Prevention of Pediatric Diabetes

Diabetes in children and adolescents is a significant and rising public health concern in the US. If the increase in diabetes, particularly type 2 diabetes-which is comorbid with the rise in childhood obesity-continues at its present rate, the financial and social consequences will overwhelm the healthcare system in the future with diabetes complications.

Because there is no known cure for diabetes, more emphasis is being placed on prevention. In terms of type 1 diabetes, two hopeful developments are the identification of genetic patterns for type 1 diabetes and improvements in islet cell transplantation. New understanding of the preclinical phase of type 2 diabetes and the importance of lifestyle intervention provide insight into the prevention of type 2 among adults, but research needs to address the efficacy of this approach for the prevention of type 2 diabetes among children.

Prevention of type 1 diabetes in youth

Identifying high-risk individuals

With type 1 diabetes, there is no simple test to identify at-risk individuals. The long prodromal phase preceding the onset of type 1 diabetes has given researchers the opportunity to begin to evaluate earlier intervention and possible prevention of type 1 diabetes. However, risk factors for type 1 diabetes include many nonmodifiable factors such as birth weight, having an older mother or relatives with the disease, ingesting nonhuman proteins at an early age, or having viral infections. Identifying pediatric patients at risk for type 1 diabetes is complex and costly. Since there is no effective intervention for people with known risk for type 1 diabetes, genetic screening for the disease is reserved for clinical study participants.

In type 1 diabetes prevention studies, high-risk children are screened for several immune and genetic markers of type 1 diabetes.[1] Tests for islet cell autoantibodies, insulin autoantibodies, and first phase insulin release may be performed. An individual testing positive for islet cell autoantibodies can then be tested for insulin autoantibodies. To have both types greatly increases risk (up to 20 times the risk).[1] The first-phase insulin release test (which is administered to children with both islet cell and insulin autoantibodies) measures the degree of β-cell damage that is already present. Taken together, information from these 3 tests and from genetic tests allows researchers to estimate a person's relative susceptibility for developing type 1 diabetes within the next five years.[1]

Type 1 diabetes prevention strategies

Type 1 diabetes prevention strategies have generally fallen into three categories:[2]

• Strategies to promote β-cell regeneration (expansion of β cells; β-cell stimulation)

• β-cell replacement efforts (β-cell and pancreatic transplants)

• Strategies to protect β cells from autoimmune destruction (eg, generalized immunosuppression, monoclonal antibodies)

Most prevention efforts have focused on β-cell protection and β-cell replacement. Research has been conducted on a number of β-cell growth and regeneration factors, including vascular endothelial growth factor, hepatocyte growth factor, regenerating gene-1, transforming growth factor (TGF) α, and islet neogenesis-associated protein. In terms of β-cell replacement, approximately 1500 whole-pancreas transplants are done annually, although the risks of this procedure are great.[3] In terms of islet cell transplants, the Edmonton Protocol, adopted in 2000, greatly improved the efficacy of this procedure, making all patients who receive them insulin independent at the time of transplant, with 85% remaining insulin independent at 1-year follow-up.[3] Although this procedure is promising, it is still quite labor intensive, requires posttransplant immunosuppressive therapy, and is limited by the availability of islets.

Future prevention strategies include targeted monoclonal antibodies to fend off the autoimmune attack. This tactic has been shown in children and adults to delay disease progression in newly diagnosed type 1 patients.[4] Other strategies include immunostimulation with agents such as Q fever antigen, inducing immune tolerance with agents such as insulin-cholera conjugate, and agents that either interrupt cell-cell interaction pathways or directly protect β cells from necrosis and oxidation.[2] Researchers are hopeful that some evolving pharmacologic agents for treating type 2 diabetes by preserving β-cell function also may help prevent both type 1 and type 2 diabetes.

Type 1 prevention trials

Several trials have attempted to establish triggers for type 1 diabetes in children with a susceptible genotype. Thus far, no results have been conclusive. Table 1 lists major clinical studies into prevention of type 1 diabetes. For more information, please visit The Prevention of Type 1 Diabetes.

Table 1. Studies on type 1 diabetes primary prevention

Type 2 diabetes

Because of the relatively recent and rapid rise of type 2 diabetes in youth, there are few pediatric clinical studies demonstrating the benefits of early intervention in high-risk children. Much of the data on prevention of pediatric diabetes is derived from studies done in adults. Unlike type 1 diabetes, there is an identifiable preclinical phase of type 2 diabetes, called prediabetes. Results from adult trials on people with prediabetes have clearly demonstrated that type 2 diabetes can be prevented or delayed through lifestyle intervention or through pharmacologic treatment.

