It's Time to Mow the GRAS in Type 1 Diabetes

Tommy (fictitious name, but a true story) did not pick a run-of-the-mill school science fair project, such as seeing whether plants grew better with Bach versus Metallica, powering a radio with a potato, or testing the absorbency of various paper towel brands. Tommy, one of our patients with type 1 diabetes, had a different motivation. His project was designed to test whether a simple dietary modification, the addition of ground grapefruit rind, would improve postprandial glucose values. This was not a randomized controlled trial with statistical power; indeed, his mother served as the data safety monitoring board, institutional review board, and the Food and Drug Administration equivalent granting regulatory approval. Yet, even with the N 5 1, the results were eye-opening. His simple experiment demonstrated improved diabetes management. This observation some 3 years ago, combined with many other like reports over the years, has convinced us that it is time to readdress this issue of large-scale clinical testing for Generally Recognized As Safe (GRAS)-like agents in settings of type 1 diabetes. Evaluating the ability of these agents to enhance glycemic control, and/or improve antiinflammatory/antioxidant/immunomoregulatory status, could identify a safe and cost-effective approach to improving lives and perhaps attenuate disease-associated complications. GRAS-like agents refers to agents covered under the Food and Drug Administration’s GRAS and dietary supplement (i.e., the Dietary Supplement Health and Education Act) regulations and, in a few cases, other constituents such as probiotics and helminthes. This was not a new idea for us, for those in the clinical research and practice communities, or for patients with type 1 diabetes. Indeed, many GRAS-like agents have been tested in type 1 diabetic patients in situations ranging from those anecdotal in design to efforts involving controlled clinical trials. Examples include coenzyme Q10, garlic, magnesium, and chromium (rev. in 1). With a majority of studies evaluating the benefits of these practices having been (perceived or realized) as negative or neutral within the medical community as a whole, a logical question would be, “What’s changed and why would we now posit the need to revisit their potential use?” To this, we would assert that changes in the “landscape in type 1 diabetes care”— including more than a generation of far too many unfulfilled promises seeking more mainstream bio-pharmaceutical solutions, all pursued with vigor while GRAS-like agents promise was incompletely explored—now demand it. Significant large-scale efforts have taken place over the last decade in an attempt to prevent and reverse type 1 diabetes (e.g., National Institutes of Health [NIH] TrialNet, Immune Tolerance Network, European Nicotinamide Diabetes Intervention Trial) (2). While such efforts have resulted in improvements in our knowledge of the natural history of the disease (both immunological and metabolic), and there is certainly cause for optimism that one form of therapy may eventually cure the disorder, the sobering reality is that no means exists, today, to practically or with assurance reverse type 1 diabetes (3). Yet, with current research emphasis on intervening in new-onset patients, a continuing “numbers” problem exists—one that has been largely ignored but deserves attention. Nearly all studies seeking to reverse type 1 diabetes require patients to be enrolled and subject to treatment within a 3-month window from the time of diagnosis. Based on NIH SEARCH for Diabetes in Youth study data (4), approximately 18,000 individuals under age 20 years are diagnosed with type 1 diabetes in U.S. each year, meaning that at any point in time only an estimated 4,500 individuals are trial eligible. It could be considered remarkable, in a way, that so much of our clinical trial efforts to halt progression of type 1 diabetes are directed at this exclusive (and quite small) group when perhaps as many as 1.5 million individuals in the U.S. live with established disease—a population for which little cure-focused research is afforded, outside of islet and/or pancreas transplantation, which is indicated for an equally narrow population of patients. Hence, reason number one to look at GRAS-like agents again: a large portion of the clinical enterprise associated with type 1 diabetes research focuses on a small minority of subjects and not the population as a whole. Second, any such listing for rationale would fall short if we failed to highlight the “S” in GRAS: safety. Within the last decade, a growing number of therapies within the diabetes universe (albeit, nearly all used for type 2 diabetes) have either not been approved or, once granted approval, have subsequently been withdrawn from the market for safety concerns (5). Beyond this, some of the more successful immunosuppressive regimens capable of attenuating loss of C-peptide in new-onset type 1 diabetes are of questionable broad-based applicability because of issues of safety, as well as the limited ability of health care providers to respond to potential adverse events if administered in a private-practice setting. Third, many of the studies performed with GRAS-like agents have been undertaken by companies whose poststudy marketing efforts often, but not exclusively, leave the medical professional with (rightly or wrongly) questions of their validity—for reasons ranging from seemingly outlandish claims of benefits to promotion on late-night cable television ads. Safe and efficacious GRAS-like agents could be within our reach, but their potential is tainted by our understandable bias against a product pitched by infomercial. Fourth, we will soon be approaching the 20th anniversary of the results reporting for the NIH Diabetes Control From the Department of Pediatrics, University of Florida, Gainesville, Florida; and the Department of Pathology, University of Florida, Gainesville, Florida. Corresponding author: Mark A. Atkinson, [email protected]. DOI: 10.2337/db11-1158 2011 by the American Diabetes Association. 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