Pilot trial to prevent type I diabetes: Progression to overt IDDM despite oral nicotinamide

Immunologic and endocrine abnormalities may be present during a latency period of several years prior to overt diabetes, while glucose tolerance still remains normal [ 1]. In particular, cytoplasmic islet cell antibodies, insulin autoantibodies, and T-cell abnormalities can be present for years prior to development of overt hyperglycemia. We have found that with the emergence of these immunologic abnormalities, the first phase insulin release following intravenous glucose is progressively lost. In relatives of patients with insulin dependent diabetes mellitus (IDDM) who were found to have circulating cytoplasmic islet cell antibodies [greater than 40 Juvenile Diabetes Foundation (JDF) units], we have developed a dual parameter model which predicts confidence intervals of the time of onset of IDDM, based on the level of competitive insulin autoantibodies (CIAA), and the degree of loss of the first phase insulin release on intravenous glucose tolerance testing (IVGTT) [2]. This model consists of the formula: years to DM=2.2+0 .017 ( IVGTT insulin) -0.007 (concentration CIAA), and makes it possible for us to identify patients with a high risk of developing IDDM within 3 years' time. In such a population, we have initiated pilot trials of preventive therapy to determine whether the development of I D D M can be halted. In an animal model of Type I diabetes (the NOD mouse), nicotinamide at supraphysiologic dosages was found to protect pancreatic islet cells and to prevent Type I diabetes [3]. In addition, nicotinamide has long been known to block the development of diabetes following streptozotocin or alloxan, and to restore proinsulin synthesis to normal following injection of streptozotocin [4]. It was also shown to promote beta cell regeneration following partial pancreatectomy in the rat [5]. In