New pieces in the puzzle of diabetes

Abstract

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;