icine, Derriford Hospital, Derriford Road, Plymouth, Devon, PL6 8DH, U.K. E-mail: terence.wilkin@phnt. ... (19,20), and a way forward has opened up. There may ...
Reviews/Commentaries/Position Statements C O M M E N T A R Y
Future Intervention Trials in Type 1 Diabetes TERRY WILKIN, MD1 JOHNNY LUDVIGSSON, MD2 CARLA GREENBAUM, MD3
JERRY PALMER, MD4 DOROTHY BECKER, MD5 JAN BRUINING, MD6
T
age, driven by some lifestyle factor, drives the immune response? A summary of intervention trials presented to the 2003 International Diabetes Federation meeting in Paris identified the principal requirements for future trials: safety (which is paramount), a viable hypothesis, and evidence that they may be expected to work. In all three respects, lifestyle intervention is arguably a prime candidate. It is safe, likely to prove effective, and underpinned by a clear hypothesis. The Accelerator Hypothesis asserts that type 1 and type 2 diabetes are one and the same disorder of insulin resistance, set against different genetic backgrounds (4). Insulin resistance, a product of modern lifestyles, accelerates the loss of -cells in both type 1 and type 2 diabetes, whereas autoimmunity— driven by -cell upregulation induced by the insulin resistance in those with a particular set of immune response (HLA) genes— accelerates the loss still further. The difference between type 1 and type 2 diabetes may mainly be one of a difference in tempo of the -cell lesion. Type 1 diabetes, the hypothesis argues, is a subset of type 2 diabetes (although some believe the converse to be true) and predictably more and more difficult to distinguish from it as the tempo of type 2 diabetes quickens and its age at presentation falls. The concepts of “type 1.5 diabetes” and “double diabetes” are conceptualizations of the same convergence in pathogenesis (5,6), and the whole area of type 1 diabe-
From the 1Department of Endocrinology and Metabolism, Peninsula Medical School, Plymouth, U.K.; the 2 Department of Pediatrics, Linkoping University, Linkoping, Sweden; the 3Department of Diabetes, Benaroya Research Institute, Seattle, Washington; the 4Department of Diabetes, VA Medical Center, Seattle, Washington; the 5Department of Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania; and the 6Department of Pediatrics, Sophia Children’s Hospital, Rotterdam, the Netherlands. Address correspondence and reprint requests to Terence J. Wilkin, MD, Department of University Medicine, Derriford Hospital, Derriford Road, Plymouth, Devon, PL6 8DH, U.K. E-mail: terence.wilkin@phnt. swest.nhs.uk. Received for publication 20 December 2003 and accepted in revised form 24 December 2003. © 2004 by the American Diabetes Association.
tes, type 2 diabetes, autoimmunity, and insulin resistance has recently been the subject of editorial critique (7). The Accelerator Hypothesis has already faced its first tests of viability in both animals and humans. In the BB rat, the incidence of type 1 diabetes falls when food intake is limited rather than available ad libitum (8). In humans, the members of two sizeable and independent cohorts with childhood type 1 diabetes were not only heavier than their peers, and by implication more insulin resistant, but crucially, their age at presentation was inversely related to their body mass— true acceleration (9,10). Lifestyle intervention to lower insulin resistance has already been shown to reduce progression to type 2 diabetes by nearly 60% (11,12). Lifestyle change should arguably rank high among interventions proposed for type 1 diabetes by targeting factors already shown to influence its progression in humans. What is the evidence that lifestyle change will be likely to prevent type 1 diabetes at a public health level? The signs may be all around us. The highest order of proof is the response to intervention and that, in a natural intervention of colossal scale, industrialized nations have shifted their BMI some 20% during the past 25 years (13,14). Few would contest that insulin resistance resulting from this rise in body weight underlies the corresponding rise in type 2 diabetes that has occurred over the same duration (15,16) or that excess nutrition and underactivity are the principal lifestyle factors responsible. It is sometimes forgotten, however, that type 1 diabetes has shown a parallel rise over the same period, doubling its incidence in the same populations (17,18). Although there is no certainty that lifestyle change and insulin resistance have caused the rise in type 1 as well as type 2 diabetes, there is strong circumstantial evidence in favor of the association and a safe intervention on hand to test it. So why have intervention panels so far not sought to trial lifestyle changes in the prevention of type 1 diabetes, as they have for type 2? One reason is logistics. Because its prevalence is only some 10%
