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Dietary Supplements: A Framework for Evaluating Safety
cosamine to cause insulin resistance. Use of this information as a signal illustrates that animal and/or in vitro data are appropriate signals to identify concern to humans.
In addition, while not a data signal per se, the high prevalence of glucosamine use among older individuals who are likely to be at risk for type 2 diabetes suggested that if risks are associated with glucosamine and biological activities that interfere with glucose control, they could have large impact on public health as this subpopulation would be particularly vulnerable to insulin problems. Thus this information about a potentially vulnerable subpopulation should encourage the evaluation of glucosamine risk sooner than some other ingredients.
Initial Review: Considering the Nature of the Evidence
The nature of the evidence in the animal studies producing the original signal was reviewed. These studies did indeed confirm that glucosamine can lead to insulin resistance in animals and the in vitro studies supported the biological plausibility of such an effect. However, the animal studies that described this effect were experimental investigations on the basic biology of glucosamine, not traditional toxicology studies, and the high blood concentrations of glucosamine (approaching 1 mM) were deemed highly unlikely to be achieved by the amounts ingested orally by humans. The insulin effects would probably be categorized as a Category B (Table 5-1) effect. It is not clear how millimolar blood glucosamine in animals compares with human glucosamine because of significant metabolism: assuming less than 1 percent of orally ingested glucosamine reaches the bloodstream would suggest lower concern, while a 1 to 10 percent assumption would suggest moderate concern.
Additional information was sought to put the animal data’s suggestion of insulin regulation problems into context. At this stage in the process, a full literature review was not conducted, but a focused search for human data relevant to insulin resistance was completed. Data from human clinical studies did not suggest an increased risk of insulin resistance, although most of the studies examined (especially older studies) were of relatively short duration and/or did not specifically report on blood or urine glucose levels.
At this point FDA could have decided that the nature of the evidence did not indicate a need to undertake an integrative evaluation, including the development of a monograph, because the level of concern remained lower to moderate. Therefore, instead of an integrative evaluation, this dietary supplement ingredient could have been designated for monitoring of both new signal-generating information and answers to particularly relevant questions. For example, a periodic search for human data suggesting problems of insulin regulation or reporting blood glucosamine levels following