Diabetes Prevention Trial-Type Research Articles

Islet Cell Antibody-Positive Relatives with Human Leukocyte Antigen DQA110102, DQB110602: Identification by the Diabetes Prevention Trial-Type 11

The presence of human leukocyte antigen (HLA) haplotype DQA1*0102, DQB1*0602 is associated with protection from type 1 diabetes. The Diabetes Prevention Trial-type 1 has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB1*0602 demonstrated no differences in gender or age; however, among racial groups, African-American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB1*0602 individuals were less likely to have additional risk factors for diabetes [insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)] than ICA+ relatives without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have IAA or low FPIR. Although half of the ICA+ DQB1*0602 relatives had a high risk second haplotype, this was not associated with the additional risk factors for diabetes. Hispanic ICA+ individuals with DQB1*0602 were more likely to be IAA positive or to have low FPIR than other racial groups. In conclusion, the presence of ICA in the relatives described here suggests that whatever the mechanism that protects DQB1*0602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, there may be different effects of DQB1*0602 between ethnic groups.

New pieces in the puzzle of diabetes

The tools of molecular and genetic medicine continue to unravel the causes of diabetes. Understanding the au to immnne process resulting in IDDM has been advanced by the identification of phogrin, a beta-cell antigen (Hawkes). Antibodies to phogrin are strongly associated with progression to IDDM, so antibodies to this new antigen may well become important in preclinical screening for IDDM. The mechanisms by which cytokines destroy beta-cells continue to be explored with the studies by Rabinovitch et al, showing that exposure of human islets to interleukin, tumour-necrosis factor alpha, and interferon,gamma significantly increases malondialdehyde and nitrite. Testing for multiple autoantibodies against islet proteins (glutamic acid decarboxylase, tyrosine phosphatase 1A-2, and insulin) is allowing increasingly accurate identification of individuals at high risk of developing IDDM. Several IDDM prevention trials in antibody-positive relatives are under way (Cleve Clin J Med 1996; 63(5): 270). The Diabetes Prevention Trial-Type 1 (DPT-1) is examining the efficacy of antigen-specific therapy with insulin, while the efficacy of nicotinamide is being tested in the European Nicotinamide Diabetes Intervention Trial (ENDIT). In the Cow's Milk Avoidance Trial, the effect of delay in feeding with cow's milk is being tested with a non-cow's-milk-containing formula in the siblings of patients with IDDM. The important role of obesity in the aetiology of NIDDM has been highlighted by the discovery of the genetic basis of obesity in ob/ob and db/db mice. In the ob/ob mouse, mutations in the ob gene result in obesity and diabetes, and administration of the recombinant ob product (leptin) causes reduction in weight and serum glucose and insulin concentrations. Naturally, there has been speculation that leptin may have similar effects in human beings. Clinical trials are under way. This year has seen the identification of the leptin receptor and confirmation that the obesity syndrome in db/db mice is caused by mutations of this receptor (Leibel). The partial sequence of the human ob gene has also been published. However, the ob gene may not be important in human obesity (Maffei). Genetic factors have a major role in the pathogenesis of obesity. One study of twins suggests that genes account for about 70% of the variation in central abdominal fat (Int J Obesity 1996;

Prevention of insulin-dependent diabetes mellitus: an overview of three trials.

Genetic, immune, and metabolic testing can reveal a person's risk of developing insulin-dependent diabetes mellitus (IDDM), and three large clinical trials are planned or underway to see if interventions can prevent IDDM in persons at risk. Researchers in diabetes prevention trials are screening first- and second-degree relatives of probands with IDDM for islet-cell antibodies. In the Cow's Milk Avoidance Trial, infant siblings of probands with IDDM will be randomized to receive either a baby formula containing a non-antigenic protein hydrolyzate or a standard cow's milk-based formula. The Diabetes Prevention Trial-Type I is randomly assigning subjects at high risk (more than a 50% probability of developing IDDM) to either receive insulin injections or undergo observation alone; subjects at intermediate risk (25% to 50%) will receive either oral insulin or placebo. In the European Nicotinamide Diabetes Intervention Trial, subjects receive either nicotinamide or placebo. If any of these trials show that IDDM can be prevented, then large-scale screening of children for IDDM risk factors may prove beneficial.

New developments in treating children with insulin-dependent diabetes mellitus

A number of new developments in the management of insulin-dependent diabetes mellitus have occurred in the past several years. Primary care providers including pediatric nurse practitioners need to be aware of these developments so that they can work effectively with specialty providers in caring for children with insulin-dependent diabetes mellitus. This article discusses the implications of the Diabetes Control and Complications Trial for children and adolescents, the Diabetes Prevention Trial-Type I, and several other recent developments in caring for children with insulin-dependent diabetes mellitus.