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 that mild, 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
). 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-year-old 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), the majority of whom had evidence of severe micro- and 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
). 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 RW pedigree can be found in references 6
. Repeated fluctuation between abnormal and normal glucose tolerance was shown to be part of the natural history of this type of diabetes in the RW pedigree (7
In 1964 at the Fifth Congress of the International Diabetes Federation in Toronto, I first used the term “maturity-onset 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: juvenile-onset 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 discontinued and there were fewer diabetes complications than expected, even though some retinopathy, including blindness, was described. With longer follow-up, typical severe microangiopathic and neuropathic complications developed in these families (13
). Although Tattersall recognized that these patients “appeared to have maturity-onset type diabetes at an unusually early age,” he did not use the term “maturity-onset diabetes of the young” (12
). Robert Tattersall spent the 1973–1974 academic years with me in Ann Arbor. On the basis of the records of the prospective study that had been ongoing in Ann Arbor since 1949, we identified, in addition to the RW pedigree, 23 other families in whom our working criteria for maturity-onset type diabetes of the young applied. We were able to differentiate between the pattern of inheritance in these families from that seen in 35 families with classical juvenile-onset type (type 1) diabetes and confirmed autosomal-dominant inheritance for the former (14
). In this article, we first used the abbreviation or acronym MODY for maturity-onset diabetes of the young. These two articles (12
) provided some of the first evidence that diabetes is genetically heterogeneous, further discussed in my Banting Memorial Lecture of 1978 (6
). Robert Tattersall deserves full credit for suggesting that the familial disease previously designated in 1964 as maturity-onset diabetes of the young is inherited in a dominant fashion. Tattersall quotes Cammidge who proposed, in 1928, dominant inheritance in a mild form of familial diabetes (15
). This was based entirely on the finding of glycosuria, even though assays for measuring blood glucose levels had been available for approximately a decade at the time. Thus in Cammidge’s pedigrees, one cannot distinguish between primary renal glycosuria or the type 3 form of MODY (MODY3 due to mutations in the gene encoding the transcription factor hepatocyte nuclear factor 1α), which is also characterized by renal glycosuria.
Since 1975, I have used autosomal-dominant inheritance consistently as one of the requirements for the definition of MODY. Although young age at diagnosis of diabetes is an important feature of MODY, age at diagnosis and time interval between diagnosis and insulin requirement should no longer be criteria for the definition of MODY as diagnosis may be made for the first time in subjects over the age of 25 years and also in subjects treated with insulin. For example, in the RW pedigree in which prospective testing started in generation IV, the mean age at diagnosis was 55 years in generations II and III, 35 years in generation IV, 20 years in generation V, and 11 years in generation VI.