03:01 and DRB1*04:01. These alleles have been linked to an increased risk for type 1 diabetes and may also convey susceptibility to a breakdown in the microvascular system. While they found tentative evidence of a link between the expression of DRB1*04:01 and the occurrence of those complications, they found something more surprising. DRB1*03:01actually appeared to offer protection against complications.
“Our data suggest that even when *03:01 and *04:01 occur in the same person, there is a reduced risk for complications. But when *04:01 occurs with any other allele, it may promote the development of complications.” Greenberg says. “Frankly, I was expecting to find that there was no influence of HLA on complications and, if there was, that it would be a different allele. I did not expect to see a protective effect.”
It’s unclear what is causing this protective effect, Greenberg says, but that’s the subject of a study currently under way. Another question he’d like to answer is whether the DRB1*03:01 allele would offer the same protection in people with type II diabetes.
“The DRB1*03:01 in our data set was protective for all complications, but most of the people who had complications in our data set had retinopathy,” Greenberg says. “Knowing that DRB1*03:01is protective, especially for retinopathy, opens up the real possibility of developing a preventive base on how it does what it does. Now we need to find out what that is.”
Lipner EM, Tomer Y, Noble JA, Monti MC, Lonsdale JT, Corso B, Stewart WCL, Greenberg DA. HLA class I and II alleles are associated with microvascular complications of type 1 diabetes. Human Immunology. 2013 May; 74(5): 538-44. doi: 10.1016/j.humimm.2013.01.013.
Diabetic Adolescents Who Received Vitamin C During Infusion Didn’t Experience Endothelial Impairment Caused by Hyperglycemia
Not all children with Prader-Willi syndrome receive relief from sleep disorders after undergoing an adenotonsillectomy, suggests a study from Nationwide Children’s Hospital.
Patients with Prader-Willi syndrome are at risk for sleep disordered breathing as a result of their hypotonia, obesity, and/or growth hormone therapy which can cause the tonsils and adenoids to enlarge.
At Nationwide Children’s Hospital, Prader-Willi patients undergo an annual sleep study and are evaluated for potential adenotonsillectomy if obstructive apnea events are present. However, there is limited and conflicting data regarding the benefit of adenotonsillectomy in children with Prader-Willi syndrome.
To evaluate the efficacy of adenotonsillectomy in the treatment of sleep apnea in Prader-Willi syndrome, investigators at Nationwide Children’s performed a retrospective chart review. Thirteen patients met the study criteria and were categorized based on severe, moderate or mild apnea/hypopnea indexes and obstructive hypoxia.
Findings showed that the 11 patients with mild-to-moderate obstructive sleep apnea or obstructive hypoventilation improved or normalized after receiving adenotonsillectomy. But of the four children with severe obstructive sleep apnea, two normalized after surgery and two continued to have severe apneas. Unexpectedly, these patients initially had obstructive sleep apnea and after surgery a central sleep apnea was also unmasked.
These findings suggest that adenotonsillectomy is effective in most children with Prader-Willi syndrome who demonstrate mild to moderate obstructive sleep apnea, but may not be curative in children with severe forms of the condition.
Investigators stress that patients should receive a repeat sleep study six-to-eight weeks postoperatively to detect central apneas that can occur in some Prader-Willi children after upper airway surgical intervention.
These findings were presented at the Pediatric Academic Societies (PAS) annual meeting April 28 – May 1, 2012.
This study measured health literacy in a population of teens in treatment for asthma or diabetes. Finding showed that teens with lower health literacy searched online for health information as often as peers with higher literacy, but were less likely to express the intent to use recommended sites. Belief in the usefulness of a Web site is the strongest attitudinal predictor of intended future use.
Access an abstract of this study: Health Literacy and Willingness to Use Online Health Information by Teens with Asthma and Diabetes. Telemed J E Health. 2011 Sep 23. [Epub ahead of print]
Recent research from Nationwide Children’s Hospital is showing that early introduction of growth hormone (GH) therapy as early as 3-4 months of age in the Prader-Willi Syndrome (PWS) population is beneficial. Not only has it resulted in improving body composition and motor skills, but is also showing subsequent improvement in cognition and language development. It is hypothesized that infants with earlier motor development (such as sitting upright) develop improved cognitive and communicative skills due to increased stimulatory interaction with surroundings.
Both gross motor and language developmental delay are prevalent in children with PWS. Historically, early milestones in children with PWS are achieved on average of double the normal age (e.g., sitting at 12 months, walking at 24 months, and first words at 2 years) 1. Since growth hormone therapy has consistently demonstrated increased muscle tone, muscle strength, and improved body composition in patients with PWS, it can be surmised that these physical changes may precede improvements in cognitive developmental progress. Although growth hormone therapy is approved for the treatment of PWS, there are no clear guidelines at what age to initiate GH therapy in these children.
The multi-disciplinary PWS clinic at Nationwide Children’s developed a protocol for early initiation of growth hormone therapy in children with PWS. Four of the five subjects in the early intervention group had formal developmental assessment screening using the Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-3). These formal developmental assessments indicate that early initiation of GH therapy may contribute to much earlier cognitive and language development than what has been historically demonstrated in patients with PWS.
Findings showed that:
The protocol for early initiation of GH therapy has demonstrated that growth hormone can be safe and effective when initiated in early infancy. In addition, our clinic ensures these patients are receiving aggressive developmental therapies (speech, PT/OT) which presumably has contributed to such superb developmental outcomes.