Mody

EARLY HISTORY—In the academic year 1949–1950, one of us (S.S.F.), while a first-year Fellow in Endocrinology and Metabolism at the University of Michigan (Jerome W. Conn, Division Chief), initiated a prospective, long-term study on the diagnosis, natural history, and clinical genetics of diabetes. Starting with known diabetic patients from the Diabetes Clinic, I recruited their apparently healthy and asymptomatic first-degree relatives (parents, brothers, sisters, and children) for routine oral glucose tolerance tests (OGTTs). As control subjects, I recruited young individuals, many of them students, physicians, nurses, dietitians, and their spouses, who did not have a family history of diabetes or of large newborn babies. The initial objectives were 1) to define the normal range for the OGTT, 2) to attempt to unmask the potential diabetic subjects who manifest normal glucose tolerance by the standard OGTT and determine whether the diabetogenic activity of cortisone could be used to uncover a subclinical defect in the metabolism of glucose, and 3) to carry out periodic follow-up over many years of the apparently healthy first-degree relatives of diabetic patients. In our first publication in 1954 (1), 19% of 152 relatives of known diabetic patients were found to have diabetes by OGTT and, moreover, some were as young as 10 years of age. The same prevalence of 19% was found when testing a larger sample of 438 relatives of known diabetic patients (2). In 1960,we reported thatmild, asymptomatic diabetes occurs in nonobese children, adolescents, and young adults. Their diabetic glucose tolerance and fasting hyperglycemia improved or normalized with the administration of sulfonylurea therapy (3–5). When I presented these results at the First International Congress of Endocrinology in Copenhagen in 1960, Professors Rolf Luft and Knud Lundbaek each remarked that they had never seen such patients and that this kind of diabetes did not exist in Europe. My response was that such diabetic subjects did not come to the physician or investigator; the investigator had to find them by testing the asymptomatic first-degree relatives of known diabetic patients. The study of asymptomatic diabetes in young people took a new direction in 1958 when I became aware of a 70-yearold male patient who was diagnosed with diabetes at the age of 41 years (Supplementary Fig. 1, individual III-5). He was blind from diabetic retinopathy at the age of 61 years and had an amputation for peripheral vascular disease. His diabetic mother had four diabetic siblings in a sibship of nine (generation II). The proband had four diabetic siblings (in a sibship of six), themajority of whomhad evidence of severe microand macrovascular disease as well as neuropathy. I recruited the 11 nonobese, apparently healthy and asymptomatic children of the proband for routine OGTT and thus began my studies of the RW pedigree. Seven of the 11 children, ranging in age from 11 to 30 years, were found to have abnormal glucose tolerance. The older three had fasting hyperglycemia (up to 370 mg/dL), one had a diabetic OGTT without fasting hyperglycemia, and three had impaired glucose tolerance (6–8). Subsequently, fasting hyperglycemia developed in these seven children. By prospective routine OGTTs, non–insulin-requiring diabetes was diagnosed in 11 of 21 members of generation V, all of whom were children of diabetic subjects in generation IV. Six members of generation VI have diabetes. Details of diagnosis, natural history, phenotypic expression, and treatment of members of the RWpedigree can be found in references 6–9. Repeated fluctuation between abnormal and normal glucose tolerance was shown to be part of the natural history of this type of diabetes in the RWpedigree (7). In 1964 at the Fifth Congress of the International Diabetes Federation in Toronto, I first used the term “maturityonset type diabetes of childhood or of the young” for this type of diabetes and emphasized its strong familial basis (10). This term was applied at that time, as the general thinking was that diabetes could be divided into two major types: juvenileonset type (now type 1) diabetes with its explosive development to insulin dependence and occurring primarily, but not exclusively, in young people; and maturity-onset (now type 2) diabetes occurring in middle-aged and older people that could be controlled by diet and oral agents and requiring insulin only after many years. With respect to genetics, it was believed in the 1960s that diabetes was a polygenic disorder, still applicable today for type 1 and type 2 diabetes (11). However in 1974, Robert Tattersall reported a “mild” form of diabetes in three families from King’s College Hospital in London and recognized that diabetes in these families had a dominant mode of inheritance (12). Tattersall thought he was dealing with a mild form of diabetes because in many patients, insulin therapy could be c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c