The proposed research is a renewal for our investigation of the epidemiology and etiology of insulin dependent diabetes mellitus (IDDM). Specifically, the research is designed to address four specific areas. The first is to continue to maintain our registries. This will enable us to examine the epidemiology of IDDM over a 20 year period (1965-1985). In addition, the registries of over 2000 cases and 8000 first degree relatives form the population pool for our genetic and metabolic studies. The second aim is designed to examine the heterogeneity of IDDM in particular with regard to genetic markers. Specifically, we will determine whether cases with different genetic markers have a different epidemiology. If this were true, this may suggest IDDM disease variants or different diseases. We will not only be measuring HLA, but also other genetic markers, including Ig allotypes and Kidd. The third specific aim is designed to determine if genetic similarity to IDDM cases is associated with increased risk, and metabolic alterations and whether such changes are maintained into adulthood. Moreover, this is designed to determine if there is linkage of HLA, Ig and/or Kidd to IDDM. The fourth area of investigation will attempt to document the events that precede the development of IDDM in the high risk group of non-diabetic siblings of cases. The interest is to prospectively identify IDDM risk factors among siblings of cases. It is our goal with these four aims to be able to monitor IDDM incidence as well as to determine the nature of the genetic, immunologic and environmental components that produce insulin dependent diabetes. A final area of research is to examine in more depth approximately 100 families where both insulin dependent and non-insulin dependent diabetes mellitus are reported with particular focus on classifying the type of diabetes in these families.