Type 2 prevention trials

Lifestyle modification

Within the prevention studies for type 2, emphasis is placed on lifestyle intervention. Four major research studies have examined prevention in people with prediabetes:

• The Malmo feasibility study[10]

• The Da Qing IGT and Diabetes Study[11]

• The Finnish Diabetes Prevention Study[12]

• Diabetes Prevention Program (DPP)[13]

Results of the clinical studies that have used lifestyle prevention for type 2 diabetes prevention are presented in Table 2.

Table 2. Prevention of type 2 diabetes with lifestyle intervention

Pharmacologic therapy

The Diabetes Prevention Program in adults showed that weight loss (5% to 7% of body weight) was twice as effective as metformin for the prevention of type 2 diabetes among adults.[13] This relative advantage of lifestyle changes over medication may apply to children as well.

Most of the pharmacologic studies in the area of type 2 diabetes prevention were done in adults and may pertain to pediatric cases. Although no medications are currently approved for the prevention of type 2 diabetes, research has been conducted to test the efficacy of different classes of glucose-lowering medications for that purpose, including biguanides, α-glucosidase inhibitors, and thiazolidinediones. The results are shown in Table 3.

Table 3. Prevention of type 2 diabetes with medication

For more details, visit the following articles:

The Prevention of Type 2 Diabetes
Type 2 Diabetes in Youth—The Importance of Lifestyle

Conclusion

Interventions to prevent diabetes in children can be intensive and costly, but they are less costly than the disease itself.[17,18] Studies in type 1 diabetes prevention have endorsed the reliability of genetic markers for diabetes and have ruled out potential preventive interventions (both pharmacologic and behavioral). For type 2 disease, studies have shown great gain with little pain in simple lifestyle changes that can prevent or delay diabetes in adults.[13,19]These findings may well be indicative of young people as well. At the same time, new doors are opening for new drugs classes and combinations of drugs that can help forestall type 2 diabetes. For more information on new drug classes, visit Emerging Therapies. In the absence of effective preventions, early intervention is the best method of reducing disease severity and delaying or preventing complications.

References

1. National Institute of Diabetes and Digestive and Kidney diseases. Type 1 diabetes prevention trials. Available at: http://www.niddk.nih.gov/patient/dpt_1/dpt_1.htm. Accessed October 12, 2004.
2. Petrovsky N, Silva D, Schatz DA. Prospects for the prevention and reversal of type 1 diabetes. Drugs. 2002;62:2617-2635.
3. Shapiro AMJ, Ryan EA, Paty BW, Lakey JRT. Pancreas and islet transplantation. In: Pickup JC, Williams G, eds. Textbook of Diabetes 2. Malden, MA; 2003:42.1-42.15.
4. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, et al. Anti CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692-1698.
5. Pozzilli P. The DPT-1 trial: a negative result with lessons for future type 1 diabetes prevention. Diabetes Metab Res Rev. 2002;18:257-259.
6. Gale EA, Bingley PJ, Emmett CL, Collier T. ENDIT Group. European Nicotinamide Diabetes Intervention Trial (ENDIT); a randomized controlled trial of intervention before the onset of type 1 diabetes. Lancet. 2004;363:925-931.
7. Barker JM, Goehrig SH, Barriga K, Hoffman M, Slover R, Eisenbarth GS, Norris JM, et al. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care. 2004;27:1399-1404.
8. Wilson BM, Buckingham B. Prevention of type 1a diabetes mellitus. Pediatr Diabetes. 2001;2:17-24.
9. TRIGR. Available at: http://trigr.epi.usf.edu/index.html. Accessed June, 2006.
10. Erikson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia. 1991;34:891-898.
11. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Diabetes Study. Diabetes Care. 1997; 20:537-544.
12. Lindstrom J, Eriksson JG, Valle TT, et al. Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial. J Am Soc Nephrol. 2003;14:S108-S113.
13. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
14. NIH STOPP-T2D. Available at: http://www.bsc.gwu.edu/stopp-t2d/index.cgi. Accessed November, 2004.
15. Chiasson LJ, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M for the STOP-NIDDM Trial Research Group. Acarbose for the prevention of type 2 diabetes mellitus: The STOP-NIDDM randomized trial. Lancet. 2002;359:2072-2077.
16. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796-2803.
17. Brown JB, Nichols GA, Glauber HS, Bakst AW, Schaeffer M, Kelleher CC. Health care costs associated with escalation of drug treatment in type 2 diabetes. Am J Health-System Pharm. 2001; 15:151-157.
18. Diabetes Prevention Program Research Group. Within-trial cost-effectiveness of lifestyle intervention or metformin for the primary prevention of type 2 diabetes. Diabetes Care. 2003; 26:2518-2523.
19. Dunn AL, Marcus BH, Kampbert JB, Garcia ME, Kohl HW III, Blair SN. Reduction in cardiovascular disease risk factors: 6-month results from Project Active. Prev Med. 1997;26:883-892.