[Diabetes-talk] Interesting story about type 1 diabetes

Tue Mar 10 22:09:29 UTC 2009

Mar 09_Metabolic Triggers : Juvenile Diabetes Research Foundation International
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research frontline 
Metabolic Triggers May Contribute to the Onset of Diabetes 
Published in JDRF's Research Frontline E-Newsletter, March 2009 
      Key Point: In some children with type 1 diabetes, metabolic disturbances can be detected well before the appearance of autoantibodies, suggesting that the immune response that leads to diabetes might not be the initial cause of the disease. This unexpected finding may point to new directions in diagnosis, treatment, and prevention.

JDRF-funded researchers from Finland have discovered that children who develop type 1 diabetes have distinct metabolic abnormalities that can sometimes be seen years before the classic signs and symptoms of the disease. 

The findings, published in the Journal of Experimental Medicine, offer intriguing new insights into what causes type 1 diabetes, and may lead to novel prevention strategies. In the near-term, scientists may be able to use these findings to predict who will eventually develop the disease.

According to researcher Olli Simell from the University of Turku and colleagues, the research suggests that autoimmunity may be a relatively late response, or reaction, to these early metabolic changes. This implies, they said, that metabolic or immune system interventions might be most effective if given during the pre-autoimmune period-before the appearance of autoantibodies to insulin, the current precursor to a diagnosis of diabetes.

Marlon Pragnell, who manages JDRF's Metabolic Control Program, said the study represents an important step towards understanding and preventing metabolic changes that precede the onset of type 1 diabetes. "We do see a progression of metabolic dysregulation leading up to diagnosis, such as impaired glucose control in response to glucose tolerance testing," Dr. Pragnell explained. "So this study adds another piece to the puzzle by implicating pre-autoimmune changes. Nobody knows what causes type 1 diabetes, or how the disease unfolds. This report of metabolic changes prior to the appearance of circulating antibodies opens the intriguing possibility that metabolic triggers contribute to the onset of disease." 

To move the research forward--Dr. Simell's study is the first to report this type of metabolic dysfunction--it will be essential to validate the findings in other large and well-characterized population groups. 

A unique scientific approach 
Dr. Simell and colleagues used a "metabolomics" strategy to study the progression of type 1 diabetes-an approach that looks to tie the chemical fingerprint within cells, tissues, and body fluids to the expression of the disease. Metabolomics encompasses the complex biochemistry of energy metabolism-or how cells make and use energy. It involves numerous molecular players and energy-related compounds called metabolites. 

"Changes in the concentrations of metabolites during early development," the researchers said, "may thus reflect both genetic and environmental factors influencing later susceptibility to chronic diseases." 

To investigate the metabolomics of type 1 diabetes, they compared blood samples from 56 children who eventually developed the disease with 73 children who remained healthy and free of autoantibodies. They specifically looked for differences in the production of metabolic building blocks such as lipids (a type of fat) and amino acids (which join to form proteins). Most of the samples used in this research were obtained from the ongoing Type 1 Diabetes Prediction and Prevention Study (DIPP), a large study launched in Finland in 1994. Participants in the DIPP study all carry a genetic risk for type 1 diabetes and are monitored closely to establish the time when the immune reaction causing diabetes begins, and when the disease is actually diagnosed.

Altered lipid and amino acid profiles
Autoantibodies to insulin typically appear before someone has any of the symptoms of diabetes, and they have been a well-established marker for people likely to develop the disease.

But the children in this study who developed diabetes had unique metabolic disturbances that appeared well before the autoantibodies did. In one nine-year-old girl, for example, metabolic disturbances were at their highest levels one to two years before any autoantibodies to insulin appeared. 

Children in the study who developed diabetes consistently exhibited: 

  a.. Reduced levels of succinic acid, an energy molecule, and the lipid phosphatidylcholine, a major component of biological membranes; these differences were even evident at birth. 
  b.. As they grew, the children showed reduced levels of triglycerides and ether phospholipids, a lipid with antioxidant properties. 
  c.. Shortly before the children had detectable autoantibodies, they had two characteristic anomalies: reduced levels of ketoleucine and elevated glutamic acid (both are amino acids). In the nine-year-old girl, glutamic acid levels were 13 times higher than normal by the time she was about six months old.
None of the differences were linked to genetic risk. Moreover, after the appearance of autoantibodies, the childrens' metabolic profiles partly returned to normal.

The cause of these metabolic changes is unclear. Nor has their relationship to autoimmunity and beta cell destruction been determined. The researchers do, however, offer several intriguing possibilities.

It is conceivable, they said, that the mother's diet and intestinal microbes affect the levels of some of these molecules in newborns, causing changes in the infant's energy metabolism and immune system. Lower levels of antioxidants, they suggest, might make the beta cells susceptible to oxidative stress and free radical damage. 

Implications for type 1 research
In a commentary accompanying the published report, diabetes experts Pierre Bougneres and Alain-Jacques Valleron, who were not involved in the study, described the scientists' metabolomics approach as a pioneering example of how we might uncover the natural history of type 1 diabetes. They argue that type 1 diabetes is on the rise in very young children-the incidence has doubled in the last 20 years-but thus far specific genetic or environmental factors cannot explain this phenomenon. The appearance of autoantibodies in the first years of life in these children points to some type of early event, they said, and suggests that "emerging or rapidly evolving environmental changes may be to blame."

Clues to solving this puzzle, they explain, may lie somewhere in the child's developmental environment, at some point between the time of conception and the time of diagnosis. New "land" to explore might include epigenetics (changes in gene expression caused by environmental influences), microbiomics (the role of the microorganisms that inhabit us), metabolic events (as this study identifies), and dietary changes. New "eyes" or paths of type 1 research could include epigenetic epidemiology (the numbers behind the epigenetics), blood markers of infections, and broad concepts such as the characterization of social ties. 

"By combining several of these techniques and appropriate statistical analyses," they explained, "it may be possible to start characterizing the type 1 diabetes environmentome," a clinical map outlining how the environment in which we live may be driving the genetic risk for type 1 diabetes into a reality.

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