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he recently completed trials using insulin (U.S.) and nicotinamide (Europe) were not effective in preventing type 1 diabetes (1,2), but they leave an important legacy of goodwill among their collaborators and expertise in the conduct of such trials and a network through which more may be carried out. A commentary on the trials has recently been published (3), and its authors urge “a different combination.” Concerned that too little is known of early immune interactions to intervene effectively in infancy, when the disease is thought to start, they propose trials of combination or “cocktail” therapy to achieve immunosuppression in newonset patients. The ultimate benefit to the pre-diabetic patient would come if it were possible to improve -cell survival in the context of reduced inflammation. Antigen-based therapies, monoclonal antibodies, and other immunoregulatory and immunosuppressive agents are listed, built around confident assertions that type 1 diabetes “has an autoimmune basis” and that, given the success of combination therapy in cancer, AIDS, and systemic lupus erythematosus, “why should type 1 diabetes be any different?” But what if type 1 diabetes is different? What if the paradigms are different? And they may be because, despite an immense research effort, the doubling of type 1 diabetes over the past 25 years in most industrialized countries still goes without explanation. What if -cell dam-
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of that of type 2 diabetes, conducting trials of type 1 diabetes implies international recruitment and more time to completion. The Accelerator Hypothesis had not cast type 1 diabetes in the mold of type 2 diabetes when the Diabetes Prevention Trial-1 and European Nicotinamide Diabetes Intervention Trial were conceived in the early 1990s. Since then, however, associations between insulin resistance and type 1 diabetes have become clearer (19,20), and a way forward has opened up. There may be sound reason to consider immune intervention in type 1 diabetes (3), as immune insulitis undoubtedly accelerates the loss of -cells. However, if insulin resistance is a driver of -cell damage and the immune response to it, there may be yet more reason to reduce insulin resistance by insulin sensitizers or behavioral change. Lifestyle intervention has proved effective in type 2 diabetes. The parents of high-risk children are likely to ensure compliance, and markers of intervention impact such as simple anthropometry, body composition by dual-energy X-ray absorptiometry or bioimpedance, autoantibody titers, and insulin resistance by homeostasis model assessment are well established in children. Given the evidence available, now seems an appropriate time to judge the merits of lifestyle change or insulin-sensitizing drugs alongside more speculative, and possibly more risky, interventions when planning the next type 1 diabetes prevention trial. References 1. Pozzilli P: The DPT-1 trial: a negative result with lessons for future type 1 diabetes prevention. Diabetes Metab Res Rev 18:
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257–259, 2002 2. Gale EA: Intervening before the onset of type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetologia 46:339 – 346, 2003 3. Schatz D, Gale AE, Atkinson MA: Why can’t we prevent type 1 diabetes? Maybe it’s time to try a different combination (Commentary). Diabetes Care 26:3326 – 3328, 2003 4. Wilkin TJ: The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia 44:914 –922, 2001 5. Palmer JP, Hirsch IB: What’s in a name: latent autoimmune diabetes of adults, type 1.5, adult-onset, and type 1 diabetes (Editorial). Diabetes Care 26:536 –538, 2003 6. Libman IM, Pietropaolo M, Arslanian SA, LaPorte RE, Becker DJ: Changing prevalence of overweight children and adolescents at onset of insulin-treated diabetes. Diabetes Care 26:2871–2875, 2003 7. Rosenbloom AL: Obesity, insulin resistance, -cell autoimmunity, and the changing clinical epidemiology of childhood diabetes (Editorial). Diabetes Care 26:2954 –2956, 2003 8. Pedersen CR, Hageman I, Bock T, Buschard K: Intermittent feeding and fasting reduces diabetes incidence in BB rats. Autoimmunity 30:243–250, 1999 9. Kibirige MS, Metcalf BS, Renuka R, Wilkin TJ: Testing the Accelerator Hypothesis: the relationship between body mass and age at diagnosis of type 1 diabetes. Diabetes Care 26:2865–2870, 2003 10. Betts P, Mulligan J, Ward P, Smith B, Wilkin T: Increasing body weight predicts the earlier onset of insulin dependent diabetes in childhood: testing the Accelerator Hypothesis (2). Diabet Med. In press 11. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V,
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Uusitupa M, Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343–1350, 2001 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM, Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393– 403, 2002 McCarthy HD, Ellis SM, Cole TJ: Central overweight and obesity in British youth aged 11–16 years: cross sectional surveys of waist circumference. BMJ 326:624 – 626, 2003 Booth ML, Chey T, Wake M, Norton K, Hesketh K, Dollman J, Robertson I: Change in the prevalence of overweight and obesity among young Australians, 1969 –1997. Am J Clin Nutr 77:29 –36, 2003 Boden G: Pathogenesis of type 2 diabetes: insulin resistance. Endocrinol Metab Clin North Am 30:801– 815, 2001 Ferrannini E: Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. Endocr Rev 19:477– 490, 1998 Onkamo P, Vaananen S, Karvonen M, Tuomilehto J: Worldwide increase of type 1 diabetes: analysis of the data on published incidence trends. Diabetologia 42: 1395–1403, 1999 Zhao HX, Stenhouse E, Soper C, Hughes P, Sanderson E, Baumer JH, Demaine AG, Millward BA: Incidence of childhood-onset type 1 diabetes mellitus in Devon and Cornwall, England, 1975–1996. Diabet Med 16:1030 –1035, 1999 Leslie RD, Taylor R, Pozzilli P: The role of insulin resistance in the natural history of type 1 diabetes. Diabet Med 14:327– 331, 1997 Greenbaum CJ: Insulin resistance in type 1 diabetes. Diabetes Metab Res Rev 18: 192–200, 2002
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