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Type 1 diabetes develops when the body can no longer produce sufficient insulin, the hormone needed for cells to convert glucose to energy. It is called an autoimmune disease, because the body's own immune system destroys the insulin-producing cells in the pancreas. Untreated, type 1 diabetes is soon fatal. People with type 1 diabetes need to take insulin artificially, either through injection or with a device known as an insulin pump. Additional information on this condition is available from the Juvenile Diabetes Research Federation website (www.jdrf.org).

The cause of type 1 diabetes has been investigated for several decades. Strong evidence suggests that environmental factors increase the risk of diabetes in people who are genetically susceptible. If these environmental factors could be identified and eliminated, it should be possible to decrease the number of children who develop type 1 diabetes.

The history for TRIGR began with observational studies that showed that breastfeeding was associated with somewhat lower rates of children developing type 1 diabetes. These studies first appeared in the mid-1980's. At virtually the same time, basic research began focusing on the role of cow's milk proteins in diabetes in animals. The reason to focus on cow's milk was motivated by the fact that cow's milk based infant formula is the foreign intact food protein most commonly encountered first by babies. Recently, studies have focused on hydrolyzed formulas—those in which a chemical reaction was used to break down the proteins into very small protein components, too small to be recognized and targeted by the immune system. Decreased rates of type 1 diabetes development were found in all animal studies that tested weaning to hydrolyzed proteins instead of intact foreign proteins. Some evidence is now available suggesting that a similar relationship may exist in humans. It appears that the immune system in young infants with genetic diabetes risk is less mature and unable to normally handle intact foreign food proteins. This sets up a chain reaction that can lead to autoimmune destruction of insulin-producing cells.

A randomized controlled trial—the standard type of research study to determine whether a medical treatment is effective in humans—was the next step to find out whether this work will lead to protection against type 1 diabetes. These years of development and study set the stage for the multinational TRIGR trial, now well underway on three continents with 2160 eligible infants randomized to test or control formulas when mothers decide to wean from exclusive breastfeeding. The participants will be monitored up to the age of 10 years for the appearance of diabetes-predictive autoantibodies and clinical type 1 diabetes.

The TRIGR study was designed not to interfere with infant feeding practices, except to emphasize and encourage breastfeeding. All mothers who participate in TRIGR are counseled and supported to exclusively breastfeed their babies for the first six months of life in accordance with the World Health Organization 2001 recommendation based on the benefits of breastfeeding for this time period (http://www.who.int/nutrition/topics/optimal_duration_of_exc_bfeeding_review_eng.pdf). However, one problem often encountered by mothers who have type 1 diabetes themselves is that exclusive breastfeeding cannot be sustained for medical reasons.

The TRIGR trial will determine whether delayed exposure to intact food proteins will reduce the chances of developing type 1 diabetes later in life. All babies in the study received the recommendation to breastfeed for at least the first six months of life. If a mother was unable to exclusively breastfeed before the baby was 8 months of age, her child was randomly assigned to one of two groups. One group of these babies received a trial formula based on extensively hydrolyzed protein; the other group received another trial formula containing a smaller amount of hydrolyzed protein. In the hydrolyzed formula, the big protein molecules have been split into very small fragments to provide a source of nutritional amino acids, but the fragments are likely too small to stimulate the immune system.

All TRIGR families have access and continued support by a local team of pediatricians, nurses, and dieticians. Perhaps because of this support and the information provided, more mothers were able to exclusively breastfeed for significantly longer periods than expected from previous research studies, including the TRIGR pilot studies that were conducted mainly in Finland. These pilot studies developed and tested the complex infrastructure required for a very large disease prevention trial such as TRIGR. For this performance reason, the TRIGR trial will also be able to analyze whether exclusive breastfeeding per se can reduce the risk of the children to develop type 1 diabetes.

The last child was randomized to the study in February 2007. All children will be observed until the age of 10 years, so we expect to have the final results of the study available in year 2017. An independent, international board continuously monitors the trial's performance, and this board also determines if significant results appear with respect to disease or signs of impending disease. This is the largest and perhaps most ambitious primary type 1 diabetes prevention trial to date.



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